CONTENTS
commonly used antibiotics
- Aminoglycosides
- Ampicillin & Ampicillin-Sulbactam
- Aztreonam
- Carbapenems (meropenem & ertapenem)
- Cephalosporins
- Clindamycin
- Daptomycin
- Doxycycline
- Fluoroquinolones
- Linezolid
- Macrolides (Azithromycin, Clarithromycin)
- Metronidazole
- Nafcillin
- Nitrofurantoin
- Penicillin G
- Piperacillin-Tazobactam
- Rifampin
- Tigecycline
- Trimethoprim-Sulfamethoxazole
- Vancomycin
specific pathogens
- Antibiogram & 1st line agents by species
- AmpC inducible beta-lactamase
- Extended-spectrum beta-lactamases (ESBL)
specific clinical scenarios
- MSSA therapy: nafcillin vs. cefazolin vs ceftriaxone
- Drug-resistant gram positive cocci: vancomycin vs. linezolid vs. daptomycin vs. ceftaroline
- Piperacillin-tazobactam vs. cefepime
- Doxycycline vs. azithromycin
- Antibiotic use in pregnancy
antimicrobial stewardship
- 1) Rational initiation of antibiotics
- 2) De-escalation antibiotics
- 3) Limiting duration of therapy
- Biomarkers (procalcitonin & CRP)
- Rational approach to treatment failure
pharmacokinetics & pharmacodynamics
- Percent protein bound
- Hydrophilic vs. lipophilic antibiotics
- CSF penetration
- Augmented Renal Clearance (ARC)
- Oral bioavailability
- Pharmacodynamics
conclusions
aminoglycoside dosing
- Gentamicin synergy for endocarditis:
- Once-daily dosing is safer and recommended in 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)
- Traditional dosing: 1 mg/kg q8hr (target 1-hr peak of 3 ug/ml, and trough <1 ug/ml). (26373316, 26320109)
- Once-daily dosing is safer and recommended in European Society of Cardiology guidelines:
- General dosing strategy is shown here: 📸.
- In morbid obesity, consider using an adjusted body weight (Adjusted Body Wt = 0.6(ideal body wt)+0.4(actual body wt)).
pharmacology
- 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 (brain, bile, prostate, meninges).
- Excellent renal penetration.
agents
- Gentamicin: Best gram-positive coverage.
- Tobramycin: Workhorse aminoglycoside, good gram-negative coverage.
- Amikacin: Best gram-negative coverage (often reserved for resistant pseudomonas).
spectrum
- Gram-positives:
- Covers MSSA and Enterococcus faecalis.
- Misses Staph. saprophyticus.
- Gram-negatives:
- Excellent coverage of Enterobacteriaceae and Pseudomonas.
- Local antibiogram: 📸
use
- Gentamicin is used for synergy against Enterococcus faecalis endocarditis, with other agents (at reduced dose of 1 mg/kg q8hr).
- Gram negative bacteremia with refractory shock.
- Urinary tract infection.
toxicity/contraindications
- Nephrotoxicity, ototoxicity.
- Neuromuscular blockade (may be an issue in severe hypocalcemia or myasthenia gravis; occasionally may cause flaccid paralysis).
ampicillin dosing
- Ampicillin
- Ampicillin-Sulbactam
pharmacology
- Excretion: 90% excreted in urine unchanged.
- Protein binding: 25%
- Vd: 0.25 L/kg
- Penetration: Widely distributed (e.g. urine, pleural fluid, lung), including inflamed meninges.
spectrum
- Ampicillin:
- Gram-positives:
- Enterococcus (~80% of E. faecalis, but only rarely covers E faecium).
- Most Streptococci.
- Most Streptococcus pneumoniae.
- Misses Staphylococcus saprophyticus. (31608743)
- Gram-negatives:
- Some E. Coli.
- Proteus mirabilis.
- Anaerobes: Similar anaerobic coverage compared to penicillin-G. This includes most Clostridium spp (not C. difficile) and oral anaerobes.
- Listeria monocytogenes.
- Gram-positives:
- 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).
- Gram-positives:
- Local antibiogram: 📸
use
- Ampicillin may be the drug of choice for:
- Enterococcus faecalis.
- Listeria monocytogenes.
- Sensitive strains of E. Coli or Proteus mirabilis.
- Ampicillin-Sulbactam:
- 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.
toxicity/contraindications
- Ampicillin:
- 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.
aztreonam dosing
- 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.
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 use in patient 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).
- Reasonable choice for patient found to have gram-negative bacteremia.
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.
carbapenem dosing
- Meropenem:
- GFR >50: 1-2 grams q8 (higher end for pseudomonas, meningitis, cystic fibrosis, or morbid obesity). (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)
- Ertapenem:
- 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.
carbapenem pharmacology
- Meropenem:
- Excreted unchanged in the urine (70%).
- Protein binding 2% (promoting wide distribution into tissues).
- Volume of distribution 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).
- Volume of distribution 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, Staph. saprophyticus).
- Misses MRSA and Enterococcus faecium.
- Gram-negative coverage:
- Overall excellent (including Pseudomonas, ESBL and AmpC multidrug resistant species).
- Some carbapenem resistance is starting to emerge among enterobacteriaceae (especially among Klebsiella pneumoniae); this varies widely depending on geography.
- Anaerobic coverage: Excellent (but doesn't cover C. difficile).
- Local antibiogram: 📸
spectrum: ertapenem
- Main differences compared to meropenem:
- 1) Lacks coverage of pseudomonas and acinetobacter.
- 2) Limited activity against enterococci.
- May be superior for non-pseudomonas gram-negatives (due to broad use of meropenem and development of meropenem resistance).
- Local antibiogram: 📸
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:
- Patient with 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)
- 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.
cefazolin dosing
- GFR >50 ml/min: 1-2 grams IV q8.
- 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.
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 which are sensitive to oxacillin.
- Gram-negatives
- Usually effective for E. coli, Klebsiella pneumoniae, and Proteus mirabilis.
- Not generally adequate for empiric therapy against gram-negative infections, but may be used as step-down therapy once sensitivities available.
- Local antibiogram: 📸
use
- Empiric coverage before culture 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, which 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
ceftriaxone dosing
- 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. (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.
- There is no good evidence that 2 grams/day increases the risk of medication side effects as compared to 1 gram/day.
- Overall a default strategy of dosing 2 grams/day could be optimal for most critically ill patients.
- Indications to consider 2 grams q24:
- 2 grams q12:
- No renal adjustment.
- Obesity: At least 2 grams IV daily, but higher doses could be considered with severe obesity.
pharmacology
- Roughly 50% is excreted unchanged by kidneys, with remainder excreted unchanged by liver. In renal failure, the liver picks up the slack so no dose adjustment 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).
- Volume of distribution 0.2 L/kg.
- Good tissue penetration, including CNS (although higher doses needed to penetrate meninges).
spectrum: ceftriaxone covers:
- Gram-positives:
- 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).
- 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.📖
- Local antibiogram: 📸
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 gallbladder causing pseudo-biliary lithiasis).
- Hepatitis.
- Neutropenia, thrombocytopenia.
- Drug rash, anaphylaxis.
- Delirium.
ceftazidime dosing
- 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 q12.
- GFR <10 ml/min: 0.5-1 gram IV q24.
pharmacology
- Widely distributed with good penetration, including CNS.
- 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. 📖
- Local antibiogram: 📸
ceftazidime is almost never the best antibiotic choice
- Cefepime is usually a better choice:
- a) Cefepime has better activity against gram-negatives, including species with inducible AmpC beta-lactamases. 📖
- b) 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)
- c) 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.
cefepime dosing
- GFR >50 ml/min: 2 grams q8-12 hours:
- 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.
pharmacology
- Excretion: 85% excreted unchanged in urine
- Protein binding: 20%
- 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 📖).
- Haemophilus influenzae.
- Neisseria meningitidis.
