IMIPENEM-CILASTATIN SODIUM

Chemistry - Imipenem monohydrate is a carbapenem antibiotic that occurs as white or off-white, non-hygroscopic, crystalline compound. At room temperature, 11 mg are soluble in 1 ml of water.
Cilastatin sodium, an inhibitor of dehydropeptidase I (DHP I), occurs as an off-white to yellowish, hygroscopic, amorphous compound. More than 2 grams are soluble in 1 ml of water.
The commercially available injections are available in a 1:1 fixed dose ratio. The solutions are clearto yellowish in color. pH after reconstitution ranges from 6.5 to 7.5. These products also havesodium bicarbonate added as a buffer. The suspensions for IM use are white to light tan in color.

Storage, Stability, Compatibility

Commercially available sterile powders for injection should bestored at room temperature (<30°C). After reconstitution with 100 ml of sterile normal saline, thesolution is stable for 10 hours at room temperature and 48 hours when refrigerated. If otherdiluents are used, stability times may be reduced (see package insert or Trissell). Do not freezesolutions. The manufacturer does not recommend admixing with other drugs.
After reconstitution the sterile powder for suspension with 1% lidocaine HCl injection, the suspension should be used within one hour.

Pharmacology - IMIPENEM-CILASTATIN SODIUM

This fixed combination of a carbapenem antibiotic (imipenem) and an inhibitor(cilastatin) of dehydropeptidase I (DHP I) has a very broad spectrum of activity. Imipenem isconsidered to be generally a bactericidal agent, but may be static against some bacteria. It has anaffinity and binds to most penicillin-binding protein sites, thereby inhibiting bacterial cel wallsynthesis.
Imipenem has activity against a wide variety of bacteria, including Gram-positive aerobic cocci(including some bacteriostatic activity against enterococci), Gram-positive aerobic bacilli (includingstatic activity against Listeria), Gram-negative aerobic bacteria (Haemophilus, Enterobacteriaceae, many strains of Pseudomonas aeruginosa), and anaerobes (including some strains of Bacteroides).
Cilastatin inhibits the metabolism of imipenem by DHP 1 on the brush borders of renal tubularcells. This serves two functions: it allows higher urine levels and may also protect against proximalrenal tubular necrosis that can occur when imipenem is used alone.

Uses, Indications

Imipenem may be useful in equine or small animal medicine to treat seriousinfections when other less expensive antibiotics are ineffective or have unacceptable adverse effectprofiles.

Pharmacokinetics - IMIPENEM-CILASTATIN SODIUM

Neither drug is absorbed appreciably from the GI tract and therefore they aregiven parenterally. Bioavailability after IM injection is approximately 95% for imipenem and 75%for cilastatin. Imipenem is distributed widely throughout the body, with the exception of the CSF.
Imipenem crosses the placenta and is distributed into milk. When given with cilastatin, imipenem iseliminated by both renal and non-renal mechanisms. Approximately 75% of a dose is excreted inthe urine and about 25% is excreted by unknown non-renal mechanisms. Half lives in patients withnormal renal function range from 1-3 hours on average.

Contraindications, Precautions, Reproductive Safety

The potential risks versus benefitsshould be carefully weighed before using imipenem/cilastatin in patients hypersensitive to it orother beta-lactam antibiotics (e.g., penicillins, cephalosporins as partial cross-reactivity may occur), in patients with renal function impairment (dosages may need to be reduced or time between doseslengthened), or in patients with CNS disorders (e.g., seizures, head trauma) as CNS adverse effectsmay be more likely to occur.
While no teratogenic effects have been noted in animal studies, safe use during pregnancy has notbeen firmly established. While imipenem enters milk, no adverse effects attributable to it have beennoted in nursing offspring.

Adverse Effects, Warnings

Potential adverse effects include: GI effects (vomiting, anorexia, diarrhea), CNS toxicity (seizures, tremors), hypersensitivity (pruritus, fever to anaphylaxis) andinfusion reactions (thrombophlebitis; too rapid IV infusions may cause GI toxicity or other untoward effects).
Rarely, transient increases in renal (BUN or serum creatinine values) or hepatic (AST/ALT/Alk
Phosphatase) function tests may be noted, as well as hypotension or tachycardias.

Overdosage, Acute Toxicity

Little information is available. The LD50 of imipenem:cilastatin ina1:1 ratio in mice and rats is approximately 1 g/kg/day. Acute overdoses should be handled byhalting therapy and treating supportively and symptomatically.

Drug Interactions

There apparently is no therapeutic benefit in adding probenecid to prolongthe half lives of imipenem/cilastatin (does not appreciably affect imipenem excretion).
Additive effects or synergy may result when aminoglycosides are added to imipenem/cilastatintherapy, particularly against Enterococcus, Staph. aureus, and Listeria monocytogenes. There isapparently neither synergy nor antagonism when used in combination against Enterobacteriaceae, including Pseudomonas aeruginosa.
Antagonism may occur when used in combination with other beta lactam antibiotics againstseveral Enterobacteriaceae (including many strains of Pseudomonas aeruginosa and some strainsof Klebsiella, Enterobacter, Serratia, Enterobacter, Citrobacter and Morganella. The clinicalimportance of this interaction is unclear, but at present it is not recommended to use imipenem inconjunction with other beta lactam antibiotics.
Synergy may occur against Nocardia asteroides when used in combination with trimethoprim/sulfa.
Chloramphenicol may antagonize the antibacterial effects of imipenem.
Laboratory Considerations - When using Kirby-Bauer disk diffusion procedures for testingsusceptibility, a specific 10 micrograms imipenem disk should be used. An inhibition zone of 16mm or more indicates susceptibility; 14-15 mm, intermediate; and 13 mm or less, resistant.
When using a dilution susceptibility procedure, an organism with a MIC of 4 micrograms/ml or less is considered susceptible; 8 micrograms /ml moderately susceptible; and 16 micrograms/ml or greater, resistant.
Imipenem may cause a false-positive urine glucose determination when using the cupric sulfate solution test (e.g., Clinitest®).