Carbapenems

Carbapenems (meropenem, imipenem-cilastatin, ertapenem, and in some markets doripenem and biapenem) are the broadest-spectrum beta-lactams and the most reliable agents for ESBL and AmpC-producing Enterobacterales. Their use should be limited to infections where their breadth is needed, since carbapenem resistance is among the most serious resistance problems worldwide.

Mechanism. PBP binding (especially PBP2 and PBP1b/1a) with bactericidal action and stability to nearly all serine beta-lactamases except carbapenemases. Time-dependent killing; the target is free concentration over the MIC for about 40 percent of the dosing interval.

Pharmacokinetics. Hydrophilic, renally eliminated with half-lives of 1 hour (meropenem, imipenem) and 4 hours (ertapenem). Imipenem is degraded by renal dehydropeptidase and so is combined with cilastatin. Ertapenem is highly protein-bound with saturable binding, so exposure falls in hypoalbuminaemia. Meropenem and imipenem penetrate tissues and (meropenem) inflamed meninges.

Spectrum. Streptococci, MSSA, E. faecalis (imipenem), Enterobacterales including ESBL and AmpC producers, P. aeruginosa and Acinetobacter (meropenem, imipenem), anaerobes, Listeria (meropenem). Inactive against MRSA, E. faecium, Stenotrophomonas, atypicals and carbapenemase producers (KPC, NDM, VIM, IMP, OXA-48, and OXA-type enzymes of Acinetobacter).

Adult regimens (normal renal function).

• Meropenem 1 g IV every 8 hours; 2 g every 8 hours for meningitis, CNS infection, cystic fibrosis exacerbation and resistant Pseudomonas. Extended infusion over 3 hours after a first 30-minute dose is used in critical illness. Maximum 6 g daily.
• Imipenem-cilastatin 500 mg IV every 6 hours (1 g every 8 hours for less susceptible organisms); maximum 4 g daily.
• Ertapenem 1 g IV or IM once daily; IM diluted in 1 percent lidocaine.
• Children: meropenem 20 mg/kg every 8 hours (40 mg/kg for meningitis; maximum 2 g each dose); ertapenem 15 mg/kg every 12 hours for ages 3 months to 12 years (maximum 1 g daily).

Selection.

• Bacteraemia or serious infection with ESBL producers: meropenem or ertapenem (ertapenem suits stable patients without Pseudomonas risk or hypoalbuminaemia).
• Sepsis with prior ESBL colonisation, severe sepsis failing first-line therapy, febrile neutropenia failing initial therapy, nosocomial meningitis.
• Reserve meropenem for Pseudomonas and Acinetobacter at risk or proven; narrow promptly after culture.
• Oral step-down for ESBL urinary infection: ciprofloxacin or co-trimoxazole where susceptible, to avoid prolonged carbapenem exposure.

Contraindications. Hypersensitivity to carbapenems; severe immediate reaction to a penicillin warrants caution, although cross-reactivity is under 1 percent. Concurrent valproate is avoided.

Serious effects. Seizures (imipenem more than meropenem and ertapenem; highest in renal impairment, CNS disease and with excessive doses); C. difficile infection; carbapenem-resistant organism selection; encephalopathy; cytopenias; raised transaminases; ertapenem-associated hallucinations in older patients.

Interactions. Valproate: serum levels fall by 60 to 100 percent within 24 hours and seizures can recur; it cannot be overcome by dose increase and the carbapenem should be replaced or an alternative antiseizure drug added. Ganciclovir with imipenem increases seizure risk. Probenecid raises carbapenem levels.

Monitoring. Renal function and dose; full blood count and liver tests weekly in prolonged courses; seizure watch in at-risk patients.

Special groups.

• Pregnancy: meropenem and ertapenem are used when indicated; breastfeeding is compatible.
• Renal impairment (meropenem): creatinine clearance 26 to 50 mL/min, 1 g every 12 hours; 10 to 25 mL/min, 500 mg every 12 hours; under 10 mL/min, 500 mg every 24 hours. Ertapenem: 500 mg daily when clearance is 30 mL/min or less. Imipenem: reduced stepwise and avoided at clearance under 15 mL/min unless dialysis is arranged.
• Hepatic impairment: no adjustment.
• Obesity and critical illness: extended infusion and full dosing; avoid reducing early in AKI.
• Region: carbapenem resistance in East Africa is reported particularly in hospital Klebsiella, Acinetobacter and Pseudomonas; access to carbapenems is uneven, which affects both empirical choice and stewardship.