- Local antibiogram: 📸
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)
- Causes more C. difficile than piperacillin-tazobactam. (24140078, 14963072)
ceftaroline dosing
- GFR >50 ml/min:
- GFR 30-50 ml/min: 400 mg q8-q12hr
- GFR 15-30 ml/min: 300-400 mg q12hr
- ESRD/HD: 200-300 mg q12hr
- Morbid obesity: no dose adjustment
pharmacology
- Excretion: 64% excreted unchanged in urine
- Protein binding: 20%
- Vd: ~0.3 L/kg.
- Penetration: Widely distributed, but only 10% CNS penetration.
spectrum
- Gram-positives: Covers MSSA, MRSA, coagulase-negative Staph., Streptococcus pneumoniae, non-enterococcal streptococci, Enterococcus faecalis.
- Gram-negatives:
- Coverage is similar to ceftriaxone.
- Misses pseudomonas and ESBL species.
- Ceftaroline is hydrolyzed by AmpC beta-lactamases.
use
- Skin/soft tissue infection.
- Pneumonia.
- Endocarditis, bacteremia:
- Empiric antibiotic regimens designed to cover MRSA.
- Additional discussion: 🥊 Drug-resistant gram positive cocci: vancomycin vs. linezolid vs. daptomycin vs. ceftaroline
toxicity/contraindications
- Nausea, diarrhea.
- Rash.
- Neutropenia (more problematic with longer courses). (28702467)
- Clostridioides difficile colitis.
- Seizure.
clindamycin dosing
- 900 mg IV q8hr.
- Generally no dose adjustment for hepatic or renal dysfunction.
- Consider reduction in combined kidney & hepatic dysfunction.
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:
- Streptococcus pneumoniae
- Non-enterococcal streptococci.
- Staphylococcus aureus (some MSSA and some MRSA).
- Anaerobic coverage is good, although increasing resistance 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.
- Local antibiogram: 📸
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.
- Rashes, fever, anaphylaxis, erythema multiforme.
- May block neuromuscular transmission, contraindicated in myasthenia gravis.
daptomycin dosing
- 4-6 mg/kg IV daily: Skin/soft tissue infections.
- 8-10 mg/kg IV daily: Bacteremia.
- 10 mg/kg IV daily: Staphylococcal endocarditis. (26373316, 26320109)
- 10-12 mg/kg IV daily: Enterococcal endocarditis. (26373316, 26320109)
- For renal insufficiency (GFR <30), increase interval to q48.
- Morbid obesity: use actual body weight. (17548489)
- 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 and vancomycin-resistant enterococci).
- Emergence of daptomycin resistance may occur while treating Staph aureus (especially if previously treated with vancomycin or large burden of bacteria).
- Local antibiogram: 📸
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.
- Monitor creatinine kinase weekly. 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.
doxycycline dosing
- 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 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)
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.
- Local antibiogram: 📸
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.
toxicity/contraindications
- Generally well tolerated (appears to reduce the risk of Clostridioides difficile). (22563022, 18171186, 27025622, 28819873, 37921728)
- 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.
- Pancreatitis reported in a few case reports. (28912911)
- Stevens-Johnson syndrome.
fluoroquinolone dosing
- Ciprofloxacin:
- 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.
- Levofloxacin:
- 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.
- Moxifloxacin: 400 mg q24 hours (regardless of route or renal function). Not recommended in severe hepatic dysfunction.
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, 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.)
- Gram positive:
- Streptococcus pneumoniae is covered by levofloxacin or moxifloxacin.
- 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).
- Local antibiogram: 📸
⚠️ 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 possibly aortic aneurysm. Consequently, the FDA has recommended avoidance of fluoroquinolones when possible in a black box warning.
- (6) Fluoroquinolones add very little to beta-lactam antibiotics when used for double-coverage of pseudomonas:
when to use a fluoroquinolone:
- Common situations when a fluoroquinolone would be utilized:
- 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 dosing
- 600 mg IV/PO q12hr (no adjustment for renal dysfunction; same dose provides meningeal coverage).
- Morbid obesity and severe infection, or co-administration with rifampin: consider 600 mg IV/PO q8hr.
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, vancomycin-resistant enterococci, streptococcal species, coagulase-negative staphylococci).
- Listeria.
- Local antibiogram: 📸
use
- Pneumonia: Arguably front-line agent for MRSA pneumonia. (22247123, 25355172, 25066668, 27208687, 24238896, 26382940, 24916853, 24420846, 23568605, 21163725, 18719064) Will also work for other gram-positive pneumonia (e.g. MSSA, Streptococcus pneumoniae).
- 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 definite or suspected 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)
- 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 which 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: Posterior reversible leukoencephalopathy (PRES), seizures, hypoglycemia.
- Note: protective against Clostridioides difficile. (22445203, 21504940)
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 methicillin-sensitive staph aureus.
- Some Group A/B/C/D/G streptococci.
- Some Streptococcus pneumoniae.
- Haemophilus influenzae and Moraxella catarrhalis (azithromycin > clarithromycin).
- Atypical organisms:
- Bordetella pertussis.
- Chlamydia pneumoniae.
- Coxiella burnetii.
- Mycoplasma pneumoniae.
- Legionella pneumophila.
- Local antibiogram: 📸
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.
- COPD exacerbation (although doxycycline may be preferable for patients recently on azithromycin).
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 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)
- Consider 50% dose reduction in Child-Pugh class C cirrhosis.
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
- Can cause encephalopathy, seizure, peripheral neuropathy, or aseptic meningitis (especially with prolonged use). (27504340) More on metronidazole induced encephalopathy here: 📖
- Rarely: Stevens-Johnson syndrome, pancreatitis, hemolytic uremic syndrome, drug fever.
nafcillin dosing
- Serious infections (e.g., endocarditis): 2 grams IV q4hr. (26373316, 26320109)
- Dose reduce by 50% in decompensated liver failure. No adjustments for renal dysfunction.
- Monitor liver function tests every week
pharmacology
- Excretion: Mostly cleared by the liver and biliary tract. 10-30% unchanged drug is excreted in the urine.
- Protein binding: 90%
- Vd: 0.2 L/kg
- Penetration: Distributes widely, including inflamed meninges (20% serum levels).
- Mechanism: Inhibits cell wall synthesis by binding to penicillin-binding proteins (primarily 1a, 1b, and 2).
spectrum
- Streptococci groups A, B.
- Pneumococci (penicillin-sensitive).
- Methicillin-sensitive staph aureus (MSSA) & methicillin-sensitive staph epidermidis.
- Local antibiogram: 📸
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)
- Synergistic en vitro with either vancomycin or daptomycin against staph aureus (clinical relevance to be determined). (22848719)
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 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)
- Local antibiogram: 📸
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.
penicillin G dosing
- GFR > 50 ml/min: 2-4 million units (MU) q4
- GFR 10-50 ml/min: 1-2 MU q4
- GFR <10 ml/min: 1-2 MU q6
pharmacology
- Excretion: 80% excreted unchanged in the urine.
- Protein binding: 60%
- Vd: 0.3 L/kg
- Penetration: most fluids and tissues, including inflamed meninges.
spectrum
- Gram positives:
- Group A, B, C, G streptococci are susceptible
- Streptococcus pneumoniae: generally susceptible for non-meningeal infections
- 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.
- 3) Neisseria meningitidis
- 4) Clostridia perfringens
toxicity/contraindications
- 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)
piperacillin-tazobactam dosing
- GFR >20 ml/min: 4.5g q8hr (extended infusion over four hours).
- GFR <20 ml/min: 4.5g q12hr (extended infusion over four hours).
- Augmented renal clearance: consider 4.5g q6hr. (Baptista 2023)
- Morbid obesity: higher doses may be required. (23228881)
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)
- Local antibiogram: 📸
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 dosing
- 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.
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 dosing
- Loading dose 100 mg, then 50 mg IV Q12hr (for serious infection 100 mg IV Q12 may be better).
- High-dose tigecycline (serious systemic infections): Loading dose of 200-400 mg IV, then 100-200 mg IV q24.
- No dose adjustment for renal dysfunction.
- In Child-Pugh Class C cirrhosis, reduce maintenance dose by 50%.
- ⚠️ 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).
- 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 (but misses Pseudomonas, most Proteus and Providencia, and 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 could theoretically be overcome by utilizing a higher dose.
toxicity/contraindications
- Nausea/vomiting (may avoid with slow infusion).
