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Antibiotics

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CONTENTS

antibiotic initiation checklist 🚀

commonly used antibiotics

specific pathogens

specific clinical scenarios

antimicrobial stewardship

antimicrobial pharmacology

common tests for bacterial infections

appendix

checklist for starting antibiotic

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[#1/9] Adequate culture +/- PCR data has been obtained (or at least ordered).

  • MRSA nares PCR should be obtained if there is concern for MRSA pneumonia.

[#2/9] Procalcitonin and/or CRP have been ordered (if appropriate). 

  • This may help with subsequent discontinuation of the antibiotic. ⚡️
  • Antibiotic initiation should not be delayed while awaiting the procalcitonin level.

[#3/9] Review available microbiology data (including recent cultures).

  • Pay attention to whether a Verigene multiplex PCR is available. ⚡️

[#4/9] Review drug allergies. 📖

[#5/9] Review recently received antibiotics.

  • Avoid antibiotics that the patient has recently been exposed to.

[#6/9] Consider contraindications to the antibiotic.

[#7/9] Evaluate for drug-drug interactions.

  • MDCalc drug interaction checker: 🧮

[#8/9] Consider GFR:

  • Reduced GFR: dose-reduce appropriately.
  • GFR >85: consider the possibility of ARC ⚡️

[#9/9] Consider BMI and relevant dosing for obesity. ⚡️

  • Consider possibility of under-estimating GFR if BMI>40.

aminoglycosides

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aminoglycoside dosing

  • Gentamicin synergy for endocarditis:
    • Once-daily dosing is safer and recommended by European Society of Cardiology guidelines:
      • 3 mg/kg (max 240 mg) IV daily.
      • Monitor gentamicin concentrations at least once weekly.
      • Trough concentration should be <1 ng/L.
      • Peak (1 hour after dose) should be ~10-12 mg/L. (37622656)
  • Aminoglycoside dosing for gram-negative infections is discussed in further detail below:
    • High-dose extended dosing for tobramycin/gentamicin. ⚡️
    • Traditional dosing for tobramycin/gentamicin: ⚡️
    • Amikacin: You can multiply gentamicin/tobramycin doses and levels by a factor of three to obtain equivalent doses and levels of amikacin. However, various sources disagree about the optimal conversion factor (with a range of 2-4!). 🌊IDSA guidelines recommend 20 mg/kg q24 for septic shock. (38304898) 
  • ECMO: (<30% protein binding; LogP <0). Volume of distribution is often increased, but aminoglycosides aren't adsorbed by the circuit. Close monitoring should be utilized. The primary drawback is nephrotoxicity and limited penetration of certain tissues.

pharmacology of various aminoglycosides is essentially the same

  • Administered only IV/IM.
  • Excreted unchanged in the urine.
  • Half-life is normally ~2.5 hours.
  • Plasma protein binding is low (~5-10%).
  • Volume of distribution (Vd) is ~0.25 L/kg.
  • Penetration:
    • Lung penetration is borderline (bronchial secretion level is 2/3rds serum level, and drug may not function well in acidic environment within consolidated lung tissue).
    • Poor penetration of many tissues (CSF, brain, bile, prostate, meninges, eye).
    • Excellent renal penetration.
  • Pharmacodynamics: aminoglycosides work poorly in acidic or hypoxic environments (e.g., purulent fluid, necrotic tissue).

spectrum

  • Gram-positives:
    • Covers MSSA and Enterococcus faecalis.
    • Misses Staph. saprophyticus.
  • Gram-negatives:
    • Excellent coverage, including:
      • Enterobacteriaceae.
      • Pseudomonas.
      • Acinetobacter spp.
    • Tobramycin misses:
      • Burkholderia cepacia.
      • Stenotrophomonas maltophilia.
  • Aminoglycoside-modifying enzymes are often transmitted on plasmids containing KPCs or ESBLs, so if aminoglycoside resistance is noted be wary for other drug resistances as well. (38391547)

selection of aminoglycoside

  • Gentamicin: Best gram-positive coverage, very good gram-negative coverage.
  • Tobramycin: Workhorse aminoglycoside, excellent gram-negative coverage. However, tobramycin may be less effective than gentamicin for some organisms (Serratia spp. and Acinetobacter spp.). (Irwin & Rippe 9e)
  • Amikacin: Best gram-negative coverage (e.g., resistant pseudomonas, ESBL-producing klebsiella that is resistant to gentamicin). Amikacin may be utilized for highly drug-resistant organisms, or empiric coverage of nosocomial pathogens in hospitals with high rates of resistance to gentamicin/tobramycin.

use of aminoglycosides

  • [1] Gentamicin is used for synergy against Enterococcus faecalis endocarditis, with other agents (at reduced dose of 1 mg/kg q8hr).
  • [2] Aminoglycoside monotherapy is only utilized in a few selected situations, e.g.:
    • Urinary tract infection (+/- bacteremia).
    • Tularemia.
    • Plague.
  • [3] Double-coverage for resistant gram-negative organisms:
    • This has generally been shown not to be beneficial in RCTs. 🌊
    • However, empiric double-coverage to increase the likelihood of covering the pathogen may be reasonable in selected situations with a high risk of multidrug-resistant organisms.

toxicity/contraindications

  • Nephrotoxicity, ototoxicity, and vestibular toxicity. Risk factors include:
    • Older age.
    • Treatment duration >1 week (some recent studies suggest no increased risk with exposure for 1-4 days). (38415563)
    • Higher drug levels.
    • Recent aminoglycoside treatment (within 1 month).
    • Additional nephrotoxic agents.
    • Additional ototoxic agents (e.g., furosemide).
    • Pre-existing organ dysfunction:
      • History of hearing loss or vestibular dysfunction.
      • Pre-existing renal dysfunction.
      • Oliguria/anuria.
  • Neuromuscular blockade (may be an issue in severe hypocalcemia or myasthenia gravis; occasionally may cause flaccid paralysis).
high-dose extended interval dosing with Hartford nomogram for tobramycin/gentamicin

contraindications to high-dose extended interval dosing

  • Pregnancy.
  • Renal dysfunction:
    • GFR <40 ml/min.
    • Acute oliguria or anuria.
    • Dosing intervals >48 hours per nomogram (functional reflection of poor renal function).
  • Cystic fibrosis.
  • Significant ascites.
  • Burns involving >20% body surface area.
  • Treatment of gram-positive infections (e.g., endocarditis).

determine dosing weight

  • Generally: actual body weight.
  • Obesity (>20% above ideal body weight): use adjusted body weight 🧮
    • Adjusted Body Wt = 0.6(ideal body wt)+0.4(actual body wt).

initial dose

  • GFR >60 ml/min: 7 mg/kg q24 hours.
  • GFR 40-60 ml/min: 7 mg/kg q36 hours.
  • (GFR <40: use traditional dosing.)

monitoring

  • Check a mid-level between 6-14 hours after the first dose. This level may be used to confirm the dosing frequency based on the Hartford nomogram. 🌊
  • Additional levels may be checked if there is concern for drug accumulation:
    • Early trough (6 hours before dose) should be <1 mcg/ml. This should be checked if there is a concern for acute renal failure that may lead to failure of extended interval dosing.
    • True trough: typically undetectable (<0.5 mcg/ml).
traditional dosing for tobramycin/gentamicin

determine the dosing weight

  • Generally: actual body weight.
  • Obesity (>20% above ideal body weight): use the adjusted body weight 🧮
    • Adjusted Body Wt = 0.6(ideal body wt)+0.4(actual body wt).

determine the dose

  • The dose is generally 1.7 mg/kg.
  • For synergy in the treatment of endocarditis, the dose is 1 mg/kg.

determine the dosing interval

  • GFR >60 ml/min: 1.7 mg/kg Q8hr.
  • GFR 40-59 ml/min: 1.7 mg/kg Q12hr.
  • GFR 20-40 ml/min: 1.7 mg/kg Q24hr.
  • GFR <20 ml/min: Give 2 mg/kg then dose by level. (Stanford Health Care Aminoglycoside dosing guideline)

follow peak and trough levels

  • Check levels after second or third dose.
  • Target peak level (30 minutes after dose):
    • Pneumonia: 7-8 mg/dL.
    • Other systemic gram-negative infections: 6-8 mg/L.
    • Endocarditis: 3-4 mg/L. (26373316, 26320109)
    • Cystitis: 3-4 mg/L. (UVM Green Book)
  • Target trough level: <1 mg/L.

aztreonam

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aztreonam dosing

  • ⚠️ Due to its potential efficacy for resistant gram-negatives such as CRE (carbapenem resistant Enterobacteriaceae), aztreonam use should be avoided when other antibiotics could be used instead.
  • GFR >30 ml/min: 1-2 grams IV q8hr (Meningitis or morbid obesity: consider 2 grams q6hr).
  • GFR <10-30 ml/min: 1-2 grams q12hr.
  • GFR <10 ml/min: 1-2 grams q24hr.
  • CRRT 1 gram q12.
  • Obesity: Consider the upper end of the normal dosing (e.g., 2 grams q6-8 hours). (36703246)

pharmacology

  • Excreted unchanged in urine: 65%.
  • Plasma protein binding: 56%.
  • Volume of distribution: 0.2 L/kg.
  • Tissue penetration: widely distributed throughout body, including CNS. High levels in bile and urine.

spectrum

  • Covers gram-negatives well (including pseudomonas), but nothing else.
  • May fail in species that have inducible AmpC beta-lactamases. 📖

use

  • Excellent gram-negative coverage, safe for patients with anaphylaxis to penicillin (but might cross-react with ceftazidime). (25124380)
  • Can be used for many gram-negative infections (e.g., pneumonia, soft tissue, urinary tract, bacteremia, meningitis).
  • It is a reasonable choice for a patient found to have gram-negative bacteremia.
  • May cause less encephalopathy, as compared to cefepime or ceftazidime.

toxicity/contraindications

  • Contraindication: Ceftazidime allergy (may be cross-allergic). (25124380) However, overall seems to have low tendency to cause allergic reaction or side-effects.
  • Abnormal liver function tests.
  • Thrombocytopenia, neutropenia.
  • Seizure.

carbapenems (meropenem, ertapenem)

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carbapenem dosing

  • Meropenem:
    • GFR >50: 1-2 grams q8 (higher end for pseudomonas, meningitis, cystic fibrosis, or morbid obesity; infuse over three hours if possible). (23147743)
    • GFR 30-50: 1-2 grams q12.
    • GFR 10-30: 500-1,000 mg q12.
    • GFR <10: 500-1,000 mg q24.
    • Augmented renal clearance: prolong infusion time as long as possible (e.g., six hours). (Baptista 2023)
    • IHD three times/week: 500-1000 mg IV daily, dosed post-dialysis on hemodialysis days.
    • CRRT:
      • Start with the standard loading dose.
      • 500 mg extended infusion over 3 hours, q8hrs. (31342772) Alternatively, 500-1000 mg q8hrs infused over 30 minutes. (LexiDrug)
    • Obesity: Doesn't seem to substantially affect kinetics, but high-end doses may be considered (up to 2 grams IV q8h extended infusion). (36703246)
    • ECMO: (2% protein binding; Vd 0.35 L/kg; LogP -0.7) Dosing similar to other critically ill patients, with several studies showing no change in pharmacokinetics due to ECMO. (29732181, 35326801, 34460303) 
    • Extending the infusion over three hours will improve the t/MIC and likelihood of PK/PD target attainment.
  • Ertapenem:
    • ⚠️ Hypoalbuminemia (<2.5 g/dL) may reduce the half-life of ertapenem, correlating with an increased risk of mortality. This may make ertapenem a suboptimal agent for the sickest ICU patients. (31369411, 25636928) 
    • GFR >30 ml/min: 1 gram IV q24hr (may consider higher dose in morbid obesity or severe illness).
    • GFR <30 ml/min: 500 mg IV q24hr.
    • Augmented renal clearance: may need 1 gram IV q12hr. (Schmidt 2024)

carbapenem pharmacology

  • Meropenem:
    • Excreted unchanged in the urine (70%).
    • Protein binding 2% (promoting wide distribution into tissues).
    • The volume of distribution is 0.35 L/kg.
    • Penetration: well distributed into most tissues, including CNS.
  • Ertapenem:
    • Excreted unchanged in urine (40%).
    • Protein binding of 95% – this creates a reservoir of drug in the blood, extending the half-life and allowing ertapenem to be given once daily. However, in critically ill patients with low albumin levels, this could reduce the half-life (more on this below).
    • The volume of distribution is 0.12 L/kg.
    • Penetration: Higher protein-binding reduces its penetration compared to meropenem (e.g., giving ertapenem poor penetration of bile, peritoneal fluid, and prostate).

spectrum: meropenem

  • Gram-positives:
    • Generally very good (including MSSA, Enterococcus faecalis, and Staph. saprophyticus).
    • Misses MRSA and Enterococcus faecium.
  • Gram-negative coverage:
    • Overall excellent, including:
      • Pseudomonas.
      • ESBL and AmpC multidrug resistant species.
      • Acinetobacter.
      • Burkholderia cepacia.
    • Misses:
      • Some carbapenem resistance is starting to emerge among enterobacteriaceae (especially among Klebsiella pneumoniae); this varies widely depending on geography. CRE (carbapenem-resistant Enterobacteriaceae) are discussed further below: ⚡️
      • Lacks activity against Stenotrophomonas maltophilia.
  • Anaerobic coverage: Excellent (but doesn't cover C. difficile).

spectrum: ertapenem

  • Main differences compared to meropenem:
    • 1) Lacks coverage of pseudomonas and acinetobacter.
    • 2) Limited activity against enterococci.

use of carbapenems in general

  • Broad-spectrum beta-lactam antibiotics with a range of potential applications, particularly for nosocomial infections (e.g., pneumonia, intra-abdominal infections, urinary tract infections, bacteremia, soft tissue infections). Unlike most beta-lactams, carbapenems decrease lipopolysaccharide release from gram-negative bacteria, which could give them a theoretical advantage in the treatment of gram-negative septic shock.
  • Multi-drug resistant gram-negative bacteria:
    • ESBL bacteria. 📖
    • Inducible AmpC beta-lactamases. 📖
  • Patient with a history of anaphylaxis following penicillin exposure who requires broad-spectrum coverage. Carbapenems (especially meropenem) have an extremely low risk of allergic reaction.📖 Using a carbapenem may be safer than a multi-drug regimen (e.g. vancomycin/aztreonam/metronidazole) and faster to administer in septic shock. Meropenem can actually be given as a bolus.

choice of ertapenem vs. meropenem 

  • Meropenem:
    • May have better tissue penetration (e.g., with a stronger track record in the treatment of meningitis).
  • Ertapenem:
    • ⚠️ Hypoalbuminemia (<2.5 g/dL) may reduce the half-life of ertapenem, correlating with an increased risk of mortality. This may make ertapenem a suboptimal agent for the sickest ICU patients. (31369411, 25636928) 
    • De-escalation to ertapenem may reduce selective pressure to develop resistance among pseudomonas and acinetobacter. (Schmidt 2024)
    • Ertapenem's longer half-life allows for once-daily dosing, which may be convenient (especially for outpatients).

toxicity/contraindications

  • Meropenem:
    • Seizure.
    • Thrombocytopenia.
    • Drug fever.
  • Ertapenem:
    • DRESS syndrome.
    • Seizures, delirium, myoclonus/tremor.

cephalosporin G1: cefazolin

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cefazolin dosing

  • ⚠️ High protein binding levels might be suboptimal in severe hypoalbuminemia (might consider cephalexin below, depending on context).⚡️
  • GFR >50 ml/min: 1-2 grams IV q8.
    • Indications for 2 grams IV q6hr:
      • Morbid obesity. (37310038)
      • CNS infection. (37310038)
      • Augmented renal clearance. (Baptista 2023, LexiDrug)
    • Indications for 2 grams IV q8hr: Endocarditis or bacteremia. (26373316, 26320109)
  • GFR 30-50 ml/min: 1-2 grams IV q12.
  • GFR 10-30 ml/min: 0.5-1 gram IV q12.
  • GFR <10 ml/min: 0.5-1 gram IV q24.
  • IHD: 2 grams after dialysis. (31342772)
  • Morbid obesity: consider the upper limit of standard dosing in severe infections (e.g., 2 grams IV q6hr). (36703246)
  • ECMO: (80% protein binding; Vd 0.2 L/kg; LogP -0.6) Standard dosing is probably adequate, but available data is sparse. (31610538, 35326801)

pharmacology

  • Excreted unchanged by kidneys (90%)
  • Protein binding: 80%
  • Vd: 0.2 L/kg
  • Penetration:
    • Good penetration of lungs, joints, bone, prostate, and bile.
    • Historically there have been concerns regarding CNS penetration. However, cefazolin does appear to have adequate CNS penetration. (37310038)

spectrum

  • Gram-positives:
    • All non-enterococcal streptococci (e.g. streptococcus groups A, B, C, G).
    • MSSA.
    • Staph. saprophyticus.
    • Coagulase-negative staph that are sensitive to oxacillin.
  • Gram-negatives
    • Often effective for community-acquired E. coli, Klebsiella pneumoniae, and Proteus mirabilis.
    • It is not generally adequate for empiric therapy against gram-negative infections, but it may be used as step-down therapy once sensitivities are available.

use

  • Empiric coverage before culture is known:
    • Cellulitis (treatment of choice for non-purulent cellulitis).
    • Endocarditis (in combination with vancomycin).
  • After culture & sensitivity are known:
    • Bacteremia and/or endocarditis.
    • Pneumonia (e.g., due to MSSA or Group A streptococcus).
    • Urinary tract infection (e.g., due to sensitive E. coli or Proteus mirabilis).
  • Cefazolin vs. nafcillin for MSSA: 📖

toxicity/contraindications

  • Penicillin allergy is not a contraindication. Cefazolin has a unique side chain that isn't cross-allergic with any other beta-lactam. (24637693) It can also be used in patients with hypersensitivity reactions to nafcillin. (24637693)
  • Drug rash, drug fever.
  • Transaminitis.
  • Neutropenia, thrombocytopenia.
  • Seizures, delirium.

cephalosporin G1: cephalexin

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cephalexin dosing

  • Usual dosing: 250-500 mg PO q6hr.
    • Uncomplicated cystitis: 250 mg PO q6hr.
    • Cellulitis: 500 mg PO q6hr.
  • Renal dosing:
    • GFR 10-30: q8-q12hr.
    • GFR <10: q12hr.
  • Obesity: Consider the upper end of standard dosing (e.g., 500-1000 mg PO q6hr). (36703246)

pharmacology

  • Excellent bioavailability (90% absorption).
  • Excreted unchanged by kidneys.
  • Protein binding: 5-15%
  • Half-life 1 hour.
  • Penetration: Good penetration of lungs, pleura, joints, and bone.

spectrum

  • 💡 First-generation cephalosporins have a virtually identical spectrum of activity (they differ only in their pharmacokinetic properties). (Irwin & Rippe 9e)
  • Gram-positives:
    • Non-enterococcal streptococci (e.g., streptococcus groups A, B, C, G).
    • MSSA.
    • Streptococcus pneumoniae that are penicillin-sensitive.
    • Staphylococcus saprophyticus.
  • Gram-negatives:
    • Often effective for E. coli, Klebsiella pneumoniae, and Proteus mirabilis.

common uses

  • Empiric:
    • Non-purulent cellulitis (covers MSSA, group A streptococcus).
    • Uncomplicated cystitis (fairly good coverage of E. coli, Klebsiella pneumoniae, Proteus mirabilis).
  • Step-down therapy:
    • Oral equivalent to IV cefazolin for many infections, e.g.:
    • Beta-hemolytic streptococcal infections.
    • Streptococcus pneumonia known to be penicillin sensitive.
    • MSSA infections (e.g., empyema).
    • Urinary tract infection with E. coli, Klebsiella pneumoniae, or Proteus mirabilis that is sensitive to cefazolin.

toxicity/contraindications

  • Generally well tolerated.
  • Allergic reactions (eosinophilia).
  • Drug rash, drug fever.
  • Transaminitis.
  • Neutropenia, thrombocytopenia.
  • CNS toxicity: Seizures, delirium.

cephalosporin G3: ceftriaxone

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ceftriaxone dosing

  • ⚠️ High protein binding levels might be suboptimal in severe hypoalbuminemia. ⚡️
  • 1-2 grams q24 hours for most infections:
    • Indications to consider 2 grams q24:
      • [1] Severe infection (e.g., endocarditis or bacteremia). (26373316, 26320109)
      • [2] Obesity.
      • [3] Patients at risk of drug-resistant organisms (higher dosing may overcome intermediate beta-lactam resistance). (27960205)
      • [4] Known/suspected severe MSSA infection. (A higher dose may be needed to achieve adequate pharmacodynamics for MSSA. Please note, however, that ceftriaxone is suboptimal for serious MSSA infection, as discussed here: ⚡️). (32521547)
      • [5] Critical illness: low albumin and/or augmented renal clearance may increase the risk of inadequate ceftriaxone dosing.
      • [6] Lyme disease with cardiac/CNS involvement.
      • [7] Bacteremia.
    • Overall a default strategy of dosing 2 grams/day could be optimal for most critically ill patients. There is no good evidence that two grams/day increases the risk of medication side effects as compared to one gram/day.
  • Indications to use 2 grams q12:
    • Meningitis or other CNS infection.
    • Synergistic use for endocarditis with cephalosporin-resistant pneumococcus or enterococcus. (26373316, 26320109)
  • Renal failure: No adjustment.
  • Obesity: At least 2 grams IV daily, but higher doses could be considered with severe obesity (2 grams IV q12h). (36703246)
  • ECMO: (90% protein binding; Vd 0.2 L/kg; LogP -1.7) Standard dosing appears to achieve therapeutic targets. (35253107; 29732181)

pharmacology

  • Roughly 50% is excreted unchanged by kidneys, with the remainder excreted unchanged by the liver. In renal failure, the liver picks up the slack, so no dose adjustment is needed. Achieves high levels in both urine and bile.
  • Protein binding of 90% promotes an unusually long half-life of ~7 hours (longer than most beta-lactams).
  • The volume of distribution is 0.2 L/kg.
  • Good tissue penetration, including CNS (although higher doses are needed to penetrate meninges).

spectrum: ceftriaxone covers:

  • Gram-positives (overall less activity than G1 cephalosporins):
    • MSSA: Ceftriaxone does cover MSSA, but it's usually not ideal (discussed further below ⚡️).
    • Staph. saprophyticus (although reduced activity). (31608743)
    • Non-enterococcal streptococci (ceftriaxone misses enterococcus), including most oral streptococci.
    • Streptococcus pneumoniae (resistant strains will usually still be cured clinically, with the exception of meningitis).
  • Haemophilus influenzae, Moraxella catarrhalis.
  • Neisseria meningitidis.
  • Gram-negatives:
    • Generally good coverage (including E. coli, Klebsiella pneumoniae, Proteus mirabilis).
    • Misses: Pseudomonas, ESBL organisms.
    • Should be avoided in species that may have inducible AmpC beta-lactamases.📖

use includes:

  • Pneumonia.
  • Community-acquired meningitis (covers nearly everything; will miss listeria and resistant streptococcus pneumoniae).
  • Urinary tract infection, including pyelonephritis (without severe septic shock).
  • Bacteremia, endocarditis.
  • SBP (spontaneous bacterial peritonitis); prophylaxis in cirrhotic patients with GI hemorrhage.

toxicity/contraindications

  • Cholecystitis (may crystallize in the gallbladder, causing pseudo-biliary lithiasis).
  • Hepatitis.
  • Neutropenia, thrombocytopenia.
  • Drug rash, anaphylaxis.
  • Delirium.

cephalosporin G3: ceftazidime

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ceftazidime dosing

  • Dosing seems to be essentially the same as for cefepime. For complex situations (e.g., obesity, CRRT) use the doses described in the section on cefepime below.
  • GFR >50 ml/min: 1-2 grams IV q8hr.
    • 2 grams for severe infection, meningitis, or morbid obesity. (22249886)
  • GFR 30-50 ml/min: 1-2 grams IV q12hr.
  • GFR 10-30 ml/min: 0.5-1 grams IV q12hr.
  • GFR <10 ml/min: 0.5-1 gram IV q24.
  • ECMO: (15% protein binding; Vd 0.3 L/kg; LogP -1.6). Pharmacokinetics unaffected by ECMO. (35326801)

pharmacology

  • The pharmacokinetics of ceftazidime are similar to cefepime. (Irwin & Rippe 9e)
  • Widely distributed with good penetration, including CNS.
  • Protein binding: 5-24%.
  • Vd: ~0.3 L/kg
  • Excretion: 85% in urine.
  • Half-life: 2 hours.
  • Superior urinary concentration compared to ceftriaxone.

spectrum:

  • Gram-positive coverage is poor:
    • Ceftazidime loses activity against MSSA and penicillin-intermediate strains of Streptococcus pneumoniae.
    • Lacks activity against Staph. saprophyticus. (31608743)
  • Haemophilus influenzae, Moraxella catarrhalis.
  • Gram-negatives:
    • Good coverage of gram-negatives, including Enterobacteriaceae and Pseudomonas.
    • Should be avoided in species that may have inducible AmpC beta-lactamases. 📖

ceftazidime is almost never the best antibiotic choice

  • Cefepime is usually a better choice for the following reasons:
    • Cefepime has better activity against gram-negatives, including species with inducible AmpC beta-lactamases. 📖
    • Cefepime has greatly superior activity against gram-positives, so it's preferable for empiric therapy in septic shock (even in patients on vancomycin, as the vancomycin level is often subtherapeutic)
    • The safety profile of cefepime and ceftazidime are similar. (17158033)
  • For a mildly ill patient with definite gram-negative infection (e.g., gram-negative rods detected in urine or blood), aztreonam is a more logical choice.
  • Ceftazidime seems to have a particularly strong tendency to select out for drug-resistant pathogens (e.g. MRSA, multi-drug resistant pseudomonas). For this reason some hospitals have removed ceftazidime from the formulary entirely. 🌊

toxicity/contraindications

  • Transaminitis.
  • Drug fever.
  • Delirium, often with myoclonus. Seizures. (12627936) Overall, ceftazidime may have a similar degree of neurotoxicity as compared to cefepime. 
  • Hemolytic anemia, neutropenia, thrombocytopenia.
  • Interstitial nephritis.

