Imipen

Approved Indications:
Imipenem + Cilastatin is approved for the treatment of the following moderate to severe infections caused by susceptible organisms:

• Complicated intra-abdominal infections
• Complicated urinary tract infections (including pyelonephritis)
• Lower respiratory tract infections, including hospital-acquired and ventilator-associated pneumonia
• Gynecological infections, such as endometritis and pelvic inflammatory disease
• Septicemia (bloodstream infections)
• Bone and joint infections
• Skin and soft tissue infections
• Bacterial endocarditis
• Polymicrobial infections, including those involving aerobic and anaerobic Gram-positive and Gram-negative organisms

Important Off-label / Clinically Accepted Uses:

• Febrile neutropenia, as empirical broad-spectrum coverage
• Multidrug-resistant (MDR) Gram-negative infections
• Post-surgical or nosocomial infections with suspected resistant organisms
• Central nervous system infections, with caution and specialist recommendation

Route:
Intravenous (IV) infusion only

Adults:

• Standard dose:
  500 mg Imipenem + 500 mg Cilastatin every 6 hours
  or
  1 g Imipenem + 1 g Cilastatin every 8 hours (for severe infections)
• Maximum daily dose (Imipenem):
  4 g/day or 50 mg/kg/day, whichever is lower

Pediatrics (>3 months of age):

• 15–25 mg/kg (based on Imipenem component) every 6 hours
• Maximum daily dose: 4 g/day (Imipenem)

Neonates (<3 months):

• Not routinely recommended; specialized dosing required in select cases

Elderly:

• No specific dose adjustment based on age, but monitor renal function closely

Renal Impairment:

• CrCl 21–50 mL/min: Reduce dose to 250 mg Imipenem + 250 mg Cilastatin every 6 or 8 hours
• CrCl 6–20 mL/min: 250 mg every 12 hours
• CrCl <5 mL/min: Not recommended unless hemodialysis is available
• Hemodialysis: Administer after dialysis; supplemental dosing may be required

Hepatic Impairment:

• No dose adjustment needed

Duration of therapy:
Typically 7–14 days, depending on infection site, severity, and patient response

Imipenem is a carbapenem-class beta-lactam antibiotic that inhibits bacterial cell wall synthesis by binding to penicillin-binding proteins (PBPs), primarily PBP-2 and PBP-1A/B. This inhibition disrupts peptidoglycan cross-linking, causing bacterial lysis and death. Cilastatin is not an antibiotic but a selective inhibitor of renal dehydropeptidase-I (DHP-I), an enzyme that rapidly degrades Imipenem in the renal tubules. By blocking this enzymatic degradation, Cilastatin prolongs the active concentration of Imipenem, enhances its antibacterial effect, and reduces nephrotoxic metabolite formation.

• Absorption: Not orally bioavailable; administered via IV only
• Distribution:
• Wide tissue distribution: peritoneum, lungs, skin, liver, bile, synovial fluid
• Variable penetration into CSF; increases with inflamed meninges
• Plasma protein binding:
• Imipenem: ~20%
• Cilastatin: ~40%
• Metabolism:
• Imipenem is degraded by DHP-I unless co-administered with Cilastatin
• Cilastatin is minimally metabolized
• Elimination:
• Primarily renal via glomerular filtration and tubular secretion
• ~70% of both drugs excreted unchanged
• Half-life:
• Imipenem: ~1 hour
• Cilastatin: ~1 hour
• Bioavailability: Not applicable (IV only)

• Pregnancy:
  FDA Category C
• Animal studies have shown adverse fetal effects
• Human data are limited; use only when benefits outweigh risks
• Lactation:
• Small amounts may be excreted in breast milk
• No reported adverse effects in nursing infants
• Use with caution and monitor infant for diarrhea or candidiasis
• Caution:
  Avoid in pregnancy unless absolutely necessary; lactation may continue if clinically justified

• Primary Class: Carbapenem antibiotic (Imipenem)
• Supportive Agent: Renal dehydropeptidase I inhibitor (Cilastatin)
• Combination Class: Broad-spectrum beta-lactam antibiotic with protective enzyme inhibitor

• Hypersensitivity to Imipenem, Cilastatin, or any beta-lactam antibiotics
• History of severe allergic reaction (e.g., anaphylaxis) to penicillins or cephalosporins
• Severe renal impairment without access to dialysis or dose adjustment
• Uncontrolled seizures or CNS disorders with high seizure risk
• Intrathecal administration (due to seizure risk)

• Seizures:
  May occur, especially in renal impairment, high doses, or CNS pathology. Monitor and adjust dose in at-risk patients.
• Hypersensitivity:
  Cross-reactivity with other beta-lactam antibiotics may cause anaphylaxis. Perform allergy history screening.
• Superinfections:
  Long-term use may lead to overgrowth of nonsusceptible organisms (e.g., Candida, Clostridioides difficile)
• Hematologic effects:
  Monitor for neutropenia, eosinophilia, thrombocytopenia with prolonged use
• Renal monitoring:
  Essential to prevent accumulation and CNS toxicity in patients with impaired renal function

Common Side Effects:

• Gastrointestinal: Nausea, vomiting, diarrhea, abdominal pain
• Neurological: Headache, dizziness
• Skin: Rash, pruritus, injection site reactions
• Hematologic: Eosinophilia, thrombocytopenia, leukopenia

Serious or Rare Side Effects:

• Seizures (especially in patients with renal dysfunction or CNS disorders)
• Anaphylaxis or severe allergic reactions
• Clostridium difficile-associated colitis
• Liver enzyme elevations (AST, ALT, bilirubin)
• Renal dysfunction or interstitial nephritis (rare)

Onset and Severity:

• Gastrointestinal and cutaneous side effects may occur early in treatment
• Seizures are dose-dependent and more likely in impaired renal function
• Hematologic changes often emerge after extended therapy (>7–10 days)

Major Drug Interactions:

• Valproic Acid:
  Significant reduction in serum levels; may trigger seizures. Avoid concomitant use.
• Probenecid:
  Competes for renal tubular secretion, increasing Imipenem and Cilastatin levels
• Cyclosporine or Tacrolimus:
  Increased nephrotoxicity risk when used together
• Other beta-lactams or aminoglycosides:
  May increase toxicity; monitor renal and auditory function closely

Enzyme Systems:

• Not metabolized by CYP450 enzymes; minimal risk of CYP-mediated interactions

Food & Alcohol:

• No interaction with food
• Alcohol does not directly interact, but caution is advised in acutely ill patients

• Extended-spectrum use confirmed:
  Imipenem + Cilastatin remains a first-line therapy for serious infections caused by extended-spectrum beta-lactamase (ESBL) producing organisms
• Triple combination therapy:
  Introduction of Imipenem + Cilastatin + Relebactam has expanded activity against carbapenem-resistant organisms
• Guideline Inclusion:
  Recommended in the latest IDSA, ESCMID, and WHO guidelines for empirical treatment of hospital-acquired infections and febrile neutropenia in high-risk patients

• Unreconstituted vials (powder):
  Store below 25°C (77°F)
  Protect from light and moisture
• After Reconstitution:
• Use immediately for best results
• Stable up to 4 hours at room temperature
• Stable up to 24 hours if refrigerated (2–8°C)
• Do Not Freeze reconstituted solution
• Handling Precautions:
  Prepare using aseptic technique
  Discard any unused solution
  Keep out of reach of children