Usage
Cilastatin + Imipenem is prescribed for a broad range of bacterial infections, including:
- Lower respiratory tract infections (e.g., pneumonia, bronchitis)
- Urinary tract infections (complicated and uncomplicated)
- Intra-abdominal infections
- Gynecological infections
- Skin and skin structure infections
- Bone and joint infections
- Bacterial septicemia
- Endocarditis
Pharmacological Classification: Antibiotic, specifically a carbapenem.
Mechanism of Action: Imipenem exerts its bactericidal effect by inhibiting bacterial cell wall synthesis. Cilastatin, a dehydropeptidase inhibitor, protects imipenem from being degraded by renal enzymes, thereby increasing its concentration and efficacy.
Alternate Names
- International Nonproprietary Name (INN): Imipenem/cilastatin
- Brand Names: Primaxin, Recarbrio (imipenem/cilastatin/relebactam combination). Regional brand name variations may exist.
How It Works
Pharmacodynamics: Imipenem binds to penicillin-binding proteins (PBPs), crucial enzymes involved in bacterial cell wall synthesis. This binding disrupts the final transpeptidation step of peptidoglycan synthesis, ultimately leading to bacterial cell death. Cilastatin has no antibacterial activity itself; its role is to inhibit renal dehydropeptidase-I, preventing imipenem’s degradation and increasing its availability at the site of infection.
Pharmacokinetics:
- Absorption: Administered intravenously (IV) or intramuscularly (IM). No oral absorption.
- Distribution: Achieves good tissue penetration, including cerebrospinal fluid (CSF), but CSF levels may not be sufficient for treating meningitis, especially in children.
- Metabolism: Imipenem is rapidly metabolized by renal dehydropeptidase-I. Cilastatin effectively inhibits this metabolism. Cilastatin is partially metabolized to N-acetyl-cilastatin.
- Elimination: Both imipenem and cilastatin are primarily eliminated via renal excretion. Dose adjustments are needed for patients with renal impairment.
Dosage
Standard Dosage
Adults:
- Mild to moderate infections: 250-500 mg IV every 6 hours or 500-750 mg IV every 12 hours.
- Severe infections: Up to 1 g IV every 6-8 hours or 1-2 g every 12 hrs up to maximum of 50 mg/kg or 4g daily. Dosage is based on the imipenem component.
- Infusion Time: Infuse doses ≤ 500 mg over 20-30 minutes; doses > 500 mg over 40-60 minutes. Slow infusion rate if nausea occurs.
Children (≥ 3 months and NOT for CNS infections):
- Non-CNS infections: 15-25 mg/kg IV every 6 hours. Do not exceed a maximum daily dose of 4 g. Not recommended for children with CNS infections due to increased risk of seizures.
- Infusion Time: As with adults, adjust based on dose.
Special Cases:
- Elderly Patients: Monitor closely for adverse reactions, especially CNS effects. Dosage adjustments based on renal function are often necessary.
- Patients with Renal Impairment: Reduce dosage based on creatinine clearance. See detailed guidelines below.
- Patients with Hepatic Dysfunction: No specific dosage adjustment is typically needed.
- Patients with Comorbid Conditions (e.g., seizures): Exercise caution and adjust dosage or consider alternative antibiotics as needed.
Clinical Use Cases:
Dosages for clinical use cases generally align with the standard adult dosages outlined above. Duration of therapy is determined by the severity and type of infection and the patient’s clinical response.
Dosage Adjustments Based on Renal Function:
- Creatinine Clearance (CrCl) ≥ 90 mL/min: Standard adult dosage.
- CrCl 60-89 mL/min: 1 g IV every 6 hours
- CrCl 30-59 mL/min: 0.75 g IV every 6 hours
- CrCl 15-29 mL/min: 0.5 g IV every 6 hours
- CrCl < 15 mL/min (Hemodialysis): 0.5g IV every 6 hrs after dialysis; not recommended unless hemodialysis is initiated within 48 hours. Peritoneal dialysis: Not recommended.
Side Effects
Common Side Effects:
- Nausea
- Vomiting
- Diarrhea
- Headache
- Pain, redness, or swelling at the injection site.
Rare but Serious Side Effects:
- Seizures (especially in patients with CNS disorders or renal impairment)
- Clostridioides difficile-associated diarrhea (CDAD)
- Allergic reactions, including anaphylaxis
- Stevens-Johnson syndrome
- Toxic epidermal necrolysis
Long-Term Effects:
Chronic complications from prolonged use are rare but may include renal dysfunction, hearing loss, and peripheral neuropathy.