cephalosporin G4: cefepime

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cefepime dosing

  • GFR >50 ml/min: 2 grams q8-12 hours:
    • Indications to use more aggressive dosing (2g q8hr):
      • [1] Pseudomonas coverage.
      • [2] CNS infections.
      • [3] Morbid obesity. (22249886)
      • [4] Febrile neutropenia.
      • [5] Possibly: bacteria with inducible AmpC beta-lactamase. ⚡️
      • [6] Augmented renal clearance. Prolonging the infusion over 3 hours may improve efficacy in augmented renal clearance. (36896122)
    • Infusion over three hours improves PK/PD target attainment.
  • GFR 30-50 ml/min: 2 grams Q12-24.
  • GFR 11-29 ml/min: 1-2 grams Q24.
  • GFR < 11 ml/min: 500-1000 mg Q24.
  • CRRT:
    • 0-1 L/hr effluent flow rate: 1 gram q8hr (=3g/d). (31342772)
    • >1.5 L/hr effluent flow rate: 1 gram q6hr (=4g/d) or 2 grams q8hr (=6g/d). (31342772)
  • Obesity: Up to 2 grams IV q8hr extended infusion. (36703246)
  • ECMO: (20% protein binding, Vd 0.3 L/kg; LogP -0.1) Unlikely to be affected by ECMO.

pharmacology

  • Excretion: 85% excreted unchanged in urine
  • Protein binding: 20%
  • Half-life: 2 hours.
  • Vd: 0.3 L/kg
  • Penetration: Good tissue penetration, including the CNS. Positively charged R2 group gives the molecule a net even charge, improving penetration of gram-negative bacteria.

spectrum

  • Gram-positives:
    • MSSA.
    • Staph. saprophyticus,
    • most coagulase-negative staph.
    • Non-enterococcal streptococci.
    • Streptococcus pneumoniae.
    • Lacks activity against enterococcus.
  • Gram-negatives:
    • Covers Pseudomonas.
    • Excellent coverage of enterobacteriaceae (including species with AmpC inducible beta-lactamases 📖).
    • Acinetobacter spp.
  • Haemophilus influenzae.
  • Neisseria meningitidis.

uses include:

  • Community-acquired septic shock.
  • Febrile neutropenia.
  • Hospital-acquired infections (including pneumonia, bacteremia, intra-abdominal infections, CNS infections).
  • AmpC beta-lactamase producing organisms.
  • 🥊 Piperacillin-tazobactam vs. cefepime discussed here: 📖

toxicity/contraindications

  • Drug fever.
  • Neutropenia, thrombocytopenia, positive Coombs test which is sometimes accompanied by clinical hemolysis.
  • CNS: Seizure (including nonconvulsive status epilepticus); delirium (often with myoclonus). (12627936)
    • ⚠️ Risk factors for neurotoxicity:
      • Elderly.
      • Renal dysfunction.
      • History of seizure.
      • Pre-existing delirium or neurological injury.
  • Causes more C. difficile than piperacillin-tazobactam. (24140078, 14963072)

cephalosporin G5: ceftaroline

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ceftaroline dosing

  • GFR >50 ml/min:
    • Mild-moderate infections: 600 mg IV q12hr.
    • Indications for 600 mg IV q8hr: (28702467, 27520326)
      • Endocarditis.
      • Staph bacteremia, especially MRSA with ceftaroline MIC of 2-4 mg/L.
      • Augmented renal clearance.
  • GFR 30-50 ml/min: 400 mg q8-q12hr
  • GFR 15-30 ml/min: 300-400 mg q12hr
  • GFR <15 or intermittent hemodialysis: 200-300 mg q12hr
  • Obesity: generally no dose adjustment (600 q12h achieves target for MIC ≦1 mg/L). (36703246) 
  • ECMO: (20% protein binding; Vd 0.3 L/kg; LogP -3.7) Unlikely to be affected by ECMO.

pharmacology

  • Excretion: 88% excreted unchanged in urine.
  • Protein binding: 20%
  • Vd: ~0.3 L/kg.
  • Penetration: Widely distributed, but only 10% CNS penetration.

spectrum

  • Gram-positives:
    • MSSA.
    • MRSA including VISA (vancomycin intermediate S. aureus). (Schmidt 2024)
    • Coagulase-negative Staph.
    • Streptococcus pneumoniae.
    • Non-enterococcal streptococci (e.g., Group A strep, Group B strep).
    • Enterococcus faecalis.
  • Gram-negative coverage is similar to ceftriaxone:
    • Misses pseudomonas and ESBL species.
    • Ceftaroline is hydrolyzed by AmpC beta-lactamases.

use

toxicity/contraindications

  • Nausea, diarrhea.
  • Rash.
  • Neutropenia (more problematic with longer courses). (28702467)
  • Clostridioides difficile colitis.
  • Seizure.

clindamycin

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clindamycin dosing

  • 900 mg IV q8hr.
  • Generally no dose adjustment for hepatic or renal dysfunction.
    • Consider reduction in combined kidney & hepatic dysfunction.
  • Obesity: high end of usual dosing (e.g., 900 mg IV q8hr). (36703246)

pharmacology

  • High oral bioavailability (~90%); however, oral clindamycin may cause more Clostridioides difficile than IV clindamycin.
  • Excretion: Metabolized by liver, only 10% excreted unchanged in urine.
  • Protein binding: 90%
  • Vd: 1 L/kg (widely distributed).
  • Penetration:
    • Good penetration of most tissues, except the CNS.
    • Actively transported into neutrophils and macrophages, causing concentration in abscesses.
    • Dissolves biofilms on hardware.
  • Mechanism: blocks protein synthesis by impeding release of protein from the 50S ribosome (same mechanism as macrolides).

spectrum

  • Gram-positives:
    • Some non-enterococcal streptococci (~50% of Group B streptococcus).
    • Staphylococcus aureus (~80% of both MSSA and MRSA).
    • Streptococcus pneumoniae.
  • Anaerobic coverage is good, but resistance is increasing among gut anaerobes (e.g., Bacteroides spp).
    • Clindamycin is no longer recommended for empiric therapy of intra-abdominal infections. (Vincent 2023)
  • Use caution if the bacteria is resistant to erythromycin, as some bacteria may be cross-resistant or have inducible resistance against clindamycin. This may be evaluated using the D-test.

use

  • Toxin suppression:
    • Severe Group A strep infections (e.g., toxic shock syndrome, necrotizing fasciitis). The combination of clindamycin plus a beta-lactam is the gold standard therapy here.
    • Clostridium perfringens: gas gangrene.
  • Anaerobic coverage (however, metronidazole is generally superior for this).
    • Clindamycin can be useful for lung abscess, due to combined coverage of anaerobes and oral streptococcal spp.

toxicity/contraindications

  • ⚠️ High tendency to induce Clostridioides difficile infection (risk up to 10%).
  • Rashes, fever, anaphylaxis, erythema multiforme.
  • May block neuromuscular transmission, contraindicated in myasthenia gravis.

daptomycin

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daptomycin dosing

  • ⚠️ Discontinue any myotoxic medications (e.g., statins).
  • ⚠️ Order serial CK levels (e.g., baseline & weekly).
  • ⚠️ High protein binding; levels might be suboptimal in severe hypoalbuminemia. ⚡️
  • Bacteremia:
    • At least 8 mg/kg IV daily.
    • 10 mg/kg IV daily: Staphylococcal endocarditis. (26373316, 26320109)
    • 10-12 mg/kg IV daily: Enterococcal endocarditis. (26373316, 26320109)
  • Osteomyelitis: 6-8 mg/kg IV daily.
  • Septic arthritis: 6 mg/kg IV daily.
  • Skin/soft tissue infections: 4-6 mg/kg IV daily.
  • Renal insufficiency (GFR <30): increase interval to q48.
  • IHD: 10 mg/kg three times weekly post-dialysis (for all indications). (UVM Green book)
  • CRRT:
    • 1-2 L/hr effluent: 6-8 mg/kg q24. (31342772)
    • 3+ L/hr effluent: 8 mg/kg q24. (31342772)
  • Obesity: Use adjusted body weight. 🧮 (36703246)
  • When in doubt, dose high. Higher-dose daptomycin may reduce the likelihood of treatment-emergent resistance, is generally well tolerated, and is not associated with excess toxicities. (2015 IDSA endocarditis guidelines; 26373316)

pharmacology

  • Excretion: 80% excreted unchanged in urine.
  • Protein binding: 92%
  • Vd: 0.1 L/kg (small Vd corresponds to plasma and interstitial fluid).
  • Penetration: Distributes to bile and urine; CSF penetration is poor.
  • Dosed once daily with a post-antibiotic effect and half-life of ~8 hours.

spectrum

  • Very broad spectrum against gram-positives, including:
    • MRSA.
    • VRE (vancomycin-resistant Enterococci).
  • Emergence of daptomycin resistance may occur while treating Staph aureus (especially if previously treated with vancomycin or large burden of bacteria).

use

  • MRSA endocarditis, bacteremia:
    • ⚠️ Be careful about using daptomycin if vancomycin MIC is >2 (increased rates of resistance).
    • Resistance can emerge during therapy, which might be avoided somewhat by co-administration of a beta-lactam (daptomycin plus ceftaroline might be ideal).
  • Skin/soft tissue infection.
  • Urinary vancomycin-resistant enterococcus infection (daptomycin secreted in urine, might be 1st line here).
  • ⚠️ Daptomycin is inactivated by surfactant in lung, so it cannot be used for pulmonary infection.
  • Additional discussion: 🥊 Drug-resistant gram positive cocci: vancomycin vs. linezolid vs. daptomycin vs. ceftaroline

toxicity & ⚠️ contraindications

  • ⚠️ Rhabdomyolysis:
    • Discontinuing statins might reduce risk.
    • Check creatinine kinase at baseline and monitor weekly during therapy. Discontinue daptomycin if creatinine kinase increases >2,000 U/L, or >1,000 U/L with symptoms of myopathy.
  • AEP (acute eosinophilic pneumonia)
    • Daptomycin is the antibiotic most commonly associated with AEP.
    • Risk may relate to the duration of therapy (with a mean onset after ~3 weeks).
  • False elevation of INR (lab artifact). This may be sorted out by repeating INR before an infusion, when daptomycin is at trough levels.
  • LFT abnormality.
  • Peripheral neuropathy.
  • Sickle-cell crisis. (Irwin & Rippe 9e)

doxycycline

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doxycycline dosing

  • ⚠️ High protein binding, levels might be suboptimal in severe hypoalbuminemia. ⚡️
  • Start with a 200 mg loading dose in severe infection (otherwise steady-state drug levels won't be reached for a few days). (28819873) This is actually a conservative loading dose (based on a half-life of 20 hours, the mathematically calculated loading dose 🌊 should be 300 mg).
  • Usual maintenance dose: 100 mg q12 PO/IV (100% oral bioavailability)
  • Meningeal dose: 200 mg q12.
  • For moderate to severe legionella: 200 mg q12 hours for 72 hours, followed by 100 mg q12. (16669925)
  • ECMO: (80% protein binding; Vd 0.75 L/kg; LogP 0.6) Data is extremely limited, but one case report found adequate pharmacokinetics. (Mehta et al.)

pharmacology

  • 100% oral bioavailability is achievable (however absorption impaired by aluminum, magnesium, calcium, iron, cholestyramine, or milk).
  • Excretion: ~30% excreted unchanged in the urine. Mostly eliminated by the liver.
  • Half-life: ~20 hours.
  • Protein binding: 82%.
  • Vd: 0.75 L/kg.
  • Penetration: Good penetration of most tissues (CSF reaches 25% serum level).
  • Serum concentrations may be unreliable. (37463564)
  • Mechanism: Inhibition of protein synthesis through 30s ribosomal binding blocking aminoacyl-tRNA (same as tigecycline).

spectrum

  • Gram-positives:
    • Most streptococci.
    • Streptococcus pneumoniae is increasingly resistant (~20% resistant).
    • Staph coverage is good (including coverage of ~80% of MRSA). However, it's unclear whether this achieves clinical cure in vivo (especially for pneumonia).
  • Gram-negatives:
    • Some E. coli.
    • Haemophilus influenzae, Moraxella catarrhalis.
  • Atypicals:
    • Mycoplasma pneumoniae.
    • Chlamydia pneumoniae.
    • Legionella.
  • Listeria monocytogenes.
  • Tick-borne illnesses:
    • Lyme.
    • Rocky Mountain Spotted Fever.
    • Tularemia.
    • Ehrlichiosis.
    • Anaplasmosis.
  • Zoonotic organisms:
    • Coxiella burnetii.
    • Yersinia pestis.
    • Chlamydia psittaci.
    • Bacillus anthracis.
    • Leptospirosis.
    • Pasteurella multocida.

use

  • Atypical pneumonia coverage, especially in the following situations:
    • (1) History of contact with animals.
    • (2) High risk for C. difficile infection (doxycycline appears to decrease risk). (37921728, 22563022)
    • (3) Patients who are at some risk for community-acquired MRSA pneumonia, but not enough risk to justify the addition of linezolid or vancomycin (doxycycline has fair activity against community-acquired MRSA, but lacks evidence for efficacy in MRSA pneumonia).
  • Tick borne illnesses (e.g. anaplasmosis, Rocky Mountain Spotted Fever). Unfortunately, doxycycline will miss babesiosis, so if your tick-exposed patient has hemolysis then babesiosis may require further investigation and specific treatment.
  • Skin and soft tissue infection due to Staph aureus (including purulent cellulitis).

toxicity/contraindications

  • Generally well tolerated (appears to reduce the risk of Clostridioides difficile). (22563022, 18171186, 27025622, 28819873, 37921728)
  • GI irritant:
    • Nausea, vomiting may occur if taken before/after meals.
    • Esophageal ulceration may result if taken orally without sufficient water.
  • Vascular irritant: Can cause phlebitis when given intravenously.
  • Pancreatitis reported in a few case reports. (28912911)
  • Stevens-Johnson syndrome.
  • Photosensitive rash (avoid excessive sun exposure).

fluoroquinolones

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fluoroquinolone dosing

  • Ciprofloxacin:
    • 🛑 Should only be used if no other viable options (discussed below).
    • ⚠️ Evaluate for drug-drug interactions before ordering.
    • Nosocomial pneumonia, or pseudomonas infection: 400 mg IV q8hr, or 750 mg PO q12hr.
    • Bone/joint infection: 400 mg IV q8-12 hours, or 500-750 mg PO q12hr.
    • Intra-abdominal infection: 400 mg IV q12hr, or 500 mg PO q12hr.
    • Urinary tract infection: 200-400 mg IV q12hr, or 250-500 mg PO q12hr.
    • Renal dosing adjustment:
      • GFR >30 ml/min: no adjustment.
      • GFR 10-30 ml/min: extend dosing interval from q12hr to q18hr.
      • GFR <10 ml/min: extend dosing interval from q12hr to q24hr.
    • Obesity: consider upper end of normal dosing range.
    • ECMO (30% protein binding; Vd 2.5 L/kg; LogP 2.3). Fluoroquinolone concentrations generally remain therapeutic with standard dosing. (29732181, 35326801)
  • Levofloxacin:
    • 🛑 Should only be used if no other viable options (discussed below).
    • ⚠️ Evaluate for drug-drug interactions before ordering.
    • Dose for serious infection: 750 mg IV/PO daily.
    • Renal dosing adjustment:
      • GFR 20-49 ml/min: 750 mg q48 hrs.
      • GFR <20 ml/min: 750 mg loading dose x1, then 500 mg q48hr.
    • Obesity: consider upper end of normal dosing range.
    • ECMO (30% protein binding; Vd 1.1 L/kg; LogP 2.1).  Fluoroquinolone concentrations generally remain therapeutic with standard dosing. (29732181, 35326801)
  • Moxifloxacin: 400 mg q24 hours (regardless of route or renal function). Not recommended in severe hepatic dysfunction. Not affected by obesity.

fluoroquinolone pharmacology 

  • Bioavailability is excellent (~100% for levofloxacin or moxifloxacin, ~70% for ciprofloxacin). However, oral dosing cannot be coadministered with polyvalent cations (e.g., magnesium, aluminum-containing antacids, sucralfate, zinc, or iron).
  • Distribution:
    • Good intracellular antibiotic penetration.
    • Concentrated in prostate tissue, kidneys, bile, lung, and neutrophils. Bronchial secretions have concentrations equal or greater than serum.
    • Fairly good CNS penetration.
    • Achieves sustained serum concentrations. (37463564)
  • Ciprofloxacin and levofloxacin are excreted in the kidney (with good efficacy against urinary tract infection).
  • Moxifloxacin is metabolized by the liver, rendering it suboptimal for urinary tract infections.

fluoroquinolone spectrum 

  • Gram negatives:
    • Generally good coverage, but E. coli resistance is increasing (especially in Europe; refer to your antibiogram).
    • Pseudomonas is usually covered by ciprofloxacin and levofloxacin (not moxifloxacin).
    • Moxifloxacin loses some gram negative coverage (misses some Providentia, Proteus, and Serratia spp.)
    • Levofloxacin covers Stenotrophomonas maltophilia.
  • Gram positive:
    • Streptococcus pneumoniae is covered by levofloxacin or moxifloxacin (including species with high-level penicillin resistance).
    • MSSA is covered by ciprofloxacin (levofloxacin and moxifloxacin have variable activity).
    • Enterococcus: Ciprofloxacin has reasonable coverage for Enterococcus faecalis, but often misses Enterococcus faecium.
  • Anaerobic coverage:
    • Only moxifloxacin has anaerobic coverage. However, resistance may be increasing among Bacteroides fragilis.
  • Fluoroquinolones cover certain respiratory pathogens, including:
    • Haemophilus influenzae.
    • Moraxella catarrhalis.
    • Atypical pathogens (e.g., Mycoplasma pneumoniae, Chlamydia pneumoniae, and Legionella pneumophila). Levofloxacin and moxifloxacin are more active than ciprofloxacin. (Irwin & Rippe, 9e)

🛑 Fluoroquinolones should be avoided if possible, for the following reasons: 🌊

  • [1] Increasing antibiotic resistance (e.g., >25% resistance of E. coli to ciprofloxacin in many locations).
  • [2] Fluoroquinolones induce the emergence of multi-drug resistant bacteria to a much greater extent than most antibiotics. Removal of fluoroquinolones from the ICU may help control pathogens such as C. difficile and MRSA.
  • [3] Fluoroquinolones have traditionally been used for patients with penicillin allergy, but we are increasingly realizing that cephalosporins are fine for such patients.
  • [4] Fluoroquinolones cause delirium.
  • [5] Fluoroquinolones have recently been implicated in causing persistent neurologic abnormalities, which may be especially problematic among intubated patients (who are unable to report neurologic side-effects). Fluoroquinolones can also cause connective tissue problems involving tendinopathy and aortic aneurysm. Consequently, the FDA has recommended avoidance of fluoroquinolones when possible in a black box warning.
    • ⚠️ This may be medicolegally problematic.
  • [6] Fluoroquinolones add very little to beta-lactam antibiotics when used for double-coverage of pseudomonas:
    • The concept of double-coverage of pseudomonas isn't generally supported by evidence. 🌊
    • If you are going to double-cover for pseudomonas, the only antibiotic that adds substantially to a beta-lactam is an aminoglycoside. 🌊

when to use a fluoroquinolone:

  • Common situations when a fluoroquinolone would be utilized:
    • [1] Step-down therapy for bacterial species with inducible AmpC beta-lactamases, if there aren't other options (e.g., resistant to trimethoprim/sulfamethoxazole). 📖
    • [2] Step-down therapy for ESBL species, if there aren't other options (e.g., resistant to trimethoprim/sulfamethoxazole). 📖
  • Infections that can be treated with a fluoroquinolone:
    • Urinary tract infections including urosepsis (either ciprofloxacin or levofloxacin; moxifloxacin is hepatically cleared so urinary levels may be suboptimal).
    • Skin/soft tissue infections.
    • Pneumonia (either levofloxacin or moxifloxacin; ciprofloxacin lacks sufficient pneumococcal coverage).
    • Meningitis (limited evidence, not for front-line therapy).
    • Abdominal infections (e.g., ciprofloxacin/levofloxacin plus metronidazole).

toxicity/contraindications

  • Contraindications:
    • QTc prolongation is a contraindication to levofloxacin or moxifloxacin.
    • Possible tuberculosis (may mask culture-positive disease and promote resistance).
    • Myasthenia gravis.
  • Adverse events:
    • Neurologic: Confusion and agitated delirium (antibiomania), tremor, seizures, peripheral neuropathy.
    • QT prolongation (levofloxacin, moxifloxacin).
    • C. difficile diarrhea.
    • Hypoglycemia or hyperglycemia.
    • Allergic reactions (may include anaphylaxis, serum sickness, Steven Johnson Syndrome).
    • Hepatitis (may be severe).
    • Tendon rupture (higher risk of >60 years old, steroid use).

linezolid

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linezolid dosing

  • 600 mg IV/PO q12hr (no adjustment for renal dysfunction; same dose provides meningeal coverage).
  • Morbid obesity: generally no change to dose. (36703246) Increasing the dose to 600 mg IV/PO q8hr in severe obesity could be considered, but this may increase the risk of complications such as thrombocytopenia.
  • ECMO: (30% protein binding; Vd 0.6 L/kg; LogP 0.9) Despite hydrophilicity, some case reports describe inadequate levels when using linezolid. (32426841, 35326801, 33239110, 23453617)
    • Ceftaroline might be preferable for therapy of MRSA pneumonia.

pharmacology

  • 100% oral bioavailability.
  • Excretion: Mostly cleared by hepatic metabolism, but 30% is excreted unchanged in the urine.
  • Protein binding: 30%.
  • Vd: 0.6 L/kg (approximately equal to total body water content).
  • Penetration: Outstanding tissue penetration, including lung and particularly CSF (may reach >70% serum levels). (22787406)

spectrum

  • Broad coverage of gram-positives, including:
    • MRSA.
    • VRSA (vancomycin resistant Staph. aureus)
    • VRE (vancomycin-resistant enterococci).
    • Coagulase-negative staphylococci.
    • Streptococcal species.
    • Streptococcus pneumoniae (including penicillin-resistant strains).
  • Listeria.
  • Nocardia.

use

  • Pneumonia: Linezolid is arguably a front-line agent for MRSA pneumonia. (22247123, 25355172, 25066668, 27208687, 24238896, 26382940, 24916853, 24420846, 23568605, 21163725, 18719064) Linezolid will also work for other gram-positive pneumonia (e.g. MSSA, Streptococcus pneumoniae), but obviously isn't a front-line agent for these organisms.
  • Bacteremia: In 2007, the FDA released a warning regarding the use of linezolid for catheter-related bloodstream infections (illustrated here: 📸). (17899228, 19072714) This seems to represent a statistical fluke, especially because subsequent studies have shown that linezolid is effective for bacteremia. (25495779, 19900794, 16195255, 17852941) Currently, vancomycin remains preferred for MRSA bacteremia. However, linezolid is FDA-approved and potentially front-line therapy for treatment of bacteremia due to vancomycin-resistant enterococcus. (27475738)
  • Urinary tract infection: Although linezolid isn't excreted in the urine, urinary concentrations greatly exceed serum levels. Linezolid may be used for urinary tract infection with vancomycin-resistant enterococci.
  • Skin and soft-tissue infections. Linezolid appears to be more effective than vancomycin. (26758498) 
  • CNS infections: Linezolid can achieve outstanding CSF penetration (~80% serum levels). Use in CNS infections hasn't been well investigated, but there is a growing evidentiary basis that linezolid is an effective therapy for CSF infections (e.g., meningitis). (23672240, 21671825, 14766894, 36838359)
  • Toxic shock and/or necrotizing fasciitis: Linezolid is increasingly a preferred agent for these infections. It provides broad-spectrum gram positive coverage (thereby abrogating the need for vancomycin) while simultaneously suppressing toxin production. 📖
  • Additional discussion: 🥊 Drug-resistant gram positive cocci: vancomycin vs. linezolid vs. daptomycin vs. ceftaroline

toxicity/contraindications

  • Serotonin syndrome may occur if combined with other serotonergic medications:
    • Ideally, serotonergic medications would be stopped and allowed to wash out prior to initiation of linezolid (especially fluoxetine, which has a half-life of several days). (15883150) However, for critical infections it is adequate to simultaneously stop the serotonergic medications and initiate linezolid. (20098528, 23424229, 29950810) Notably, when linezolid and serotonergic agents are co-administered, the rate of serotonin syndrome is extremely low. The risk of serotonin syndrome with linezolid has likely been considerably overblown. (37310038)
  • Nausea/vomiting and diarrhea are most common side effects.
  • Prolonged courses (>10-14 days) are difficult to tolerate due to a variety of toxicities that usually emerge late:
    • Reversible myelosuppression (thrombocytopenia is more common than neutropenia or anemia).
    • Optic neuropathy (reversible) and peripheral neuropathy (can be irreversible if treatment isn't stopped).
    • Lactic acidosis.
  • Rarely side-effects:
    • Posterior reversible leukoencephalopathy (PRES), seizures.
    • Hypoglycemia.
  • Note: Linezolid is protective against Clostridioides difficile. (22445203, 21504940)

macrolides (azithromycin, clarithromycin)

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macrolide dosing

  • Azithromycin:
    • Community-acquired pneumonia or COPD: Front-loaded regimen with 500 mg IV daily for three days is preferred. (Azithromycin has a very long half-life in tissues, so its biological effect will be prolonged. Front-loading achieves high levels rapidly and reduces administration costs.)
    • Legionella pneumonia: 500 mg IV daily for 5-10 days.
  • Clarithromycin:
    • 500 mg PO twice daily (immediate-release formulation).
    • GFR 10-30 ml/min: Reduce dose by 50%.
    • GFR <10 ml/min: 250-500 mg q24hr.
    • No dose adjustment in hepatic dysfunction.

pharmacology

  • Azithromycin:
    • Oral bioavailability of azithromycin is 37% (food decreases absorption).
    • Excretion in the bile, only 6% excreted unchanged in urine.
    • Protein binding: 50%
    • Vd: 30 L/kg
    • Penetration: Concentrates intracellularly within tissues, with a long half-life (2-4 days). Penetrates most tissues, but not urine or meninges.
  • Clarithromycin:
    • Oral bioavailability is 50%.
    • Excretion: Mostly excreted in the liver. 25% excreted unchanged in urine.
    • Protein binding: 60%
    • Vd: 3 L/kg
    • Penetration: Concentrates intracellularly (tissue concentration > serum concentration), poor CSF penetration.
  • Mechanism: blocks the protein from exiting the 50S ribosomal unit (same mechanism as clindamycin).

spectrum

  • Gram-positive coverage:
    • Some Staph. aureus (~70% of MSSA; ~10% of MRSA).
    • Some Group A/B/C/D/G streptococci.
    • Some Streptococcus pneumoniae (~66%).
  • Haemophilus influenzae and Moraxella catarrhalis (azithromycin > clarithromycin).
  • Atypical organisms:
    • Bordetella pertussis.
    • Chlamydia pneumoniae.
    • Coxiella burnetii.
    • Mycoplasma pneumoniae.
    • Legionella pneumophila.

