Microbiology

Colistimethate sodium is a surface  active agent which penetrates into and disrupts the bacterial cell membrane.  It has been shown to have bactericidal activity against most strains of the following microorganisms, both in vitro and in clinical infections as described in INDICATIONS AND USAGE.

Aerobic gram-negative microorganisms

Enterobacter aerogenes, Escherichia coli, Klebsiella pneumoniae, and Pseudomonas aeruginosa.

Susceptibility Tests

Colistimethate sodium is no longer listed as an antimicrobial for routine testing and reporting by clinical microbiology laboratories.

General

Since colistimethate is eliminated mainly by renal excretion, it should be used with caution when the possibility of impaired renal function exists.  The decline in renal function with advanced age should be considered.

When actual renal impairment is present, colistimethate may be used, but the greatest caution should be exercised and the dosage should be reduced in proportion to the extent of the impairment.  Administration of amounts of colistimethate in excess of renal excretory capacity will lead to high serum levels and can result in further impairment of renal function, initiating a cycle which, if not recognized, can lead to acute renal insufficiency, renal shutdown, and further concentration of the antibiotic to toxic levels in the body.  At this point, interference of nerve transmission at neuromuscular junctions may occur and result in muscle weakness and apnea (see OVERDOSAGE). 

Signs indicating the development of impaired renal function include: diminishing urine output, rising BUN and serum creatinine and decreased creatinine clearance.  Therapy with colistimethate should be discontinued immediately if signs of impaired renal function occur. However, if it is necessary to reinstate the drug, dosing should be adjusted accordingly after drug plasma levels have fallen (see DOSAGE AND ADMINISTRATION). 

Prescribing Colistimethate for Injection, USP in the absence of a proven or strongly suspected bacterial infection or a prophylactic indication is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria.

Drug Interactions

Certain other antibiotics (aminoglycosides and polymyxin) have also been reported to interfere with the nerve transmission at the neuromuscular junction. Based on this reported activity, they should not be given concomitantly with colistimethate except with the greatest caution.

Curariform muscle relaxants (e.g., tubocurarine) and other drugs, including ether, succinylcholine, gallamine, decamethonium and sodium citrate, potentiate the neuromuscular blocking effect and should be used with extreme caution in patients being treated with colistimethate. 

Sodium cephalothin may enhance the nephrotoxicity of colistimethate.  The concomitant use of sodium cephalothin and colistimethate should be avoided.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Long-term animal carcinogenicity studies and genetic toxicology studies have not been performed with colistimethate sodium.  There were no adverse effects on fertility or reproduction in rats at doses of 9.3 mg/kg/day (0.3 times the maximum daily human dose when based on mg/m2).

Pregnancy - Teratogenic Effects

Pregnancy Category C

Colistimethate sodium given intramuscularly during organogenesis to rabbits at 4.15 and 9.3 mg/kg resulted in talipes varus in 2.6% and 2.9% of fetuses, respectively.  These doses are 0.25 and 0.55 times the maximum daily human dose based on mg/m2.  In addition, increased resorption occurred at 9.3 mg/kg. Colistimethate sodium was not teratogenic in rats at 4.15 or 9.3 mg/kg.  These doses are 0.13 and 0.3 times the maximum daily human dose based on mg/m2. There are no adequate and well-controlled studies in pregnant women.  Since colistimethate sodium is transferred across the placental barrier in humans, it should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Nursing Mothers

It is not known whether colistimethate sodium is excreted in human breast milk.  However, colistin sulphate is excreted in human breast milk.  Therefore, caution should be exercised when colistimethate sodium is administered to nursing women.

Geriatric Use

Clinical studies of colistimethate sodium did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects.  Other reported clinical experience has not identified differences in responses between the elderly and younger patients.  In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.  This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function.  Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.

Pediatric Use

In clinical studies, colistimethate sodium was administered to the pediatric population (neonates, infants, children and adolescents).  Although adverse reactions appear to be similar in the adult and pediatric populations, subjective symptoms of toxicity may not be reported by pediatric patients.  Close clinical monitoring of pediatric patients is recommended.

Information for Patients

Patients should be counseled that antibacterial drugs including Colistimethate for Injection, USP should only be used to treat bacterial infections.  They do not treat viral infections (e.g., the common cold).  When Colistimethate for Injection, USP is prescribed to treat a bacterial infection, patients should be told that although it is common to feel better early in the course of therapy, the medication should be taken exactly as directed.  Skipping doses or not completing the full course of therapy may (1) decrease the effectiveness of the immediate treatment and (2) increase the likelihood that bacteria will develop resistance and will not be treatable by Colistimethate for Injection, USP or other antibacterial drugs in the future.

Important

Colistimethate for Injection, USP is supplied in vials containing colistimethate sodium equivalent to 150 mg colistin base activity per vial.

Reconstitution

The 150 mg vial should be reconstituted with 2 mL Sterile Water for Injection, USP.  The reconstituted solution provides colistimethate sodium at a concentration equivalent to 75 mg/mL colistin base activity.

During reconstitution swirl gently to avoid frothing. 

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.  If these conditions are observed, the product should not be used.

Dosage

Adults and pediatric patients-Intravenous or Intramuscular Administration

Colistimethate for Injection, USP should be given in 2 to 4 divided doses at dose levels of 2.5 to 5 mg/kg per day for patients with normal renal function, depending on the severity of the infection.

In obese individuals, dosage should be based on ideal body weight. 

The daily dose should be reduced in the presence of renal impairment.  Modifications of dosage in the presence of renal impairment are presented in Table 1.

TABLE 1. Suggested Modification of Dosage Schedules of Colistimethate for Injection, USP for Adults with Impaired Renal Function

Note: The suggested unit dose is 2.5 to 5 mg/kg; however, the time INTERVAL between injections should be increased in the presence of impaired renal function.