Carbapenem Resistant Gram Negative Infection Pharmacotherapy

Carbapenem-resistant Gram-negative bacilli include carbapenem-resistant Enterobacterales (CRE), carbapenem-resistant Acinetobacter baumannii (CRAB) and carbapenem-resistant Pseudomonas aeruginosa (CRPA). The mechanisms differ and decide treatment: carbapenemases (KPC, class A; NDM, VIM and IMP, class B metallo-enzymes; OXA-48-like, class D), or non-enzymatic resistance from porin loss with AmpC or ESBL, and efflux (common in Pseudomonas). Infection carries high mortality and spreads in hospitals.

Treatment principles.

• Identify the carbapenemase type, because the choice of drug depends on it.
• Use a new active beta-lactam-inhibitor combination when available instead of colistin-based regimens.
• Achieve source control; give high doses by extended infusion; involve infectious diseases and microbiology.
• Isolate patients and screen contacts.

Adult regimens (normal renal function; specialist-led).

• Ceftazidime-avibactam 2.5 g IV every 8 hours over 2 hours. Meropenem-vaborbactam 4 g IV every 8 hours over 3 hours. Imipenem-cilastatin-relebactam 1.25 g IV every 6 hours over 30 minutes.
• For metallo-beta-lactamase producers: ceftazidime-avibactam 2.5 g every 8 hours with aztreonam 2 g every 8 hours, given together; or cefiderocol 2 g IV every 8 hours over 3 hours.
• CRAB: ampicillin-sulbactam delivering 9 g of sulbactam daily as extended infusion; polymyxin B (2 to 2.5 mg/kg load, then 1.25 to 1.5 mg/kg every 12 hours); minocycline 200 mg IV every 12 hours or tigecycline 200 mg then 100 mg every 12 hours; sulbactam-durlobactam 1 g/1 g every 6 hours over 3 hours with imipenem-cilastatin 1 g/1 g every 6 hours.
• CRPA: ceftolozane-tazobactam 3 g (2 g/1 g) every 8 hours for pneumonia, 1.5 g every 8 hours for urinary or abdominal infection.
• When newer drugs are unavailable (common in East Africa): a polymyxin (colistin loading dose 9 million international units, then 4.5 million every 12 hours, or polymyxin B) combined with high-dose extended-infusion meropenem if the MIC is not high, and/or an aminoglycoside (amikacin 15 to 20 mg/kg daily), fosfomycin or high-dose tigecycline, chosen by susceptibility results. Randomised studies of adding meropenem to colistin in carbapenem-resistant infection showed no mortality benefit, so the combination is used mainly to protect against emergence of resistance.
• Urinary infection: aminoglycoside (amikacin, plazomicin), fosfomycin, or the agents named for each mechanism.
• Duration: 7 to 14 days, depending on site, source control and response.

Selection. Avoid colistin monotherapy and tigecycline monotherapy for bacteraemia or pneumonia. Repeat susceptibility testing if the patient fails to respond.

Principal risks. Polymyxin nephrotoxicity and neurotoxicity; aminoglycoside nephro- and ototoxicity; tigecycline nausea, pancreatitis and a mortality signal; cefiderocol higher mortality in one study of Acinetobacter infections; carbapenem seizures; C. difficile infection.

Monitoring. Creatinine daily and drug-dose review; electrolytes; liver tests; repeat cultures; neurological state; polymyxin and aminoglycoside levels where available.

Infection control. Contact isolation, rectal screening of high-risk patients, cohort nursing, environmental decontamination, and antimicrobial restriction.

Special groups. Pregnancy: use the safest active agent; avoid aminoglycosides, tetracyclines and tigecycline if alternatives exist. Children: specialist dosing. Renal impairment: dose-adjust ceftazidime-avibactam, meropenem-vaborbactam, imipenem-relebactam, cefiderocol and colistin; polymyxin B unchanged. Region: availability of new agents and carbapenemase testing is limited in East Africa, so local policy, laboratory support and referral routes should be agreed in advance.

Referral and escalation. All carbapenem-resistant infection warrants infectious diseases input, infection prevention review and, where possible, referral to a centre with access to new agents.