- Pancreatitis, hepatitis.
- Coagulopathy (low fibrinogen; prolonged PT and PTT).
- Anaphylactoid reactions.
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. (37463564)
- 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.
- Obese patients: consider using actual body weight for severe infections, but inadequate data is available to support this approach. (Hopkins Antibiotic Guide).
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, but in fact TMP-SMX does cover Group A streptococci.)(37310038)
- Staphylococcus saprophyticus.
- MSSA, and >90% of MRSA isolates. (20507860)
- Streptococcus pneumoniae (~70%).
- 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.
- Local antibiogram: 📸
use
- Pneumocystis jirovecii.
- Listeria, toxoplasmosis, legionella.
- MRSA infections (particularly cellulitis; appears inferior to vancomycin for MRSA bacteremia). (20507860, 25977146)
- Pneumonia (but limited by increasing resistance among streptococcus pneumoniae).
- Urinary tract infections and prostatitis (due to sensitive organisms, not as empiric therapy).
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).
- Pregnancy, lactation.
vancomycin dosing
- Loading dose of 25 mg/kg may be considered (critical illness, endocarditis, pneumonia, CNS infections).
- Maintenance dose is 15 mg/kg, with the conventional dosing interval dependent on renal function:
- GFR >70: q12.
- GFR 30-70: q24.
- GFR 20-30: q48.
- GFR <20 or continuous renal replacement therapy (CRRT): serially check levels q24hr, re-dose when sub-therapeutic (roughly q3-7 days).
- Intermittent hemodialysis (IHD): Load with 20 mg/kg, then administer 8 mg/kg during the last hour of each hemodialysis session.
- 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.
- 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: 0.7 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 (but less effective than beta-lactams).
- MRSA (although efficacy depends on MIC).
- 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.
- Local antibiogram: 📸
interpreting vancomycin MIC in the context of MRSA
- MIC 1 ug/ml or below: Susceptible
- 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
use
- Empiric coverage for MRSA, usually in the context of known/suspected:
- Bloodstream infection (endocarditis, vascular catheter infection).
- Skin/soft tissue infection.
- Pneumonia.
- Surgical site infection.
- Known MRSA infections.
- Great choice for patients on chronic dialysis (the main drawback of vancomycin is nephrotoxicity).
- Additional discussion: Drug-resistant gram positive cocci: vancomycin vs. linezolid vs. daptomycin vs. ceftaroline
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).
Antibiograms vary greatly in different geographic locales. Whenever possible, it's preferable to use local data.
First-line agents for common gram-positive pathogens (28961942)
- MSSA – Cefazolin or nafcillin. Nafcillin required for CNS penetration.
- MRSA – Vancomycin, linezolid (not preferred for bacteremia), or daptomycin (ineffective in pneumonia)
- Staphylococcus lugdunensis (“slug”) – Vancomycin empirically, narrow to oxacillin if sensitive.
- Enterococcus faecalis – Ampicillin preferred (99% sensitive), may be superior to vancomycin.
- Enterococcus faecium (VRE) – Linezolid is first-line, daptomycin 2nd line.
- Enterococcus faecium (non-VRE) – Vancomycin or linezolid
- Streptococcus anginosus – Penicillin G is 1st line, ceftriaxone is 2nd line
- Streptococcus pyogenes (Group A strep) or Streptococcus agalactiae (Group B strep) – Penicillin G is 1st line, cefazolin is 2nd line
- Streptococcus pneumoniae (not meningitis) – Ceftriaxone is 1st line, Vancomycin is 2nd line in severe allergy.
- Listeria spp. – Ampicillin is 1st line, trimethoprim/sulfamethoxazole is 2nd line.
Treatment of gram-negative pathogens (before sensitivity data is available)
- E. coli, Klebsiella pneumoniae, Klebsiella oxytoca.
- No risk factors for ESBL species: Ceftriaxone or cefepime.
- Risk factors for ESBL species: Carbapenem.
- Proteus species: Piperacillin-tazobactam or cefepime.
- Enterobacter or Citrobacter: Cefepime or carbapenem.
- Pseudomonas: Piperacillin-tazobactam, cefepime, or meropenem.
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 be trusted. However, cefepime may be considered in infections with high bacterial burden and limited source control (e.g., endocarditis, ventriculitis).
treatment of bacteria with suspected AmpC inducible beta-lactamase
cefepime 💉
- Cefepime is recommended if the organism is cefepime-susceptible (MIC 2 ug/mL or less).
- ⚠️ If the MIC for cefepime is 4-8 ug/mL, this suggests a high likelihood of ESBL (extended spectrum beta-lactamase production). (34864936) Unfortunately, many labs may report out organisms with MIC of 4-8 ug/mL as “sensitive” to cefepime.
carbapenem 💉
- Carbapenem is recommended for cefepime-resistant organisms (MIC 4 ug/mL or more), assuming the organism is carbapenem sensitive.
non-beta lactam antibiotics
- As a general principle, AmpC-inducible beta-lactamase will not affect non-beta lactam antibiotics. These may be utilized based on culture and sensitivity data.
- 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). 💉
⚠️ piperacillin-tazobactam is not recommended
- There is no high-quality evidence that piperacillin-tazobactam causes worse clinical outcomes, but this has been suggested by two observational studies. (34864936, 37463564)
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.
diagnosis
- 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.
- ESBL may be suspected on the basis of an unusual in vitro sensitivity pattern:
- 🚩 Nonsusceptibility to ceftriaxone is often used as a proxy for ESBL production, although this has limited specificity. (37463564) ESBL are generally resistant to both 3rd and 4th generation cephalosporins.
- Sensitive to cephamycins (cefoxitin, cefotetan, cefmetazole)
- Often sensitive in vitro to beta-lactamase inhibitors (e.g., piperacillin-tazobactam).
- Verigene microarray may detect the CTX-M gene. 🌊 If detected, this reveals the presence of an ESBL. However, 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
- Preferred: Trimethoprim-sulfamethoxazole, ciprofloxacin, or levofloxacin. (37463564)
- Alternative: Ertapenem, meropenem, imipenem, aminoglycosides for a full treatment course. (37463564)
uncomplicated cystitis
- Preferred: Nitrofurantoin, trimethoprim-sulfamethoxazole.
- Alternative: Ciprofloxacin, levofloxacin, carbapenems, single-dose IV aminoglycosides. (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)
advantages of cefazolin 💉
- Cefazolin is better tolerated (especially with lower rates of kidney injury and hepatitis).
- 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)
advantages of nafcillin 💉
- 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)
⚠️ 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:
- (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.
bottom line
- Both cefazolin and nafcillin are solid choices, so you're unlikely to go wrong either way.
- Overall, both agents seem to have similar efficacy.
- Cefazolin may be better tolerated and easier to administer.
therapy for resistant gram positives: vancomycin vs. linezolid vs. daptomycin vs. ceftaroline
therapy for resistant gram positives: vancomycin vs. linezolid vs. daptomycin vs. ceftaroline
getting started: basic considerations
- [1] Source?
- Bloodstream infection (e.g., endocarditis, line infection):
- 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 wrath of antimicrobial stewards.
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)
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. 📖
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:
- 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.
⚠️ 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; potential risk of newborn hemolytic anemia when used near delivery, so it shouldn't be used in the third trimester). (Hopkins Antibiotic Guide)
🟡 antibiotics which may be used with caution
- 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.
- Doxycycline may cause tooth discoloration and congenital defects (Class D).
- Trimethoprim-sulfamethoxazole: Use in avoided in first trimester 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.
when to start antibiotics?
- Antibiotics shouldn't be started blindly (without a defined source of infection) unless the patient has septic shock or neutropenic fever.
- A positive culture may represent infection or colonization (bacteria present without causing disease). Colonization commonly occurs in the bladder of anuric or catheterized patients, or sputum of intubated patients. Don't treat colonization except in very specific situations (e.g. urinary colonization in pregnancy).
- Obtain cultures before starting antibiotics, whenever possible.
- Check a procalcitonin level:
- Use of procalcitonin has been shown to limit antibiotic exposure, while possibly improving patient outcomes.