use

  • Atypical coverage for community-acquired pneumonia. Evidence suggests mortality benefit in severe community-acquired pneumonia, possibly due to anti-inflammatory effects.
    • ⚠️ Even if cultures demonstrate a pathogen sensitive to beta-lactam antibiotics, the azithromycin course should generally be continued.
  • Legionella pneumonia (note that high doses are needed).
  • COPD exacerbation (although doxycycline may be preferable for patients recently on azithromycin).
  • Pharyngitis due to Group A Streptococci.

toxicity/contraindications

  • ⚠️ Contraindicated in myasthenia gravis.
  • Extremely well tolerated (most common side effect is nausea or diarrhea with oral administration).
  • Relatively low rate of Clostridioides difficile, compared to most other antibiotics.
  • May cause transaminitis; cholestasis (azithromycin).
  • Clarithromycin:
    • May increase QTc and risk of torsade de pointes (not seen clinically with azithromycin).🌊
    • May cause delirium (antibiomania).

metronidazole

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metronidazole dosing

  • Traditional dose: 500 mg IV/PO q8 (no adjustment for renal function).
  • Reduced dose: 500 mg IV/PO q12 is supported by some evidence as being equivalent in most cases (excluding for example CNS or C. difficile infections). (29796265, Jizba 2023, 33965559) 
  • Renal failure: no adjustment.
  • Child-Pugh class C cirrhosis: consider 50% dose reduction.
  • Obesity: 500 mg IV/PO q8hr (this dose is probably higher than needed for non-obese patients). (36703246)
  • ECMO: (20% protein binding; Vd 0.7 L/kg; LogP -0.18) Unlikely to be affected by ECMO.

pharmacology

  • Absorption: Oral bioavailability approaches 100%.
  • Distribution:
    • Protein binding: 20%
    • Vd: 0.7 L/kg
    • Penetration: Lipophilicity and low protein-binding cause metronidazole to distribute widely throughout the total body water (including abscess cavities and CNS).
  • Metabolism: Metabolized in the liver into five metabolites, one of which (1-(2-hydroxy-ethyl)-2-hydroxy methyl-5-nitroimidazole) is about half as biologically active as metronidazole.
  • Elimination:
    • 20% is excreted unchanged in urine; mostly excreted in bile.
    • Half-life of metronidazole is ~8 hours; the half-life of the hydroxy metabolite is ~10 hours.
  • Mechanism: Metronidazole is a Trojan horse that is converted into bactericidal metabolites by the electron transport chain of anaerobic bacteria. Metronidazole seems to exhibit concentration-dependent killing.

spectrum

  • Best anti-anaerobic agent (better coverage & fewer problems with Clostridioides difficile compared to clindamycin).
  • Only covers anaerobes.

use

  • Anaerobic coverage (e.g., metronidazole plus cefepime produces broad-spectrum coverage). Can be used in broad range of infections (e.g. abdominal, CNS, gynecologic, respiratory, bacteremia, or soft tissue).
  • Clostridioides difficile (inferior to oral vancomycin; may be used as add-on agent in severe cases or in patients unable to take oral medications).
  • Generally avoid adding it to piperacillin-tazobactam or meropenem (these agents have great anaerobic coverage; the only thing that metronidazole adds is Clostridioides difficile coverage).

toxicity/contraindications

  • Nausea, diarrhea, dysgeusia
  • Metronidazole induced encephalopathy: can cause encephalopathy, seizure, peripheral neuropathy, or aseptic meningitis (especially with prolonged use). (27504340) More here: 📖
  • Rarely:
    • Stevens-Johnson syndrome.
    • Pancreatitis.
    • Hemolytic uremic syndrome.
    • Drug fever.
    • Neutropenia.

nafcillin

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nafcillin dosing

  • ⚠️ High protein binding, levels might be suboptimal in severe hypoalbuminemia. ⚡️
  • Serious infections (e.g., endocarditis): 2 grams IV q4hr. (26373316, 26320109)
  • Skin, soft tissue infections: 1-2 grams IV q4hr.
  • Decompensated liver failure: dose reduce by 50%.
  • Renal dysfunction: No adjustment.
  • Obesity: Consider upper limit of dosing in severe infections  (e.g., 2 grams IV q4hr). (36703246)
  • Monitor liver function tests every week.

nafcillin pharmacology

  • Excretion: Mostly cleared by the liver and biliary tract. 10-30% unchanged drug is excreted in the urine.
  • Protein binding: 90%
  • Half-life: 30-90 minutes.
  • Vd: 0.2 L/kg
  • Penetration: Distributed widely, including inflamed meninges (20% serum levels).
  • Mechanism: Inhibits cell wall synthesis by binding to penicillin-binding proteins (primarily 1a, 1b, and 2).

nafcillin spectrum

  • Streptococci groups A, B.
  • Pneumococci (penicillin-sensitive).
  • Methicillin-sensitive staph aureus (MSSA) & methicillin-sensitive staph epidermidis.

nafcillin use

  • MSSA infection is the primary use (including: endocarditis, hepatic abscess, skin/soft tissue infections, pneumonia).
    • Selection of nafcillin vs. cefazolin for MSSA: 📖
  • Sensitive strains of coagulase-negative staph (Staph epidermidis, Staph haemolyticus, Staph lugdunensis).
  • Nonpurulent cellulitis.
  • Synergistic en vitro with either vancomycin or daptomycin against staph aureus (clinical relevance to be determined). (22848719)

nafcillin toxicity/contraindications

  • Rash (10% of patients), interstitial nephritis, drug fever
  • Thrombocytopenia, leukopenia, hemolytic anemia (may also cause false-positive Coombs test without hemolytic anemia)
  • Seizure or myoclonus may occur with high doses
  • Phlebitis

nitrofurantoin

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nitrofurantoin dosing

  • Nitrofurantoin monohydrate/macrocrystals (Macrobid), 100 mg PO BID.
  • Nitrofurantoin macrocrystals (Furadantin suspension, Macrodantin), 50-100 mg q6hr.

pharmacology

  • Well absorbed (especially with food), with ~40% excreted unchanged in the urine.
  • Protein binding: 60%.
  • Volume of distribution: 0.8 L/kg. Relatively little drugs enters the gastrointestinal tract, so there is minimal effect on fecal flora and low risk of C. difficile. (22546769)
  • Penetration: Active drug is excreted by the kidneys, thereby achieving therapeutic concentrations in the urine. Alkalotic urine may reduce its efficacy. Drug levels in the blood are not high enough to be effective against bacteremia.
  • Mechanism of action: Nitrofurantoin is converted by bacterial flavoproteins into highly reactive electrophilic metabolites that have numerous activities, ultimately with bactericidal effect. (30765904)

spectrum: nitrofurantoin covers:

  • Gram positives:
    • Most Staph saprophyticus
    • Most Enterococcus faecalis and Enterococcus faecium, including vancomycin resistant enterococci (VRE). (31608743)
    • Some Staphylococcus aureus.
  • Gram negatives:
    • Covers most E. coli, most Citrobacter spp., many Klebsiella spp., and some Enterobacter spp (including ESBL and AmpC species).
    • Misses: Morganella spp., Proteus mirabilis, Providencia spp., Pseudomonas aeruginosa, Serratia marcescens, Stenotrophomonas maltophilia, Acinetobacter spp., carbapenem-resistant enterobacteriaceae (CRE). (22546769, 31608743)
  • Drug levels in the urine are generally 50-300 mcg/ml, which is often well above the susceptibility breakpoint of 64 mcg/ml. Thus, nitrofurantoin may be clinically effective, despite in vitro “intermediate susceptibility.”(22546769)

use

  • Uncomplicated cystitis.
  • Catheter-associated bacteriuria (in the absence of pyelonephritis, sepsis, or bacteremia). (22546769, 25004793) Predominantly useful as step-down therapy if the pathogen is known to be sensitive.

toxicity/contraindications

  • ⚠️ Generally considered to be contraindicated if GFR < 30 ml/min. However, a large retrospective study suggested that cure rates were unaffected by GFR even when below 30 ml/min. (27100576) Lower GFR does increase the risk of pneumonitis.
  • ⚠️ Caution in patients with G6PD deficiency, as nitrofurantoin may increase the risk of hemolytic anemia.
  • Prolonged prophylactic use may cause chronic hepatitis or peripheral neuropathy. Pneumonitis can occur over a shorter time frame, although pneumonitis is more likely among patients taking nitrofurantoin for weeks.
  • Rare complications include pancreatitis and lactic acidosis.

penicillins (PCN G, ampicillin, amoxicillin, amp/sulbactam)

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dosing of penicillins

  • Penicillin G:
    • GFR >50 ml/min: 1-4 million units (MU) q4-6hr.
      • Indications for 4 MU q4hrs (24 MU daily):
        • [1] Endocarditis (e.g., with beta-hemolytic streptococci or endocarditis). For enterococcal endocarditis the dosing range is 18-30 MU/day divided into six doses. (26373316, 26320109)
        • [2] CNS infection.
    • GFR 30-50 ml/min: 100% dose, administered q6hr.
    • GFR 10-30 ml/min: 100% dose, administered q6-q8hr.
    • GFR <10 ml/min: 100% dose, administered q8-q12hr.
  • Ampicillin:
    • 1-2 grams IV q4-6.
      • 2 grams IV q4hr for meningitis, endocarditis, or osteomyelitis (but q6hr for other indications). (26373316, 26320109) This provides a total of 12 grams/day of ampicillin, which is still lower than regimens used to treat CRAB (18 g/day; see below). 
    • Renal failure:
      • GFR 30-50 ml/min: extend dosing interval to q8.
      • GFR 10-30 ml/min: extend dosing interval to q8-q12.
      • GFR <10 ml/min: extend dosing interval to q12-q16.
    • Obesity: Consider upper limit of dosing in severe infections  (e.g., 2 grams IV q4hr). (36703246)
    • ECMO: (25% protein binding; Vd 0.25 L/kg; LogP 1.4) Standard dosage appears to achieve therapeutic targets, but available clinical data is sparse. (37243488)
  • Amoxicillin:
    • High dose amoxicillin (1,000 mg PO q8hr):
      • Step-down therapy for ampicillin-sensitive gram negative bacteremia: 1 gram PO q8hrs. (Stanford Antimicrobial Guide)
      • Community-acquired pneumonia therapy for patients at risk for drug-resistant S. pneumoniae.
    • Standard dose amoxicillin (250-500 mg PO q8hr):
      • Urinary tract infection.
      • Nonpurulent cellulitis.
    • Renal failure:
      • GFR >30: Usual dose q8hr.
      • GFR 10-30: Same dose given q12hr.
    • Obesity: consider the upper lmite of normal dosing in severe infections, e.g. up to 1 gram PO q8hr. (36703246)
  • Ampicillin-Sulbactam: (3 grams = ampicillin 2g + sulbactam 1 g)
    • 1.5-3 grams q6hrs (usually 3 grams q6hr, especially for endocarditis). (26373316, 26320109)
    • GFR 30-50 ml/min: extend dosing to q6-q8.
    • GFR 10-30 ml/min: extend dosing to q12.
    • GFR <10: extend dosing to q24.
    • CRAB: One of the following two options: (IDSA 12/23)
      • 9 grams (6 grams ampicillin & 3 grams sulbactam) IV q8h infused over four hours.
      • 27 grams (18 grams ampicillin & 9 grams sulbactam) continuous infusion over 24 hours.

pharmacology

  • Penicillin G:
    • Excretion: 80% excreted unchanged in the urine.
    • Protein binding: 60%
    • Vd: 0.3 L/kg
    • ⚠️ Half-life: 20-50 minutes.
    • Penetration: most fluids and tissues, including inflamed meninges.
  • Ampicillin:
    • Excretion: 90% excreted in urine unchanged.
    • Protein binding: 25%
    • Half-life: 1-1.8 hours.
    • Vd: 0.25 L/kg
    • Penetration: Widely distributed (e.g. urine, pleural fluid, peritoneal fluid, lung, bone, bile), including inflamed meninges.
  • Amoxicillin:
    • Oral bioavailability is ~80% (ranging 74-92%). Absorption seems to be saturable (perhaps at ~750 mg), so more frequent dosing may improve the likelihood of PK/PD target attainment. (31811919)
    • Excretion: 90% excreted in urine unchanged.
    • Protein binding: 20%.
    • Half-life: 1.3 hours.
    • Vd: 0.36 L/kg (more lipid soluble than ampicillin).
    • Penetration: Widely distributed (e.g. urine, pleural fluid, peritoneal fluid, lung, bile). CSF penetration is likely inadequate with oral amoxicillin. (31811919)

spectrum & use

  • Penicillin G:
    • Gram positives:
      • Group A, B, C, G streptococci are susceptible.
      • Streptococcus pneumoniae: generally susceptible for non-meningeal infections.
      • (Does not cover Staph. aureus as most strains produce a penicillinase.)
    • Neisseria meningitidis.
    • Anaerobes:
      • Clostridia (excluding Clostridioides difficile) are uniformly susceptible.
      • Most oral anaerobes (e.g., Peptostreptococcus spp.).
    • Use:
      • Rarely used for empiric therapy, but it is definitive therapy for susceptible organisms. Most common examples of this are as follows:
      • [1] Group A, B, C, G streptococci (uniformly susceptible)
      • [2] Streptococcus pneumoniae known to be PCN-sensitive:
        • Infection outside CSF: Susceptible if MIC 2 mcg/ml or lower.
        • CNS infection: Susceptible if MIC is 0.06 mcg/ml or lower. However, ceftriaxone 2 grams q12 is often preferred, even for sensitive organisms.
      • [3] Neisseria meningitidis.
      • [4] Clostridium perfringens.
  • Use of penicillin G vs. ampicillin
    • Penicillin sensitive organisms are generally ampicillin sensitive as well, so in most scenarios either choice is fine. Ampicillin has a longer half-life, which allows for q6hr dosing (except for endocarditis, meningitis, or osteomyelitis). When comparing the two agents, it's notable that many organisms are exquisitely sensitive to penicillin (with a very low MIC), so even if penicillin levels are relatively low penicillin may remain pharmacodynamically active. (17184285) Since penicillin G is older, penicillin G has a stronger track record in some situations.
    • Situations where penicillin G has been traditionally favored include the following:
      • Endocarditis due to certain streptococcal species.
      • Meningococcal meningitis (Neisseria meningitidis).
      • Clostridium perfringens (gas gangrene).
      • Syphilis.
    • Ampicillin is generally preferred for enterococcus.
  • Ampicillin or amoxicillin (ampicillin sensitivity infers amoxicillin sensitivity).
    • Gram positives:
      • Enterococcus (~80% of E. faecalis, but only rarely covers E faecium).
      • Most Streptococci (Group A, B, C, G streptococci are susceptible).
      • Most Streptococcus pneumoniae (if penicillin-sensitive).
      • (Does not cover Staph. aureus as most strains produce a penicillinase.)
    • Gram negatives:
      • Some E. Coli (~65%, mostly due to beta-lactamase production).
      • Proteus mirabilis (~85%).
      • H. influenzae (~60%, only beta-lactamase negative strains).
    • Anaerobes: Similar anaerobic coverage as compared to penicillin-G. This includes most Clostridium spp (not C. difficile) and oral anaerobes.
    • Other:
      • Neisseria meningitidis.
      • Listeria monocytogenes.
      • Lyme.
    • Use of ampicillin:
      • Clinical syndromes/sites:
        • Bacteremia due to sensitive organisms.
        • Non-purulent cellulitis.
        • Pharyngitis (including S. pyogenes).
        • Meningitis due to sensitive organisms.
        • Pneumonia due to sensitive organisms.
        • Urinary tract infection due to sensitive organisms.
      • Definitive therapy for susceptible organisms, including:
        • Enterococcus faecalis (drug of choice for PCN-sensitive Enterococcus spp.).
        • Listeria monocytogenes (drug of choice, superior to meropenem).
        • Sensitive strains of E. Coli or Proteus spp.
        • Haemophilus influenzae that is beta-lactamase negative (first-line).
    • Use of amoxicillin: Use is overall similar to ampicillin. Amoxicillin is the preferred oral penicillin due to less frequent dosing and superior bioavailability. (Hopkins Antibiotic Guide). 
  • Ampicillin-Sulbactam:
    • Gram-positives:
      • Enterococcus (improved coverage of E. faecium compared to ampicillin).
      • Most streptococci.
      • Most Streptococcus pneumoniae.
      • MSSA.
      • Staph. saprophyticus.
    • Haemophilus influenzae, Moraxella catarrhalis.
    • Gram-negatives:
      • Better than ampicillin, but still mediocre coverage, with increasing resistance including among E. coli (overall inferior to ceftriaxone).
      • Best coverage for Klebsiella pneumoniae and Proteus mirabilis.
    • Anaerobic coverage is much better than ampicillin (e.g., 90% coverage of Bacteroides fragilis).
    • Use:
      • Community-acquired empyema (may easily transition to oral amoxicillin-clavulanic acid).
      • Epiglottitis (covers Haemophilus influenzae).
      • Oral and odontogenic infections.
      • Bite wounds (human and animal).
      • Diabetic foot infection, mild.
      • Susceptible Acinetobacter baumannii infections (note: sulbactam is active component).

toxicity/contraindications

  • Penicillin G:
    • Hypersensitivity (rash, anaphylaxis, interstitial nephritis, hepatitis, drug fever).
    • Neurotoxicity at high doses (myoclonus, seizure, confusion).
    • Thrombocytopenia, leukopenia, hemolytic anemia (may also cause false-positive Coombs test without hemolytic anemia).
  • Ampicillin or amoxicillin:
    • Skin rash (more common with mononucleosis, CLL, or allopurinol use).
    • Cytopenias (Coombs-positive hemolytic anemia, neutropenia, thrombocytopenia).
    • Acute interstitial nephritis, hepatitis, drug fever.
    • Seizure, myoclonus (especially high doses in renal failure).
  • Ampicillin-Sulbactam:
    • Similar to ampicillin.
    • Increased risk of cholestatic hepatitis.

piperacillin-tazobactam

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piperacillin-tazobactam dosing

  • GFR >20 ml/min: 4.5g q8hr (1st dose = bolus; subsequent doses extended infusion over four hours).
  • GFR <20 ml/min: 4.5g q12hr (1st dose = bolus; subsequent doses extended infusion over four hours).
  • Augmented renal clearance: consider 4.5g q6hr. (Baptista 2023)
  • CRRT: 4.5 gram loading dose, then 3.375-4.5 grams q12 hrs as an extended infusion over four hours.
  • Obesity:
    • 4.5 grams q8hr (extended infusion over 4 hr) or 4.5 grams q6hr (30 minute infusion). (36703246)
    • Creatinine clearance 100-150 ml/min: 4.5 grams IV q6hr (extended infusion over 4 hours). (36703246)
  • ECMO: (30% protein binding; Vd 0.3 L/kg; LogP 0.5) Dosing may be similar to other critically ill patients. (29732181, 34460303, 33569597) 

pharmacology

  • Excretion: ~70% excreted unchanged in the urine.
  • Protein binding: ~30%.
  • Vd: ~0.3 L/kg.
  • Penetration is excellent, including some entry into inflamed meninges. Extremely high penetration of the bile may make this a good choice for biliary tract infections.
  • Mechanism: inhibits synthesis of bacterial cell wall.

spectrum

  • Gram-positive coverage:
    • Covers: MSSA, non-enterococcal streptococci, vancomycin-sensitive enterococcus, Staph. saprophyticus.
    • Misses: MRSA, vancomycin-resistant enterococci, coagulase-negative staph.
  • Gram-negative coverage: Excellent coverage of most Enterobacteriaceae and Pseudomonas.
    • ⚠️ Be careful with bacteria that are resistant to ceftriaxone and sensitive to piperacillin-tazobactam (especially E. coli & Klebsiella pneumoniae); this sensitivity pattern suggests extended-spectrum beta-lactamase resistant bacteria, which may be better treated with a carbapenem (see ESBL below). (30208454)
  • Anaerobic coverage: Excellent (misses C. difficile)

use

  • Septic shock.
  • Intra-abdominal infections, biliary sepsis, urosepsis.
  • Nosocomial pneumonia.
  • 🥊 Piperacillin-tazobactam vs. cefepime discussed here: 📖

toxicity/contraindications

  • Piperacillin-tazobactam is not nephrotoxic. Piperacillin does inhibit creatinine reuptake in the renal tubules, so piperacillin absolutely does increase the creatinine level (pseudo-nephrotoxicity). However, the best available evidence suggests that this increase in creatinine does not reflect actual kidney injury (e.g., elevated renal biomarkers, or impaired kidney function). (35833959, 33526494, 35007142, 32011685) Further discussion: 🌊
  • Rash, drug fever.
  • Leukopenia, thrombocytopenia.
  • Associated with lower rate of C. difficile than broad-spectrum cephalosporins (e.g., cefepime).
  • Prolonged prothrombin time (specifically in renal failure). (31608743)

rifampin

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rifampin dosing

  • ⚠️ High protein binding, levels might be suboptimal in severe hypoalbuminemia. ⚡️
  • Meningitis: 600 mg q12. (26320109)
  • Prosthetic valve endocarditis: 300 mg q8. (26373316, 26320109)
    • 🛑 Consider delaying initiation of rifampin until after 3-5 days of effective therapy (this may avoid rifampin resistance).
  • Tuberculosis: 600 mg daily.
  • Anaplasmosis (2nd line): 300 mg BID.

pharmacology

  • Oral bioavailability: 95%
  • Excretion: Hepatic metabolism, mostly excreted into bile. 15% excreted unchanged in urine.
  • Protein binding: 80%
  • Vd: 0.9 L/kg
  • Penetration:
    • Good penetration of most tissues including bone, joint, and meninges (~10-20% penetration of meninges; compare to vancomycin's 1-5% penetration). (28870736)
    • Excellent penetration of biofilms, may help sterilize foreign bodies which cannot be removed (e.g. prosthetic valve endocarditis).
  • Mechanism: Inhibits bacterial RNA polymerase

spectrum

  • Staph aureus (including MRSA), coagulase-negative staph
  • Streptococcus pneumoniae, Group A streptococcus
  • Acinetobacter baumannii
  • Legionella, listeria
  • Mycobacteria, including tuberculosis

use

  • Note: Rifampin is generally used as an adjunctive agent to avoid emergence of resistance.
  • Prosthetic valve endocarditis
  • Prosthetic joint infections
  • Meningitis
    • Community-acquired: targeted especially at treatment of PCN-resistant Streptococcus pneumoniae.
    • Nosocomial: used in hardware-associated meningitis/ventriculitis.
  • Legionella infections
  • Tuberculosis

toxicity/contraindications

  • Interacts with many medications (strong inducer of cytochrome P450-3a4 enzymes).
  • Discoloration of bodily fluids.
  • Hepatitis (often hyperbilirubinemia).
  • Nausea/vomiting, abdominal pain.
  • Rarely: Thrombocytopenia, leukopenia, hemolytic anemia.

tigecycline

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tigecycline dosing

  • ⚠️ High protein binding, levels might be suboptimal in severe hypoalbuminemia. ⚡️
  • [1] Standard dose: Loading dose 100 mg, then 50 mg IV Q12hr.
  • [2] Intermediate dose: For serious infection: 200 mg IV load followed by 100 mg IV Q12 may be better (especially for organisms with MIC ≧2 ug/mL). This is the dose recommended by IDSA for septic shock and also for drug-resistant organisms. (38304898, 12/23 resistant GNR) Tigecycline at 50 q12hr was inferior to imipenem for treatment VAP, but tigecycline dosed at 100 q12hr achieved higher response rates than imipenem. (Schmidt 2024)
  • [3] High dose: Loading dose of 200-400 mg IV, then 100-200 mg IV q24. A dose of 200 mg/day may be needed to treat VRE. (Irwin & Rippe 9e)
  • Renal dysfunction: no dose adjustment.
  • In Child-Pugh Class C cirrhosis, reduce maintenance dose by 50%.
  • Obesity: Consider high dose (100 mg q12hr) fo resistant gram-negative organisms. (36703246)
  • ⚠️ Consider monitoring CBC, INR, lipase, and LFTs q48hr. (29363242)

pharmacology

  • Excretion:
    • Mostly excreted unchanged by the liver into the bile.
    • 10-20% excreted unchanged in urine.
    • Half-life is long (37-64 hours).
  • Protein binding: 80%.
  • Volume of distribution is very high (~8 L/kg, or 500-700 L). (16080071)
  • Penetration
    • Extensively enters the tissues (e.g., concentrated in alveolar macrophages, gallbladder, and colon). For example, concentrations in epithelial lining fluid and alveolar cells are similar/higher than serum. (Schmidt 2024)
    • Low levels in blood and urine (not good for bacteremia; maybe OK for urinary tract infection).
    • CSF penetration is low. (Vincent 2023)
  • Mechanism: Inhibition of protein synthesis through 30s ribosomal binding blocking aminoacyl-tRNA (same as doxycycline).

spectrum

  • Covers all gram-positive cocci (including MRSA and vancomycin-resistant enterococci).
  • Good gram-negative coverage:
    • Covers:
      • ESBL organisms (e.g., E. coli and Klebsiella pneumoniae).
      • Carbapenem-resistant Acinetobacter (although resistance has been reported to evolve during treatment with tigecycline).
    • Misses:
      • Pseudomonas.
      • Most Proteus and Providencia.
      • Some Morganella.
  • Covers most anaerobes, including Clostridioides difficile.
  • Covers listeria, Mycoplasma pneumoniae, Chlamydia pneumoniae.

use

  • (1) Add-on agent for fulminant Clostridioides difficile (suppresses toxin production by Clostridioides while simultaneously working against colonic flora which have translocated out of the bowel). (29363242)
  • (2) Extremely drug-resistant bacteria (approved for community-acquired pneumonia, skin/soft tissue infection, and complicated intra-abdominal infection)
  • Tigecycline is FDA approved for soft tissue infection, complicated intra-abdominal infections, and pneumonia. However, tigecycline is usually not utilized, given concerns about potential of increased mortality (see FDA communication here). This may reflect low drug levels in the blood, which makes tigecycline suboptimal for the treatment of bacteremia.

toxicity/contraindications

  • Nausea/vomiting (may avoid with slow infusion).
  • Pancreatitis, hepatitis.
  • Coagulopathy (low fibrinogen; prolonged PT and PTT).
  • Anaphylactoid reactions.

trimethoprim-sulfamethoxazole

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dosing (based on trimethoprim component)

