Imipenem-Cilastatin (Primaxin)
imipenem and cilastatin sodium
Indications
| Indication | Approved Population | Therapy Type | Status |
|---|---|---|---|
| Lower respiratory tract infections | Adults & pediatrics | Monotherapy | FDA Approved |
| Urinary tract infections (complicated & uncomplicated) | Adults & pediatrics | Monotherapy | FDA Approved |
| Intra-abdominal infections | Adults & pediatrics | Monotherapy | FDA Approved |
| Gynecologic infections | Adults & pediatrics | Monotherapy | FDA Approved |
| Bacterial septicemia | Adults & pediatrics | Monotherapy | FDA Approved |
| Bone and joint infections | Adults & pediatrics | Monotherapy | FDA Approved |
| Skin and skin structure infections | Adults & pediatrics | Monotherapy | FDA Approved |
| Endocarditis (S. aureus) | Adults | Monotherapy | FDA Approved |
Imipenem-cilastatin is a broad-spectrum Group 2 carbapenem with activity against a wide range of gram-positive aerobes (including penicillinase-producing S. aureus and Enterococcus faecalis), gram-negative aerobes (including Pseudomonas aeruginosa, Acinetobacter species, and Enterobacterales), and anaerobes (including Bacteroides fragilis). Unlike ertapenem, imipenem-cilastatin retains activity against P. aeruginosa and Acinetobacter, making it suitable for nosocomial infections. Cilastatin is co-formulated at a 1:1 ratio to block renal dehydropeptidase-I, which would otherwise rapidly inactivate imipenem in the kidneys. MRSA and most Enterococcus faecium strains are resistant.
Febrile neutropenia (empiric monotherapy): IDSA and NCCN guidelines list imipenem-cilastatin as an option for empiric monotherapy in high-risk febrile neutropenia. Evidence quality: High.
Nosocomial pneumonia / HAP / VAP: International guidelines include imipenem-cilastatin as empiric therapy for hospital-acquired and ventilator-associated pneumonia when multidrug-resistant pathogens are suspected. Evidence quality: High.
Multidrug-resistant gram-negative infections: Used for serious infections caused by ESBL-producing or AmpC-producing Enterobacterales when susceptible. Evidence quality: Moderate.
Dosing
Adult Dosing by Clinical Scenario (CrCl ≥90 mL/min)
| Clinical Scenario | Starting Dose | Maintenance Dose | Maximum Dose | Notes |
|---|---|---|---|---|
| Moderate infection — susceptible organism (e.g., uncomplicated UTI, community-acquired IAI) | 500 mg IV q6h | 500 mg IV q6h | 2 g/day | Infuse over 20–30 min Adjust to culture results when available |
| Severe infection — susceptible organism (e.g., bacteremia, nosocomial pneumonia, complicated IAI) | 1 g IV q8h | 1 g IV q8h | 3 g/day | Infuse over 40–60 min Preferred for Pseudomonas coverage |
| Life-threatening infection or organism with intermediate susceptibility | 1 g IV q6h | 1 g IV q6h | 4 g/day | Infuse over 40–60 min Maximum recommended daily dose; slow infusion to reduce nausea |
| Febrile neutropenia — empiric therapy | 500 mg IV q6h | 500 mg IV q6h | 4 g/day | Escalate to 1 g q6h if inadequate response Per IDSA/NCCN febrile neutropenia guidelines (off-label) |
Pediatric Dosing (Non-CNS Infections)
| Clinical Scenario | Starting Dose | Maintenance Dose | Maximum Dose | Notes |
|---|---|---|---|---|
| Children ≥3 months | 15–25 mg/kg IV q6h | 15–25 mg/kg IV q6h | 4 g/day | Higher end for severe infections Infuse over 20–30 min (≤500 mg) or 40–60 min (>500 mg) |
| Neonates 4 weeks to 3 months (≥1,500 g) | 25 mg/kg IV q6h | 25 mg/kg IV q6h | 4 g/day | Do not use diluents with benzyl alcohol |
| Neonates 1–4 weeks | 25 mg/kg IV q8h | 25 mg/kg IV q8h | 4 g/day | Longer interval reflects neonatal renal maturation |
| Neonates <1 week | 25 mg/kg IV q12h | 25 mg/kg IV q12h | 4 g/day | Most conservative interval for immature renal function |
Renal Impairment Dosing (Adults)
| Clinical Scenario | Starting Dose | Maintenance Dose | Maximum Dose | Notes |
|---|---|---|---|---|
| CrCl 60–89 mL/min (500 mg q6h base) | 400 mg IV q6h | 400 mg IV q6h | 1.6 g/day | Mild reduction |
| CrCl 30–59 mL/min (500 mg q6h base) | 300 mg IV q6h | 300 mg IV q6h | 1.2 g/day | Moderate reduction |
| CrCl 15–29 mL/min (500 mg q6h base) | 200 mg IV q6h | 200 mg IV q6h | 800 mg/day | Increased seizure risk at this level Monitor closely for neurotoxicity |
| CrCl <15 mL/min (no HD) | Not recommended unless hemodialysis instituted within 48 hours | |||
| Hemodialysis | Per CrCl 15–29 table | Per CrCl 15–29 table | Per CrCl 15–29 table | Administer after hemodialysis session; time intervals from end of HD Both components are hemodialyzable |
Nausea is directly related to infusion speed. Doses of 500 mg should be infused over 20–30 minutes, and doses of 1 g over 40–60 minutes. If nausea develops during infusion, slow the rate further. Unlike ertapenem, imipenem-cilastatin requires multiple daily dosing (q6–8h) due to its short 1-hour half-life and is not suitable for once-daily outpatient parenteral therapy.