- Antibiotic initiation should not be delayed while awaiting the procalcitonin level.
choosing drug & dose
- Review which antibiotics patient has been exposed to recently; try to avoid these if possible.
- Review recent culture data. Try to choose antibiotics that cover pathogens that the patient has grown in the recent past.
- Septic patients may have increased drug clearance, so antibiotics should generally be dosed on the higher end of dose ranges.
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.
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).
- Clinical stability criteria:
- 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
- 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
- For uncomplicated gram-negative bacteremia, 7 days of therapy is sufficient (as demonstrated by three RCTs). (30535100, 34508886, 32484534)
- 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.
- 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.
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)
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.
- CRP elevates largely in response to interleukin 6, with additional inputs from interleukin-1 beta and tumor necrosis factor alpha. (19400486) 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:
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:
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).
- 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: 📖)
- 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.
- Beta-lactams:
- High percent protein binding (>90%) may have the following consequences:
- 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).
- Depending on the clinical context, a high percent protein binding could be helpful (e.g. long half-life extends dosing interval) or harmful (e.g. impaired tissue penetration).
- Reduced albumin levels in critical illness may have the following effect on these medications:
- Increase in the volume of distribution (with increased distribution into the tissues).
- Increase in the drug clearance.
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).
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.
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 entirely accurate, 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 2009 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.
- 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.)
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%):
- Clindamycin (but oral administration may increase risk of C. difficile). 📖
- Metronidazole. 📖
- Trimethoprim-sulfamethoxazole. 📖
- Doxycycline. 📖
- Linezolid. 📖
- Rifampin. 📖
- Cephalexin.
- Nitrofurantoin. 📖
- Fluoroquinolones. 📖
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)
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References
- Special Acknowledgement: Pharmacokinetics and doses listed above were largely drawn from the Hopkins Antibiotic Guide and Antibiotic Essentials 15th Ed. by Cunha & Cunha.
- 12627936 Chow KM, Szeto CC, Hui AC, Wong TY, Li PK. Retrospective review of neurotoxicity induced by cefepime and ceftazidime. Pharmacotherapy. 2003 Mar;23(3):369-73. doi: 10.1592/phco.23.3.369.32100 [PubMed]
- 14763949 Orhan F, Odemis E, Yaris N, Okten A, Erduran E, Durmaz M, Yayla S. A case of IgE-mediated hypersensitivity to cefepime. Allergy. 2004 Feb;59(2):239-41. doi: 10.1046/j.1398-9995.2003.00376.x [PubMed]
- 14766894 Krueger WA, Kottler B, Will BE, Heininger A, Guggenberger H, Unertl KE. Treatment of meningitis due to methicillin-resistant Staphylococcus epidermidis with linezolid. J Clin Microbiol. 2004 Feb;42(2):929-32. doi: 10.1128/JCM.42.2.929-932.2004 [PubMed]
- 14963072 Alston WK, Ahern JW. Increase in the rate of nosocomial Clostridium difficile-associated diarrhoea during shortages of piperacillin-tazobactam and piperacillin. J Antimicrob Chemother. 2004 Mar;53(3):549-50. doi: 10.1093/jac/dkh127 [PubMed]
- 15883150 Morales N, Vermette H. Serotonin syndrome associated with linezolid treatment after discontinuation of fluoxetine. Psychosomatics. 2005 May-Jun;46(3):274-5. doi: 10.1176/appi.psy.46.3.274 [PubMed]
- 16080071 Meagher AK, Ambrose PG, Grasela TH, Ellis-Grosse EJ. The pharmacokinetic and pharmacodynamic profile of tigecycline. Clin Infect Dis. 2005 Sep 1;41 Suppl 5:S333-40. doi: 10.1086/431674 [PubMed]
- 16195255 Shorr AF, Kunkel MJ, Kollef M. Linezolid versus vancomycin for Staphylococcus aureus bacteraemia: pooled analysis of randomized studies. J Antimicrob Chemother. 2005 Nov;56(5):923-9. doi: 10.1093/jac/dki355 [PubMed]
- 16723596 Gavin PJ, Suseno MT, Thomson RB Jr, Gaydos JM, Pierson CL, Halstead DC, Aslanzadeh J, Brecher S, Rotstein C, Brossette SE, Peterson LR. Clinical correlation of the CLSI susceptibility breakpoint for piperacillin- tazobactam against extended-spectrum-beta-lactamase-producing Escherichia coli and Klebsiella species. Antimicrob Agents Chemother. 2006 Jun;50(6):2244-7. doi: 10.1128/AAC.00381-05 [PubMed]
- 17158033 Roberts JA, Webb SA, Lipman J. Cefepime versus ceftazidime: considerations for empirical use in critically ill patients. Int J Antimicrob Agents. 2007 Feb;29(2):117-28. doi: 10.1016/j.ijantimicag.2006.08.031 [PubMed]
- 17548489 Pai MP, Norenberg JP, Anderson T, Goade DW, Rodvold KA, Telepak RA, Mercier RC. Influence of morbid obesity on the single-dose pharmacokinetics of daptomycin. Antimicrob Agents Chemother. 2007 Aug;51(8):2741-7. doi: 10.1128/AAC.00059-07 [PubMed]
- 17852941 Mancino P, Ucciferri C, Falasca K, Pizzigallo E, Vecchiet J. Methicillin-resistant Staphylococcus epidermidis (MRSE) endocarditis treated with linezolid. Scand J Infect Dis. 2008;40(1):67-73. doi: 10.1080/00365540701509915 [PubMed]
- 17899228 Lentino JR, Narita M, Yu VL. New antimicrobial agents as therapy for resistant gram-positive cocci. Eur J Clin Microbiol Infect Dis. 2008 Jan;27(1):3-15. doi: 10.1007/s10096-007-0389-y [PubMed]
- 18171186 Baxter R, Ray GT, Fireman BH. Case-control study of antibiotic use and subsequent Clostridium difficile-associated diarrhea in hospitalized patients. Infect Control Hosp Epidemiol. 2008 Jan;29(1):44-50. doi: 10.1086/524320 [PubMed]
- 18719064 Wunderink RG, Mendelson MH, Somero MS, Fabian TC, May AK, Bhattacharyya H, Leeper KV Jr, Solomkin JS. Early microbiological response to linezolid vs vancomycin in ventilator-associated pneumonia due to methicillin-resistant Staphylococcus aureus. Chest. 2008 Dec;134(6):1200-1207. doi: 10.1378/chest.08-0011 [PubMed]