  • Basics:
    • Single-strength tablet = 80 mg trimethoprim & 400 mg sulfamethoxazole.
    • Double-strength tablet = 160 mg trimethoprim & 400 mg sulfamethoxazole.
  • Pneumocystis jirovecii:
    • 15 mg/kg/day in 3-4 divided doses is the traditional dosing. Oral dosing to achieve this could be as follows:
    • 5 mg/kg q8hr (for patients ~64 kg, two double-strength tabs q8hr).
    • 3.75 mg/kg q6hr (for patients ~85 kg, two double-strength tabs q6hr).
    • 10 mg/kg/day may provide efficacy with less toxicity, based on an emerging evidence basis. (32391402) Oral dosing to achieve this could be as follows: 
    • 2.5 mg/kg q6hr (for patients ~64 kg, one double-strength tab q6hr).
    • 3.3 mg/kg q8 (for patients ~72 kg, three single-strength tabs q8hr).
    • 2.5 mg/kg q6hr (for patients ~96 kg, three single-strength tabs q6hr).
    • For moderate/severe disease or lack of enteral access, intravenous administration is indicated. Otherwise, oral therapy may be used.
  • Serious bacterial infection in ICU: daily dose of 10 mg/kg divided twice-three times daily. (37463564, 38304898)
  • Skin/soft tissue infection: Guidelines recommend a dose of 1-2 double-strength tabs q12 hours. One study suggested a reduced risk of treatment failure with daily doses ≧ 5 mg/kg. (Melgarejo 2022) Higher doses may be appropriate for patients with higher weight, trauma-induced skin and soft tissue infection, or immunosuppression.
  • Urinary tract infection: daily dose of ~5 mg/kg (~one double-strength tablet q12hr). (21930870)
  • Renal dosing:
    • GFR 15-30 ml/min: use 50-75% of usual dose.
    • GFR <15 ml/min: avoid unless Pneumocystis jirovecii; use 25-50% of usual dose.
  • Obesity: Use adjusted body weight. 🧮 (36703246)

pharmacology

  • Absorption:
    • >90% oral bioavailability.
  • Distribution:
    • Vd: 1.8 L/kg trimethoprim; 0.3 L/kg sulfamethoxazole.
    • Protein binding: 70% (sulfamethoxazole), 50% (trimethoprim).
    • Excellent penetration of most tissues, including CSF (40% serum levels).
    • Can achieve sustained serum concentrations. (37463564)
  • Metabolism:
    • Extensively metabolized by the liver.
    • Half life: 11 hours (trimethoprim), 9 hours (sulfamethoxazole).
  • Excretion:
    • ~20% of sulfamethoxazole and ~60% of trimethoprim are excreted in the urine (achieving a high urinary drug concentration).

spectrum: TMP-SMX covers:

  • Gram-positives:
    • Group A and B streptococci (a common myth is that TMP-SMX lacks coverage of Group A streptococcal species. In fact, TMP-SMX does cover Group A streptococci.) (37310038)
    • MSSA and ~60% of MRSA isolates.
    • Streptococcus pneumoniae (~70%).
    • Staphylococcus saprophyticus.
    • Misses Enterococcus spp.
  • Gram-negatives:
    • Overall very good (better than ampicillin/sulbactam).
    • Sensitivity of E. coli is falling in many regions. However, TMP-SMX may be more effective against other enterobacteriaceae (e.g., Enterobacter spp., Serratia spp.).
    • Misses Pseudomonas, but covers Stenotrophomonas maltophilia.
  • Anaerobes: Covers most gram-negative anaerobes, including Bacteroides
  • Weird stuff: Legionella, Pneumocystis jirovecii, Nocardia, Listeria monocytogenes, toxoplasmosis.

use

  • Diseases:
    • Pneumonia (but limited by increasing resistance among streptococcus pneumoniae).
    • Urinary tract infections and prostatitis (due to sensitive organisms, not as empiric therapy).
    • Intra-abdominal infections.
    • Purulent cellulitis.
  • Organisms:
    • MRSA infections (particularly cellulitis; appears inferior to vancomycin for MRSA bacteremia). (20507860, 25977146)
    • Pneumocystis jirovecii.
    • Listeria, toxoplasmosis, legionella.

toxicity/contraindications

  • Overall generally well tolerated, but in the context of HIV causes lots of hypersensitivity reactions.
  • Hypersensitivity
    • Rash, rarely Stevens Johnson syndrome. Mild rash may be treated through. (Fishman 2023)
    • Drug fever
    • Aseptic meningitis
  • Renal dysfunction (usually this is pseudo-elevation of creatinine, but can also cause interstitial nephritis or crystalluria with genuine renal dysfunction).
  • Hyperkalemia (avoid use in combination with ACEi/ARB or spironolactone).
  • Severe nausea/vomiting, hepatitis, cholestasis, liver failure, pancreatitis.
  • Methemoglobinemia or hemolysis in patients with severe G6PD deficiency.
  • Cytopenias (Neutropenia, thrombocytopenia, leukopenia with high doses).
  • Pregnancy, lactation.

vancomycin (intravenous)

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vancomycin dosing

  • Loading dose of 25 mg/kg actual body weight should be considered (critical illness, endocarditis, pneumonia, CNS infections). Consider a maximum dose of 3000 mg. (36703246)
  • Maintenance dose is 15 mg/kg, with the conventional dosing interval dependent on renal function:
    • GFR >70: q8-q12. (38304898) Dosing q12 is likely adequate for most patients, but consider q8 dosing in patients with augmented renal clearance.
    • GFR 30-70: q24.
    • GFR 20-29: q48.
    • GFR <20 : check levels q24hr, re-dose when sub-therapeutic (roughly q3-7 days).
  • Conventional vancomycin dosing is based on trough levels:
    • Skin/soft tissue infection: target 10-15 mcg/ml.
    • Bacteremia, endocarditis, pneumonia, meningitis: target 15-20 mcg/ml.
    • Troughs <10 mcg/ml may promote emergence of resistant bacteria.
  • IHD:
    • Initial loading dose is unchanged (25 mg/kg).
    • 10 mg/kg administered during the final hour of each hemodialysis session. (UVM Green Book)
    • Levels may rebound following IHD, so avoid checking a vancomycin level right after dialysis.
  • CRRT:
    • Initial loading dose is unchanged (25 mg/kg).
    • Subsequent maintenance dose of 7.5-10 mg/kg IV q12hr. (Schmidt 2024)
    • Therapeutic drug monitoring is needed.
    • ⚠️ Consider linezolid or daptomycin in patients with acute kidney injury who may recover kidney function. These agents have the advantage of not being nephrotoxic.  Linezolid ⚡️ is hepatically cleared, so it requires no dose adjustment in CRRT. Further discussion of the selection of agents to cover MRSA is here: ⚡️
  • Obesity: Consider a maximum loading dose of 3,000 mg and a maximal maintenance dose of 4,500 mg per day. (36703246)
  • ECMO: (50% protein binding; Vd 0.7 L/kg; LogP -3.1). Dosing similar to other critically ill patients (e.g., loading dose of 25-30 mg/kg followed by 30-40 mg/kg/day). (35326801) Careful monitoring of levels is required. (29732181) Vancomycin use should be avoided if possible, to reduce the risk of renal failure.
  • It's probably preferable to dose vancomycin based on individual patient pharmacokinetics. 🌊 Institutional approaches to vancomycin dosing vary widely.

pharmacology

  • Excretion: 90% excreted unchanged in urine.
  • Protein binding: ~50% protein binding
  • Vd: 0.4 L/kg
  • Penetration:
    • Penetrates body fluids well, but limited penetration of lung or CSF.
    • Intravenous vancomycin has no meaningful activity against Clostridioides difficile (it must be given orally for that application).
  • Mechanism: cell wall synthesis inhibited by binding to D-alanyl-D-alanine precursor and inhibiting peptidoglycan polymerization.

spectrum: all gram-positives except for vancomycin-resistant enterococci (VRE)

  • MSSA (covers MSSA but less effective than beta-lactams, should rarely be used for known MSSA infections).
  • MRSA (although efficacy depends on MIC).
    • MIC 1 ug/ml or below: Susceptible (97% of Staph aureus worldwide). (Schmidt 2024)
    • MIC 1.5 ug/mL is intermediate. Avoid vancomycin if possible. If vancomycin must be used, an AUC24 of at least 600 should be ensured to achieve efficacy (unfortunately this dose of vancomycin will increase the risk of nephrotoxicity). (26105168)
    • MIC 2 ug/mL or higher: Resistant
  • Coagulase-negative staphylococci. 
  • Streptococcus pneumoniae (including drug-resistant strains)
  • Other streptococci
  • Enterococci:
    • Enterococcus faecalis is generally sensitive to vancomycin. (However, for bacteremia or endocarditis, ampicillin or gentamicin is added for synergy.)
    • Enterococcus faecium often has reduced sensitivity to vancomycin.

use

toxicity/contraindications

  • Nephrotoxicity is the primary concern.
  • Red person syndrome, aka vancomycin infusion reaction (VIR):
    • Rapid infusion of vancomycin can cause histamine release with erythema and hypotension (an anaphylactoid reaction).
    • Red person syndrome is not an IgE-mediated allergic reaction. It may be treated symptomatically using antihistamines, with resumption of the vancomycin infusion at a slower rate.
    • True IgE-mediated allergic reaction to vancomycin is exceedingly rare. A literature review could only find seven reported cases of probable allergic reaction to vancomycin between 1982-2015. (35092578) The vast majority of patients reporting an “allergy” to vancomycin experienced red person syndrome and can likely be safely treated with vancomycin (perhaps with a graded challenge approach, in a monitored setting). 
  • Fever/chills, phlebitis.
  • Cytopenias:
    • Neutropenia, especially with prolonged use.
    • Thrombocytopenia: may cause drug-induced immune thrombocytopenia (D-ITP) 📖. This is acute and severe.
  • Severe dermatologic reactions: drug rash with eosinophilia and systemic symptoms (DRESS), acute generalized exanthematous pustulosis (AGEP).
  • Ototoxicity is uncommon and reversible.

Citrobacter freundii complex

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clinical comments

  • Often a nosocomial pathogen.
  • Common foci of infection include urinary tract infection, line infection, or pneumonia.

treatment of Citrobacter freundii

  • ⚠️ High-risk for having an inducible Amp-C gene. ⚡️
  • Antibiogram:
    • Cefepime. (2023 UVM:100%)
    • Carbapenems. (2023 UVM:100%)
    • Trimethoprim-sulfamethoxazole. (2023 UVM:95%)
    • Ciprofloxacin.
    • Aminoglycosides (tobramycin or amikacin).
  • Empiric therapy:
    • Cefepime may be a reasonable empiric therapy (if there is a low risk for ESBL organisms).

Enterobacter cloacae complex

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clinical comments

  • Often a nosocomial pathogen.

treatment of Enterobacter cloacae

  • ⚠️ High-risk for having an inducible Amp-C gene. ⚡️
  • ⚠️ Resistance to ceftriaxone +/- cefepime is a red flag for ESBL species.
  • Antibiogram:
    • Cefepime. (2023 UVM:98%, DHMC:93%) 
    • Meropenem. (2023 UVM:100%, DHMC:99%) 
    • Trimethoprim-sulfamethoxazole. (2023 UVM:95%, DHMC:91%) 
    • Ciprofloxacin. (2023 UVM:95%)
    • Aminoglycosides.
  • Empiric coverage:
    • Cefepime may be a reasonable empiric therapy (if there is a low risk for ESBL organisms).

Enterococcus

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clinical comments

  • Sources of infection include:
    • Endocarditis.
    • Urinary tract infection.
    • Ascending cholangitis, intra-abdominal infection.
    • Nosocomial pathogen (e.g., line infection).
  • Enterococcus isn't highly virulent, but it is often difficult to eradicate.
  • 💡 Sensitivity to ampicillin implies that the organism is also sensitive to broad-spectrum penicillins (e.g., piperacillin).

Enterococcus faecalis

  • Sensitivity:
    • High rates of ampicillin sensitivity, so ampicillin is often a front-line agent. (2023 UVM:100%, DHMC:100%)
    • Highly sensitive to vancomycin, daptomycin, or linezolid (but these are usually unnecessary).
    • For cystitis, nitrofurantoin is generally active.
  • Treatment:
    • Most infections: ampicillin monotherapy.
    • Endocarditis: ampicillin + ceftriaxone (discussed below).

Enterococcus faecium

  • Ampicillin resistance is common, so ampicillin shouldn't be used empirically.
  • Vancomycin sensitivity is variable across different sites. (2023 UVM:97%, DHMC:33%).
    • Verigene PCR detection of VAN-A or VAN-B genes can promote early detection of vancomycin resistant organisms. There are other genes that can mediate vancomycin resistance as well (VAN-C, -D, -E, and -G). Therefore the absence of VAN-A or VAN-B makes vancomycin resistance less likely, but doesn't absolutely exclude it.
  • VRE (vancomycin-resistant enterococcus):
    • Cystitis: nitrofurantoin may also be utilized.
    • Pyelonephritis: linezolid or daptomycin (both are excreted in the urine).
    • Bacteremia: linezolid or daptomycin 10-12 mg/kg may be used. (37014953)
    • Endocarditis: combination therapy as outlined below.

Enterococcal endocarditis

  • Beta-lactam susceptible:
    • Ampicillin 2 grams IV q4hr + Ceftriaxone 2 grams IV q12 hours. Preferred to reduce risk of nephrotoxicity with gentamicin.
    • Alternative: Ampicillin 2 grams IV q4hr + gentamicin 💉. Cannot be used for strains that are gentamicin-resistant.
  • Beta-lactam resistant but vancomycin sensitive:
    • Vancomycin plus gentamicin 💉.
    • ⚠️ This is a highly nephrotoxic regimen, if nephrotoxicity develops the regimens below for vancomycin-resistant enterococci could be considered.
  • Vancomycin-resistant:
    • Daptomycin 10-12 mg/kg/day plus one of the following beta-lactams: (37622656)
      • Ampicillin 300 mg/kg/day in 4-6 divided doses.
      • Ceftaroline 1800 mg/day in three divided doses.
    • Alternative: Linezolid 600 mg BID. (37622656)
      • Linezolid achieved a cure in 17/22 patients with Enterococcus faecium. (12522747) Note that linezolid isn't synergistic with other agents.

related sections:

  • Enterococcal endocarditis: 📖

Escherichia coli

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treatment for E. coli bacteremia

  • ⚠️ Ceftriaxone resistance may be considered a sign of being ESBL. ⚡️
  • Antibiogram:
    • Ceftriaxone is often reasonable, especially for milder infections. (2023 UVM:95%, DHMC:91%)
    • Cefepime is somewhat better than ceftriaxone. (2023 UVM:99%, DHMC:92%)
    • Piperacillin-tazobactam provides good coverage. (2023 UVM:97%, DHMC:94%)
    • Carbapenems, tobramycin, and amikacin have excellent coverage.
  • Empiric coverage:
    • Generally a G3-G4 cephalosporin is adequate.
    • Carbapenems may be considered if there is concern for ESBL species (e.g., nosocomial acquisition, recent antibiotics, overseas travel to high-ESBL areas).

Haemophilus influenzae

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H. influenzae pneumonia

  • H. influenzae is a small, facultatively anaerobic, pleomorphic gram-negative coccobacillus.
  • Encapsulated vs. unencapsulated H. flu:
    • Encapsulated strains are typed (serotypes a through f). Haemophilus influenzae B (HIB) used to be a dominant form, but this has decreased due to vaccination. Encapsulation helps bacteria to evade immune clearance, potentially leading to bacteremia.
    • Unencapsulated strains are non-typeable, less virulent, and cannot be prevented by current vaccines. Currently, ~80% of cases of H. influenzae in adults are non-typeable. Non-typeable H. influenzae rarely cause bacteremia. (Brown 2021)
  • H. influenzae causes COPD exacerbation more often than it causes pneumonia, so isolation from the respiratory tract doesn't necessarily prove an invasive pneumonia.

H. influenzae pneumonia: epidemiology

  • Haemophilus influenzae may cause ~5% of community-acquired pneumonia.
  • Risk factors include older age, medical comorbidity, and smoking.

H. influenzae pneumonia: clinical presentation

  • Clinically, this is similar to other bacterial pneumonias.
  • H. influenzae tends to have a lower morbidity/mortality than other bacterial pneumonias.

H. influenzae pneumonia: radiographic pattern is variable 

  • H. influenzae may cause lobar or segmental consolidation, simulating pneumococcal pneumonia. However, patchy bronchopneumonia may also be seen.
  • CT scan may show a tree-in-bud pattern, indicating infectious bronchiolitis.
  • (It's likely that encapsulated versus non-encapsulated species produce different patterns. By combining both types together, we lose the ability to discern any radiographic pattern.)

H. influenzae pneumonia: laboratory tests

  • Gram stain is often negative, since the organisms are small and easily overlooked.
  • Sputum culture is positive in about half of patients, but this is confusing since H. influenzae can cause asymptomatic colonization among patients with COPD. (Murray 2022)

Haemophilus influenzae pneumonia: treatment

  • Empiric therapy:
    • 🏆 Generally a third-generation cephalosporin (e.g., ceftriaxone) is preferred.
    • Ampicillin-sulbactam.
    • Doxycycline.
    • Fluoroquinolones.
  • Some strains (~40%) produce beta-lactamase causing resistance to ampicillin (but not resistance to ceftriaxone). For beta-lactamase negative strains, therapy can be narrowed to ampicillin or amoxicillin.

Klebsiella species

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clinical comments

  • Community-acquired infections:
    • Klebsiella pneumoniae may cause community-acquired pneumonia.
    • Urinary tract infection.
  • Nosocomial infections include: pneumonia, line infection, surgical site infections, catheter-associated urinary tract infection.

treatment of Klebsiella aerogenes (formerly: Enterobacter aerogenes)

  • ⚠️ K. aerogenes is high-risk for having an inducible Amp-C gene. ⚡️
  • ⚠️ Resistance to ceftriaxone, ceftazidime, or aztreonam may indicate an ESBL. 📖

treatment of Klebsiella oxytoca

  • ⚠️ Resistance to ceftriaxone, ceftazidime, or aztreonam may indicate an ESBL. 📖
  • Antibiogram:
    • Ceftriaxone (2023 UVM:97%, DHMC:88%).
    • Ceftazidime (2023 UVM:98%, DHMC:100%).
    • Cefepime (2023 UVM:99%).
    • Carbapenems 99-100%.
    • Aminoglycosides 97-100%.
    • TMP-SMX (2023 UVM:97%, DHMC:100%).
    • Fluoroquinolones >95%.
    • Piptazo isn't great. (2023 DHMC:88%)
  • Empiric coverage:
    • No risk factors for ESBL species: G3-G4 cephalosporin (depending on local antibiogram).
    • Risk factors for ESBL species (e.g., nosocomial acquisition): Carbapenem.

treatment of Klebsiella pneumoniae

  • ⚠️ Resistance to ceftriaxone, ceftazidime, or aztreonam may indicate an ESBL. 📖
  • Antibiogram:
    • Ceftriaxone (2023 UVM:93%, DHMC:88%).
    • Ceftazidime (2023 UVM:95%, DHMC:87%).
    • Cefepime (2023 UVM:97%, DHMC:86%).
    • Carbapenems: 98-100%.
    • Aminoglycosides: ~97-100%.
    • TMP-SMX (2023 UVM:91%, DHMC:88%).
    • Piptazo (2023 UVM:96%, DHMC:92%).
    • Ciprofloxacin (2023 UVM:93%, DHMC:88%).
  • Empiric coverage:
    • No risk factors for ESBL species: cefepime is usually adequate.
    • Risk factors for ESBL species (e.g., nosocomial acquisition): Carbapenem.
  • Consider antibiotic penetration in the context of abscesses or necrotizing pneumonia.
Klebsiella pneumonia 

⚠️ This probably represents a subset of hvKp (hypervirulent Klebsiella pneumoniae; see section below).

epidemiology

  • Community-acquired pneumonia:
    • Rare cause of community-acquired pneumonia (~3-5%).
    • Risk factors include:
      • Alcoholism.
      • Diabetes.
      • Chronic lung disease (e.g., COPD).
      • Cigarette smoking.
  • Nosocomial pneumonia: Klebsiella pneumonia is a common cause of nosocomial pneumonia (~10-15%).

clinical presentation

  • Usual presentation:
    • Clinical presentation is generally similar to that of other pneumonias.
    • Traditionally, Klebsiella was associated with “currant jelly” sputum.
  • Rarely, a chronic necrotizing pneumonia may develop, which can mimic tuberculosis.
  • Pneumonia is often associated with bacteremia.

radiology

  • Lobar consolidation is usually seen:
    • Frequently involves the right upper lobe.
    • Traditionally, Klebsiella has been associated with a bulging fissure sign (exuberant inflammation causes an increase in volume of the affected lobe). However, the bulging fissure sign may be associated with a variety of pathogens, as discussed further here: 📖
  • Effusion (~65%) and empyema frequently occur. Effusion may be contralateral to parenchymal involvement.
  • Aggressive lung necrosis may occur: Klebsiella may cause rapid necrosis, with cavitation and abscess formation. Before cavitation occurs, necrotic areas may be noted on CT scans as areas of the lung that fail to opacify with contrast normally. 
  • Various outcomes of lung necrosis may include: (Rosado-de-Christenson 2022)
    • (1) Lung abscess.
    • (2) Pulmonary gangrene may occur due to vascular and bronchial obstruction, which results in massive necrosis of the lung.
    • (3) Chronic pneumonia may occur. Occasionally the infection may fail to resolve, progressing instead into a chronic phase. Radiological features may include cavitation or low-attenuation necrotic areas within pulmonary consolidation. (Walker 2019) Overall this may mimic a mycobacterial or fungal pneumonia. 
hypervirulent Klebsiella pneumoniae (hvKp)

epidemiology of hvKp

  • hvKp may affect patients of any age or degree of immunocompetence.
  • hvKp was traditionally community-acquired, but is increasingly nosocomially acquired (further discussion below).
  • Diabetes is a risk factor present in roughly a third of patients. (31092506, 35904343)
  • hvKp rates vary dramatically across different geographic locales. In parts of the Pacific rim, hvKp is endemic. hvKp is being increasingly encountered within Europe and the  United States.

clinical features of community-acquired hvKp

  • General clinical features of hvKp:
    • hvKp is an Enterobacteriaceae that often behaves similarly to community-acquired MRSA. Specifically: 
    • [1] hvKp often causes metastatic infection involving multiple sites (a feature not usually seen among Enterobacteriaceae).
    • [2] Infections are usually monomicrobial. (31092506)
    • [3] Abscess formation is common (most often involving the liver, but also potentially involving the spleen, brain, lung, prostate, muscle, or epidural abscess). (38047929)
  • Liver abscess (~80%) is the most notorious signature clinical manifestation of hvKp. For example, in one study, a liver abscess predicted the presence of hvKp with a risk ratio of +9. (36813165) Unlike most other liver abscesses, hvKp causes monomicrobial abscesses without underlying biliary pathology. Regional thrombophlebitis of the hepatic veins may occur in about a third of patients. (38047929) In areas with rising hvKp prevalence, hvKp is a common cause of liver abscess. (31092506)
  • Community-acquired pneumonia (~25%): hvKp likely underlies the traditional description of severe community-acquired Klebsiella pneumonia (“Friedlander's pneumonia”), as discussed in the section above. (31092506) Pneumonia is often accompanied by empyema, lung abscess, bacteremia, and/or septic shock. (38047929) Hepatic vein thrombophlebitis due to liver abscesses may lead to septic pulmonary emboli 📖 (manifesting with multiple pulmonary nodules that frequently cavitate). 
  • Endogenous endophthalmitis (~20%): Symptoms may include painful ocular swelling, redness, and a sudden onset of blurry vision. Bilateral involvement may be diagnostically helpful but only occurs in ~20%. (31092506) The infection may progress rapidly and threaten vision. 
  • Meningitis (~20%): hvKp is an emerging cause of severe gram-negative community-acquired meningitis.  Meningitis may occur as a primary infection or a metastatic complication of another primary focus of infection elsewhere. Other CNS manifestations of hvKp may include brain abscesses, ventriculitis, or subdural empyema.
  • Soft tissue infection:
    • Necrotizing fasciitis is increasingly caused by hvKp in endemic areas.
    • Psoas abscess may be caused by hvKp.
    • Osteomyelitis may occur, sometimes at multiple sites resembling disseminated malignancy.
    • Pyomyositis, other muscular abscesses, deep neck space infections, and septic arthritis may also be seen. (31677303)
  • Genitourinary infections: Pyelonephritis due to hvKp usually reflects bacteremia that hematogenously seeds the kidneys (similar to Staph. aureus urinary tract infection). This may lead to prostate abscesses.
  • Bacteremia: This is often noted before identifying any primary source. (31092506) About 80% of patients may have bacteremia. (35904343)

clinical features of nosocomial hvKp

  • hvKp has traditionally been primarily a community-acquired infection. However, more recently, the emergence of drug resistance has allowed hvKp to persist within hospitals and cause nosocomial outbreaks.
  • Ventilator-associated pneumonia may be the most common clinical presentation. (31677303)
  • Nosocomial hvKp carries high mortality for several reasons:
    • Hospitalized patients already have organ failure and compromised physiology.
    • Diagnosis of the infection may be delayed due to the complexity of the patient's other active problems.
    • The hvKp strains involved are often multi-drug resistant, so definitive antimicrobial therapy may be delayed or impossible.

early laboratory clues that may suggest the diagnosis

  • High-grade Klebsiella bacteremia, especially in the absence of an obvious source such as urosepsis.
  • Bacterial colonies on agar plates usually display a positive string test. If an inoculation loop is touched to the colony and lifted, a string of mucus >5 mm results (see picture: 📄).  (35904343)

management

  • ☣️ Immediate isolation is required if hvKp is suspected.
  • Antimicrobial therapy:
    • hvKp is increasingly multidrug resistant. For example, carbapenem-resistant hypervirulent Klebsiella pneumoniae (CR-hvKp) is increasingly prevalent globally. In particular, hvKp sequence type (ST) 23 is increasingly reported in Europe (including nosocomial transmission). Currently, most strains of ST23 have acquired carbapenemase resistance genes (especially OXA-48).
    • Treatment should be based on available information and local resistance patterns.  For example, if a gene conferring carbapenem resistance (e.g., OXA) is detected, the therapy could entail treatments based on that gene. ⚡️
    • In the absence of data suggesting drug resistance, empiric therapy with meropenem 💉 may be reasonable for critically ill patients with hvKp. (31677303)
  • Broad radiological evaluation should be undertaken to exclude occult metastatic abscess formation (e.g., within the liver).
  • Aggressive source control may be required. Abscess contents are often viscous and difficult to drain, so larger bore drains with more frequent flushing may be required. (31092506)
  • Consider lumbar puncture for patients with altered mental status. (31092506)
  • Ophthalmologic consultation is needed for any ocular symptoms (emergent vitrectomy and intravitreal antibiotics may be required). (31092506)

Moraxella catarrhalis

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basics

  • Moraxella catarrhalis is an unencapsulated, gram-negative diplococcus.
  • This is a low-virulence organisms that is clinically similar to non-typeable Haemophilus influenzae.
  • The most common clinical manifestation is COPD exacerbation, but pneumonia may also occur.

epidemiology of M. catarrhalis pneumonia

  • Pneumonia seldom occurs in previously healthy people. (Walker 2019; 33172398)
  • The most common risk factors:
    • Elderly.
    • Underlying lung disease (COPD, asthma, bronchiectasis).
  • Other risk factors:
    • Cardiopulmonary comorbidity.
    • Alcoholism, malnutrition.
    • Malignancy with neutropenia.
  • Infection may be more common in the winter. (33172398)

clinical presentation of M. catarrhalis pneumonia

  • Often causes a mild pneumonia.
  • Cough is productive of purulent sputum.
  • Pleuritic chest pain or high fever are uncommon. (Murray 2022)

radiology of M. catarrhalis pneumonia

  • May cause patchy bronchopneumonia, often predominantly in the lower lobes and generally (90%) bilaterally. (33172398)
  • Pleural effusion is uncommon.
  • (Okada et al. includes examples of CT radiology: 📄 )

laboratory tests for M. catarrhalis pneumonia

  • Moraxella catarrhalis is frequently part of the normal upper respiratory tract flora, so growth in sputum doesn't necessarily indicate invasive disease. (Murray 2022)
    • High-quality sputum on Gram stain may support the diagnosis of pneumonia.
    • Intracellular gram-negative diplococci also support a true infection. (Murray 2022)

treatment for M. catarrhalis pneumonia

  • Most species produce a beta-lactamase, rendering amoxicillin or ampicillin ineffective.
  • Treatment options include:
    • Third generation cephalosporin.
    • Beta-lactam/beta-lactamase combination (e.g., ampicillin-sulbactam).
    • Fluoroquinolones.
    • Doxycycline.
    • Trimethoprim-sulfamethoxazole.