Pharmacology
Mechanism of Action
Imipenem is a thienamycin-derived carbapenem that exerts bactericidal activity by binding to penicillin-binding proteins (PBPs). It shows highest affinity for PBP 1A, PBP 1B, and PBP 2 of gram-negative bacteria. Binding to PBP 2 causes the formation of osmotically unstable spheroplasts rather than the filamentous forms seen with cephalosporins (which preferentially bind PBP 3). This unique PBP profile results in rapid bactericidal activity. Imipenem is highly resistant to hydrolysis by most serine beta-lactamases, including ESBLs, AmpC enzymes, and many penicillinases. However, it is inactivated by metallo-beta-lactamases (NDM, VIM, IMP) and class A carbapenemases (KPC). Cilastatin is co-administered in a 1:1 ratio to inhibit renal dehydropeptidase-I (DHP-I), which would otherwise hydrolyse imipenem in the proximal tubule, resulting in low urinary concentrations and potential nephrotoxicity from the accumulation of toxic metabolites.
ADME Profile
| Parameter | Value | Clinical Implication |
|---|---|---|
| Absorption | IV administration only; 100% bioavailability; Cmax 21–58 mcg/mL (500 mg dose) | Peak levels at end of infusion; IV-only formulation ensures reliable drug delivery in critically ill patients |
| Distribution | Vd ~0.2–0.35 L/kg; protein binding ~20% (imipenem), ~40% (cilastatin); penetrates respiratory tract, peritoneal fluid, bone, skin, fascia | Low protein binding means drug exposure is less affected by hypoalbuminaemia; good tissue penetration except CSF (not recommended for meningitis) |
| Metabolism | Imipenem hydrolysed by renal DHP-I (blocked by cilastatin); no CYP involvement; cilastatin metabolised to N-acetyl form | No hepatic drug interactions via CYP pathways; cilastatin protection enables ~70% urinary recovery of intact imipenem |
| Elimination | t½ ~1 h (both); ~70% excreted unchanged in urine (with cilastatin); hemodialyzable; plasma levels <1 mcg/mL by 4–6 h post-dose | Short half-life necessitates q6–8h dosing; dose reduction required when CrCl <90 mL/min; no accumulation with q6h dosing in normal renal function |
Side Effects
No individual adverse reaction reached an incidence of ≥10% in adult pivotal trials (n = 1,723). The highest-frequency clinical event was phlebitis/thrombophlebitis at 3.1%. In neonates (<3 months), convulsions were reported in 5.9% of patients.
| Adverse Effect | Incidence | Clinical Note |
|---|---|---|
| Phlebitis / thrombophlebitis | 3.1% | Most common adverse event; rotate IV sites and infuse at recommended rate |
| Nausea | 2.0% | Rate-related; reduce by slowing infusion speed |
| Diarrhoea | 1.8% | Usually mild; evaluate for C. difficile if persistent or bloody |
| Vomiting | 1.5% | Often accompanies nausea; improves with slower infusion |
| Rash | 0.9% | Maculopapular; assess for hypersensitivity if widespread or progressive |
| Adverse Effect | Estimated Frequency | Typical Onset | Required Action |
|---|---|---|---|
| Seizures | 0.4% (adults); 5.9% (neonates) | Variable; higher risk with excessive doses or renal impairment | Evaluate neurologically; initiate anticonvulsant therapy; reduce dose or discontinue imipenem-cilastatin |
| CNS toxicity (myoclonus, confusional states, encephalopathy, hallucinations) | <0.5% | Days to weeks; dose-dependent | Discontinue or reduce dose; neurological assessment; often resolves with drug removal |
| Anaphylaxis / severe hypersensitivity | Rare | Minutes to hours after infusion | Immediate discontinuation; epinephrine and emergency treatment; permanent avoidance |
| Clostridioides difficile-associated diarrhoea (CDAD) | Uncommon | During or up to 2 months post-therapy | Test for C. difficile toxin; discontinue imipenem-cilastatin; initiate targeted therapy |
| Hepatotoxicity (hepatitis, hepatic failure, jaundice) | Rare (postmarketing) | Variable | Discontinue if transaminases significantly elevated or clinical hepatitis develops |
| Severe dermatological reactions (SJS, TEN) | Very rare (postmarketing) | Days to weeks | Immediate discontinuation; dermatology consultation; supportive care |
| Pancytopenia / bone marrow depression | Rare (postmarketing) | Variable | Monitor CBC; discontinue if significant cytopenias develop |
Imipenem-cilastatin carries the highest seizure risk among carbapenems, particularly in patients with renal impairment (CrCl ≤30 mL/min), pre-existing CNS disorders, or when doses exceed recommendations. The seizure incidence was 0.4% in adults in clinical trials but is higher in neonates (5.9%) and in patients with compromised renal function. Strict adherence to renal dosing guidelines is essential. Imipenem-cilastatin is contraindicated for CNS infections in paediatric patients and not indicated for meningitis in any age group due to inadequate CSF penetration and seizure risk.