Adverse Drug Reactions (ADR):
Clinically significant ADRs requiring immediate intervention include anaphylaxis, severe skin reactions (SJS/TEN), seizures, and severe CDAD.
Contraindications
- Hypersensitivity to imipenem, cilastatin, or other carbapenems.
- History of severe hypersensitivity reactions to other beta-lactam antibiotics (penicillins, cephalosporins).
- Meningitis in children (meropenem is preferred).
Drug Interactions
- Valproic Acid/Divalproex Sodium: Imipenem/cilastatin can decrease valproic acid levels, potentially leading to seizures. Avoid concomitant use.
- Ganciclovir/Valacyclovir: Increased risk of seizures with co-administration. Avoid if possible.
- Probenecid: Increases imipenem/cilastatin levels by reducing renal clearance. Dosage adjustment may be necessary.
- Cyclosporine: May increase the neurotoxic effects of imipenem. Monitor closely.
- Anticoagulants (e.g., warfarin): Enhanced anticoagulant effects. Monitor INR.
Pregnancy and Breastfeeding
- Pregnancy: Limited data in humans; use only if the potential benefit outweighs the risk. FDA category C for imipenem-cilastatin, B3 for Australian TGA.
- Breastfeeding: Imipenem and cilastatin are excreted in breast milk. While generally considered compatible with breastfeeding, exercise caution and monitor the infant for potential adverse effects.
Drug Profile Summary
- Mechanism of Action: Inhibits bacterial cell wall synthesis. Cilastatin prevents imipenem degradation.
- Side Effects: Nausea, vomiting, diarrhea, headache, injection site reactions, seizures, CDAD, allergic reactions.
- Contraindications: Hypersensitivity to carbapenems, severe beta-lactam allergy, meningitis in children.
- Drug Interactions: Valproic acid, ganciclovir, probenecid, cyclosporine, anticoagulants.
- Pregnancy & Breastfeeding: Limited data; use with caution if benefits outweigh risks. Compatible with breastfeeding.
- Dosage: Varies based on infection, renal function, and age. See detailed guidelines above.
- Monitoring Parameters: Renal function, liver function, complete blood count (CBC), signs of hypersensitivity or neurological effects.
Popular Combinations
Imipenem/cilastatin may be used in combination with other antibiotics, such as aminoglycosides, for synergistic effects against certain resistant bacteria, especially Pseudomonas aeruginosa. However, Imipenem/cilastatin should not be physically mixed with other antibiotics in the same IV bag.
Precautions
- History of seizures or CNS disorders
- Renal impairment
- History of gastrointestinal disease (e.g., colitis)
- Monitor for signs of hypersensitivity reactions.
FAQs (Frequently Asked Questions)
Q1: What is the recommended dosage for Cilastatin + Imipenem?
A: See detailed dosage guidelines above.
Q2: What are the most common side effects?
A: Nausea, vomiting, diarrhea, and headache are the most commonly reported side effects.
Q3: Can Cilastatin + Imipenem be used to treat meningitis?
A: It is generally not recommended for meningitis in children due to the risk of seizures. Meropenem is often preferred. In adults, use with caution.
Q4: How is Cilastatin + Imipenem administered?
A: It is administered intravenously (IV) or intramuscularly (IM).
Q5: Are there any significant drug interactions?
A: Yes. Avoid concomitant use with valproic acid/divalproex sodium and ganciclovir/valacyclovir. Use with caution with probenecid, cyclosporine, and anticoagulants.
Q6: Can Cilastatin + Imipenem be used during pregnancy?
A: Use only if the potential benefit outweighs the potential risk to the fetus. Consult specialist advice.
Q7: Is Cilastatin + Imipenem safe for breastfeeding mothers?
A: Generally considered compatible with breastfeeding, but monitor the infant for potential side effects.
Q8: What should I monitor in patients receiving Cilastatin + Imipenem?
A: Monitor renal function, liver function, CBC, and signs of hypersensitivity or neurological effects.
Q9: How should Cilastatin + Imipenem be stored?
A: Store the powder at room temperature. Reconstituted solutions should be used within 4 hours at room temperature or within 24 hours if refrigerated. Do not freeze.