Morganella morganii

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clinical comments

  • Most commonly causes urinary tract infection (splits urea, may increase urinary pH).

treatment

  • Morganella morganii is low risk for inducible AmpC resistance:
    • Most infections can be treated based on local antibiograms and susceptibility data (without concern for AmpC resistance).
    • For infections with high bacterial burden and poor source control (e.g., endocarditis, CNS infections), treat as a high-risk organism (e.g., with cefepime).
    • Further discussion of AmpC resistance: ⚡️
  • Antibiogram:
    • Ceftriaxone (2023 UVM:87%).
    • Cefepime (2023 UVM:93%).
    • Piperacillin-tazobactam (2023 UVM:93%).
    • Carbapenems: ~100%.
    • Trimethoprim-sulfamethoxazole (2023 UVM:89%).
    • Ciprofloxacin (2023 UVM:90%).
  • Empiric therapy?
    • Cefepime, piperacillin-tazobactam are usually adequate.
    • Nosocomial acquisition: consider carbapenem.

Proteus species

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clinical comments on Proteus spp.

  • Urease-splitting organism may increase urine pH (others may include: Pseudomonas aeruginosa, Providencia spp, Klebsiella pneumoniae). Elevated pH may cause struvite stones which lead to recurrent infection.
  • 90% of infections are due to Proteus mirabilis.
  • Frequent cause of catheter-associated urinary tract infections.

treatment of Proteus mirabilis

  • Historically there was concern regarding inducible AmpC genes, but current guidelines indicate that Proteus is low risk for inducible AmpC resistance.
  • ⚠️ Ceftriaxone resistance may be considered a sign of being ESBL. ⚡️
  •  Antibiogram:
    • Ceftriaxone (2023 UVM:98%, DHMC:98%).
    • Cefepime (2023 UVM:98%).
    • Meropenem 99-100%.
    • Piperacillin-tazobactam: 99-100%.
    • Ampicillin (2023 UVM: 87%).
    • Trimethoprim-sulfamethoxazole (2023 UVM:86%, DHMC:90%).
  • Empiric therapy: Seems to be adequately covered by most broad-spectrum gram negative agents (e.g., ceftriaxone, cefepime, piperacillin-tazobactam, carbapenems).

Pseudomonas aeruginosa

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clinical comments: common manifestations

  • Rarely causes community-acquired pneumonia in patients with specific risk factors.
  • Cystic fibrosis or bronchiectasis exacerbation.
  • Otitis externa, malignant otitis externa.
  • Ventilator-associated pneumonia.
  • Neutropenic bacteremia.
  • Other nosocomial infections (e.g., urinary tract infection, line infection, surgical site infection).

treatment of Pseudomonas

  • Antibiogram:
    • Ceftazidime (2023 UVM:94%, DHMC 83%)
    • Cefepime (2023 UVM:95%, DHMC:86%).
    • Piperacillin-tazobactam (2023 UVM:97%, DHMC:90%).
    • Meropenem (2023 UVM:94%, DHMC:93%).
    • Tobramycin (2023 UVM:98%, DHMC:98%).
  • Double coverage?
    • Evidence does not generally support double coverage. However, in some locales with a high rate of drug-resistant organisms, initiating therapy with two agents may be reasonable to improve the likelihood of covering the patient's isolate. IDSA/ATS guidelines recommend the use of two antipseudomonal agents for management of ventilator-associated pneumonia in ICUs where >10% of gram-negative isolates are resistant to the agent being considered for monotherapy. (34743315)
    • Further discussion on double-coverage: 📖
Pseudomonas pneumonia

epidemiology

  • Pseudomonas is a rare cause of community-acquired pneumonia (only 1-2%). However, pseudomonas is a very common cause of ventilator-associated pneumonia (likely related to breeching of the upper airway defenses by the endotracheal tube).
  • Risk factors for Pseudomonas in patients with CAP (community-acquired pneumonia):
    • (1) Structural lung disease:
      • Bronchiectasis (especially cystic fibrosis).
      • Prior tracheostomy.
      • Severe COPD (especially with FEV1 <30% predicted, or recurrent exacerbations requiring steroid and antibiotic use). (32561442)
    • (2) Immunosuppression:
      • Neutropenia/hematologic malignancy.
      • HIV with CD4 count <50/uL.
    • (3) Prior colonization/infection with Pseudomonas.
  • 💡If a patient with no apparent risk factors develops a Pseudomonas pneumonia, consider evaluation for HIV or structural lung disease (e.g., bronchiectasis).

clinical presentation

  • The initial presentation is generally similar to that of other pneumonias.
  • If initial empiric therapy doesn't cover Pseudomonas, the pneumonia will fail to respond to therapy (e.g., with worsening infiltrates and often radiographic cavitation).
  • Among patients with bacteremia, physical examination may show ecthyma gangrenosum.

radiology

  • Bronchopneumonia is usually the primary radiographic form of pneumonia, e.g.:
    • Peribronchovascular ground-glass opacities.
    • Centrilobular nodules (including tree-in-bud nodules).
    • Bronchial wall thickening.
    • Eventually, lobular consolidations may become confluent leading to large areas of consolidation (similar to a primarily lobar pneumonia).
  • Necrosis with cavity formation is common, especially among immunocompromised hosts. (Rosado-de-Christenson 2022)
  • Pleural effusion is common.

laboratory tests

  • Pseudomonas is a common colonizer of the oropharynx in debilitated or hospitalized patients, so simply culturing Pseudomonas from sputum doesn't prove invasive pneumonia.
  • A positive culture for Pseudomonas is much more convincing it if is paired with a high-quality Gram stain (>25 leukocytes and <10 squamous cells per low-power field) showing a predominance of gram-negative bacilli.
    • 💡 The sputum Gram stain may help judge the accuracy of the culture result (e.g., whether the sputum truly represents material from the lower respiratory tract, or saliva). 

Serratia species

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clinical comments

  • Only Serratia marcescens commonly causes clinical disease.
  • This generally occurs as a nosocomial infection (e.g., central line associated bacteremia, urinary tract infection, pneumonia). However, Serratia be cause infection due to IVDU (e.g., endocarditis).

treatment for Serratia marcescens

  • S. marcescens is low risk for inducible AmpC resistance:
    • Most infections can be treated based on local antibiograms and susceptibility data.
    • For infections with high bacterial burden and poor source control (e.g., endocarditis, CNS infections), treat as a high-risk organism (e.g., with cefepime).
    • Further discussion of AmpC resistance: ⚡️
  • Antibiogram:
    • Ceftriaxone (2023 UVM:96%, DHMC:82%).
    • Ceftazidime (2023 UVM:98%, DHMC:84%).
    • Cefepime (2023 UVM:100%, DHMC:93%).
    • Carbapenems: ~100%.
    • Aminoglycosides: superior coverage with gentamicin (2023 UVM:100%, DHMC:99%). 
    • Trimethoprim-sulfamethoxazole (2023 UVM:98%, DHMC:99%).
  • Empiric therapy?
    • There is no clinical data to indicate a superior therapy.
    • Some sources refer to dual coverage, but this seems unnecessary based on high levels of sensitivity to several different agents.

Staph: coagulase negative (CoNS)

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general principles of CoNS

  • CoNS are often contaminants (with the exception of SLUG as discussed below).
  • When pathogenic, CoNS are often associated with foreign bodies and biofilm formation.
  • CoNS may be treated similarly to Staph aureus (if it is deemed to represent a truly invasive infection, rather than contamination).
    • Methicillin-sensitive CoNS can be treated similarly to MSSA.
    • Methicillin-resistant CoNS can be treated similarly to MRSA.

Staphylococcus epidermidis

  • Antibiogram:
    • Oxacillin = Cefazolin (2023 UVM:43%).
    • Clindamycin (2023 UVM:63%).
    • Doxycycline (2023 UVM:91%)
    • Daptomycin, linezolid, vancomycin: ~100%.
  • Clinical approach:
    • Similar to the approach to Staph aureus.
    • Generally initiate therapy with vancomycin pending sensitivities.

Staphylococcus lugdunensis (SLUG)

  • Clinical comments about SLUG:
    • SLUG are more virulent than other species of CoNS, so they're more likely to represent a true invasive infection.
    • SLUG should always be taken seriously in a blood culture, similarly to Staph aureus.
    • Like other CoNS, SLUG should be treated similarly to Staph. aureus.
  • Antibiogram:
    • Oxacillin = Cefazolin (2023 UVM:92%, DHMC:95%).
    • Trimethoprim/sulfa (2023 UVM:99%, DHMC:98%).
    • Clindamycin (2023 UVM:91%, DHMC:81%).
    • Doxycycline (2023 UVM:100%, DHMC:93%).
    • Azithromycin (2023 UVM:89%, DHMC:81%).
    • Vancomycin, daptomycin: ~100%.
  • Clinical approach:
    • General similar to the approach to Staph aureus.
    • For bacteremia or endocarditis, vancomycin is reasonable initially (pending sensitivity).
    • For less severe infections (e.g., cellulitis), trimethoprim/sulfamethoxazole may be adequate. Note that trimethoprim/sulfamethoxazole doesn't perform well for treatment of staphylococcal bacteremia. (20507860, 25977146)

Staph: MSSA

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MSSA antibiogram

  • Cefazolin ~100%.
  • Nafcillin ~100%.
  • Vancomycin, linezolid, daptomycin: ~100%
  • Doxycycline (2023 UVM:99%, DHMC:96%)
  • TMP-SMX (2023 UVM:97%, DHMC:98%)

cefazolin 💉 versus nafcillin 💉

  • Evidence generally shows similar clinical outcomes.
  • Cefazolin is better tolerated (especially with lower rates of kidney injury and hepatitis).
  • Nafcillin traditionally has been felt to have superior CNS penetration, so nafcillin is often recommended in patients with CNS involvement (e.g., MSSA meningitis, MSSA endocarditis with septic emboli). However, cefazolin may also have activity against CNS infections. (36521869)
  • Theoretically, cefazolin may fail due to an “inoculum effect” wherein a large burden of staph produces enough staphylococcal penicillinase to inactivate cefazolin. (29977970, 32757525) However, overall there seems to be a growing body of evidence that cefazolin has superior or equivalent clinical efficacy compared to nafcillin. (30476572, 30928559, 36838359)

⚠️ ceftriaxone is generally not optimal

  • Ceftriaxone does cover MSSA. This may be useful in various situations, for example:
    • (1) Designing an empiric antibiotic regimen that includes MSSA coverage.
    • (2) Treatment of a patient who has cellulitis plus pneumonia using a single antibiotic.
  • Ceftriaxone is not optimal for treatment of MSSA, for the following reasons:
    • (1) Some studies have found ceftriaxone to be inadequate for more serious MSSA infections:
      • (i) Ceftriaxone appears to be inferior to cefazolin or nafcillin for MSSA bacteremia. (28942574, 36800065) 
      • (ii) Ceftriaxone dosed at 1 gram q24 hours often fails in MSSA pneumonia. (26531307)
    • (2) In order to cover MSSA, ceftriaxone may need to be dosed at 2-4 grams/day. However, in practice this dosage is usually not utilized. (26531307)
    • (3) Ceftriaxone causes a higher risk of C. difficile colitis. (29462280)
    • (4) Ceftriaxone is an unnecessarily broad antibiotic to cover MSSA. Overutilization of ceftriaxone in situations where it is unnecessary will increase resistance to ceftriaxone.

MSSA endocarditis

  • Preferred primary therapy:
    • Cefazolin 2 grams IV q8hrs
      • No high-quality data that the inoculum effect is clinically important. Recent data suggests that cefazolin is equally effective against MSSA, with a lower adverse event rate than oxacillin/nafcillin. (37523190)
    • Nafcillin/oxacillin/(flu)cloxacillin 2 grams IV q4hrs
      • May be preferred therapy for treatment of methicillin-sensitive coagulase-negative Staphylococci.
      • Theoretically, these may have superior penetration of the CNS as compared to cefazolin so they might be preferred in patients with CNS emboli. However, recent data indicates that cefazolin has reasonable CNS penetration as well.
  • Adjunctive for prosthetic valve endocarditis, add rifampin 300 mg TID (either PO or IV). (37622656)
  • Alternatives:
    • Vancomycin dosed by level.
    • Daptomycin 8-10 mg/kg/d plus another anti-staphylococcal antibiotic (e.g., ceftaroline). (37622656)
    • Linezolid. (37523190)
  • Aminoglycoside is no longer recommended. (37622656)

MSSA pneumonia

  • 🏆 Cefazolin is often preferred.
  • Nafcillin has equivalent efficacy, but may be less well tolerated as compared to cefazolin (discussed further above).
  • Ceftriaxone is not preferred therapy (discussed further above).

related sections

  • MSSA endocarditis 📖
  • MSSA pneumonia 📖
Staph pneumonia (including MSSA and MRSA)

basics

  • Staphylococcus aureus may either be methicillin sensitive (MSSA) or methicillin resistant (MRSA). There are roughly two different types of MRSA, which may tend to behave in different ways:
  • HA-MRSA (hospital-acquired methicillin-resistant Staphylococcus aureus).
    • This often represents a form of nosocomial Staphylococcus aureus with broad drug resistance (e.g., resistant to erythromycin, clindamycin, aminoglycosides, and fluoroquinolones).
    • Clinically, HA-MRSA behaves similarly to MSSA.
  • CA-MRSA (community-acquired methicillin-resistant Staphylococcus aureus).
    • This is a strain of Staphylococcus which has achieved methicillin resistance while simultaneously becoming more virulent. These bacteria generally harbor Panton-Valentine leukocidin genes that increase virulence by causing tissue destruction (with a tendency to cause very aggressive, necrotizing pneumonia; often in young adults).
    • Unlike HA-MRSA, CA-MRSA is often susceptible to numerous non-beta-lactam antibiotics (e.g., clindamycin, aminoglycosides, trimethoprim-sulfamethoxazole, fluoroquinolones, doxycycline). (32521547)
  • Staphylococcus aureus often causes tricuspid endocarditis, which leads to septic pulmonary emboli. The presentation and radiology of septic pulmonary emboli is distinct from that of primary pneumonia. Septic pulmonary emboli are discussed here: 📖

epidemiology

  • Risk factors for Staphylococcus aureus pneumonia:
    • Stronger risk factors:
      • Diabetes.
      • Hemodialysis.
      • Prior influenza or RSV infection.
    • Other risk factors:
      • Immunocompromise.
      • HIV.
      • COPD, other chronic heart or lung diseases.
  • Risk factors for MRSA: see below ⚡️

clinical presentation

  • Patients are generally acutely ill.
  • Purulent sputum production is the rule.
  • There is a syndrome of necrotizing community-acquired pneumonia in young patients (usually due to CA-MRSA strains harboring Panton-Valentine leukocidin genes):
    • (#1) Prodrome may include a flu-like illness. Alternatively, skin or soft-tissue infection (e.g., abscesses) may be present in ~20% of patients.
    • (#2) Fulminant respiratory failure subsequently occurs, often with shock. Leukopenia commonly occurs. (Murray 2022) Radiology may show early cavitation, lung necrosis, rapidly increasing infiltrates, and/or a rapidly increasing pleural effusion. Massive hemoptysis may occur, which is unlike most other community-acquired pneumonias. (32521547).
    • Erythroderma may occur, as a component of staphylococcal toxic shock syndrome. (32521547).

radiology

  • Primary process is often a bronchopneumonia:
    • Findings may include ground-glass opacities, patchy consolidation, bronchial wall thickening, and/or centrilobular nodules. (Rosado-de-Christenson 2022)
    • Inflammatory exudate may fill airways, leading to segmental collapse.
    • Air bronchograms are rarely seen. (Walker 2019)
  • Necrotizing pneumonia often occurs:
    • Abscess formation and cavitation are relatively common.
    • Necrosis increases the risk of bronchopleural fistula (pneumothorax).
    • Pneumatoceles 📖 may be seen, which can mimic abscess formation.
  • Empyema is relatively common:
    • Pleural effusion occurs in ~40% of patients, with half being empyema. (Walker 2019)

laboratory tests

  • Neutropenia may occur. (32521547)
  • Nares PCR may be useful to largely exclude Staphylococcus aureus if negative, but a positive result may simply reflect colonization.
  • Staphylococcus aureus is generally easy to recover from respiratory secretions (even following several doses of antibiotic). The presence of intracellular organisms may further support the presence of an invasive pneumonia.

treatment

  • MSSA pneumonia treatment is above.
  • MRSA pneumonia treatment is below.

Staph: MRSA

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MRSA antibiogram

  • ~100%: Vancomycin, daptomycin, linezolid, ceftaroline.
  • Doxycycline (2023 UVM:97%, DHMC:88%).
  • TMP-SMX (2023 UVM:57%, DHMC:78%).

MRSA endocarditis

  • Preferred primary therapy:
    • Vancomycin dosed by level.
    • Daptomycin 10 mg/kg/d plus {cloxacillin or ceftaroline}. (37622656) ESC guidelines recommend the addition of a beta-lactam antibiotic, whereas WikiGuidelines do not. (37622656, 37523190) 
  • Adjunctive for prosthetic valve endocarditis, add rifampin 300 mg TID (either PO or IV). (37622656)
  • Alternatives: Possibly linezolid 600 mg BID. (37523190)
  • ⚠️ If the MIC for vancomycin is >1 ug/mL, vancomycin should be avoided.

MRSA pneumonia

  • 🏆 Linezolid may be preferable over vancomycin, especially for toxin suppression in patients with CA-MRSA. (32521547)
  • Note that daptomycin is not adequate for treatment of pneumonia, since it is degraded by surfactant in the lung.
MRSA risks stratification

risk factors for MRSA in general

  • Stronger risk factors:
    • Prior MRSA infection/colonization.
    • Recurrent skin infections.
    • Hospitalization with parenteral antibiotic therapy within three months (especially cephalosporins or fluoroquinolones). (37176628)
  • Other risk factors:
    • Chronic hemodialysis. (32521547)
    • Residence in a nursing home.

risk factors for CA-MRSA (community-acquired MRSA)

  • Soldiers, prisoners, and athletes (especially contact sports).
  • IV drug use.
  • Household contact with CA-MRSA.
  • Men who have sex with men.
  • Recurrent skin infections.
  • Recurrent MRSA infection/colonization.

indications for MRSA coverage in the context of CAP (community-acquired PNA) 📖

  • Shorr score of 6-10, based on summation of:
    • Age <30 or >79 = 1 point.
    • Hospitalized >1d in last 3 mos = 2 points.
    • Nursing home / facility in last 3 months = 1 point.
    • IV antibiotics in last month = 1 point.
    • Sick enough to need ICU = 2 points.
    • Cerebrovascular disease = 1 point.
    • Dementia = 1 point.
    • Female with diabetes = 1 point.
  • Cavitary pneumonia.
  • IV drug use.
  • Skin pustules suggestive of MRSA.
  • Known prior colonization with MRSA.

related sections

  • MRSA endocarditis 📖
  • Staph pneumonia (including MSSA and MRSA) ⚡️

Strep, group A (GAS)

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antibiogram

  • 💡 For severe infection, consider the addition of clindamycin or linezolid as adjunctive therapy for toxin suppression. 📖
  • GAS is reliably susceptible to beta-lactams which are generally considered front-line, including:
    • Penicillin.
    • Ampicillin.
    • Cefazolin.
    • Ceftriaxone.
  • TMP-SMX is reliably effective (may be utilized for skin infection; advantage of covering MSSA and some MRSA as well.)

pneumonia due to GAS

  • Streptococcus pyogenes should be sensitive to a range of beta-lactams (e.g., penicillin, cefazolin, ceftriaxone).
  • Combination therapy with a beta-lactam (e.g., penicillin G) plus clindamycin for toxin suppression may be ideal for sicker patients.

endocarditis due to GAS

  • Uniformly susceptible to beta-lactams.
  • Penicillin G is the treatment of choice; ceftriaxone is a reasonable alternative.

related sections

  • Endocarditis due to GAS: 📖
GAS pneumonia

epidemiology

  • Group A Streptococcus is an uncommon cause of pneumonia (<5% of bacterial pneumonia)
  • Outbreaks may occur (e.g., nursing homes, military barracks).
  • Infection may be more common in the winter and spring. (27738486)
  • Risk factors:
    • Influenza is the most important risk factor.
    • Older age.
    • Alcoholism, diabetes, cancer, or COPD.

clinical presentation

  • Initial pneumonia may be marked by a very high incidence of pleuritic chest pain.
  • Exudative streptococcal pharyngitis may occasionally be seen.
  • Numerous complications occur, with an overall high rate of mortality.
    • Toxic shock syndrome (25-33% of patients). (27027618)
    • Empyema (~20%). About half of patients have pleural effusion – and these are very frequently infected.
    • Necrotizing pneumonia with abscess formation and cavitation.
    • Less common complications include pericarditis, pneumothorax, and mediastinitis. (Murray 2022)

radiology

  • Necrotizing pneumonia with cavity formation may occur.
  • Pleural effusion with empyema may occur.

laboratory tests

  • Bacteremia is very common (~75%). (27738486)
  • Streptococci may colonize the oropharynx, so growth on a sputum culture isn't necessarily diagnostic of pneumonia.

treatment

  • Aggressive therapy is warranted, since the mortality of group A streptococcal pneumonia is quite high (~20-50%). (27738486) Infection can be rapidly fatal, even in previously healthy individuals – likely driven by toxic shock syndrome. (27027618)
  • Antibiotics are discussed above.
  • Steroid: Given the high rate of systemic inflammation, adjunctive steroid may be advisable. More on the role of steroid in community-acquired pneumonia here: 📖
  • Management of toxic shock syndrome:
    • About a third of patients may develop toxic shock syndrome.
    • For patients with multiple organ failures, consider IVIG.
    • More on the diagnosis and management of streptococcal toxic shock here: 📖
  • Pleural effusion management:
    • Given the very high rate of empyema, pleural effusions should be treated aggressively. It might be reasonable to insert a pigtail drain for any moderate or large effusion.

Strep, group B (GBS, Streptococcus agalactiae)

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general treatment for GBS

  • Sensitivity pattern is similar to GAS:
    • Penicillin or cefazolin are usually considered front-line agents.
    • Other options include ceftriaxone, ampicillin, nafcillin.
  • GBS is slightly more resistant to penicillin than GAS, so the addition of synergistic gentamicin may be considered for serious GBS infection (e.g., 1 mg/kg Q8hr IV).

endocarditis due to GBS

  • GBS may be slightly harder to kill than Group A streptococci.
  • The cornerstone of therapy is still penicillin or ceftriaxone, but addition of gentamicin for the first two weeks may be considered (AHA guidelines) or recommended (ESC guidelines).
  • The most recent ESC guidelines recommend treating these the same as oral streptococci. (37622656)

related sections:

  • Endocarditis due to GBS: 📖

Streptococcus pneumoniae (pneumococcus)

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antibiogram

  • Penicillin sensitivity:
    • Non-CSF (2023 UVM:98%).
    • CSF (2023 UVM:83%).
  • Ceftriaxone sensitivity:
    • Non-CSF (2023 UVM:98%).
    • CSF (2023 UVM:96%).
  • Levofloxacin: (2023 DHMC:100%).
  • Vancomycin: (2023 DHMC:100%).

Pneumococcal pneumonia: initial coverage

  • For severe pneumonia, the combination of a beta-lactam plus macrolide correlates with improved outcomes. Therefore, even if the patient is identified to have pneumococcus, macrolide therapy should generally be continued (e.g., 3-day course of azithromycin 500 mg IV daily).
  • Initial therapy generally involves a third-generation cephalosporin (e.g., ceftriaxone).
    • In the United States, ~95-98% of isolates are susceptible or intermediately susceptible to ceftriaxone (MIC ≦1 ug/mL, or MIC >1ug/mL and ≦ 2ug/mL, respectively).
    • 2 grams/day ceftriaxone IV should generally be utilized. Antibiotic resistance to beta-lactams may occasionally be overcome by utilizing higher doses. (27960205)

Pneumococcal pneumonia: coverage based on sensitivity

  • Penicillin-sensitive for non-CNS infections. Treatment options include:
    • Penicillin G 💉
    • Ampicillin or amoxicillin 💉
    • Third-generation cephalosporin (e.g., ceftriaxone) 💉 Ceftriaxone is more active in vitro than penicillin G. The main drawback of ceftriaxone is increased risk of C. difficile.
  • Penicillin-resistant for non-CNS infections. Treatment options include the following (depending on sensitivity):
    • Respiratory fluoroquinolone 💉 (levofloxacin or moxifloxacin; resistance is very low). (Evans 2021)
    • Ceftriaxone 💉 2 grams IV q24 hours may be used only if the strain is cephalosporin-sensitive.
    • Linezolid 💉
    • Vancomycin 💉 (may be used for cephalosporin-resistant strains).
  • Doxycycline and azithromycin resistances are increasing, limiting their empiric use against pneumococcus in many areas.

