Elephant specific information, if available, is in blue.

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 clear to yellowish in color. pH after reconstitution ranges from 6.5 to 7.5. These products also have sodium 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 be stored at room temperature (<30°C). After reconstitution with 100 ml of sterile normal saline, the solution is stable for 10 hours at room temperature and 48 hours when refrigerated. If other diluents are used, stability times may be reduced (see package insert or Trissell). Do not freeze solutions. 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 – 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 is considered to be generally a bactericidal agent, but may be static against some bacteria. It has an affinity and binds to most penicillin-binding protein sites, thereby inhibiting bacterial cell wall synthesis.

 

Imipenem has activity against a wide variety of bacteria, including Gram-positive aerobic cocci (including some bacteriostatic activity against enterococci), Gram-positive aerobic bacilli (including static 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 tubular cells. This serves two functions: it allows higher urine levels and may also protect against proximal renal tubular necrosis that can occur when imipenem is used alone.

 

Uses/Indications – Imipenem may be useful in equine or small animal medicine to treat serious infections when other less expensive antibiotics are ineffective or have unacceptable adverse effect profiles.

 

Pharmacokinetics – Neither drug is absorbed appreciably from the GI tract and therefore they are given 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 is eliminated by both renal and non-renal mecha­nisms. Approximately 75% of a dose is excreted in the urine and about 25% is excreted by unknown non-renal mechanisms. Half lives in patients with normal renal function range from 1-3 hours on average.

 

Contraindications/Precautions/Reproductive Safety – The potential risks versus benefits should be carefully weighed before using imipenem/cilastatin in patients hypersensitive to it or other 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 doses lengthened), or in patients with CNS disorders (e.g., seizures, head trauma) as CNS adverse effects may be more likely to occur.

 

While no teratogenic effects have been noted in animal studies, safe use during pregnancy has not been firmly established. While imipenem enters milk, no adverse effects at­tributable to it have been noted in nursing offspring.

 

Adverse Effects/Warnings – Potential adverse effects include: GI effects (vomiting, anorexia, diarrhea), CNS toxicity (seizures, tremors), hypersensitivity (pruritus, fever to anaphylaxis) and infusion 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 in a1:1 ratio in mice and rats is approximately 1 g/kg/day. Acute overdoses should be handled by halting therapy and treating supportively and symptomati­cally.

 

Drug Interactions – There apparently is no therapeutic benefit in adding probenecid to prolong the half lives of imipenem/cilastatin (does not appreciably affect imipenem excre­tion).

 

Additive effects or synergy may result when aminoglycosides are added to imipenem/cilastatin therapy, particularly against Enterococcus, Staph. aureus, and Listeria monocytogenes. There is apparently 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 against several Enterobacteriaceae (including many strains of Pseudomonas aeruginosa and some strains of Klebsiella, Enterobacter, Serratia, Enterobacter, Citrobacter and Morganella. The clinical importance of this interaction is unclear, but at present it is not recommended to use imipenem in conjunction 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 test­ing susceptibility, a specific 10 micrograms imipenem disk should be used. An inhibition zone of 16 mm 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®).

 

Doses –

Horses:

For susceptible infections: 15 mg/kg IV (over a 20 minute period) q 4- 6 hours (Walker 1992)

 

 

Monitoring Parameters – 1) Efficacy; 2) Adverse effects (including renal and hepatic function tests if treatment is prolonged or patient’s renal or hepatic function are in ques­tion)

 

Client Information – Imipenem/cilastatin should be administered in an inpatient setting. Clients should be informed of the cost of using this medication.

 

Dosage Forms/Preparations/FDA Approval Status/Withholding Times –

 

Veterinary-Approved Products: None

 

Human-Approved Products:

Imipenem:Cilastatin Parenteral for Injection for IV infusion: 250 mg:250 mg (with 10 mg sodium bicarbonate), 500 mg:500 mg (with 20 mg sodium bicarbonate); Primaxin® I.V.  (Merck); (Rx)

 

     Imipenem:Cilastatin Suspension for IM Injection: 500 mg:500 mg, 750 mg:750 mg; Primaxin® I.M.  (Merck); (Rx)