Cilastatin

Cilastatin is always administered in a fixed combination with Imipenem. Therefore, this entry will address the combined drug Imipenem/Cilastatin.

Usage

Imipenem/Cilastatin is a broad-spectrum antibiotic prescribed for a wide range of bacterial infections. This includes:

• Lower Respiratory Tract Infections: Pneumonia, bronchitis, lung abscesses, and empyema.
• Urinary Tract Infections: Cystitis, pyelonephritis, and complicated UTIs.
• Intra-abdominal Infections: Peritonitis, intra-abdominal abscesses, and other infections within the abdominal cavity.
• Gynecological Infections: Pelvic inflammatory disease, endometritis, and other female reproductive tract infections.
• Skin and Skin Structure Infections: Cellulitis, wound infections, and abscesses.
• Bacterial Septicemia: Bloodstream infections.
• Bone and Joint Infections: Osteomyelitis and septic arthritis.
• Endocarditis: Infection of the heart valves.

Pharmacological Classification: Carbapenem Antibiotic

Mechanism of Action: Imipenem exerts its bactericidal action by inhibiting bacterial cell wall synthesis. It binds to penicillin-binding proteins (PBPs), disrupting the final step of peptidoglycan synthesis. Cilastatin, a renal dehydropeptidase inhibitor, protects Imipenem from being broken down by the kidneys, thereby increasing its effectiveness.

Alternate Names

While Cilastatin itself doesn’t have alternate names, the combination Imipenem/Cilastatin does have some regional variations.

Brand Name: Primaxin (most common), Recarbrio (with the addition of Relebactam)

How It Works

Pharmacodynamics: Imipenem/Cilastatin has bactericidal activity against a broad spectrum of Gram-positive and Gram-negative bacteria, including many aerobic and anaerobic species. Cilastatin itself has no antibacterial activity; its role is to protect imipenem.

Pharmacokinetics:

• Absorption: Imipenem/Cilastatin is administered intravenously (IV) or intramuscularly (IM). IV administration leads to rapid distribution into most body tissues and fluids, including cerebrospinal fluid.
• Metabolism: Imipenem is rapidly metabolized by renal dehydropeptidase I. Cilastatin effectively inhibits this metabolism. Cilastatin is partially metabolized renally.
• Elimination: Primarily renal excretion. Approximately 70% of both Imipenem and Cilastatin are excreted unchanged in the urine within 10 hours of administration.

Mode of Action: Imipenem irreversibly inhibits bacterial cell wall synthesis by binding to PBPs, ultimately leading to cell death.

Elimination Pathways: Renal excretion (both Imipenem and Cilastatin).

Dosage

Standard Dosage

Adults:

• IV: 250 mg to 1 g every 6 to 8 hours, or 500-750 mg every 12 hours IM, depending on the severity of the infection.
• Maximum Daily Dose: Usually not exceeding 4 g/day.

Children (≥ 1 year):

• IV: 15-25 mg/kg every 6 hours for non-CNS infections. For infections with less susceptible bacteria or severe infections: 25 mg/kg every 6 hours.
• Maximum Daily Dose: Should not exceed 2 g/day in children under 40 kg or 4 g/day in children over 40 kg.

Special Cases:

• Elderly Patients: Dose adjustments based on creatinine clearance are essential.
• Patients with Renal Impairment: Dosage reduction is mandatory based on creatinine clearance (see detailed dosing tables in sources).
• Patients with Hepatic Dysfunction: No dosage adjustment is typically necessary.
• Patients with Comorbid Conditions: Caution is advised in patients with CNS disorders (e.g., seizures), myasthenia gravis, or history of colitis.

Clinical Use Cases Dosages for these specific clinical situations are generally within the standard adult and pediatric ranges described above and are determined by the severity and type of infection. Consideration of renal function and body weight is important.

Dosage Adjustments

As mentioned in the special cases, dose modifications are based on creatinine clearance for renal impairment.

Side Effects

Common Side Effects:

• Nausea
• Vomiting
• Diarrhea
• Injection site reactions (pain, swelling, redness)
• Rash
• Dizziness

Rare but Serious Side Effects:

• Seizures (especially in patients with CNS disorders or renal impairment)
• Clostridioides difficile-associated diarrhea
• Allergic reactions (including anaphylaxis)
• Stevens-Johnson syndrome
• Toxic epidermal necrolysis

Long-Term Effects: Superinfections (e.g., fungal infections) can occur with prolonged use.

Adverse Drug Reactions (ADR): Any sign of hypersensitivity (rash, itching, hives, swelling, difficulty breathing) requires immediate discontinuation of the drug and appropriate medical intervention.