Pneumococcal endocarditis

  • ⚠️ S. pneumoniae endocarditis is often associated with meningitis, consider meningeal dosing of ceftriaxone if there is any concern for possible meningitis.
  • Sensitivity unknown:
    • Ceftriaxone 2 grams IV q12 (will provide coverage for PCN-sensitive or PCN-resistant strains)
  • Penicillin-sensitive:
  • Penicillin-resistant, ceftriaxone sensitive:
  • Ceftriaxone-resistant (MIC >2 ug/mL):
    • High-dose ceftriaxone seems to work regardless (e.g. 2 grams IV q12, as long as no meningeal involvement).
    • For meningeal involvement, consider addition of vancomycin and rifampin (AHA guidelines).

related sections

  • Endocarditis due to Streptococcus pneumoniae: 📖
  • Pneumonia due to Streptococcus pneumoniae: 📖
pneumococcal pneumonia

epidemiology

  • Pneumococcal pneumonia is of the most common causes of pneumonia, including severe pneumonia.
  • Pneumococcus is spread via droplets in a person-to-person fashion.
    • Outbreaks may occur among adults living in crowded conditions (e.g., jail, military barracks).
    • Infections are most common in the winter and early spring. (Murray 2022)
    • Different serotypes of pneumococcus may have varying tendencies to cause invasive disease or empyema.
  • Risk factors for pneumococcal pneumonia include: (Fishman 2023, 27960205)
    • Smoking.
    • Previous influenza or RSV infection.
    • Older age.
    • Chronic conditions:
      • Chronic pulmonary disease (e.g., COPD, asthma).
      • Chronic liver disease.
      • Chronic renal failure.
      • Diabetes.
      • Alcoholism.
    • Immune dysfunction:
      • Asplenia, sickle cell disease, celiac disease.
      • HIV: Pneumococcus is a leading cause of pneumonia among people living with HIV (even among patients with normal CD4 counts). Patients may be at increased risk of recurrent disease.
      •  B-cell defects, multiple myeloma.
      • Immunosuppressive medications (chemotherapy, antimetabolites, steroid).
      • Solid organ transplantation

clinical presentation

  • Classic presentation:
    • Abrupt onset of severe chills/rigors, followed by fever.
    • Severe pleuritic chest pain.
    • Cough productive of blood-tinged, tenacious “rusty” sputum.
    • (Nausea/vomiting or diarrhea can be prominent.)
  • Alternative/unusual presentations:
    • Elderly patients: fatigue or altered mental status.
    • Asplenic patients: shock and hemorrhagic skin lesions due to DIC.
    • Right lower lobe pneumonia may cause hyperbilirubinemia, masquerading as acute cholecystitis.
  • Clinical course:
    • Empyema or parapneumonic effusion is common.
    • 💡 Consider repeating POCUS to evaluate for effusion every few days, since these effusions may pop up when you're least expecting them to.

radiology

  • Pneumococcus generally causes a lobar pneumonia:
    • This often causes relatively large, homogeneous consolidation with air bronchograms.
    • Consolidations may be unifocal or multifocal.
    • An isolated round area of consolidation may occur (“round pneumonia”).
  • Given how common pneumococcal pneumonia is, unusual radiographic patterns will also be encountered (e.g., patchy bronchopneumonia can occur). (Walker 2019)
  • Pleural effusion is common (affecting about a third of critically ill patients).
  • CT scan may show some lymphadenopathy in about half of cases. (Walker 2019)
  • Cavitation is rare (if seen, this might suggest a superimposed co-infection or alternative diagnosis).

general laboratory tests

  • Neutropenia is occasionally seen, especially among patients with a history of alcoholism. The association of neutropenia, alcoholism, and bacteremic pneumococcal pneumonia has historically been labeled as “ALPS” (alcoholic leukopenic pneumococcal sepsis). Therapy for ALPS includes standard treatments for pneumonia as well as supportive care for alcoholism (e.g., folate, thiamine, treatment of alcohol withdrawal). There is no need for exogenous granulocyte stimulating factors, since endogenous cytokine levels are high and the leukocyte levels will rebound naturally over time.

specific laboratory studies

  • Sputum Gram stain may show slightly elongated (“lancet-shaped”) gram-positive cocci in pairs or chains. However, sputum culture is often negative (since pneumococcal bacteria are fastidious and difficult to grow).
  • Blood culture is positive in ~25% of patients.
  • Pneumococcal urinary antigen has a sensitivity of ~75% and specificity of ~95%. False-positive results may occur if the patient had a pneumococcal pneumonia in the past three months.

treatment

  • Antibiotics are discussed above.
  • Steroid:
    • Based on evidence regarding the use of steroid in pneumococcal meningitis, steroid is be expected to be especially beneficial for patients with pneumococcal pneumonia.
    • A general discussion of the role of steroid in bacterial pneumonia is here: 📖

AmpC inducible beta-lactamase

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basics

  • Normally the AmpC gene is suppressed, so bacteria may initially test “susceptible” to beta-lactamases. Following treatment with a beta-lactam, the AmpC gene is induced in vivo. This causes the bacteria to become antibiotic resistant.
  • In the ICU, this is most often a problem with third-generation cephalosporins.
  • Enzyme induction takes some time (one day to a couple of weeks). So if patients are started on empiric therapy with ceftriaxone, this may be effective for a day or two (long enough for culture results to return). If ceftriaxone is continued, then treatment failure may eventually occur.
  • Different antibiotics vary in their ability to induce beta-lactamases, and in their susceptibility to induced beta-lactamases. (Garcia B 2022; 22477821)
  • In clinical practice, it's impossible to test whether a bacteria has an inducible AmpC beta-lactamase. This must be guessed based on the bacterial species, as outlined below.
bacteria which tend to harbor inducible AmpC beta-lactamase 
  • Moderate-to-high risk (~20%): (37463564)
    • EnteroBACTER cloacae.
    • CitroBACTER freundii.
    • Klebsiella aerogenes (formerly: Enterobacter aerogenes).
    • Management: Avoid ceftriaxone or ceftazidime (regardless of sensitivity results).
  • Intermediate/unclear risk (limited data)
    • Hafnia alvei.
    • Citrobacter youngae.
    • Yersinia enterocolitica.
    • Management: It is reasonable to use sensitivity data (e.g., ceftriaxone) – but exercise caution.
  • Low risk (<5%): (37463564)
    • Serratia marcescens.
    • Morganella morganii.
    • Providencia spp.
    • Management: Antibiotic susceptibility results can generally be trusted. However, cefepime may be considered in infections with high bacterial burden and limited source control (e.g., endocarditis, ventriculitis, brain abscess).
treatment of bacteria with suspected AmpC inducible beta-lactamase

cefepime 💉

    • Cefepime is recommended if the organism is cefepime-susceptible.

carbapenem 💉

  • Carbapenem is recommended for cefepime-resistant organisms, assuming the organism is carbapenem sensitive.

non-beta lactam antibiotics

  • (AmpC-inducible beta-lactamase cannot affect non-beta lactam antibiotics. These may be utilized based on culture and sensitivity data as per usual.)
  • Trimethoprim-sulfamethoxazole 💉 or fluoroquinolones. 💉
    •  Step down to oral therapy with one of these agents may be utilized if the following criteria have been met: (37463564)
    • (1) Susceptibility to an appropriate oral agent.
    • (2) Patient is hemodynamically stable.
    • (3) Reasonable source control measures have occurred.
    • (4) Concerns about insufficient intestinal absorption are not present.
  • Nitrofurantoin (for cystitis). 💉
  • Aminoglycosides (e.g., for pyelonephritis or complicated urinary tract infection). 💉
  • Tetracyclines (for infections that these could be effective for).

treatments that are not recommended

  • 3rd generation cephalosporins.
  • Aztreonam.
  • Piperacillin-tazobactam: There is no high-quality evidence that piperacillin-tazobactam causes worse clinical outcomes, but this has been suggested by two observational studies. (34864936, 37463564)

extended-spectrum beta-lactamases (ESBL)

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basics 

ESBL refers to enzymes which inactivate most penicillins, cephalosporins, and aztreonam. However, they do not affect carbapenems and cephamycins (cefoxitin, cefotetan, and cefmetazole). ESBL enzymes themselves don't affect susceptibility to non-beta-lactam antibiotics, but these agents may nonetheless tend to be multi-drug resistant.

ESBL can occur in a variety of gram-negative bacilli, but they are most common among: (35942862)

  • E. coli.
  • Klebsiella pneumoniae.
  • Klebsiella oxytoca.
  • Proteus mirabilis.
diagnosis

risk factors (pre-test probability)

  • Prior infection/colonization with ESBL in the last 12 months. (37176628)
  • Regional epidemiology.
  • Recent travel to a high-prevalence area.
  • Recent exposure to antimicrobials (especially fluoroquinolones, third-generation cephalosporin).
  • Recurrent urinary tract infections.
  • Permanent urinary catheterization.
  • PEG tube (percutaneous endoscopic gastrostomy).
  • Recent hospitalization.
  • Prolonged hospitalization (>10 days, especially in ICU). (34751185, 37176628)

in vitro sensitivity pattern

  • 🚩 Nonsusceptibility to ceftriaxone is often used as a proxy for ESBL production, although this has limited specificity. (37463564) The MERINO trial investigated ceftriaxone-resistant, piptazo-sensitive strains (discussed below). ESBL are generally resistant to both 3rd and 4th generation cephalosporins. 
  • Often sensitive in vitro to beta-lactamase inhibitors (e.g., piperacillin-tazobactam).
    • ⚠️ This is a trap because you shouldn't use piperacillin-tazobactam! (discussed below)
  • Sensitive to cephamycins (cefoxitin, cefotetan, cefmetazole).

Verigene PCR assay ⚡️

  • Genetic assays may detect the CTX-M gene. If detected, this reveals the presence of an ESBL.
  • Unfortunately, the absence of CTX-M doesn't exclude an ESBL species (because there are other ESBL genes).
treatment of ESBL enterobacteriaceae in various situations

infections beyond of the urinary tract (most infections)

  • Initial therapy:
    • 🏆 Meropenem or imipenem are the gold standard therapy in critical illness or hypoalbuminemia.
    • Ertapenem may be adequate for less severe infection. ESCMID guidelines only recommend ertapenem for patients without septic shock. (35942862) More on the limitations of ertapenem in critical illness above. 💉
  • Step-down therapy:
    • Once patients are clinically improved, they may be transitioned to trimethoprim-sulfamethoxazole or a quinolone.
    • Criteria for stepping down: (37463564)
      • (1) Demonstrated susceptibility of the organism.
      • (2) Patient is hemodynamically stable.
      • (3) Reasonable source control has occurred.
      • (4) Concerns about insufficient intestinal absorption are not present.

pyelonephritis or complicated urinary tract infection

  • Definition of complicated urinary tract infection: presence of foreign bodies (calculi or catheter), anatomic abnormalities, obstruction, immunosuppression, renal failure, kidney transplant, or neurogenic bladder. (UVM Green Book)
  • Options include:
    • Trimethoprim-sulfamethoxazole.
    • Ciprofloxacin or levofloxacin (dose-reduced).
    • Carbapenem.
    • Aminoglycosides for a full treatment course. (37463564)

uncomplicated cystitis

  • Nitrofurantoin.
  • Trimethoprim-sulfamethoxazole.
  • Single-dose aminoglycoside.
  • Fosfomycin (only for E. coli cystitis).
  • Carbapenems.
  • Fluoroquinolones (ciprofloxacin, levofloxacin; reduce dose from standard dosages). (31369411, 37463564)
discussion of specific agents for ESBL enterobacteriaceae

avoid piperacillin-tazobactam

  • MERINO trial:
    • RCT of patients with E. coli or K pneumoniae bacteremia resistant to ceftriaxone and “sensitive” to piperacillin-tazobactam (87% were ultimately confirmed to have ESBL genes). About 60% had bacteremia due to a urinary tract source. Patients were randomized to receive piperacillin-tazobactam (4.5 grams q6hr) or meropenem (1 gram q8hr). (30208454)
    • 30-day mortality was 12% (23/187) in piperacillin-tazobactam group vs. 4% (7/191) in the meropenem group (p=0.002 with fragility index of five).
    • Overall this is the highest quality evidence available, and it shows a signal of harm with piperacillin-tazobactam.
  • Piperacillin-tazobactam is not generally recommended as therapy for ESBL bacteria (regardless of susceptibility results).
  • If piperacillin-tazobactam was started as empiric therapy for uncomplicated cystitis caused by an organism later identified to be an ESBL species and clinical improvement occurs, no change is necessary. (37463564)

avoid cefepime

  • Even if ESBL-producing species test susceptible to cefepime, testing may be inaccurate or poorly reproducible.
  • Cefepime shouldn't be utilized, regardless of sensitivity results. (37463564)
  • A RCT comparing cefepime versus piperacillin-tazobactam and ertapenem in nosocomial urinary tract infection due to ESBL-producing E. coli was stopped early due to a high failure rate in the cefepime arm. (37148398)
  • If cefepime was started as empiric therapy for uncomplicated cystitis caused by an organism later identified to be an ESBL species and clinical improvement occurs, no change is necessary. (37463564)

CRE (carbapenem-resistant Enterobacterales)

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⚠️ Infectious disease consultation is recommended. The following is based on the IDSA 2024 guidelines. 📄

definition of CRE & general comments

  • Definition of CRE:
    • Member of Enterobacterales resistant to at least one carbapenem or producing a carbapenemase enzyme.
    • For bacteria intrinsically less sensitive to imipenem (e.g., Proteus spp., Morganella spp., Providencia spp.), resistance to a different carbapenem is required to qualify as CRE.
  • Aside from resistance to carbapenems, these bacteria are often highly resistant (with increased rates of resistance to other antibiotics).

types of CRE

  • [1] Carbapenemase-producing (~60% or more).
    • KPC (K. pneumoniae carbaapenemases; ~80%) which aren't limited to K. pneumoniae.
      • Main mechanism of carbapenem resistance in the United States, especially the northeast.
    • Metallo-beta-lactamses (MBLs)
      • NDMs (New Delhi metallo-beta-lactamases; ~10%).
      • VIMs (Verona integron-encoded metallo-beta-lactamases; <1%).
      • IMPs (imipenem-hydrolyzing metallo-beta-lactamases; 1-5%).
    • Oxacillinases (e.g., OXA-48-like; ~5%).
  • [2] Not carbapenemase-producing. This may result from amplification of other beta-lactamase genes (e.g., ESBL genes) with concurrent outer membrane porin disruption.
  • The Verigene multiplex PCR assay evaluates for common causes of CRE (IMP, KPC, NDM, OXA, VIM genes). ⚡️

treatment of uncomplicated cystitis 2/2 CRE

  • If sensitive, the following are preferred therapies: nitrofurantoin, TMP-SMX, ciprofloxacin/levofloxacin. However, the likelihood of sensitivity for any of these agents is low.
  • Other options:
    • Aminoglycoside (single dose may be utilized for cystitis).
    • Oral fosfomycin (only for E. coli cystitis).
    • Colistin (noting potential nephrotoxicity).
    • Ceftazidime-avibactam.
    • Meropenem-vaborbactam.
    • Imipenem-cilastatin-relebactam.
    • Cefiderocol.

treatment of pyelonephritis or complicated urinary tract infection 2/2 CRE

  • If sensitive, the following are preferred therapies: TMP-SMX, ciprofloxacin/levofloxacin. However, the likelihood of sensitivity for any of these agents is low.
  • Also preferred options:
    • Ceftazidime-avibactam.
    • Meropenem-vaborbactam.
    • Imipenem-cilastatin-relebactam.
    • Cefiderocol.
  • Aminoglycosides are alternative options.

CRE without carbapenemase: treatment of infections beyond urinary tract:

  • Resistant to ertapenem but sensitive to meropenem & imipenem: may use meropenem or imipenem (with extended infusion).
  • Not sensitive to any carbapenem: options include:
    • Ceftazidime-avibactam.
    • Meropenem-vaborbactam.
    • Imipenem-cilastatin-relebactam.

 CRE with KPC: treatment of infections beyond urinary tract

  • Preferred options:
    • (1) Meropenem-vaborbactam (might be most effective).
    • (2) Ceftazidime-avibactam (highest likelihood of resistance emergence).
    • (3) Imipenem-cilastatin-relebactam (limited clinical data).
  • Alternative option: cefiderocol.

CRE with metallo-beta-lactamase (NDM, VIM, IMP): treatment of infections beyond urinary tract:

  • Preferred options are as follows:
  • [1] Ceftazidime-avibactam plus aztreonam with a goal of functionally creating aztreonam-avibactam. (NDMs hydrolyze penicillins, cephalosporins, and carbapenems but not aztreonam. However, aztreonam may be hydrolyzed by other serine beta-lactamases that are often present such as ESBLs, AmpCs, KPCs, or OXA-48-like enzymes. Avibactam is used to protect aztreonam from these enzymes.)
  • [2] Cefiderocol monotherapy.

CRE with OXA-48: treatment of infections beyond urinary tract:

  • Ceftazidime-avibactam is preferred.
  • Cefiderocol is an alternative option.

resistant GNRs: advanced agents

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⚠️ Infectious disease consultation is recommended. The following is merely some basic information intended to provide a general foundation of understanding.

ceftolozane-tazobactam

  • Coverage:
    • ESBL organisms.
    • MDR pseudomonas – seems to be it's primary use. (34751185)
    • MDR Acinetobacter baumannii.
  • Efficacy demonstrated for nosocomial pneumonia, complicated urinary tract infections, and complicated intra-abdominal infections (in combination with metronidazole).
  • Dosing:
    • Standard dosing: 1.5 grams q8hr.
    • Higher dosing (3 grams q8hr) is recommended for treatment of pneumonia to ensure adequate pulmonary penetration, and often utilized for other critically ill patients (especially augmented renal clearance). (Schmidt 2024)

ceftazidime-avibactam

  • Coverage:
    • ESBL organisms.
    • AmpC-hyperproducing Enterobacteriaceae.
    • Many MDR pseudomonas.
    • CRE 2/2 KPC.
    • CRE 2/2 OXA-48. (34751185)
    • Ceftazidime-avibactam plus aztreonam: CRE 2/2 metallo beta-lactamases.
  • Efficacy demonstrated for nosocomial pneumonia, complicated urinary tract infections, bacteremia, and complicated intra-abdominal infections.

meropenem-vaborbactam

  • Activity:
    • [1] All the activity of meropenem (e.g., many Pseudomonas and Acinetobacter spp.).  The addition of vaborbactam doesn't really improve coverage of Pseudomonas or Acinetobacter spp.
    • [2] Plus CRE 2/2 KPC. (34751185)
  • Efficacy has been demonstrated for KPC causing various infections (pneumonia, intra-abdominal infections, bacteremia).

imipenem/cilastatin-relebactam

  • Activity in vitro includes:
    • ESBL.
    • AmpC.
    • CRE.
    • Pseudomonas aeruginosa (including those with overproduction of AmpC causing imipenem resistance).
  • Clinical utilization is still being elucidated.

cefiderocol

  • Activity is extremely broad for gram negatives, including:
    • MDR/XDR Acinetobacter (including carbapenem-resistant acinetobacter).
    • MDR/XDR Pseudomonas.
    • CRE of all types (including metallo-beta-lactamase such as NDM, VIM, IMP). (34751185)
    • Stenotrophomonas maltophilia (including carbapenem-resistant strains).
    • Burkholderia cepacia complex (including carbapenem-resistant strains).
    • (Seems to have poor activity for anaerobes, gram positives.)
  • Dosing:
    • Standard dosing: 2 grams q8hr.
    • Augmented renal clearance: 2 grams q6hr.

septic shock checklist

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evaluation: order tests & review available data

  • General labs:
    • CBC with differential.
    • Electrolytes with Ca/Mg/Phos.
    • Liver function tests.
    • INR, PTT.
    • Lactate. 📖
    • Procalcitonin (+/- CRP in renal failure). ⚡️
  • Microbiology:
    • Peripheral blood culture x2.
    • Culture of any line in place >48 hours.
    • Sputum gram stain & culture if intubated.
    • Urinalysis and culture.
    • Other relevant sites (e.g., CSF, ascites).
  • Imaging:
    • Chest radiograph.
    • ECG.
    • POCUS + formal echocardiogram.
    • Consider CT abdomen/pelvis if no definite source.
  • Additional testing to evaluate source: 📖
  • If no clear infection: consider sepsis mimics: 📖

antibiotic overview

  • Review:
    • Prior culture data.
    • Prior antibiotic exposure.
    • Best treatments based on suspected site of infection.
    • ✔ Antibiotic checklist above ⚡️
  • Key points:
    • First dose is STAT.
    • Give a FULL loading dose (regardless of renal function).
  • Beta-lactam backbone, usually:
  • MRSA coverage?
    • Indications include: soft tissue infection, line infection, selected CAP patients, nosocomial infections such as surgical site infection & VAP.
    • Risk factors for MRSA & indications for tx CAP: ⚡️
    • Treatment options:
  • Community-acquired pneumonia:
    • Azithromycin: ⚡️
    • Doxycycline: ⚡️
    • Selection of azithromycin vs. doxycycline: ⚡️
  • Tick-borne illness: Doxycycline ⚡️ (at a minimum).
  • C. difficile: oral vancomycin +/- IV metronidazole ⚡️.

source control 

  • Hardware removal? (e.g., port, tunneled line, central line).
  • Other drainage/debridement (e.g., decompress hydronephrosis, ERCP for cholangitis, abscess drainage).

adjunctive therapies

  • Hydrocortisone 100 mg IV then 50 mg IV q6hr (unless contraindicated). 📖
  • DVT prophylaxis first dose now (may improve endothelial glycocalyx, DIC).
  • GI prophylaxis (e.g., 40 mg pantoprazole daily, PO/IV). 📖
  • Bicarbonate: Consider for NAGMA, uremic metabolic acidosis, or refractory shock with severe acidemia (e.g., pH <~7.1). (37176628)
  • Methylene blue 💉: Consider if dual-pressed & not responding favorably.
  • Thiamine: If malnourished or alcoholism (100 mg IV daily).
  • Acetaminophen: Consider for pain or fever (antipyresis may reduce vasodilation).
  • Refractory vasodilatory shock: additional treatments here: 📖

review medications & fluid administration

  • Have antibiotics been administered?
  • Are antibiotics scheduled and dosed optimally?
  • Reasonable fluid resuscitation performed?
  • Review the medication list:
    • D/C antihypertensives (e.g., alpha-blockers for BPH).
    • D/C nephrotoxins (as able).

bedside re-assessment: HUMSSS

  • Heart Rate 📖
    • Heart rate <~80 b/m: Consider epinephrine challenge 📖.
    • Heart rate >~140 b/m: Consider switch to vasopressors without beta-agonist activity (e.g., phenylephrine, vasopressin).
  • Urine output 📖
  • MAP: Consider a vasopressor challenge (increase MAP to >80 mm to see if this improves urine output) if:
    • Chronic HTN.
    • Cirrhosis with hepatorenal physiology.
  • 3 measures of Skin perfusion 📖
    • [1] Mottling.
    • [2] Cool extremities.
    • [3] Capillary refill.

repeat lactate 📖

  • Rising/persistent lactate should prompt global re-evaluation of the patient (not reflexive fluid administration).
  • ⚠️ Epinephrine infusions will increase lactate, rendering serial lactate measurement meaningless.

antibiotic use in pregnancy

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⚠️ The latest data available on electronic pharmacopoeias should always be checked, to look for updates on the information below. The consequences of uncontrolled maternal infection for the fetus are often catastrophic, so the first priority is adequate infection control. Most of the workhorse antibiotics of the ICU are quite safe in pregnancy:

🟢 systemic antibiotics that are generally considered safe in pregnancy

  • Beta-lactams:
    • Penicillins, aminopenicillins, combinations with beta-lactamase inhibitors, cephalosporins, and carbapenems are all generally considered safe.
    • Aztreonam is probably safe, should be used with some caution due to a lack of evidence. (26598097)
  • Gram-positive agents:
    • Vancomycin (class C).
    • Daptomycin (class B).
  • Anaerobic agents:
    • Metronidazole (class B; however the manufacturer and CDC consider metronidazole to be contraindicated in the first trimester). (Hopkins Antibiotic Guide)
    • Clindamycin (class B).
  • Azithromycin (class B).
  • Nitrofurantoin (class B. Can be used in 1st-2nd trimesters. Shouldn't be used in the third trimester due to potential risk of newborn hemolytic anemia when used near delivery). (Hopkins Antibiotic Guide, 37906240)

🟡 antibiotics which may be used with caution

  • Doxycycline
    • Traditionally doxycycline was avoided due to concerns regarding tooth discoloration and congenital defects. However, a more recent review article questions this. (26680308)
    • Doxycycline is currently considered as the treatment of choice for anaplasmosis in pregnancy. Suboptimally treated anaplasmosis in pregnancy may have severe consequences. (36116840)
  • Linezolid: Some animal studies suggest toxicity, but there is not substantial human data (Class C).
  • Fluoroquinolones have been suggested to be teratogenic in some older animal studies. However, recent evidence does not suggest increased teratogenicity. (34352843) Ciprofloxacin, levofloxacin, and moxifloxacin are Class C. 

