Chiron launches Cubicin, the first in a new class of antibiotics

Cubicin (daptomycin) is a novel antibiotic indicated for the treatment of complicated skin and soft tissue infections.

Brand Name: Cubicin.

Legal category: POM.

Active ingredient: Daptomycin 350 mg.

Description: Lyophilised powder for concentrate for solution for infusion in vial.

Presentation: Single vial, £62.00.

Indications: Treatment of complicated skin and soft tissue infections. Active against Gram positive bacteria only. In mixed infections where Gram negative and/or certain types of anaerobic bacteria are suspected, co-administer with appropriate antibacterial agents.

Pharmacology: As drug resistance continues to reduce the number of effective treatments available for serious infections, the introduction of a new class of antibiotics provides a welcome therapeutic option. Daptomycin is the first cyclic lipopeptide antibacterial agent that has been developed for the treatment of serious skin and soft tissue infections such as major abscesses, post-surgical skin wound infections and infected ulcers. It is indicated for use against susceptible strains of Gram positive bacteria but is not effective against Gram negative organisms.

Although its exact mode of action has not been fully elucidated, daptomycin is thought to bind to the bacterial cell membranes of growing and stationary phase cells. By binding it forms an ion conduction structure which allows a potassium efflux and rapid depolarisation of the membrane. This in turn leads to disruption of protein, DNA and RNA synthesis and hence bacterial cell death with negligible cell lysis. As daptomycin is not able to penetrate the outer membrane of Gram negative organisms, it is ineffective against such infections.

Following intravenous infusion, the pharmacokinetics of daptomycin are generally linear with steady-state concentrations achieved by the third daily dose. Tissue distribution studies have shown that it is preferentially distributed into highly vascularised tissues and to a lesser degree penetrates the blood-brain barrier and placental barrier. It is reversibly bound to human plasma proteins and in healthy volunteers protein binding averaged around 90%. Daptomycin undergoes little or no systemic metabolism and is excreted primarily via the kidneys.

In vitro, daptomycin has been shown to exhibit rapid, concentration dependent bactericidal activity and in animal models MIC values correlate with efficacy and predicted bacterial kill at doses equivalent to 4 mg/kg in man.

The safety and efficacy of daptomycin has been demonstrated in clinical trials involving over 1400 patients. In these studies daptomycin was shown to have activity against Staphylococcus aureus (including methicillin-resistant strains), Streptococcus agalactiae, Streptococcus dysgalactiae subsp equisimilis, Streptococcus pyogenes. In terms of the successful treatment of complicated skin and skin structure infections, daptomycin was found to be equivalent to standard therapies such as vancomycin or semi-synthetic penicillins such as oxacillin or nafcillin.

Most adverse events reported during these studies were mild to moderate in nature. Elevations in CPK have been reported and, uncommonly, were associated with muscle pain, myositis and rhabdomyolysis. Baseline and weekly CPK measurements are advised for all patients, or more frequently in those patients with a higher risk of developing myopathy or with higher CPK levels.

Adult dose: 4 mg/kg by intravenous infusion over 30 minutes once every 24 hours for 7-14 days or until infection resolved.

Child dose: Under 18 years, not recommended.

Special precautions: Ineffective in pneumonia, limited experience in bacteraemia. Renal insufficiency, dialysis, CAPD. Severe hepatic impairment. Elderly. Monitor plasma CPK before and during treatment. Monitor for signs of myopathy and advise patients to report unexplained muscle pain. Peripheral neuropathy; consider discontinuation. Obesity. Monitor for signs of colitis or symptoms indicative of pseudomembranous colitis. Pregnancy, lactation.

Interactions: Drugs associated with myopathy or those known to reduce renal filtration. Interference with PT/INR results.

Adverse reactions: Headache, nausea, vomiting, diarrhoea, muscle pain, fungal infections, rash, infusion site reaction, increased CPK, abnormal liver enzymes.
? Report any adverse reaction to CSM.

Further information: Chiron Corporation Ltd, Symphony House, Cowley Business Park, Cowley, Uxbridge UB8 2AD. Tel: (020) 8580 4000.

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