Imipenem Cilastatin

Imipenem cilastatin is a broad-spectrum carbapenem combined with an inhibitor of renal dehydropeptidase. It is used for severe hospital-acquired and polymicrobial infection and ESBL or AmpC infection. Its seizure risk is higher than that of meropenem.

Classification. Beta-lactam, carbapenem. Doses are written as the imipenem content: 500 mg imipenem is given with 500 mg cilastatin.

Mechanism. Imipenem blocks penicillin-binding proteins and resists most beta-lactamases, including ESBL and AmpC; cilastatin prevents renal hydrolysis of imipenem.

Spectrum. MSSA, streptococci, Enterococcus faecalis, Enterobacterales including ESBL and AmpC producers, Pseudomonas aeruginosa, Acinetobacter (variable), Bacteroides and other anaerobes. Not active against MRSA, Enterococcus faecium, Stenotrophomonas, or carbapenemase producers.

Pharmacokinetics. IV (IM formulation exists in some regions). Half-life about 1 hour. Imipenem about 70% excreted unchanged in urine with cilastatin. Penetrates most tissues; CNS use is avoided.

No loading dose. Maximum 4 g daily in adults.

Adults.

• Mild to moderate infection: 250 to 500 mg IV every 6 hours.
• Severe infection, Pseudomonas, hospital-acquired pneumonia, intra-abdominal sepsis, febrile neutropenia: 500 mg IV every 6 hours or 1 g every 8 hours; up to 1 g every 6 hours for resistant Pseudomonas.
• Duration: intra-abdominal infection 4 to 7 days after source control; pneumonia 7 days; bacteraemia 7 to 14 days.

Children 3 months and over. 15 to 25 mg/kg every 6 hours; maximum 2 g daily for susceptible organisms and 4 g daily for moderately susceptible organisms. Not advised for meningitis. Neonates: 20 mg/kg every 12 hours in the first week and every 8 hours from 7 to 28 days (specialist advice).

Alternatives. Meropenem, ertapenem (no Pseudomonas cover), piperacillin tazobactam for non-ESBL organisms.

Contraindications. Hypersensitivity to carbapenems or any component; severe hypersensitivity to other beta-lactams. Cross-reactivity with penicillin allergy is under 1%.

Adverse effects. Nausea and vomiting (infusion-rate related), diarrhoea, rash, phlebitis, raised liver enzymes, eosinophilia. Serious: seizures, anaphylaxis, Clostridioides difficile infection, severe skin reactions, interstitial nephritis, cytopenias.

Seizure risk. Higher with high doses, kidney impairment (unadjusted dose), previous CNS disease, older age and low body weight.

Interactions. - Valproate: carbapenems lower valproate levels by 60 to 100% within 24 hours, causing seizures; avoid the combination. - Ganciclovir: increased seizure risk. - Probenecid raises imipenem levels. - Warfarin: INR changes.

Common prescribing errors. Using it for meningitis, giving full doses in renal failure, giving with valproate, and infusing too fast.

Special groups.

• Pregnancy: use only if the benefit outweighs risk. Breastfeeding: limited data.
• Older adults: lower dose by kidney function.
• Kidney impairment, for the 500 mg every 6 hours regimen: creatinine clearance 41 to 70 mL/min 500 mg every 8 hours; 21 to 40 mL/min 250 mg every 6 hours. Creatinine clearance 6 to 20 mL/min 250 mg every 12 hours; under 6 mL/min avoid unless dialysis starts within 48 hours.

For the 1 g every 8 hours regimen: 41 to 70 mL/min 500 mg every 6 hours; 21 to 40 mL/min 500 mg every 8 hours; 6 to 20 mL/min 500 mg every 12 hours. Haemodialysis: dose after the session. - Liver impairment: no adjustment.

Preparation. Dilute in 100 mL of 0.9% sodium chloride. Infuse doses of 500 mg or less over 20 to 30 minutes and 1 g over 40 to 60 minutes; slow the infusion if nausea occurs.

Baseline and monitoring. - Baseline: allergy history, medication review (valproate), creatinine, cultures, full blood count. - During treatment: creatinine and neurological status daily in acute illness; full blood count and liver tests twice weekly. - No therapeutic drug monitoring.

Stop rules. Stop for seizures, anaphylaxis, severe skin reaction or cytopenia.

Referral and escalation. Infectious diseases involvement for resistant Gram-negative infection, and neurology input for seizures.