🔴 antibiotics which are generally best avoided

  • Aminoglycosides: There may be a small risk of fetal hearing loss, especially if administered in the first trimester and especially with streptomycin. (26598097) A risk of fetal nephrotoxicity may also exist. Consequently, tobramycin, gentamicin, and amikacin are all class D. Short courses of aminoglycosides may be used in pregnancy with careful monitoring. (26598097) However, in the context of a modern antibiotic armamentarium there are almost always safer options available. 
  • Trimethoprim-sulfamethoxazole:
    • First trimester: avoid due to due to major congenital malformations.
    • After 32 weeks gestation exposure may increase risk of kernicterus. Trimethoprim-sulfamethoxazole is Class C, but conditionally Class D when pregnancy is near term.
    • Use in the second trimester may be OK (13-27 weeks gestation). However, this is probably best avoided if there are alternatives. (37906240)

azithromycin vs. doxycycline

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spectrum: doxycycline has numerous advantages over azithromycin

  • Advantages of doxycycline: 💉 
  • (1) Superior coverage of Mycoplasma pneumoniae: Resistance to azithromycin is increasing among mycoplasma in many regions of the world (although this doesn't seem to be a major problem in the United States yet).
  • (2) Superior coverage of Streptococcus pneumoniae: There is increasing resistance to Streptococcus pneumoniae among both azithromycin and doxycycline, but doxycycline is often a bit better.
  • (3) Superior coverage of zoonotic pneumonias:
    • Coxiella burnetii (Q-fever) – usually seen in farmers or veterinarians due to contact with cattle, sheep, goats, cats, dogs, or rabbits.
    • Tularemia – acquired from rabbits.
    • Leptospirosis – acquired from animal urine.
    • Psittacosis – acquired from birds.
  • (4) Reasonable coverage of community-acquired MRSA in vitro. The use of doxycycline for invasive MRSA infections (e.g., pneumonia) has not been established. However, this might be beneficial for patients who are at some risk for community-acquired MRSA pneumonia, but not enough risk to justify addition of linezolid or vancomycin.
  • (5) Gram negative coverage: Doxycycline has reasonably good coverage for E. coli, Enterobacter spp., and Klebsiella spp. Doxycycline alone probably isn't sufficient to treat severe infections due to these organisms, but it may bolster coverage provided by the beta-lactam.
  • (6) Prior azithromycin exposure: Patients often receive substantial exposure to azithromycin prior to admission. For such patients, doxycycline could be more likely to cover organisms in their microbiome.
  • (7) Coverage of most tick borne illnesses (Lyme, Rocky mountain spotted fever, anaplasmosis, and ehrlichiosis).
  • Advantage of azithromycin: 💉 The primary advantage of azithromycin is that it may provide superior coverage of legionella. Doxycycline should cover legionella as well, but there is greater experience with azithromycin.

antimicrobial stewardship

  • 🏆 Doxycycline has advantages here:
    • (1) Doxycycline appears to reduce the risk of C. difficile. (37921728, 22563022, 18171186, 27025622, 28819873) 
    • (2) Doxycycline is generally regarded as a “low resistance potential” antibiotic. Despite extensive use, relatively little resistance against doxycycline has arisen (with the exception of Streptococcus pneumoniae). (28819873)
  • Azithromycin: in the MORDOR trial, broad utilization of azithromycin in African children increased resistance to azithromycin as well as beta-lactams. (33176084) This suggests that azithromycin may promote resistance to a variety of antibiotics.
  • In the WHO AWaRe classification for antimicrobial stewardship, doxycycline is grouped in the access group, whereas azithromycin is in the watch group – indicating a preference for doxycycline.

immunomodulation

  • Azithromycin may have immunomodulatory effects, that could be beneficial for patients with pneumonia. Retrospective studies suggest a mortality benefit among patients treated with azithromycin, even in pneumococcal pneumonia sensitive to beta-lactams.
  • However, immunomodulatory effects were demonstrated to be beneficial in an era prior to the widespread use of steroid for community-acquired pneumonia. Among patients who are receiving steroid, it's unknown whether this effect would still remain beneficial.

logistics

  • Azithromycin may be given as three-day intravenous regimen of 500 mg daily. This is easy for patients with IV access and it ensures that a full antibiotic course is provided.
  • Doxycycline has superior bioavailability as compared to azithromycin, so oral doxycycline may be utilized in patients with limited IV access (however absorption impaired by aluminum, magnesium, calcium, iron, cholestyramine, or milk).

safety

  • Both agents are extremely safe.
  • Azithromycin:
    • There is a myth that azithromycin prolongs the QT interval, thereby leading to malignant arrhythmias. Best available data (i.e., RCTs) indicate that azithromycin is safe in this regard. (24893087) 🌊
    • ⚠️ Azithromycin is contraindicated in myasthenia gravis.
  • Doxycycline: Potential risks include:
    • GI irritant: Nausea, vomiting if taken before/after meals; esophageal ulceration if taken orally without sufficient water.
    • Vascular irritant: Can cause phlebitis when given IV.

piperacillin-tazobactam vs. cefepime

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Both piperacillin-tazobactam and cefepime are often utilized for similar indications (e.g., community-acquired septic shock). Selection may vary depending on local antibiograms and practice patterns. Some factors to consider when making this choice include the following:

advantages of piperacillin-tazobactam

  • Provides coverage of anaerobes.
  • Provides coverage for enterococcus faecalis (which may be involved in urinary or biliary tract infections).
  • Reduced rates of neurologic toxicity as compared to cefepime.
  • Piperacillin-tazobactam may cause lower rates of C. difficile. (28444166, 33382398, Liu 2024)

advantages of cefepime

  • Cefepime has superior CNS penetration, allowing it to cover CNS infection (e.g., meningitis, brain abscess).
  • Cefepime provides coverage for species with inducible AmpC genes. 📖

therapy for resistant gram positives: vancomycin vs. linezolid vs. daptomycin vs. ceftaroline

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getting started: basic considerations

  • [1] Source?
    • Bloodstream infection (e.g., endocarditis, line infection):
      • Daptomycin or vancomycin are often utilized.
      • Daptomycin plus ceftaroline probably optimizes outcomes. (36838359)
      • Linezolid probably effective, but not typically preferred (discussed above 💉).
    • Pneumonia:
      • Linezolid and ceftaroline have the best tissue penetration and supporting evidence. Ceftaroline has been studied more in community-acquired pneumonia, whereas linezolid has been studied more in ventilator-associated pneumonia.
      • Vancomycin may be utilized, but meta-analyses suggest inferior outcomes compared to linezolid. (36838359) 
      • Daptomycin: Does not work at all.
    • CNS coverage:
      • Vancomycin has some CNS penetration, so it is often recommended for CNS infection.
      • Linezolid has outstanding CNS penetration (~60-80%). It's not robustly investigated, but some authors recommend linezolid as a front-line therapy for CNS infections due to MRSA. (36838359) In particular, linezolid has been demonstrated to be effective as salvage therapy for patients who failed to respond to vancomycin. (32859532)
      • Ceftaroline has limited CNS penetration.
      • Daptomycin doesn't have effective CNS penetration.
  • [2] Prior culture data?
  • [3] Drug allergies?
  • [4] Recent antibiotic exposure? (consider choosing something different)
  • [5] Renal function?
    • Acute kidney injury: Vancomycin might aggravate.
    • Augmented renal clearance: Subtherapeutic levels may occur with vancomycin, daptomycin, or ceftaroline.
  • [6] Serotonergic medications?
    • List of medications here: 📖
    • Contraindication to linezolid if unable to discontinue serotonergic agents.

vancomycin 💉

  • Advantages:
    • Inexpensive and widely available.
    • Reasonable track record for treatment of a variety of MRSA infections.
    • Least likely to provoke the wrath of antimicrobial stewards.
  • Disadvantages:
    • Nephrotoxicity.
    • Levels are erratic (unless there is high-level pharmacokinetic monitoring).
    • May miss enterococcus faecium (depending on local antibiogram).

linezolid 💉

  • Advantages:
    • Excellent tissue penetration (including lungs, meninges).
    • Toxin suppression may be helpful in toxic shock and community-acquired toxigenic MRSA (e.g., USA-300 strain).
    • Easy to dose correctly and achieve therapeutic levels (especially in augmented renal clearance).
    • Listeria coverage may be useful for patients with undifferentiated CNS infections.
  • Disadvantages:
    • Risk of serotonin syndrome (if concomitant serotonergic medications).
    • Difficult to tolerate for several weeks (e.g., thrombocytopenia).
    • Efficacy in bloodstream infections is controversial (discussed above 💉).

daptomycin 💉

  • Advantages:
    • Strong evidentiary basis for bloodstream infection and endocarditis.
    • Single dose provides coverage for 48 hours in patient with GFR <30 ml/min. This may be used to provide empiric coverage, with further doses administered if blood cultures are positive.
  • Disadvantages:
    • Ineffective for pneumonia.

ceftaroline 💉

  • Advantages:
    • Broad spectrum may allow single-agent coverage of gram-positives and gram-negatives (e.g., pneumonia).
  • Disadvantages:
    • Most likely to provoke the wrath of antimicrobial stewards.

2) de-escalation of antibiotics

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general concepts

  • As a general rule, Anti-MRSA therapy should be discontinued within <48 hours unless there is some objective evidence that the patient actually has MRSA. Note that a negative nares PCR is usually sufficient evidence to discontinue MRSA coverage in the context of pneumonia.
  • If culture results reveal an organism and the patient has a mono-microbial infectious process (e.g., urinary tract infection, endocarditis, pneumonia), then antibiotics should be narrowed to focus on the identified organism.
  • Below is the WHO 2023 AWaRe grouping of antibiotics (listing agents most relevant to critical care). This is a rough categorization into three groups, depending on the potential to induce antimicrobial resistance. This may be useful cognitive rubric to help encourage de-escalation (even if that may be inconvenient). Of course, it's always essential to choose an antibiotic with sufficient pharmacokinetic and pharmacodynamic properties to effectively treat the infection.

WHO AWaRe grouping of antibiotics (2023)

  • Access 🟢
    • Aminoglycosides: Amikacin, gentamicin.
    • Beta-lactams:
      • Amoxicillin, ampicillin, amox/clav, amp/sulbactam.
      • Cephalosporins Generation #1.
      • Nafcillin.
      • Penicillin G.
    • Clindamycin.
    • Doxycycline.
    • Metronidazole.
    • Nitrofurantoin.
    • Trimethoprim/sulfamethoxazole.
  • Watch 🟡
    • Aminoglycoside: Tobramycin.
    • Azithromycin.
    • Beta-lactams:
      • Carbapenems.
      • Cephalosporins Generation #2-4.
      • Piperacillin-tazobactam.
    • Fluoroquinolones.
    • Rifampicin.
    • Vancomycin.
  • Reserve 🔴
    • Aztreonam.
    • Daptomycin.
    • Linezolid.
    • Tigecycline.
    • Ceftazidime/avibactam, meropenem/vaborbactam, etc.

3) limiting duration of therapy

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Traditional treatment durations for most infections are excessive. An emerging body of literature indicates that shorter antibiotic duration may be equally efficacious, while limiting costs and toxicity. Recently over one hundred RCTs have compared shorter versus longer courses of antibiotics, with the overwhelming majority demonstrating equivalent outcomes.

The underlying pathophysiologic concept is that human beings are not petri dishes – antibiotics don't need to fully sterilize the body, but rather only to minimize the burden of infection until the patient's immune system is capable of clearing remaining bacteria.

COPD exacerbation: duration of antibiotics
  • Antibiotic therapy should be limited to ≦ 5 days. (33819054)
  • The following antibiotic regimens are often utilized:
    • Azithromycin 500 mg IV daily x3 days.
    • Azithromycin 500 mg on day #1, then 250 mg daily on days #2-5.
    • Five day course of doxycycline.
community acquired pneumonia: duration of antibiotics 

conventional duration of therapy: 

  • Guidelines recommend 5-7 days of treatment.
  • After 5 days of therapy, antibiotics should generally be discontinued if patients meet criteria for clinical stability: (33819054, 27455166)
    • Clinical stability criteria:
      • Temperature 37.8 or less for two days.
      • No more than one CAP-associated sign of clinical instability:
        • Systolic Bp < 90 mm.
        • Heart rate >100/min.
        • Respiratory rate >24/min.
        • Oxygen saturation <90% on room air.
    • Exclusion criteria for 5-day therapy may include: (27455166)
      • HIV infection.
      • Asplenia.
      • Solid organ transplantation.
      • Immunosuppressive medications (e.g., 10 mg prednisone for a month).
      • Neutropenia.
      • Infection with uncommon pathogen (e.g., Pseudomonas, Staphylococcus).
  • Potential indications for longer treatment:
    • Bacteremic infection with Staphylococcus aureus.
    • Legionella pneumonia.
    • Metastatic infection involving other organs (e.g., meningitis).
    • Anatomic complication (e.g. necrotizing pneumonia, lung abscess, empyema).

three-day therapy

  • Two RCTs have suggested that antibiotics can be discontinued after three days, among patients with rapid clinical improvement who didn't require ICU admission. (16763247, 33773631)
  • Some requirements for three-day therapy in the larger RCT included: (33773631)
    • Temperature >38C within 48 hours prior to admission.
    • Not admitted to ICU.
    • Not immunocompromised (e.g., asplenia, neutropenia, agammaglobulinemia, transplant patient, myeloma, lymphoma, HIV, sickle-cell disease, Child-Pugh class C cirrhosis).
    • Clinical stability criteria met after three days, specifically:
      • Afebrile (<37.8 C).
      • Heart rate <100 b/m.
      • Respiratory rate <24/min.
      • Saturating >90% on usual mode of oxygenation.
      • Systolic Bp >90 mm.
    • No complication (e.g., abscess, massive pleural effusion).
    • No suspected/confirmed legionellosis or intracellular bacteria.
    • No advanced renal failure (GFR <30 ml/min).
  • Overall, three-day therapy seems reasonable for patients who are carefully selected using evidence-based criteria. (36718940)

(procalcitonin-based strategy is only rarely helpful)

  • As a general rule, procalcitonin levels may be helpful to support a decision to stop antibiotics. Alternatively, if other indicators indicate that antibiotics can be discontinued and the procalcitonin remains elevated, the procalcitonin shouldn't be used to a support a decision to continue antibiotics.
  • The following suggest discontinuation of antibiotic:
    • Procalcitonin level <0.25 ng/ml.
    • Procalcitonin has fallen to <20% the peak value.
  • Procalcitonin levels may be useful to support antibiotic discontinuation in a patient who remains clinically ill for non-infectious reasons (e.g. COPD exacerbation, ARDS).
  • Procalcitonin isn't applicable in following situations:
    • Immunocompromise.
    • Renal dysfunction (PCT may have sluggish kinetics).
    • Patient has other causes of elevated procalcitonin (e.g. other site of infection, burns, trauma, surgery, pancreatitis).
nosocomial pneumonia: duration of antibiotics
  • The IDSA/ATS guidelines generally recommend a seven-day course of antibiotics (even for Pseudomonas). (27418577, 37148398)
  • Potential indications for prolonged therapy:(32157357, 30601179)
    • Empyema.
    • Lung abscess, necrotizing pneumonia.
    • Bacteremia with certain gram-positive organisms (e.g., Staph. aureus).
    • Severe immunodeficiency (e.g., ongoing neutropenia).
    • Bronchiectasis exacerbation (e.g., cystic fibrosis).
  • Procalcitonin may occasionally be useful to shorten the duration of therapy:
    • Procalcitonin levels falling below 20% of the initial value or <<0.25 ng/ml suggests that it is safe to discontinue antibiotics (if this also seems clinically reasonable).
complicated urinary tract infection & pyelonephritis: duration of antibiotics 
  • Definition of complicated urinary tract infection: factors that predispose to relapsing or persistent infection, such as:
    • Presence of foreign bodies (calculi or catheter).
    • Anatomic abnormalities (including kidney transplantation).
    • Obstruction.
    • Immunosuppression.
    • Renal failure.
    • Male anatomy.
    • Neurogenic bladder. (UVM Green Book)
  • 7 days of therapy is sufficient (even if there is gram-negative bacteremia; see the section below).
  • 5 days of therapy is probably adequate for uncomplicated pyelonephritis (but this is not an entity that will be encountered in the hospital).
gram-negative bacteremia: duration of antibiotics 

In general, enterobacteriaceae have a lower tendency to cause metastatic infection or endocarditis, as compared to gram-positive organisms such as Staphylococcus aureus. Therefore, shorter durations of antibiotic are sufficient. (35852791)

  • For uncomplicated gram-negative bacteremia, 7 days of therapy is sufficient (as demonstrated by three RCTs). (30535100, 34508886, 32484534)
  • Situations where seven-day therapy is generally appropriate include:
    • Urinary tract infection.
    • Pneumonia (either community or hospital acquired).
    • Intra-abdominal infection with source control.
  • Reasons to consider longer therapy might include: (37148398)
    • Endocarditis or endovascular infection, necrotizing fasciitis, osteomyelitis, CNS infection, empyema, abdominal pathology without definitive source control. (30535100)
    • Salmonella spp. or Brucella spp. (30535100)
    • Sustained bacteremia (repeated cultures separated by >24 hours). (30535100)
    • Persistent fever.
    • Metastatic infection.
    • Implanted prosthesis.
    • Prolonged neutropenia.
intravascular catheter infection

The following is a rough guide to treatment duration for uncomplicated infections. (32894389)

Staphylococcus aureus, Staphylococcus lugdunensis (SLUG), or Candida spp.

  • Line colonization (culture from line positive, but peripheral blood cultures negative): 3-5 days.
  • Line infection without remote complications: 14 days.
  • Line infection with remote complications: 4-6 weeks.

enterobacteriaceae, Enterococci, coagulase-negative Staphylococcus

  • Line colonization (culture from line positive, but peripheral blood cultures negative): There may be no need for antibiotics at all.
  • Line infection, without distant complications: 7 days.
  • Line infection with remote complications: 4-6 weeks.

Pseudomonas aeruginosa or Acinetobacter baumannii

  • Line colonization (culture from line positive, but peripheral blood cultures negative): 3-5 days.
  • Line infection, without distant complications: 7 days.
  • Line infection with distant complications: 4-6 weeks.
cellulitis: duration of antibiotics 
  • For nonpurulent cellulitis, a 5-6 day course of antibiotics active against streptococci is adequate. (33819054)
  • (Please note that MRSA coverage is generally unnecessary for nonpurulent cellulitis.)
neutropenic fever: duration of antibiotics 
  • Traditional regimen: Continue antibiotics until afebrile and clinically improved for three days and the neutrophil count has increased to >500.
  • Short-course regimen: Continue antibiotics until afebrile and clinically improved for three days (without requiring the recovery of neutrophil counts). (29153975, 35691326)
  • Realistically, these patients will generally be co-managed with infectious disease specialists. However, it's important to understand that antibiotics don't necessarily need to be continued for the duration of neutropenia (some patients may have persistent neutropenia for weeks).
intra-abdominal infection: duration of antibiotics 
  • Intra-abdominal infections are challenging, because this is a broad and somewhat heterogeneous group of infections. If definitive source control can be achieved, extended courses of antibiotics are probably unnecessary.
  • Ascending cholangitis: One RCT found no difference between 4 vs. 8 days of therapy. (37732816) This is consistent with a meta-analysis as well. (37274798) Once source control has been obtained (e.g., relief of obstruction of the biliary tree), there is probably no need for prolonged antibiotic therapy. 
  • Complicated intra-abdominal infection status post source control: The STOP-IT RCT found that four days of therapy was adequate. 🌊 (25992746)
  • Complex appendicitis status post appendectomy: Two RCTs found that a 1-2 day duration of therapy was sufficient. (36669519, 30308538) This is perhaps the clearest example that once definitive source control has been achieved, prolonged antibiotic therapy is unnecessary.
  • Postoperative intraabdominal infection: The DURAPOP trial found no difference between 8 versus 15 days of therapy. (29484469)

procalcitonin & CRP (C-reactive protein)

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basic biology of procalcitonin & CRP

  • Procalcitonin is an index of inflammation, which is especially sensitive to typical bacterial pathogens (especially gram negative bacilli). Procalcitonin is elevated most strongly by interleukin-1 beta, with additional inputs from tumor necrosis factor alpha and interleukin-6. Alternatively viral infections tend to elevate levels of interferon gamma, which inhibits the production of tumor necrosis alpha and thereby decreases the procalcitonin level. Procalcitonin is released from neuroendocrine cells in the lungs and intestines. (Schmidt 2024)
  • CRP elevates largely in response to interleukin 6, with additional inputs from interleukin-1 beta and tumor necrosis factor alpha. (19400486) CRP is produced mostly by hepatocytes and alveolar macrophages. (Schmidt 2024) Compared to procalcitonin, CRP is less specific for bacterial infection. Rather, CRP functions more as an index of systemic inflammation.

biomarkers are antibiotic-stopping tools

  • ⚠️ Biomarkers aren't validated as a trigger for making the initial diagnosis of sepsis, nor as a trigger for the initiation of antibiotics.
  • Biomarkers are validated as an antibiotic-stopping tool. RCTs have demonstrated that procalcitonin use reduces antibiotic exposure and might even decrease mortality. (31990655) Evidence supporting CRP is less robust, but some studies indicate that it may be used in the same manner as procalcitonin. (23921272, 36592205, 32487263)
limitations & comparisons between procalcitonin & CRP

causes of false-negative values

  • Procalcitonin:
    • Too soon: Procalcitonin may remain low early on during infection. Procalcitonin usually elevates within ~4 hours, peaking around 12-48 hours. (27283067)
    • Immunosuppression, including: (36592205)
      • Neutropenia.
      • Steroid (primarily at high doses).
    • Secondary infection (second hit). (36592205)
    • Localized or chronic infections that don't cause acute systemic inflammation. (30721141)
    • Atypical bacteria often don't elevate procalcitonin (e.g., mycoplasma pneumoniae).
  • CRP:
    • Too soon: CRP rises within ~6 hours of systemic inflammation, peaking ~36-50 hours later. (24286072, 36592205)
    • Fulminant hepatic failure: CRP is synthesized by the liver, causing it to be falsely low in fulminant hepatic failure (but not in patients with cirrhosis). (34544183)

causes of false-positive values

  • Procalcitonin:
    • Renal failure.
    • Some elevation can occur with fungal, viral infections.
    • Some rheumatologist disorders (e.g., Adult Still's disease, granulomatosis with polyangiitis).
    • Some cancers (e.g., small-cell lung cancer, medullary thyroid carcinoma).
    • Methamphetamine intoxication. (35104712)
    • Pancreatitis, ischemic bowel, surgery, trauma, burns.
    • Status post cardiac arrest.
  • CRP >100 mg/L may be caused by:
    • Infection (including bacterial, fungal, or viral infection).
    • Lupus flair (usually with vasculitis or serositis).
    • Serotonin syndrome.
    • Pancreatitis, severe trauma, burns, or cardiac surgery.
    • Silicone/fat embolization syndrome.
    • Status post cardiac arrest. (23313427, 19400486)

CRP vs. procalcitonin

  • In general, there is better support for the use of procalcitonin to limit antimicrobial use.
  • Situations where CRP has an advantage over procalcitonin:
    • (1) Renal failure.
    • (2) Immunosuppression (e.g., neutropenia).
    • (3) Procalcitonin is unavailable, or has a slow turnaround time.
general approach to using biomarkers

The most successful multicenter RCT involved measuring procalcitonin when starting antibiotics and then once daily, until after antibiotics are discontinued. (26947523) The following three triggers may be used to support a decision to stop antibiotics. (Of course, clinical judgement is always required.)

#1/3) The biomarker is low (at any point in time)

  • Low biomarker levels suggest that either an infection has been treated adequately, or it never existed in the first place.
  • CRP and procalcitonin take a day to fully elevate. If admission levels are low and there is a high suspicion for infection, it's generally wise to continue antibiotics and repeat the level the following day.
  • Procalcitonin interpretation: (30721141)
    • <0.5 ug/L suggests an absence of severe bacterial infection (e.g., septic shock).
    • <0.25 ug/L suggests an absence of moderate-severity bacterial infection (e.g., typical bacterial pneumonia).
  • CRP interpretation: <25-35 mg/L supports antibiotic discontinuation. (32487263, 23921272)

#2/3) The biomarker has fallen substantially

  • If the biomarker has fallen substantially, this implies that an infectious has been treated successfully.
  • Procalcitonin <20% of peak value supports antibiotic discontinuation. (36592205, 26947523, 30721141)
  • CRP: If the initial CRP level was >100 mg/L, then a decrease to <50% of the peak value supports antibiotic discontinuation. (36592205, 23921272) However, caution is required here, since this has a relatively weak evidentiary basis as compared to more robust data on procalcitonin. 

#3/3) End of the timed antibiotic course

  • If the patient finishes the standard length of their antibiotic course, antibiotics should generally be discontinued (even if biomarkers are still elevated).
  • Remember: biomarkers are intended as an antibiotic-stopping tool. If you would otherwise clinically discontinue antibiotics, then elevated biomarkers shouldn't dissuade you from doing that.
biomarkers in pneumonia

procalcitonin in pneumonia

  • Procalcitonin <0.25 ng/mL argues against a typical bacterial pneumonia.
  • ⚠️ However, procalcitonin is often not elevated among patients with atypical infections.(32127438) For patients with a negative procalcitonin it may be reasonable to discontinue beta-lactam antibiotics, but continue coverage for atypical pathogens (with azithromycin or doxycycline).

CRP in pneumonia

  • CRP <20 mg/L should prompt reconsideration of whether the patient actually has pneumonia. (26472401; 34544183, 19416992) Especially in a patient with critical illness due to pneumonia, the CRP would be expected to be substantially above 20 mg/L. 
  • CRP >150 mg/L indicates a high inflammatory response, which suggests greater utility of steroid. (25688779)
  • CRP >250 mg/L may raise suspicion for Legionella pneumonia. (12762360)
  • If CRP is markedly elevated and procalcitonin is normal, this suggests an inflammatory pneumonitis which isn't caused by typical bacterial pathogens (e.g., viral pneumonia, acute eosinophilic pneumonia, diffuse alveolar hemorrhage).

rational approach to treatment failure

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  • If a patient is failing antibiotic therapy, broadening coverage is usually not the answer.
  • Common causes of treatment failure include:
    • Wrong initial diagnosis.
    • Under-dosing of the antibiotic (e.g., due to augmented renal clearance).
    • Development of a new hospital-related problem (e.g. volume overload, superinfection at different site, drug fever).
    • Requirement for surgical/percutaneous drainage.
  • (Further discussion: see the section on pneumonia unresponsive to therapy here: 📖)

percent protein binding

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  • Protein binding refers to the percent of drug in the blood which is bound to albumin. Only unbound drug is active against bacteria.
  • Antibiotics with high levels of protein binding include:
    • Beta-lactams:
      • Cefazolin.
      • Nafcillin.
      • Ceftriaxone.
      • Ertapenem.
    • Clindamycin.
    • Daptomycin.
    • Doxycycline.
    • Rifampin.
    • Tigecycline.
  • Consequences of high protein binding:
    • Creates a reservoir of drug which is bound to albumin (which may extend the drug's half-life).
    • Reduces renal clearance (only free drug is cleared).
    • Reduces tissue penetration (only free drug is able to leave the bloodstream and penetrate tissues).
  • Effect of low albumin level on these medications: 
    • Increase in the volume of distribution (with increased distribution into the tissues).
    • Increase in the drug clearance.
    • ⚠️ Increased clearance and increased distribution into the tissues may cause treatment failure, especially for intravascular infections (e.g., endocarditis, bacteremia). This explains why ertapenem use in critically ill patients with low albumin levels (<2.5 g/dL) is associated with increased mortality.
  • Management of antimicrobial therapy in patients with low albumin levels?
    • [1] Consider increased dose and/or more frequent dosing (unfortunately there is little evidence to guide this).
    • [2] Consider choosing an antimicrobial agent with less protein binding (e.g., meropenem rather than ertapenem).
    • (Administration of albumin may not work, since exogenous albumin doesn't appear to have the same binding properties as naturally synthesized albumin). (15046641)

hydrophilic vs lipophilic antibiotics

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hydrophilic antibiotics 

general pharmacokinetic properties of hydrophilic antibiotics

  • Low volume of distribution (Vd).
  • Low intracellular penetration.
  • Many have high binding to albumin (e.g., ceftriaxone, cefazolin, ertapenem, and daptomycin). (26348420)

alteration of pharmacokinetics in the ICU

  • Increased volume of distribution (e.g., due to systemic inflammation).
  • Reduced interstitial penetration.
  • Antibiotics with high albumin-binding will be affected by hypoalbuminemia:

clinical utility

  • Hydrophilic antibiotics may be more likely to maintain an adequate drug level in the blood, allowing them to be effective for bacteremia.

hydrophilic antibiotics

  • Highly hydrophilic (volume of distribution <0.3 L/kg, corresponding with the extracellular fluid).
    • Aminoglycosides.
    • Beta-lactams (nearly all):
      • Penicillins.
      • Cephalosporins.
      • Carbapenems.
    • Daptomycin.
  • Moderately hydrophilic (volume of distribution is ~0.7-1 L/kg, corresponding to the extracellular and intracellular fluid volume).
    • Clindamycin.
    • Doxycycline.
    • Linezolid.
    • Metronidazole.
    • Rifampin.
    • Vancomycin.
lipophilic antibiotics

general pharmacokinetic properties of lipophilic antibiotics

  • High volume of distribution (Vd).
  • High intracellular penetration.

alteration of pharmacokinetics in the ICU

  • Volume of distribution remains stable.
  • Interstitial penetration remains stable.

clinical utility

  • Lipophilic antibiotics often have excellent tissue penetration, but this may come at the cost of reduced blood concentrations.

lipophilic antibiotics (Vd >1 L/kg)

  • Fluoroquinolones:
    • Levofloxacin (1 L/kg).
    • Ciprofloxacin (2-3 L/kg).
    • Moxifloxacin (1.7-2.7 L/kg).
  • Macrolides:
    • Azithromycin (30 L/kg).
    • Clarithromycin (3 L/kg).
  • Tigecycline (8 L/kg).
  • Trimethoprim (2 L/kg).

