IMISTIN 2G

Indications

• Infection treatment with imipenem
• Prevention of renal toxicity associated with high doses of imipenem

Dosage

Children: Refer to the BNF for Children for appropriate pediatric dosing information.

Adults: Refer to the BNF for specific dosing guidelines as they may vary based on indication and patient factors.

Mechanism of action

Cilastatin inhibits the enzyme renal dehydropeptidase-I, which is responsible for the hydrolysis of imipenem in the renal tubules. This inhibition prevents the degradation of imipenem, allowing it to maintain its antimicrobial activity.

Pharmacodynamics

Cilastatin acts by blocking the action of renal dehydropeptidase, thereby protecting imipenem from being metabolized and increasing its renal excretion as unchanged drug. While cilastatin does not display any direct antibacterial activity, its role in preserving imipenem levels helps mitigate the risk of nephrotoxicity associated with high doses of imipenem.

Pharmacokinetics

The pharmacokinetics of cilastatin involves its administration alongside imipenem, with cilastatin enhancing the pharmacological profile of imipenem. Cilastatin is administered intravenously, and its half-life and metabolic pathways are closely tied to those of imipenem. The renal clearance of cilastatin is significant, and it plays a protective role against renal damage from imipenem.

Pregnancy

Cilastatin should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. There are no adequate and well-controlled studies in pregnant women.

Breast-feeding

Cilastatin is excreted in human milk. Caution should be exercised when administering to breastfeeding women.

Storage

Store at room temperature, away from light and moisture. Do not freeze.

Formulations

• Cilastatin sodium for injection

Indications

• Complicated intra-abdominal infections
• Complicated urinary tract infections
• Pneumonia caused by susceptible bacteria
• Bacterial meningitis
• Sepsis
• Febrile neutropenia

Dosage

Children: Refer to the BNF for Children for appropriate dosing based on the child’s age, weight, and specific condition being treated.

Adults: Refer to specific guidelines for dosing based on the indication and renal function. Dosing adjustments may be necessary for patients with renal impairment.

Mechanism of action

Imipenem exerts its antibacterial effect by inhibiting bacterial cell wall synthesis. It binds to penicillin-binding proteins (PBPs), which are essential for the cross-linking of peptidoglycan layers in bacterial cell walls. This action disrupts the structural integrity of the bacterial cell wall, leading to cell lysis and death, particularly in actively dividing bacteria.

Pharmacodynamics

Imipenem demonstrates time-dependent killing, meaning that the duration of time that serum concentrations remain above the minimum inhibitory concentration (MIC) is critical for its efficacy. It shows a low propensity for resistance development due to its broad spectrum and the fact that it is not typically affected by common beta-lactamases. Its activity is characterized by a rapid bactericidal effect against susceptible organisms.

Pharmacokinetics

After intravenous administration, imipenem is rapidly distributed throughout the body. It has a volume of distribution of approximately 0.2 to 0.3 L/kg. The drug is primarily eliminated through renal mechanisms, with around 70% excreted unchanged in urine. Its half-life is about 1 hour. Cilastatin is co-administered to inhibit the renal enzyme that metabolizes imipenem, thus prolonging its action and maintaining effective plasma levels.

Contra-indications

• History of hypersensitivity to imipenem, cilastatin or any of the excipients
• Severe renal impairment
• Seizure disorders

Adverse effects

• Nausea
• Vomiting
• Diarrhea
• Rash
• Seizures
• Candidiasis
• Anemia
• Thrombocytopenia

Interactions

• Probenecid may increase imipenem levels
• Concurrent use with valproic acid may decrease valproic acid levels, potentially leading to seizures

Precautions

• Use with caution in patients with renal impairment
• Monitor for signs of superinfection
• May cause CNS effects like seizures, particularly in those with a history of seizure disorders

Pregnancy

Imipenem is categorized as pregnancy category B. Animal studies have not shown harm, but there are no adequate studies in pregnant women.

Breast-feeding

Imipenem is excreted in breast milk, caution is advised when administering to nursing mothers.

Storage

Store in a cool, dry place. Protect from light. After reconstitution, it should be used immediately or stored at 2 to 8 degrees Celsius for a limited time.

Formulations

• Injection for intravenous use
• Combination with cilastatin

Mechanism of action

Cilastatin is a renal dehydropeptidase-I inhibitor. Since the antibiotic, imipenem, is hydrolyzed by dehydropeptidase-I, which resides in the brush border of the renal tubule, cilastatin is administered with imipenem to block the metabolism of imipenem.

Pharmacodynamics

Cilastatin is a chemical compound which inhibits the human enzyme dehydropeptidase. Renal Dehydropeptidase degrades the antibiotic [imipenem]. Cilastatin is therefore combined intravenously with imipenem in order to protect it from dehydropeptidase and prolong its antibacterial effect. However, cilastatin in and of itself does not have any antibacterial activity. The increased renal excretion of unchanged imipenem appears to prevent proximal tubular necrosis associated with high doses of imipenem.