Daptomycin

Some of the views expressed in the following notes on newly approved products should be regarded as preliminary, as there may have been limited published data at the time of publication, and little experience in Australia of their safety or efficacy. However, the Editorial Executive Committee believes that comments made in good faith at an early stage may still be of value. Before new drugs are prescribed, the Committee believes it is important that more detailed information is obtained from the manufacturer's approved product information, a drug information centre or some other appropriate source.

Cubicin (Novartis)
vials containing 350 mg and 500 mg as powder for reconstitution
Approved indications: skin infections, Staphylococcus aureus bacteraemia
Australian Medicines Handbook section 5.1

Daptomycin is a cyclic lipopeptide derived from a natural product of Streptomyces roseosporus. Its bactericidal effects stem from its ability to rapidly depolarise the membrane potential of Gram-positive bacteria. This causes inhibition of DNA, RNA and protein synthesis, and results in cell death.

It is indicated for adults with complicated skin and skin structure infections who require initial parenteral therapy and who are intolerant of alternative antibiotics (including those with penicillin allergy). It should only be used for infections suspected to be caused by susceptible Gram-positive bacteria.

Steady-state concentrations of daptomycin are reached after the third daily intravenous infusion. It is primarily excreted by the kidneys (mainly as unchanged drug) so dose adjustment is required for patients with severe renal insufficiency. Renal function and creatine kinase should be frequently monitored in these patients. In patients requiring haemodialysis, daptomycin should be administered after the procedure.

The efficacy of daptomycin (4 mg/kg intravenously once daily for 7-14 days) has been compared to a penicillin (cloxacillin, nafcillin, oxacillin or flucloxacillin) or vancomycin in two randomised trials with similar designs totalling 1092 participants. These patients were hospitalised mainly with complicated skin infections including wound infections, major abscesses, infected diabetic ulcers or other ulcers. Patients with mixed infections involving Gram-negative or anaerobic organisms were given concomitant aztreonam or metronidazole as appropriate. Among the clinically evaluable patients, treatment success rates for daptomycin were comparable to the comparator (83% vs 84%). However, in both groups success rates for methicillin-resistant Staphylococcus aureus infections were lower than for methicillin-sensitive S. aureus (75% vs 86% for daptomycin and 69% vs 87% for comparator). Success rates were also lower in patients aged 65 years or older.¹

In another analysis of the trials looking only at patients with diabetic ulcers (mainly of the foot), 66% (31/47) of clinically evaluable patients benefited from daptomycin treatment compared with 70% (39/56) of patients treated with a penicillin or vancomycin. Methicillin-resistant S. aureus was isolated from ten patients; one received daptomycin and the rest received a comparator. After a course of treatment, infection was cleared in three of the comparator-treated patients but not in the daptomycin-treated patient.²

Adverse events were similar between groups with gastrointestinal disorders being the most common. Fifteen of the 534 patients (2.8%) receiving daptomycin developed elevated creatine kinase levels compared to ten of the 558 (1.8%) receiving the comparator.¹

In Australia, daptomycin has also been approved for adults with bacteraemia caused by S. aureus, including those with right-sided native valve infective endocarditis caused by methicillin-susceptible or methicillin-resistant isolates. This approval was based on an open label randomised trial of patients with bacteraemia with or without left- or right-sided endocarditis. Daptomycin (6 mg/kg intravenously once daily) was compared to standard treatment consisting of gentamicin plus a penicillin (nafcillin, oxacillin or flucloxacillin) or vancomycin. (Patients in the daptomycin group who had left-sided endocarditis were also given gentamicin for the first four days.) The median duration of therapy was 14 days for daptomycin and 15 days for standard treatment.

Successful outcomes were reported in 53 of 120 (44%) patients receiving daptomycin and 48 of 115 (42%) patients receiving the comparator. In patients infected with methicillin-resistant isolates, success rates were similar for daptomycin but lower with standard treatment (44% vs 32%). Treatment failure was more often associated with persistent or relapsing S. aureus infection in the daptomycin group (15.8% of patients), whereas in the comparator group failure was more frequently associated with treatment-limiting adverse events. Therapy failed in all nine patients who had left-sided endocarditis caused by methicillin-resistant S. aureus, regardless of which treatment they received.³

Creatine kinase elevations were twice as common with daptomycin than with standard treatment (25% vs 12.5%). Adverse events related to the peripheral nervous system were also more common with daptomycin than with standard treatment (9.2% vs 1.7%), whereas renal impairment was more common with standard treatment than with daptomycin (18.1% vs 6.7%).³

Patients should be monitored for the development of muscle pain or weakness. Creatine kinase should be monitored weekly and more frequently in patients who have a higher risk of developing myopathy, such as those with severe renal insufficiency or taking other drugs that are associated with myopathy (HMG-CoA reductase inhibitors, fibrates, cyclosporin). Consider temporarily stopping HMG-CoA reductase inhibitors while patients are receiving daptomycin.

In patients taking concomitant warfarin, anticoagulant activity should be monitored during the first week of daptomycin therapy. Caution is urged when co-administering daptomycin with tobramycin.

Daptomycin-resistant bacteria have emerged in patients enrolled in the clinical trials. To reduce the development of daptomycin resistance, this antibiotic should only be used to treat or prevent infections that are proven or strongly suspected to be caused by susceptible bacteria. Daptomycin does not seem to be effective for infections caused by enterococci, including Enterococcus faecalis and E. faecium. Susceptibility of bacterial isolates should be monitored during the course of treatment.

Daptomycin provides another option for hospitalised adults with serious infections caused by Gram-positive pathogens. However, its efficacy may be lower in older adults. It can also be used for mixed infections involving Gram-negative or anaerobic bacteria if co-administered with appropriate antibiotics.

This antibiotic is not effective for left-sided endocarditis, or for pneumonia because it binds to surfactant and is inactivated. The efficacy of daptomycin in patients with prosthetic heart valves has not been demonstrated.

manufacturer provided only the product information

The Transparency Score () is explained in New drugs: transparency', Vol 37 No 1, Aust Prescr 2014;37:27.

Notes on references

At the time the comment was prepared, information about this drug was available on the web site of the Food and Drug Administration in the USA (www.fda.gov).

At the time the comment was prepared, a scientific discussion about this drug was available on the website of the European Medicines Agency (www.emea.europa.eu).