CSF penetration

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meningeal penetration

  • The pharmacokinetics of treating meningitis depends primarily on three factors:
    • 1) Serum drug level.
    • 2) What percent of the serum drug enters the meninges (greater if smaller molecular weight, more lipophilic, and less protein binding).
    • 3) How high a level is required to inhibit bacterial growth (minimum inhibitory concentration; MIC)
  • The section below shows the fraction of serum levels achieved in the meninges for different antibiotics. This is useful, but it's only one piece of the puzzle (#2 above). It's not intended to dictate which antibiotics may be used to treat meningitis, but rather to provide a general concept of relative CNS penetration.
  • For patients without CNS infection, having a low entry into the CNS may be desirable to avoid neurologic adverse events (the blood-brain barrier was designed for a reason!).

CSF penetration of different antibiotics (depending on whether the meninges are inflamed)

  • Aminoglycosides
    • Gentamicin: <1% uninflamed; 20% inflamed
    • Tobramycin: <1% uninflamed; 20% inflamed
    • Amikacin: 15% uninflamed; 20% inflamed
  • Aztreonam: 1% uninflamed; 40% inflamed.
  • Carbapenems:
    • Ertapenem 1% uninflamed; 5-20% inflamed.
    • Meropenem: 10% uninflamed; 15% inflamed (good penetration).
  • Cephalosporins
    • Cefazolin: 1% uninflamed; <10% inflamed (low penetration).
    • Ceftriaxone: 1% uninflamed; 10% inflamed (moderate penetration).
    • Cefepime: 1% uninflamed; 15% inflamed (moderate penetration).
    • Ceftaroline: <10% uninflamed; <10% inflamed.
  • Clindamycin: 1% uninflamed; <10% inflamed.
  • Daptomycin: 2% uninflamed; 5% inflamed.
  • Doxycycline: 25% uninflamed; 25% inflamed (moderate penetration).
  • Linezolid: ? uninflamed; 70% inflamed (excellent penetration).
  • Metronidazole: 30% uninflamed; 100% inflamed (good penetration).
  • Penicillins
    • Penicillin G: 1% uninflamed; 5% inflamed (moderate penetration)
    • Nafcillin: 1% uninflamed; 20% inflamed (moderate penetration).
    • Ampicillin & Ampicillin-Sulbactam: 1% uninflamed; 20% inflamed (moderate penetration).
    • Piperacillin-tazobactam: 1% uninflamed; 30% inflamed (regarded as poor penetration, not recommended for CNS infection).
  • Rifampin: 1% uninflamed; 10% inflamed.
  • Tigecycline: 1% uninflamed; 8% inflamed.
  • Trimethoprim-sulfamethoxazole: 10% uninflamed; 40% inflamed (good penetration).
  • Vancomycin: <1% uninflamed; 15% inflamed.

augmented renal clearance

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basics

  • Augmented Renal Clearance (ARC) refers to supranormal kidney function (GFR >130 ml/min/1.73 m2). This may result from hyperdynamic circulation in the context of physiological stress. ARC may also be known as “renal hyperfiltration.”
  • ARC leads to occult underdosing of renally cleared medications (especially antibiotics). The significance of antibiotic underdosing can be difficult to prove, because ARC also correlates with patients who have robust organ function reserves who tend to fare well regardless. (32055559)
epidemiology

ARC is relatively common, if this is rigorously sought out. One prospective study found that ARC may occur in most patients during their first week of critical illness. (24201175)

risk factors for ARC

  • Age <50 years.
  • Male sex.
  • Less profound illness (e.g., absence of multiorgan failure).
  • Renal parameters:
    • Absence of chronic renal insufficiency.
    • Absence of diabetes.
    • Absence of oliguria.
    • Low serum creatinine (<0.7 mg/dL or <62 uM).
  • Certain diseases:
    • Sepsis.
    • Burns.
    • Trauma.
    • Severe neurologic injury, especially:
      • Traumatic brain injury.
      • Subarachnoid hemorrhage.
      • CNS infections. (30723936)
diagnosis of ARC

🥇 directly measure GFR

  • Urine collection for 8 hours allows measurement of the actual creatinine clearance.
  • This is the most definitive approach to diagnose ARC. (Baptista 2023)

🥈 measurement of drug clearance

  • If you are using a renally-cleared medication with measurement of levels (e.g., vancomycin, aminoglycoside), it is possible to quantitatively measure drug clearance.
  • For example: if two vancomycin levels are known, these may be used to determine the effective glomerular filtration rate using pharmacokinetic formulas. 🌊
  • 💡 The most common “clinical presentation” of ARC is a patient whose vancomycin levels are extremely low.

🥉 GFR estimation using CKD-EPI formula

  • The fastest approach is usually to estimate the GFR using the CKD-EPI formula. This isn't perfect, but in many cases it may help rule-in or rule-out ARC. Attention should be paid to factors which may cause spurious increases or decreases in creatinine, some of which are listed below.
  • Using the CKD-EPI formula for creatinine 🧮 : (32552817)
    • GFR >87 ml/min/1.73m2 was 96% sensitive & 58% specific for ARC.
    • GFR >96.5 ml/min/1.73m2 was 86% sensitive & 71% specific for ARC.
    • GFR >125 ml/min/1.73m2 was 31% sensitive & 95% specific for ARC.
    • So:
      • GFR <85 ml/min: ARC is unlikely.
      • GFR >100-125: ARC is increasingly likely.
  • Consider causes of spuriously high creatinine:
    • Rhabdomyolysis, fenofibrate therapy.
    • Impaired secretion (e.g., trimethoprim, dronedarone, pyrimethamine, dapsone).
  • Consider causes of spuriously low creatinine:
    • Low muscle mass (cachexia, amputation).
management of ARC

Review the medication list, and consider the possibility that any renally-cleared medication may be underdosed. Aside from antibiotics, ARC may cause subtherapeutic dosing of other medications (especially enoxaparin and levetiracetam). (Baptista 2023)

if using a renally cleared antibiotic:

  • Use the maximal approved dosage. (32659898)
  • Monitor drug levels, if possible (e.g., vancomycin).
  • Administer doses in a prolonged infusion (for antibiotics with time-dependent pharmacodynamics 📖, such as beta-lactams).

consider switching to an antibiotic less dependent on renal clearance:

  • Beta-lactams:
  • Atypical coverage:
  • Anaerobic coverage:
  • Linezolid. 📖
  • (Other less useful agents: tigecycline, rifampin, moxifloxacin.)

renal replacement therapy

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medications unaffected by RRT

  • Medications that aren't cleared by the kidneys aren't affected by RRT.
  • This is the same list of medications that aren't affected by augmented renal clearance (see the section above).

factors affecting drug clearance by RRT

  • Molecular size:
    • Larger molecular weight: less affected by RRT.
  • Protein binding:
    • High protein binding (>80%): less affected by RRT since free drug levels are relatively lower. (31342772)
    • Hypoalbuminemia may increase free drug concentration and RRT clearance.
  • Vd (volume of distribution):
    • Larger volume of distribution (>1 L/kg): less affected by RRT since these agents distribute into the tissues. (31342772)
  • Residual renal function:
    • During renal recovery, drug may be cleared by RRT and native kidneys.
    • ⚠️ Guides to drug dosing in RRT generally assume a lack of endogenous kidney function.
  • Non-renal drug clearance:
    • Hepatic clearance: less affected by RRT.

IHD

  • Following IHD: Drug levels may be low, but can subsequently rebound several hours later as drug redistributes out of the tissues. (31342772)

CRRT

  • Effluent rate is roughly equivalent to the clearance rate (GFR).
  • CRRT dosing of commonly utilized medications discussed above:
  • U. Nebraska CRRT dosing guide here: 📄

antibiotic dosing in obesity

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definition of obesity

  • Obesity: BMI >30.
    • Class I: BMI 30-34.
    • Class II: BMI 35-39.
    • Class III: BMI >40 (aka severe obesity).

different weight metrics

  • Ideal body weight (IBW):
    • Estimates of fat-free mass based on height and gender.
    • Doesn't take into account actual body weight.
    • Will fail in the context of obesity.
  • Adjusted body weight:
    • Estimate of fat-free mass based on gender, height, and actual weight.
    • Adjusted wt = IBW + 0.4 (total weight – ideal weight).
  • Lean body weight:
    • Formula estimates fat-free mass.
    • LBW male in kg = [9270 × actual body weight in kg]/[6680 + (216 × BMI)]
    • LBW female in kg = [9270 × actual body weight in kg]/[8780 + (244 × BMI)]
    • May be most accurate assessment of volume of distribution for aminoglycosides. (21670189)

problems with estimated GFR

  • CKD-EPI formulas for estimation of GFR don't take weight into account.
    • Obesity: CKD-EPI will underestimate the GFR. This may promote underdosing of antibiotics in the context of morbid obesity.
    • Malnutrition, cirrhosis: CKD-EPI will overestimate the GFR.
  • Using the Crockoft-Gault equation 🧮 with an adjusted body weight 🧮 might be the most accurate way to evaluate GFR in the context of morbid obesity. (22576791)

oral bioavailability

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Oral bioavailability isn't generally a major consideration in the ICU. However, this may become relevant in some situations (e.g., limited IV access, volume overload).

agents with very high bioavailability (>~90%, allowing 1:1 conversion)

  • Cephalexin.
  • Clindamycin (but oral administration may increase risk of C. difficile). 📖
  • Doxycycline. 📖
  • Fluoroquinolones. 📖
  • Linezolid. 📖
  • Metronidazole. 📖
  • Nitrofurantoin. 📖
  • Rifampin. 📖
  • Trimethoprim-sulfamethoxazole. 📖

agents with reliable absorption

  • Amoxicillin.
  • Amoxicillin-clavulanate.

pharmacodynamics

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Antibiotics vary in the pharmacodynamic parameters required to achieve successful infection control. Roughly three groups may be distinguished:

concentration-dependent

  • The key parameter is (maximal concentration)/MIC.
  • These agents can often be dosed less frequently (e.g., once daily).
  • Agents in this group: (26348420)
    • Metronidazole.
    • Daptomycin.
    • Aminoglycosides are often included here, although they're probably best characterized as concentration-dependent with time dependence (section below).

concentration-dependent with time-dependence

  • The key parameter is the integrated concentration over time (AUC) compared to the MIC.
  • These agents can often be dosed less frequently (e.g., once daily).
  • Agents in this group: (26348420)
    • Aminoglycosides.
    • Fluoroquinolones.
    • Azithromycin.
    • Tetracyclines.
    • Vancomycin.
    • Linezolid.
    • Tigecycline.

time-dependent

  • The key parameter is the duration of time spent with a concentration over the MIC.
  • These agents are ideally dosed as a continuous infusion, or in frequent divided doses.
  • Agents in this group: (26348420)
    • Beta-lactams.
    • Carbapenem.
    • Clarithromycin.
    • Clindamycin.

(note: bactericidal vs. bacteriostatic doesn't matter)

  • An antibiotic which is bactericidal kills bacteria, whereas an antibiotic which is bacteriostatic stops bacteria from dividing.
  • Traditionally it was believed that cidality was desirable for severe infections. However, cidality may actually be dangerous if this leads to rapid lysis of bacteria leading to a huge release of bacterial products (e.g. endotoxin) causing uncontrolled inflammation.
    • For example: Antibiotics which inhibit protein synthesis (e.g. clindamycin and linezolid) cause immediate cessation of toxin secretion in patients with toxic shock. They are used specifically for this reason – to shut down toxin synthesis (rather than necessarily immediately destroying all the bacteria).
  • The concept that bactericidal antibiotics are superior is based on a petri-dish model of infectious disease, wherein the antibiotic is relied upon to kill the bacteria. However, this model isn't very accurate – in vivo, the antibiotic is just assisting the patient's immune system in containing the infection.
    • Severe neutropenia is one situation where the petri-dish model may actually be accurate, so cidal antibiotics might be desirable in that context.
  • Overall, the focus on cidality is probably misplaced. In some situations this may be important, but other factors may be equally if not more important (e.g. tissue penetration, pharmacokinetics). Just because an antibiotic is bacteriostatic doesn't mean that it's not extremely effective.
    • A recent analysis of over fifty RCTs found no benefit of cidal antibiotics compared to static antibiotics, so the clinical superiority of cidal antibiotics may be mostly mythological. (29293890)

blood culture

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approach to 1 set of positive cultures showing GPC (gram-positive cocci)

basic definitions: sets vs bottles

  • One set of cultures = two bottles drawn from a single site (one bottle is sent for anaerobic culture, the other bottle is sent for aerobic culture).
  • Patients will usually have two sets of blood cultures drawn from different sites. The purpose obtaining two sets of cultures is to sort out whether a positive culture represents contamination:
    • 1 of 2 sets positive: often reflects contamination.
    • 2 of 2 sets positive: implies true infection.

if 1 set turns positive

  • This will usually represent contamination.
  • Factors suggesting true infection:
    • If the culture grows within <24 hours.
    • Patient has clinical features of infection.
    • Patient has indwelling intravascular hardware (e.g., central line).
    • Gram positive cocci in chains.
  • Clinical judgement is needed to determine next steps. Importantly, a single blood culture doesn't necessarily mandate initiation of antibiotics.
  • Potential management steps could include:
    • Careful observation:
      • If the first culture is real, the second set will often turn positive shortly thereafter.
      • If the Verigene PCR result is pending in a few hours, this can rapidly clarify next steps.
    • Obtaining additional cultures.
    • Initiation of antibiotic (e.g., for patients with signs/symptoms of sepsis).
low-virulence vs. high-virulence organisms

low-virulence skin organisms (often contaminants)

  • These include the following:
    • Coagulase negative staphylococci (not including Staph. lugdunensis).
    • Corynebacterium spp.
    • Bacillus spp.
    • Malassezia furfur
    • Micrococcus spp.
    • Cutibacterium spp. (previously: Propionibacterium spp.).
  • A single culture of these organisms frequently reflects colonization. However, in the presence of indwelling hardware (such as a central line), there may be a greater likelihood of infection.

high-virulence organisms (unlikely to be contaminant)

  • Even a single culture of these organisms should be taken seriously (and initially assumed to represent infection).
  • These organisms include the following:
    • Staph aureus.
    • Staph. lugdunensis.
    • Enterococcus spp.
    • Gram negative bacilli.
    • Candida spp., fungi, and molds.

related topics

  • Differential time to positivity for culture of line infection: 📖
  • Likelihood that various organisms reflect endocarditis: 📖
Verigene multiplex PCR assay

This test allows for rapid detection of various bacterial species and common resistance genes (further discussion here: 🌊).

gram positive organism targets

  • Species:
    • Staph. aureus
    • Staph. epidermidis.
    • Staph. lugdunensis.
    • Staph. pneumoniae.
    • Streptococcus pyogenes (GAS).
    • Streptococcus agalactiae (GBS).
    • Streptococcus anginosus.
    • Enterococcus faecalis.
    • Enterococcus faecium.
    • Listeria spp.
  • Resistance genes:
    • MEC-A (MRSA).
    • VAN-A and VAN-B genes (VRE).

gram negative organism targets

  • Species:
    • Acinetobacter spp.
    • Citrobacter spp.
    • Enterobacter spp.
    • Proteus spp.
    • Escherichia coli.
    • Klebsiella pneumoniae.
    • Klebsiella oxytoca.
    • Pseudomonas aeruginosa.
  • Resistance genes:
    • CTX-M (marker of ESBL organisms).
    • IMP, KPC, NDM, OXA, VIM (markers for different carbapenemases).

gram stain interpretation

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Gram-staining morphology cannot definitively identify the bacterial species, but it may provide some useful clues. Below are lists of the most common types of bacteria that cause various morphologies on Gram-staining. 

gram-positive species

gram-positive cocci (GPCs)

  • Clusters:
    • Staphylococcus aureus.
    • Coagulase-negative Staphylococcus (e.g., Staphylococcus epidermidis).
    • (Less likely: Micrococcus, Pediococcus, Aerococcus, Stomatococcus.)
  • Pairs:
    • Streptococcus pneumoniae (although this may also cause short chains).
  • Pairs / chains:
    • Streptococci:
      • Streptococcus pyogenes (group A Streptococcus).
      • Streptococcus agalactiae (group B Streptococcus).
      • Groups C, F, G streptococci.
      • Streptococcus viridans.
      • Streptococcus pneumoniae.
    • Enterococci.
    • Anaerobes:
      • More likely: Peptostreptococcus, Peptococcus.
      • Rarely: Leuconostoc, Abiotrophia, Granulicatella, Gemella, Finegoldia.

gram-positive bacilli (rods)

  • Small (e.g., coccobacilli) or medium size:
    • Listeria morphology is variable (but suggested by small gram-positive coccobacilli).
    • Coryneform (“diphtheroid”) – pleomorphic or club-shaped and arranged in parallel formations that may resemble Chinese letters:
      • Corynebacterium spp. (including C. jeikeium, C. diphtheriae).
      • Cutibacterium (formerly Propionibacterium).
      • Listeria.
    • Gardnerella.
    • Lactobacillus.
    • Bifidobacterium.
    • Eubacterium.
    • Rhodococcus (weakly acid fast).
  • Large, boxcar shaped:
    • Clostridium spp. (anaerobic).
    • Bacillus anthrax (aerobic).
  • Branching:
    • Nocardia spp. (aerobic).
    • Actinomyces spp. (anaerobic).
    • Streptomyces and Cutibacterium may also be possible.
    • (See: Nocardia vs. Actinomyces 📖)
gram-negative species

gram-negative cocci

  • Neisseria spp. are typically in pairs (diplococci):
    • Neisseria meningitidis.
    • Neisseria gonorrhoeae.
  • Moraxella catarrhalis.
  • Acinetobacter spp. may have this appearance.
  • Anaerobic Veillonella spp.

gram-negative coccobacilli

  • Haemophilus influenzae.
  • Moraxella catarrhalis.
  • Bordetella pertussis.
  • Yersinia pestis.
  • Tularemia.
  • Ehrlichiosis.
  • Anaplasmosis.
  • Pasteurella spp.
  • Brucella spp.

gram-negative bacilli (rods)

  • Lactose fermenting:
    • Oxidase positive:
      • Aeromonas.
      • Pasteurella multocida.
      • Capnocytophaga canimorsus.
      • Vibrio.
    • Oxidase negative:
      • E. coli.
      • Klebsiella.
      • Enterobacter.
      • Citrobacter.
  • Non-lactose fermenting:
    • Oxidase positive:
      • Pseudomonas.
      • Moraxella.
    • Oxidase negative:
      • Proteus.
      • Serratia.
      • Acinetobacter (although occasionally this may also appear as gram positive).
      • Stenotrophomonas.
      • Morganella.
      • Salmonella.
      • Shigella
  • Anaerobes include:
    • Bacteroides.
    • Prevotella.
    • Porphyromonas.
    • Fusobacterium.

MRSA nares PCR

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  • In community-acquired pneumonia: MRSA nares PCR can be reliably used to guide empiric and targeted antibiotic therapy, with a negative predictive value of 96-99%. (32127438, 32101906)
  • In ventilator-associated pneumonia: MRSA coverage isn't necessary in patients with a negative nares PCR.(33004324, 29340593)
    • Nares PCR is only ~70% sensitive for MRSA, so this doesn't entirely exclude the diagnosis of MRSA pneumonia. However, for patients at an average risk of MRSA (e.g., ~5% likelihood), a negative nares PCR reduces the likelihood of MRSA to <2%. At this level, the risk of antibiotic toxicity likely overshadows the benefits of antibiotic therapy.
    • In ICUs with extraordinarily high rates of MRSA, MRSA coverage may be considered even among patients with a negative nares PCR.

sputum gram stain

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sputum quality

  • A high-quality sputum sample should have >25 leukocytes and <10 squamous cells per low-power field. (Murray 2022) >10 squamous epithelial cells per low-power field indicates excessive oropharyngeal contamination, so the specimen should be discarded.
  • If a good-quality sputum culture reveals a single dominant morphology of bacteria on gram stain, that is strong evidence regarding the etiology of pneumonia.
  • If numerous different morphologies of bacteria are seen in similar amounts, then the sputum gram stain is often meaningless (reflective of normal flora).

sensitivity of sputum culture for different organisms

  • Streptococcus pneumoniae or Haemophilus influenzae are fastidious organisms that are difficult to grow. Consequently, sputum culture is often negative.
  • Staphylococcus aureus and gram-negatives tend to grow exuberantly, even if they merely represent colonization. If sputum culture is positive for Staphylococcus aureus or a gram-negative organism but this isn't seen in a high-quality sputum sample, it's dubious whether the sputum culture truly reflects pneumonia.(Murray 2022)

urinalysis & urine culture

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Overall, urinalysis is generally sensitive but nonspecific. Abnormal urinalysis is common among healthy elderly patients due to colonization with bacteria (asymptomatic bacteriuria).

pyuria (WBCs)

  • Definition of pyuria?
    • Pyuria is generally defined as >10 WBC per high-power field. (31532742) This cutoff is used to define urinary tract infection by the FDA and EMA (the European FDA). (37426954)
    • However, studies have used cutoffs varying between ~5-25 WBC per high-power field. (10724053, 35580716)
  • Diagnostic performance?
    • Sensitivity is very high (unless the patient is neutropenic or urinary obstruction is present). Consequently, absence of pyuria largely excludes urosepsis.
    • Specificity is poor (pyuria may occur in the context of asymptomatic bactiuria).

leukocyte esterase

  • Leukocyte esterase functions as a surrogate marker for pyuria.
  • Causes of false-negatives include:
    • Neutropenia or urinary obstruction (similar to pyuria).
    • Nitrofurantoin administration.
  • Causes of false-positives include: asymptomatic bacteriuria.

squamous cells

  • May indicate contamination of the specimen.

urine nitrites

  • Nitrites are generated by gram-negative enteric pathogens (Enterobacteriaceae), but not gram-positives.(29135902, 10923955)
    • In urinary tract infection with Pseudomonas or gram-positives (enterococcus, S. saprophyticus), nitrites are detected only rarely (~5% of cases). (31563203)
    • In urinary tract infection with gram-negative Enterobacteriaceae, nitrites are commonly detected albeit with low sensitivity (~40% of cases).
  • False-positive nitrites may result from the use of phenazopyridine (an over-the-counter urinary analgesic). (37906240)
  • Interpretation of urine nitrites in the context of known urosepsis:
    • Positive nitrites has a likelihood ratio for gram-negative infection of ~8.
    • Negative nitrites has a likelihood ratio for gram-negative infection of ~0.6 (this provides little useful information). Nitrite generation requires urine incubation with bacteria for roughly 4 hours, so nitrite may be falsely negative if urine is collected <4 hours after the last urination.
    • Given that the prevalence of gram-negative infection is ~95% to begin with, a positive urinary nitrite result results in post-test probability of gram-negative infection >99%. This might be useful in determining the necessity of covering for gram-positive pathogens, if a urinary gram stain isn't available.

pH

  • pH >8 may suggest urease-producing organisms (classically Proteus spp., but also a variety of organisms including Providencia spp., Pseudomonas spp., Klebsiella spp., Ureaplasma urealyticum, or Staphylococcus saprophyticus).
  • Ammonia generation with increases in pH may favor the production of “triple-phosphate” crystals – struvite and apatate.

urine culture

  • >100,000 CFU/ml (10^5) of a single relevant uropathogen is generally regarded as positive. This cutoff is used to define urinary tract infection by the FDA and EMA (the European FDA). (37426954) However, there is some variability in this cutoff across studies (ranging from >1,000 CFU/ml to >100,000 CFU/ml). (37426954)
  • Polymicrobial bacteriuria may suggest: chronic catheterization, enterovesical fistula, or complicated infection associated with obstruction or foreign bodies. (Irwin 2024)

(urine gram stain)

  • A few hospitals may be able to perform STAT gram stains on urine.
  • This may be helpful if the test is available.
    • Gram-positive detected: May tailor therapy to focus on enterococcus and Group B streptococci.
    • Gram-negative detected: Focus on gram-negative coverage.

questions & discussion

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To keep this page small and fast, questions & discussion about this post can be found on another page here.

Guide to emoji hyperlinks 🔗

  • 🧮 = Link to online calculator.
  • 💊 = Link to Medscape monograph about a drug.
  • 💉 = Link to IBCC section about a drug.
  • 📖 = Link to IBCC section covering that topic.
  • 🌊 = Link to FOAMed site with related information.
  • 🎥 = Link to supplemental media.
  • 📸 = Link to image (will open in a different browser window).

References

  • Moved to keep this chapter fast: find them here.

Cite this post as:

Josh Farkas. Antibiotics. EMCrit Blog. Published on November 24, 2023. Accessed on December 10th 2025. Available at [https://cmefix.emcrit.org/ibcc/antibiotics/ ].

Financial Disclosures:

The course director, Dr. Scott D. Weingart MD FCCM, reports no relevant financial relationships with ineligible companies. This episode’s speaker(s) report no relevant financial relationships with ineligible companies unless listed above.

CME Review

Original Release: November 24, 2023
Date of Most Recent Review: Jul 1, 2024
Termination Date: Jul 1, 2027

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The Internet Book of Critical Care is an online textbook written by Josh Farkas (@PulmCrit), an associate professor of Pulmonary and Critical Care Medicine at the University of Vermont.


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