Drug Interactions
Imipenem-cilastatin does not undergo CYP-mediated hepatic metabolism. The principal interactions are pharmacodynamic (seizure potentiation) and pharmacokinetic (interference with renal excretion or valproic acid metabolism).
Monitoring
- Renal FunctionBaseline, then every 2–3 days
RoutineSerum creatinine and estimated CrCl. Dose adjustment is required for any CrCl below 90 mL/min. Patients with CrCl <15 should not receive imipenem-cilastatin unless on hemodialysis. - Neurological StatusThroughout therapy
RoutineMonitor for tremors, myoclonus, seizures, confusion, hallucinations. Higher risk with renal impairment (CrCl ≤30), excessive dosing, pre-existing CNS conditions, and concurrent ganciclovir or cyclosporine therapy. - Hepatic FunctionBaseline, then periodically
RoutineTransaminase (ALT/AST), alkaline phosphatase, and bilirubin elevations reported during clinical trials. Fulminant hepatitis reported postmarketing. Monitor during prolonged therapy. - Complete Blood CountBaseline, then weekly
RoutineEosinophilia, thrombocytopenia, neutropenia, leucopenia, and pancytopenia have been reported. Positive direct Coombs test possible. Periodic CBC advisable during prolonged courses. - GI SymptomsThroughout and post-therapy
Trigger-basedEvaluate for C. difficile infection if diarrhoea develops. CDAD can present during therapy or up to 2 months after discontinuation. - Valproic Acid LevelsIf co-administered
Trigger-basedRapid VPA level decline expected. Monitor daily if concurrent use unavoidable; supplemental anticonvulsant therapy may be needed.
Contraindications & Cautions
Absolute Contraindications
- Known hypersensitivity to any component of imipenem-cilastatin
- History of anaphylaxis to any beta-lactam antibiotic
Relative Contraindications (Specialist Input Recommended)
- CNS infections / meningitis: Not indicated due to inadequate CSF penetration and increased seizure risk. Not recommended in paediatric patients with CNS infections.
- CrCl <15 mL/min without hemodialysis access: Drug accumulation significantly increases seizure risk. Should not be used unless hemodialysis can be instituted within 48 hours.
- Concurrent valproic acid therapy: Generally not recommended due to rapid reduction in VPA levels with seizure risk.
- Concurrent ganciclovir: Avoid unless benefit clearly outweighs seizure risk.
Use with Caution
- Renal impairment (CrCl <90 mL/min): Dose reduction required; risk of seizure increases as renal function declines, especially at CrCl ≤30.
- Pre-existing CNS disorders (seizure history, brain lesions): Increased risk of seizures even at appropriate doses.
- Paediatric patients <30 kg with renal impairment: No data available; not recommended.
- History of non-anaphylactic penicillin allergy: Cross-reactivity rate is low (<1%); use with monitoring.
- Neonates: Do not reconstitute with diluents containing benzyl alcohol.
Serious and occasionally fatal hypersensitivity (anaphylactic) reactions have been reported in patients receiving therapy with beta-lactams. These reactions are more likely in individuals with a history of sensitivity to multiple allergens. Before initiating imipenem-cilastatin, careful inquiry should be made concerning previous hypersensitivity reactions to penicillins, cephalosporins, other beta-lactams, and other allergens. If an allergic reaction occurs, the drug should be discontinued immediately.
Patient Counselling
Purpose of Therapy
Imipenem-cilastatin is a powerful injectable antibiotic used to treat serious bacterial infections. It contains two components: imipenem destroys bacteria by breaking down their cell walls, while cilastatin protects imipenem from being broken down by the kidneys. It is given by intravenous infusion several times a day and is typically administered in a hospital setting.