- 19072714 Wilcox MH, Tack KJ, Bouza E, Herr DL, Ruf BR, Ijzerman MM, Croos-Dabrera RV, Kunkel MJ, Knirsch C. Complicated skin and skin-structure infections and catheter-related bloodstream infections: noninferiority of linezolid in a phase 3 study. Clin Infect Dis. 2009 Jan 15;48(2):203-12. doi: 10.1086/595686 [PubMed]
- 19900794 Beibei L, Yun C, Mengli C, Nan B, Xuhong Y, Rui W. Linezolid versus vancomycin for the treatment of gram-positive bacterial infections: meta-analysis of randomised controlled trials. Int J Antimicrob Agents. 2010 Jan;35(1):3-12. doi: 10.1016/j.ijantimicag.2009.09.013 [PubMed]
- 20098528 Quinn DK, Stern TA. Linezolid and serotonin syndrome. Prim Care Companion J Clin Psychiatry. 2009;11(6):353-6. doi: 10.4088/PCC.09r00853 [PubMed]
- 20507860 Goldberg E, Paul M, Talker O, Samra Z, Raskin M, Hazzan R, Leibovici L, Bishara J. Co-trimoxazole versus vancomycin for the treatment of methicillin-resistant Staphylococcus aureus bacteraemia: a retrospective cohort study. J Antimicrob Chemother. 2010 Aug;65(8):1779-83. doi: 10.1093/jac/dkq179 [PubMed]
- 21163725 Pletz MW, Burkhardt O, Welte T. Nosocomial methicillin-resistant Staphylococcus aureus (MRSA) pneumonia: linezolid or vancomycin? – Comparison of pharmacology and clinical efficacy. Eur J Med Res. 2010 Nov 30;15(12):507-13. doi: 10.1186/2047-783x-15-12-507 [PubMed]
- 21504940 Baines SD, Noel AR, Huscroft GS, Todhunter SL, O'Connor R, Hobbs JK, Freeman J, Lovering AM, Wilcox MH. Evaluation of linezolid for the treatment of Clostridium difficile infection caused by epidemic strains using an in vitro human gut model. J Antimicrob Chemother. 2011 Jul;66(7):1537-46. doi: 10.1093/jac/dkr155 [PubMed]
- 21671825 Sipahi OR, Bardak S, Turhan T, Arda B, Pullukcu H, Ruksen M, Aydemir S, Dalbasti T, Yurtseven T, Zileli M, Ulusoy S. Linezolid in the treatment of methicillin-resistant staphylococcal post-neurosurgical meningitis: a series of 17 cases. Scand J Infect Dis. 2011 Oct;43(10):757-64. doi: 10.3109/00365548.2011.585177 [PubMed]
- 21930870 Cadena J, Nair S, Henao-Martinez AF, Jorgensen JH, Patterson JE, Sreeramoju PV. Dose of trimethoprim-sulfamethoxazole to treat skin and skin structure infections caused by methicillin-resistant Staphylococcus aureus. Antimicrob Agents Chemother. 2011 Dec;55(12):5430-2. doi: 10.1128/AAC.00706-11 [PubMed]
- 22057699 Perez F, Bonomo RA. Can we really use ß-lactam/ß-lactam inhibitor combinations for the treatment of infections caused by extended-spectrum ß-lactamase-producing bacteria? Clin Infect Dis. 2012 Jan 15;54(2):175-7. doi: 10.1093/cid/cir793 [PubMed]
- 22057701 Rodríguez-Baño J, Navarro MD, Retamar P, Picón E, Pascual Á; Extended-Spectrum Beta-Lactamases–Red Española de Investigación en Patología Infecciosa/Grupo de Estudio de Infección Hospitalaria Group. β-Lactam/β-lactam inhibitor combinations for the treatment of bacteremia due to extended-spectrum β-lactamase-producing Escherichia coli: a post hoc analysis of prospective cohorts. Clin Infect Dis. 2012 Jan 15;54(2):167-74. doi: 10.1093/cid/cir790 [PubMed]
- 22247123 Wunderink RG, Niederman MS, Kollef MH, Shorr AF, Kunkel MJ, Baruch A, McGee WT, Reisman A, Chastre J. Linezolid in methicillin-resistant Staphylococcus aureus nosocomial pneumonia: a randomized, controlled study. Clin Infect Dis. 2012 Mar 1;54(5):621-9. doi: 10.1093/cid/cir895 [PubMed]
- 22249886 Rich BS, Keel R, Ho VP, Turbendian H, Afaneh CI, Dakin GF, Pomp A, Nicolau DP, Barie PS. Cefepime dosing in the morbidly obese patient population. Obes Surg. 2012 Mar;22(3):465-71. doi: 10.1007/s11695-011-0586-8 [PubMed]
- 22445203 Valerio M, Pedromingo M, Muñoz P, Alcalá L, Marin M, Peláez T, Giannella M, Bouza E. Potential protective role of linezolid against Clostridium difficile infection. Int J Antimicrob Agents. 2012 May;39(5):414-9. doi: 10.1016/j.ijantimicag.2012.01.005 [PubMed]
- 22546769 Cunha BA, Schoch P, Hage JE. Oral therapy of catheter-associated bacteriuria (CAB) in the era of antibiotic resistance: nitrofurantoin revisited. J Chemother. 2012 Apr;24(2):122-4. doi: 10.1179/1120009X12Z.00000000013 [PubMed]
- 22563022 Doernberg SB, Winston LG, Deck DH, Chambers HF. Does doxycycline protect against development of Clostridium difficile infection? Clin Infect Dis. 2012 Sep;55(5):615-20. doi: 10.1093/cid/cis457 [PubMed]
- 22787406* Ager S, Gould K. Clinical update on linezolid in the treatment of Gram-positive bacterial infections. Infect Drug Resist. 2012;5:87-102. doi: 10.2147/IDR.S25890 [PubMed]
- 22848719 Leonard SN. Synergy between vancomycin and nafcillin against Staphylococcus aureus in an in vitro pharmacokinetic/pharmacodynamic model. PLoS One. 2012;7(7):e42103. doi: 10.1371/journal.pone.0042103 [PubMed]
- 22915465 Vardakas KZ, Tansarli GS, Rafailidis PI, Falagas ME. Carbapenems versus alternative antibiotics for the treatment of bacteraemia due to Enterobacteriaceae producing extended-spectrum β-lactamases: a systematic review and meta-analysis. J Antimicrob Chemother. 2012 Dec;67(12):2793-803. doi: 10.1093/jac/dks301 [PubMed]
- 23147743 Hites M, Taccone FS, Wolff F, Cotton F, Beumier M, De Backer D, Roisin S, Lorent S, Surin R, Seyler L, Vincent JL, Jacobs F. Case-control study of drug monitoring of β-lactams in obese critically ill patients. Antimicrob Agents Chemother. 2013 Feb;57(2):708-15. doi: 10.1128/AAC.01083-12 [PubMed]
- 23228881 Cheatham SC, Fleming MR, Healy DP, Chung CE, Shea KM, Humphrey ML, Kays MB. Steady-state pharmacokinetics and pharmacodynamics of piperacillin and tazobactam administered by prolonged infusion in obese patients. Int J Antimicrob Agents. 2013 Jan;41(1):52-6. doi: 10.1016/j.ijantimicag.2012.09.004 [PubMed]
- 23424229 Woytowish MR, Maynor LM. Clinical relevance of linezolid-associated serotonin toxicity. Ann Pharmacother. 2013 Mar;47(3):388-97. doi: 10.1345/aph.1R386 [PubMed]
- 23568605 Jiang H, Tang RN, Wang J. Linezolid versus vancomycin or teicoplanin for nosocomial pneumonia: meta-analysis of randomised controlled trials. Eur J Clin Microbiol Infect Dis. 2013 Sep;32(9):1121-8. doi: 10.1007/s10096-013-1867-z [PubMed]
- 23672240 Sipahi OR, Bardak-Ozcem S, Turhan T, Arda B, Ruksen M, Pullukcu H, Aydemir S, Dalbasti T, Yurtseven T, Sipahi H, Zileli M, Ulusoy S. Vancomycin versus linezolid in the treatment of methicillin-resistant Staphylococcus aureus meningitis. Surg Infect (Larchmt). 2013 Aug;14(4):357-62. doi: 10.1089/sur.2012.091 [PubMed]
- 24140078 Muldoon EG, Epstein L, Logvinenko T, Murray S, Doron SI, Snydman DR. The impact of cefepime as first line therapy for neutropenic fever on Clostridium difficile rates among hematology and oncology patients. Anaerobe. 2013 Dec;24:79-81. doi: 10.1016/j.anaerobe.2013.10.001 [PubMed]
