Extended Spectrum Beta Lactamase Infections Pharmacotherapy

Extended spectrum beta-lactamases (ESBLs) are plasmid-borne class A enzymes (most often CTX-M, in E. coli and Klebsiella pneumoniae) that hydrolyse penicillins, cephalosporins (first to fourth generation) and aztreonam, but not carbapenems or cephamycins. Plasmids carrying ESBL genes often also carry resistance to aminoglycosides, fluoroquinolones and trimethoprim-sulfamethoxazole, which narrows oral options.

Risk and spread. Risk factors include prior antibiotic use, hospital stay, urinary catheters, travel to high-prevalence regions, and previous ESBL colonisation. Community-onset infection is common in East Africa. Fluoroquinolone and third generation cephalosporin use drive carriage.

Treatment principles. Treat only infection, not colonisation. Use a carbapenem for severe infection and bacteraemia. Use oral or non-carbapenem options for mild urinary infection. Reduce carbapenem use when a safe active alternative exists, to limit carbapenem resistance.

• Carbapenems (meropenem, ertapenem, imipenem): most reliable; the reference for severe infection.
• Piperacillin-tazobactam: appears active in vitro but gives worse outcomes in ESBL bacteraemia than a carbapenem.
• Cefepime: unreliable for ESBL infection.
• Oral and non-carbapenem urinary agents: nitrofurantoin, fosfomycin, pivmecillinam and temocillin (where available), co-trimoxazole, ciprofloxacin or levofloxacin (if susceptible), aminoglycosides (single dose or short course).
• Newer agents (carbapenem-sparing): ceftolozane-tazobactam, ceftazidime-avibactam, cefepime-enmetazobactam; reserve use.
• Tigecycline and eravacycline: intra-abdominal infection when carbapenems are unsuitable.

Adult regimens (normal renal function).

• Bacteraemia, pneumonia, sepsis, meningitis: meropenem 1 g IV every 8 hours (2 g every 8 hours for meningitis), over 30 minutes or by extended infusion in critical illness.
• Stable patient without Pseudomonas risk and with normal albumin: ertapenem 1 g IV once daily.
• Oral step-down after clinical improvement, source control and a susceptible isolate: co-trimoxazole 960 mg every 12 hours, ciprofloxacin 500 to 750 mg every 12 hours, or levofloxacin 750 mg daily. Total duration 7 days for bacteraemia from a controlled urinary or abdominal source.
• Cystitis: nitrofurantoin 100 mg modified-release every 12 hours for 5 days; fosfomycin 3 g once (repeated every 48 to 72 hours for 3 doses in complicated infection); pivmecillinam 400 mg every 8 hours for 3 to 5 days where available.
• Pyelonephritis and complicated urinary infection: ertapenem or meropenem, or amikacin 15 mg/kg once daily for up to 3 days, then oral step-down.
• Intra-abdominal infection: ertapenem or meropenem with source control; duration about 4 days after adequate source control.
• Children: meropenem 20 mg/kg every 8 hours (maximum 1 g, or 2 g in meningitis); ertapenem 15 mg/kg every 12 hours for ages 3 months to 12 years.

Selection. Do not use ceftriaxone, cefepime or aztreonam for ESBL infection. Piperacillin-tazobactam is avoided in bacteraemia and may be considered in low-risk urinary infection only if susceptibility is proven.

Principal risks. Carbapenem seizures in renal impairment and with valproate (levels fall by 60 to 100 percent; avoid co-prescription); C. difficile infection; fluoroquinolone tendon and CNS toxicity; nitrofurantoin lung and liver toxicity in prolonged use; aminoglycoside nephrotoxicity and ototoxicity; co-trimoxazole hyperkalaemia and marrow suppression.

Monitoring. Renal function and dose adjustment; clinical response at 48 to 72 hours; repeat blood cultures in persistent fever; liver and blood tests for prolonged courses.

Special groups. Pregnancy: meropenem, ertapenem and fosfomycin are acceptable; nitrofurantoin before term; avoid fluoroquinolones and aminoglycosides unless essential. Breastfeeding: carbapenems acceptable. Renal impairment: meropenem 1 g every 12 hours at creatinine clearance 26 to 50 mL/min; ertapenem 500 mg daily at 30 mL/min or less. Region: ESBL carriage is common in East Africa; screening is rarely available, so empirical carbapenem use for severe sepsis with prior hospitalisation or antibiotics is reasonable, followed by prompt de-escalation.