Contraindications

• Hypersensitivity to Imipenem, Cilastatin, or other carbapenems.
• Severe hypersensitivity to other beta-lactam antibiotics (penicillins, cephalosporins).

Drug Interactions

• Valproic Acid/Divalproex Sodium: Imipenem/Cilastatin can decrease valproic acid levels, increasing the risk of seizures. This combination should generally be avoided.
• Ganciclovir: Increased risk of seizures when co-administered.
• Probenecid: Increases Imipenem levels (although this interaction is not usually clinically significant).
• Anticoagulants (e.g., warfarin): Monitor for increased bleeding risk.

Pregnancy and Breastfeeding

• Pregnancy: Limited human data. Animal studies show an increased risk of embryonic loss. Use only if the potential benefit justifies the potential risk to the fetus. FDA Pregnancy Category C (old system).
• Breastfeeding: Imipenem and Cilastatin are excreted in breast milk. Use with caution, considering the potential risk to the infant.

Drug Profile Summary

• Mechanism of Action: Inhibits bacterial cell wall synthesis. Cilastatin protects Imipenem from renal degradation.
• Side Effects: Nausea, vomiting, diarrhea, injection site reactions, rash, seizures, allergic reactions.
• Contraindications: Hypersensitivity to carbapenems or beta-lactam antibiotics.
• Drug Interactions: Valproic acid, ganciclovir, probenecid.
• Pregnancy & Breastfeeding: Use with caution. Potential risk to fetus/infant.
• Dosage: See detailed sections above.
• Monitoring Parameters: Renal function, signs of hypersensitivity, neurological status, signs of superinfection.

Popular Combinations

Imipenem/Cilastatin is sometimes used in combination with other antibiotics (e.g., aminoglycosides) for synergistic effects against resistant Pseudomonas aeruginosa.

Precautions

• General Precautions: Assess renal function, monitor for hypersensitivity reactions, and watch for Clostridioides difficile-associated diarrhea.
• Specific Populations: See sections above on dosage for elderly, renal impairment, pregnancy, and breastfeeding.
• Lifestyle Considerations: No specific lifestyle restrictions are typically necessary.

FAQs (Frequently Asked Questions)

Q1: What is the recommended dosage for Imipenem/Cilastatin?

A: Please refer to the detailed Dosage section above, as it varies based on patient age, renal function, and infection severity.

Q2: What are the most serious side effects of Imipenem/Cilastatin?

A: Seizures, allergic reactions (including anaphylaxis), Stevens-Johnson Syndrome, and toxic epidermal necrolysis are the most serious potential side effects.

Q3: Can Imipenem/Cilastatin be used in pregnant women?

A: It should be used with caution during pregnancy and only if the potential benefit outweighs the potential risk to the fetus.

Q4: How is Imipenem/Cilastatin administered?

A: It is administered intravenously (IV) or intramuscularly (IM).

Q5: What is the role of Cilastatin in the Imipenem/Cilastatin combination?

A: Cilastatin is a renal dehydropeptidase I inhibitor. It prevents the breakdown of Imipenem in the kidneys, thereby increasing its effectiveness.

Q6: What types of infections is Imipenem/Cilastatin used to treat?

A: It is used to treat a wide range of bacterial infections, including lower respiratory tract infections, urinary tract infections, intra-abdominal infections, gynecological infections, skin and skin structure infections, bacterial septicemia, bone and joint infections, and endocarditis.

Q7: What are the common drug interactions with Imipenem/Cilastatin?

A: The most significant interaction is with valproic acid, as Imipenem/Cilastatin can lower valproic acid levels and increase the risk of seizures. It also interacts with ganciclovir, increasing the risk of seizures.

Q8: How should Imipenem/Cilastatin dosage be adjusted in patients with renal impairment?

A: Dosage adjustments are essential in patients with renal impairment. The dose should be reduced based on the patient’s creatinine clearance. Specific dosage recommendations can be found in the sources provided.

Q9: Can Imipenem/Cilastatin be used in patients with hepatic impairment?

A: No dosage adjustment is usually necessary in patients with hepatic dysfunction, as it is primarily excreted renally.

Q10: What is the difference between Primaxin and Recarbrio?

A: Primaxin contains Imipenem and Cilastatin. Recarbrio contains Imipenem, Cilastatin, and Relebactam (a beta-lactamase inhibitor). Relebactam broadens the spectrum of activity, particularly against certain resistant organisms.

This information is current as of February 16, 2025, and is intended for qualified medical professionals. Always consult up-to-date guidelines and resources.