- 24238896 Chavanet P. The ZEPHyR study: a randomized comparison of linezolid and vancomycin for MRSA pneumonia. Med Mal Infect. 2013 Dec;43(11-12):451-5. doi: 10.1016/j.medmal.2013.09.011 [PubMed]
- 24420846 Caffrey AR, Morrill HJ, Puzniak LA, Laplante KL. Comparative effectiveness of linezolid and vancomycin among a national veterans affairs cohort with methicillin-resistant Staphylococcus aureus pneumonia. Pharmacotherapy. 2014 May;34(5):473-80. doi: 10.1002/phar.1390 [PubMed]
- 24637693 Blumenthal KG, Youngster I, Shenoy ES, Banerji A, Nelson SB. Tolerability of cefazolin after immune-mediated hypersensitivity reactions to nafcillin in the outpatient setting. Antimicrob Agents Chemother. 2014 Jun;58(6):3137-43. doi: 10.1128/AAC.02504-13 [PubMed]
- 24916853 Peyrani P, Wiemken TL, Kelley R, Zervos MJ, Kett DH, File TM Jr, Stein GE, Ford KD, Scerpella EG, Welch V, Ramirez JA; IMPACT-HAP Study Group. Higher clinical success in patients with ventilator-associated pneumonia due to methicillin-resistant Staphylococcus aureus treated with linezolid compared with vancomycin: results from the IMPACT-HAP study. Crit Care. 2014 Jun 10;18(3):R118. doi: 10.1186/cc13914 [PubMed]
- 25004793 Cunha BA, Lee P, Kaouris N, Raza M. The safety of nitrofurantoin for the treatment of nosocomial catheter-associated bacteriuria (CAB) and cystitis. J Chemother. 2015 Feb;27(2):122-3. doi: 10.1179/1973947814Y.0000000202 [PubMed]
- 25066668 Niederman MS, Chastre J, Solem CT, Wan Y, Gao X, Myers DE, Haider S, Li JZ, Stephens JM. Health economic evaluation of patients treated for nosocomial pneumonia caused by methicillin-resistant Staphylococcus aureus: secondary analysis of a multicenter randomized clinical trial of vancomycin and linezolid. Clin Ther. 2014 Sep 1;36(9):1233-1243.e1. doi: 10.1016/j.clinthera.2014.06.029 [PubMed]
- 25124380 Terico AT, Gallagher JC. Beta-lactam hypersensitivity and cross-reactivity. J Pharm Pract. 2014 Dec;27(6):530-44. doi: 10.1177/0897190014546109 [PubMed]
- 25355172 Wang Y, Zou Y, Xie J, Wang T, Zheng X, He H, Dong W, Xing J, Dong Y. Linezolid versus vancomycin for the treatment of suspected methicillin-resistant Staphylococcus aureus nosocomial pneumonia: a systematic review employing meta-analysis. Eur J Clin Pharmacol. 2015 Jan;71(1):107-15. doi: 10.1007/s00228-014-1775-x [PubMed]
- 25495779 Chuang YC, Wang JT, Lin HY, Chang SC. Daptomycin versus linezolid for treatment of vancomycin-resistant enterococcal bacteremia: systematic review and meta-analysis. BMC Infect Dis. 2014 Dec 13;14:687. doi: 10.1186/s12879-014-0687-9 [PubMed]
- 25977146 Paul M, Bishara J, Yahav D, Goldberg E, Neuberger A, Ghanem-Zoubi N, Dickstein Y, Nseir W, Dan M, Leibovici L. Trimethoprim-sulfamethoxazole versus vancomycin for severe infections caused by methicillin resistant Staphylococcus aureus: randomised controlled trial. BMJ. 2015 May 14;350:h2219. doi: 10.1136/bmj.h2219 [PubMed]
- 26105168 Labreche MJ, Graber CJ, Nguyen HM. Recent Updates on the Role of Pharmacokinetics-pharmacodynamics in Antimicrobial Susceptibility Testing as Applied to Clinical Practice. Clin Infect Dis. 2015 Nov 1;61(9):1446-52. doi: 10.1093/cid/civ498 [PubMed]
- 26320109 Habib G, Lancellotti P, Antunes MJ, et al. ESC Scientific Document Group. 2015 ESC Guidelines for the management of infective endocarditis: The Task Force for the Management of Infective Endocarditis of the European Society of Cardiology (ESC). Endorsed by: European Association for Cardio-Thoracic Surgery (EACTS), the European Association of Nuclear Medicine (EANM). Eur Heart J. 2015 Nov 21;36(44):3075-3128. doi: 10.1093/eurheartj/ehv319 [PubMed]
- 26348420 Tsai D, Lipman J, Roberts JA. Pharmacokinetic/pharmacodynamic considerations for the optimization of antimicrobial delivery in the critically ill. Curr Opin Crit Care. 2015 Oct;21(5):412-20. doi: 10.1097/MCC.0000000000000229 [PubMed]
- 26373316 Baddour LM, Wilson WR, Bayer AS, et al.; American Heart Association Committee on Rheumatic Fever, Endocarditis, and Kawasaki Disease of the Council on Cardiovascular Disease in the Young, Council on Clinical Cardiology, Council on Cardiovascular Surgery and Anesthesia, and Stroke Council. Infective Endocarditis in Adults: Diagnosis, Antimicrobial Therapy, and Management of Complications: A Scientific Statement for Healthcare Professionals From the American Heart Association. Circulation. 2015 Oct 13;132(15):1435-86. doi: 10.1161/CIR.0000000000000296 [PubMed]
- 26382940 Reveles KR, Mortensen EM, Attridge RT, Frei CR. Comparative-effectiveness of vancomycin and linezolid as part of guideline-recommended empiric therapy for healthcare-associated pneumonia. BMC Res Notes. 2015 Sep 17;8:450. doi: 10.1186/s13104-015-1396-1 [PubMed]
- 26542304 Harris PN, Wei JY, Shen AW, Abdile AA, Paynter S, Huxley RR, Pandeya N, Doi Y, Huh K, O'Neal CS, Talbot TR, Paterson DL. Carbapenems versus alternative antibiotics for the treatment of bloodstream infections caused by Enterobacter, Citrobacter or Serratia species: a systematic review with meta-analysis. J Antimicrob Chemother. 2016 Feb;71(2):296-306. doi: 10.1093/jac/dkv346 [PubMed]
- 26598097 Bookstaver PB, Bland CM, Griffin B, Stover KR, Eiland LS, McLaughlin M. A Review of Antibiotic Use in Pregnancy. Pharmacotherapy. 2015 Nov;35(11):1052-62. doi: 10.1002/phar.1649 [PubMed]
- 26758498 Yue J, Dong BR, Yang M, Chen X, Wu T, Liu GJ. Linezolid versus vancomycin for skin and soft tissue infections. Cochrane Database Syst Rev. 2016 Jan 7;(1):CD008056. doi: 10.1002/14651858.CD008056.pub3 [PubMed]
- 27025622 Hung YP, Lee JC, Lin HJ, Liu HC, Wu YH, Tsai PJ, Ko WC. Doxycycline and Tigecycline: Two Friendly Drugs with a Low Association with Clostridium Difficile Infection. Antibiotics (Basel). 2015 Jun 19;4(2):216-29. doi: 10.3390/antibiotics4020216 [PubMed]
- 27100576 Santos JM, Batech M, Pelter MA, Deamer RL. Evaluation of the Risk of Nitrofurantoin Lung Injury and Its Efficacy in Diminished Kidney Function in Older Adults in a Large Integrated Healthcare System: A Matched Cohort Study. J Am Geriatr Soc. 2016 Apr;64(4):798-805. doi: 10.1111/jgs.14072 [PubMed]
- 27208687 Tong MC, Wisniewski CS, Wolf B, Bosso JA. Comparison of Linezolid and Vancomycin for Methicillin-Resistant Staphylococcus aureus Pneumonia: Institutional Implications. Pharmacotherapy. 2016 Jul;36(7):731-9. doi: 10.1002/phar.1771 [PubMed]