How to Take
Imipenem-cilastatin is given as an intravenous infusion over 20 to 60 minutes, depending on the dose. It is usually given every 6 to 8 hours. The full course of treatment should be completed as directed, even if you feel better, to prevent antibiotic resistance.
Sources
- Primaxin IV (imipenem and cilastatin) prescribing information. Merck Sharp & Dohme LLC. DailyMed. DailyMed Primary source for all FDA-approved dosing, indications, contraindications, adverse reactions, and pharmacokinetic data.
- Primaxin (imipenem and cilastatin) FDA label, 2016 revision. FDA Historical FDA label with complete clinical pharmacology, microbiology, and clinical trial data.
- Primaxin IV (imipenem and cilastatin) package insert. Merck & Co. Merck Manufacturer’s prescribing information including renal dose adjustment tables and paediatric dosing.
- Solomkin JS, Mazuski JE, Bradley JS, et al. Diagnosis and management of complicated intra-abdominal infection in adults and children: guidelines by the SIS and IDSA. Clin Infect Dis. 2010;50(2):133-164. doi:10.1086/649554 IDSA/SIS guideline listing imipenem-cilastatin as a recommended single-agent option for health care-associated intra-abdominal infections.
- Freifeld AG, Bow EJ, Sepkowitz KA, et al. Clinical practice guideline for the use of antimicrobial agents in neutropenic patients with cancer: 2010 update by IDSA. Clin Infect Dis. 2011;52(4):e56-93. doi:10.1093/cid/cir073 IDSA guideline listing imipenem-cilastatin as empiric monotherapy option for high-risk febrile neutropenia.
- Kalil AC, Metersky ML, Klompas M, et al. Management of adults with hospital-acquired and ventilator-associated pneumonia: 2016 clinical practice guidelines by IDSA and ATS. Clin Infect Dis. 2016;63(5):e61-e111. doi:10.1093/cid/ciw353 IDSA/ATS HAP/VAP guideline including imipenem-cilastatin as an empiric therapy option when MDR risk factors are present.
- Tamma PD, Aitken SL, Bonomo RA, et al. IDSA 2023 guidance on the treatment of antimicrobial-resistant gram-negative infections. Clin Infect Dis. 2023;ciad428. doi:10.1093/cid/ciad428 Current IDSA AMR guidance positioning carbapenems including imipenem-cilastatin in treatment algorithms for resistant gram-negative infections.
- Rodloff AC, Goldstein EJC, Torres A. Two decades of imipenem therapy. J Antimicrob Chemother. 2006;58(5):916-929. doi:10.1093/jac/dkl354 Comprehensive review of imipenem’s mechanism, spectrum, clinical efficacy, and safety over two decades of use.
- Papp-Wallace KM, Endimiani A, Taracila MA, Bonomo RA. Carbapenems: past, present, and future. Antimicrob Agents Chemother. 2011;55(11):4943-4960. doi:10.1128/AAC.00296-11 Detailed review of carbapenem pharmacology, beta-lactamase stability, and resistance mechanisms including PBP binding profiles.
- Drusano GL, Standiford HC, Fitzpatrick B, et al. Pharmacokinetics of imipenem in healthy volunteers. Antimicrob Agents Chemother. 1984;26(5):715-720. doi:10.1128/AAC.26.5.715 Foundational PK study establishing imipenem half-life (~1 h), volume of distribution, and effect of cilastatin on urinary recovery (~70%).
- Fish DN, Teitelbaum I, Abraham E. Pharmacokinetics and pharmacodynamics of imipenem during continuous renal replacement therapy in critically ill patients. Antimicrob Agents Chemother. 2005;49(6):2421-2428. doi:10.1128/AAC.49.6.2421-2428.2005 PK study demonstrating increased imipenem clearance during CVVH/CVVHDF, informing dose adjustment in critically ill patients on CRRT.
- Chen W, Zhang D, Lian W, et al. Imipenem population pharmacokinetics: therapeutic drug monitoring data collected in critically ill patients with or without ECMO. Antimicrob Agents Chemother. 2020;64(6):e00385-20. doi:10.1128/AAC.00385-20 Population PK study confirming low protein binding (~20%), primarily renal excretion (70%), and significantly altered PK in ECMO patients.
- Miller AD, Ball AM, Bookstaver PB, Dornblaser EK, Bennett CL. Epileptogenic potential of carbapenem agents: mechanism of action, seizure rates, and clinical considerations. Pharmacotherapy. 2011;31(4):408-423. doi:10.1592/phco.31.4.408 Comprehensive review of carbapenem seizure risk; imipenem-cilastatin seizure rates reported at 3–33% in high-risk populations versus <1% for other carbapenems.