- 37300522 August BA, Kale-Pradhan PB, Giuliano C, Johnson LB. Biomarkers in the intensive care setting: A focus on using procalcitonin and C-reactive protein to optimize antimicrobial duration of therapy. Pharmacotherapy. 2023 Sep;43(9):935-949. doi: 10.1002/phar.2834 [PubMed]
- 27475738 Chuang YC, Lin HY, Chen PY, Lin CY, Wang JT, Chang SC. Daptomycin versus linezolid for the treatment of vancomycin-resistant enterococcal bacteraemia: implications of daptomycin dose. Clin Microbiol Infect. 2016 Oct;22(10):890.e1-890.e7. doi: 10.1016/j.cmi.2016.07.018 [PubMed]
- 27504340 Roy U, Panwar A, Pandit A, Das SK, Joshi B. Clinical and Neuroradiological Spectrum of Metronidazole Induced Encephalopathy: Our Experience and the Review of Literature. J Clin Diagn Res. 2016 Jun;10(6):OE01-9. doi: 10.7860/JCDR/2016/19032.8054 [PubMed]
- 27520326 Burnett YJ, Echevarria K, Traugott KA. Ceftaroline as Salvage Monotherapy for Persistent MRSA Bacteremia. Ann Pharmacother. 2016 Dec;50(12):1051-1059. doi: 10.1177/1060028016664361 [PubMed]
- 27960205 Feldman C, Anderson R. The Role of Streptococcus pneumoniae in Community-Acquired Pneumonia. Semin Respir Crit Care Med. 2016 Dec;37(6):806-818. doi: 10.1055/s-0036-1592074 [PubMed]
- 28034519 Moy S, Sharma R. Treatment Outcomes in Infections Caused by “SPICE” (Serratia, Pseudomonas, Indole-positive Proteus, Citrobacter, and Enterobacter) Organisms: Carbapenem versus Noncarbapenem Regimens. Clin Ther. 2017 Jan;39(1):170-176. doi: 10.1016/j.clinthera.2016.11.025 [PubMed]
- 28320724 Cheng L, Nelson BC, Mehta M, Seval N, Park S, Giddins MJ, Shi Q, Whittier S, Gomez-Simmonds A, Uhlemann AC. Piperacillin-Tazobactam versus Other Antibacterial Agents for Treatment of Bloodstream Infections Due to AmpC β-Lactamase-Producing Enterobacteriaceae. Antimicrob Agents Chemother. 2017 May 24;61(6):e00276-17. doi: 10.1128/AAC.00276-17 [PubMed]
- 28702467* Cosimi RA, Beik N, Kubiak DW, Johnson JA. Ceftaroline for Severe Methicillin-Resistant Staphylococcus aureus Infections: A Systematic Review. Open Forum Infect Dis. 2017 May 2;4(2):ofx084. doi: 10.1093/ofid/ofx084 [PubMed]
- 28819873 Cunha BA, Baron J, Cunha CB. Similarities and differences between doxycycline and minocycline: clinical and antimicrobial stewardship considerations. Eur J Clin Microbiol Infect Dis. 2018 Jan;37(1):15-20. doi: 10.1007/s10096-017-3081-x [PubMed]
- 28870736 Lee CY, Huang CH, Lu PL, Ko WC, Chen YH, Hsueh PR. Role of rifampin for the treatment of bacterial infections other than mycobacteriosis. J Infect. 2017 Nov;75(5):395-408. doi: 10.1016/j.jinf.2017.08.013 [PubMed]
- 28942574 Lother SA, Press N. Once-Daily Treatments for Methicillin-Susceptible Staphylococcus aureus Bacteremia: Are They Good Enough? Curr Infect Dis Rep. 2017 Sep 23;19(11):43. doi: 10.1007/s11908-017-0599-0 [PubMed]
- 28961942 Avdic E, Wang R, Li DX, Tamma PD, Shulder SE, Carroll KC, Cosgrove SE. Sustained impact of a rapid microarray-based assay with antimicrobial stewardship interventions on optimizing therapy in patients with Gram-positive bacteraemia. J Antimicrob Chemother. 2017 Nov 1;72(11):3191-3198. doi: 10.1093/jac/dkx267 [PubMed]
- 29293890 Wald-Dickler N, Holtom P, Spellberg B. Busting the Myth of “Static vs Cidal”: A Systemic Literature Review. Clin Infect Dis. 2018 Apr 17;66(9):1470-1474. doi: 10.1093/cid/cix1127 [PubMed]
- 29363242 Bishop EJ, Tiruvoipati R, Metcalfe J, Marshall C, Botha J, Kelley PG. The outcome of patients with severe and severe-complicated Clostridium difficile infection treated with tigecycline combination therapy: a retrospective observational study. Intern Med J. 2018 Jun;48(6):651-660. doi: 10.1111/imj.13742 [PubMed]
- 29950810* Hashemian SMR, Farhadi T, Ganjparvar M. Linezolid: a review of its properties, function, and use in critical care. Drug Des Devel Ther. 2018 Jun 18;12:1759-1767. doi: 10.2147/DDDT.S164515 [PubMed]
- 30125680 McKamey L, Venugopalan V, Cherabuddi K, Borgert S, Voils S, Shah K, Klinker KP. Assessing antimicrobial stewardship initiatives: Clinical evaluation of cefepime or piperacillin/tazobactam in patients with bloodstream infections secondary to AmpC-producing organisms. Int J Antimicrob Agents. 2018 Nov;52(5):719-723. doi: 10.1016/j.ijantimicag.2018.08.007 [PubMed]
- 30208454 Harris PNA, Tambyah PA, Lye DC, et al.; MERINO Trial Investigators and the Australasian Society for Infectious Disease Clinical Research Network (ASID-CRN). Effect of Piperacillin-Tazobactam vs Meropenem on 30-Day Mortality for Patients With E coli or Klebsiella pneumoniae Bloodstream Infection and Ceftriaxone Resistance: A Randomized Clinical Trial. JAMA. 2018 Sep 11;320(10):984-994. doi: 10.1001/jama.2018.12163 [PubMed]
- 30476572 Lee BJ, Wang SK, Constantino-Corpuz JK, Apolinario K, Nadler B, McDanel JS, Scheetz MH, Rhodes NJ. Cefazolin vs. anti-staphylococcal penicillins for treatment of methicillin-susceptible Staphylococcus aureus bloodstream infections in acutely ill adult patients: Results of a systematic review and meta-analysis. Int J Antimicrob Agents. 2019 Mar;53(3):225-233. doi: 10.1016/j.ijantimicag.2018.11.013 [PubMed]
- 30721141 Schuetz P, Beishuizen A, Broyles M, Ferrer R, Gavazzi G, Gluck EH, González Del Castillo J, Jensen JU, Kanizsai PL, Kwa ALH, Krueger S, Luyt CE, Oppert M, Plebani M, Shlyapnikov SA, Toccafondi G, Townsend J, Welte T, Saeed K. Procalcitonin (PCT)-guided antibiotic stewardship: an international experts consensus on optimized clinical use. Clin Chem Lab Med. 2019 Aug 27;57(9):1308-1318. doi: 10.1515/cclm-2018-1181 [PubMed]
- 30723936 Cook AM, Hatton-Kolpek J. Augmented Renal Clearance. Pharmacotherapy. 2019 Mar;39(3):346-354. doi: 10.1002/phar.2231 [PubMed]
- 30765904 Gardiner BJ, Stewardson AJ, Abbott IJ, Peleg AY. Nitrofurantoin and fosfomycin for resistant urinary tract infections: old drugs for emerging problems. Aust Prescr. 2019 Feb;42(1):14-19. doi: 10.18773/austprescr.2019.002 [PubMed]
- 31369411 Gudiol C, Cuervo G, Carratalà J. Optimizing therapy of bloodstream infection due to extended-spectrum β-lactamase-producing Enterobacteriaceae. Curr Opin Crit Care. 2019 Oct;25(5):438-448. doi: 10.1097/MCC.0000000000000646 [PubMed]
- 31608743 Bader MS, Loeb M, Leto D, Brooks AA. Treatment of urinary tract infections in the era of antimicrobial resistance and new antimicrobial agents. Postgrad Med. 2020 Apr;132(3):234-250. doi: 10.1080/00325481.2019.1680052 [PubMed]
- 31782385 Sharland M, Gandra S, Huttner B, Moja L, Pulcini C, Zeng M, Mendelson M, Cappello B, Cooke G, Magrini N; EML Expert Committee and Antibiotic Working Group. Encouraging AWaRe-ness and discouraging inappropriate antibiotic use-the new 2019 Essential Medicines List becomes a global antibiotic stewardship tool. Lancet Infect Dis. 2019 Dec;19(12):1278-1280. doi: 10.1016/S1473-3099(19)30532-8 [PubMed]
- 32011685 Pais GM, Liu J, Avedissian SN, Hiner D, Xanthos T, Chalkias A, d'Aloja E, Locci E, Gilchrist A, Prozialeck WC, Rhodes NJ, Lodise TP, Fitzgerald JC, Downes KJ, Zuppa AF, Scheetz MH. Lack of synergistic nephrotoxicity between vancomycin and piperacillin/tazobactam in a rat model and a confirmatory cellular model. J Antimicrob Chemother. 2020 May 1;75(5):1228-1236. doi: 10.1093/jac/dkz563 [PubMed]
- 32055559 Atkinson AJ Jr. Augmented renal clearance. Transl Clin Pharmacol. 2018 Sep;26(3):111-114. doi: 10.12793/tcp.2018.26.3.111 [PubMed]
- 32391402 Butler-Laporte G, Smyth E, Amar-Zifkin A, Cheng MP, McDonald EG, Lee TC. Low-Dose TMP-SMX in the Treatment of Pneumocystis jirovecii Pneumonia: A Systematic Review and Meta-analysis. Open Forum Infect Dis. 2020 Apr 2;7(5):ofaa112. doi: 10.1093/ofid/ofaa112 [PubMed]
- 32552817 Gijsen M, Wilmer A, Meyfroidt G, Wauters J, Spriet I. Can augmented renal clearance be detected using estimators of glomerular filtration rate? Crit Care. 2020 Jun 18;24(1):359. doi: 10.1186/s13054-020-03057-4 [PubMed]
- 32659898 Chen IH, Nicolau DP. Augmented Renal Clearance and How to Augment Antibiotic Dosing. Antibiotics (Basel). 2020 Jul 9;9(7):393. doi: 10.3390/antibiotics9070393 [PubMed]
- 33526494 He M, Souza E, Matvekas A, Crass RL, Pai MP. Alteration in Acute Kidney Injury Potential with the Combination of Vancomycin and Imipenem-Cilastatin/Relebactam or Piperacillin/Tazobactam in a Preclinical Model. Antimicrob Agents Chemother. 2021 Mar 18;65(4):e02141-20. doi: 10.1128/AAC.02141-20 [PubMed]
- 33819054 Lee RA, Centor RM, Humphrey LL, Jokela JA, Andrews R, Qaseem A; Scientific Medical Policy Committee of the American College of Physicians; Akl EA, Bledsoe TA, Forciea MA, Haeme R, Kansagara DL, Marcucci M, Miller MC, Obley AJ. Appropriate Use of Short-Course Antibiotics in Common Infections: Best Practice Advice From the American College of Physicians. Ann Intern Med. 2021 Jun;174(6):822-827. doi: 10.7326/M20-7355 [PubMed]
- 34352843 Pacheco LD, Saad AF, Saade GR. A Practical Approach to Antibiotic Use in Critically Ill Obstetric Patients. Obstet Gynecol. 2021 Sep 1;138(3):459-465. doi: 10.1097/AOG.0000000000004473 [PubMed]
- 34544183 Póvoa P, Coelho L. Which Biomarkers Can Be Used as Diagnostic Tools for Infection in Suspected Sepsis? Semin Respir Crit Care Med. 2021 Oct;42(5):662-671. doi: 10.1055/s-0041-1735148 [PubMed]
- 34864936 Tamma PD, Aitken SL, Bonomo RA, Mathers AJ, van Duin D, Clancy CJ. Infectious Diseases Society of America Guidance on the Treatment of AmpC β-Lactamase-Producing Enterobacterales, Carbapenem-Resistant Acinetobacter baumannii, and Stenotrophomonas maltophilia Infections. Clin Infect Dis. 2022 Jul 6;74(12):2089-2114. doi: 10.1093/cid/ciab1013 [PubMed]
- 35007142 Chang J, Pais GM, Valdez K, Marianski S, Barreto EF, Scheetz MH. Glomerular Function and Urinary Biomarker Changes between Vancomycin and Vancomycin plus Piperacillin-Tazobactam in a Translational Rat Model. Antimicrob Agents Chemother. 2022 Mar 15;66(3):e0213221. doi: 10.1128/aac.02132-21 [PubMed]
- 35833959 Miano TA, Hennessy S, Yang W, Dunn TG, Weisman AR, Oniyide O, Agyekum RS, Turner AP, Ittner CAG, Anderson BJ, Wilson FP, Townsend R, Reilly JP, Giannini HM, Cosgriff CV, Jones TK, Meyer NJ, Shashaty MGS. Association of vancomycin plus piperacillin-tazobactam with early changes in creatinine versus cystatin C in critically ill adults: a prospective cohort study. Intensive Care Med. 2022 Sep;48(9):1144-1155. doi: 10.1007/s00134-022-06811-0 [PubMed]
- 35942862 Burillo A, Bouza E. Controversies over the management of infections caused by Amp-C- and ESBL-producing Enterobacterales : what questions remain for future studies? Curr Opin Infect Dis. 2022 Dec 1;35(6):575-582. doi: 10.1097/QCO.0000000000000863 [PubMed]
- 36592205 Póvoa P, Coelho L, Dal-Pizzol F, Ferrer R, Huttner A, Conway Morris A, Nobre V, Ramirez P, Rouze A, Salluh J, Singer M, Sweeney DA, Torres A, Waterer G, Kalil AC. How to use biomarkers of infection or sepsis at the bedside: guide to clinicians. Intensive Care Med. 2023 Feb;49(2):142-153. doi: 10.1007/s00134-022-06956-y [PubMed]
- 36718940 Dinh A, Crémieux AC, Guillemot D. Short treatment duration for community-acquired pneumonia. Curr Opin Infect Dis. 2023 Apr 1;36(2):140-145. doi: 10.1097/QCO.0000000000000908 [PubMed]
- 36800065 Yetmar ZA, Khodadadi RB, Go JR, Chesdachai S, Abu Saleh OM. Post-treatment outcomes of ceftriaxone versus antistaphylococcal penicillins or cefazolin for definitive therapy of methicillin-susceptible Staphylococcus aureus bacteremia. Eur J Clin Microbiol Infect Dis. 2023 Apr;42(4):423-430. doi: 10.1007/s10096-023-04575-z [PubMed]
- 36838359 Gatti M, Viaggi B, Rossolini GM, Pea F, Viale P. Targeted Therapy of Severe Infections Caused by Staphylococcus aureus in Critically Ill Adult Patients: A Multidisciplinary Proposal of Therapeutic Algorithms Based on Real-World Evidence. Microorganisms. 2023 Feb 3;11(2):394. doi: 10.3390/microorganisms11020394 [PubMed]
- 36896122 Rico-Fontalvo J, Correa-Guerrero J, Martínez-Ávila MC, Daza-Arnedo R, Rodriguez-Yanez T, Almanza-Hurtado A, Cabrales J, Mendoza-Paternina CJ, Frías-Salazar A, Morales-Fernández J. Critically Ill Patients with Renal Hyperfiltration: Optimizing Antibiotic Dose. Int J Nephrol. 2023 Feb 28;2023:6059079. doi: 10.1155/2023/6059079 [PubMed]
- 37148398 Mokrani D, Chommeloux J, Pineton de Chambrun M, Hékimian G, Luyt CE. Antibiotic stewardship in the ICU: time to shift into overdrive. Ann Intensive Care. 2023 May 6;13(1):39. doi: 10.1186/s13613-023-01134-9 [PubMed]
- 37310038 McCreary EK, Johnson MD, Jones TM, Spires SS, Davis AE, Dyer AP, Ashley ED, Gallagher JC. Antibiotic Myths for the Infectious Diseases Clinician. Clin Infect Dis. 2023 Jun 13:ciad357. doi: 10.1093/cid/ciad357 [PubMed]
- 37463564 Tamma PD, Aitken SL, Bonomo RA, Mathers AJ, van Duin D, Clancy CJ. Infectious Diseases Society of America 2023 Guidance on the Treatment of Antimicrobial Resistant Gram-Negative Infections. Clin Infect Dis. 2023 Jul 18:ciad428. doi: 10.1093/cid/ciad428 [PubMed]
- 37533805 Ture Z, Güner R, Alp E. Antimicrobial stewardship in the intensive care unit. J Intensive Med. 2022 Nov 15;3(3):244-253. doi: 10.1016/j.jointm.2022.10.001 [PubMed]
- Baptista, L., Moura, I., Silva, C.M. et al. What is New in Augmented Renal Clearance in Septic Patients?. Curr Infect Dis Rep (2023). https://doi.org/10.1007/s11908-023-00816-6