"Daptomycin Is Clinically More Rapidly Effective Than Comparator for Treatment of Complicated Skin and Skin-Structure Infections: Presented at ECCMID-ICC"
By Chris Berrie
MUNICH, GERMANY -- April 5, 2007 -- The cyclic lipopeptide antibiotic daptomycin elicits statistically significant earlier responses than vancomycin or semi-synthetic penicillin as comparators in the treatment of patients with complicated skin and skin-structure infections (cSSSIs), according to a subpopulation analysis from 2 large, blinded, randomised phase 3 studies.
Lawrence Friedrich, PharmD, Co-Investigator and Senior Clinical Scientific Director, Cubist Pharmaceuticals Inc., Lexington, Massachusetts, United States, presented the findings here at the joint 17[th European Congress of Clinical Microbiology and Infectious Diseases and 25th International Congress on Chemotherapy (ECCMID-ICC).
"[Daptomycin] is a relatively new antibiotic, and it can be differentiated from some of the older antibiotics like vancomycin as it is rapidly bactericidal and can be given once a day," Dr. Friedrich said in a presentation on April 1st.
Daptomycin has been shown to have a rapid concentration-dependent bactericidal activity in vitro against most clinically relevant Gram-positive bacteria, including methicillin-resistant Staphylococcus aureus (MRSA). Furthermore, daptomycin was shown to be as effective as the comparator for the resolution of clinical signs and symptoms in patients with cSSSIs in 2 phase 3 trials.
With these 2 trials performed in potentially heterogeneous populations from multiple countries with differing patient population characteristics, there may have been tendencies between the treatment regimens that were lost.
The patient population from South Africa represents some 40% of the clinically evaluable patients with cSSSIs, therefore, the rationale behind the present subgroup analysis was to provide a large enough population under conditions of minimal differences in health-care resources and utilisation, and in treatment patterns among the original patient populations.
The original study populations were based on the enrolment of patients with cSSSIs due to Gram-positive microorganisms requiring hospitalisation and parenteral antimicrobial therapy for at least 96 hours. Exclusion criteria included minor and superficial infections, concomitant infections, or the requirement for surgery.
The treatment protocols consisted of either daptomycin 4 mg/kg IV per day, or comparator -- either semi-synthetic penicillin 4-12 g IV per day, in equally divided doses, or vancomycin 1 g IV every 12 hours.
The 356 South African patients were initially included in this analysis. However, as patients with 2 or more comorbid conditions were not equally represented between the 2 combined South African treatment arms, these were removed from the present analysis (5 daptomycin and 25 comparator patients).
This thus supplied 326 patients for this subpopulation analysis, with the treatment groups for daptomycin (n = 174; mean age, 40 years; male, 56%) and comparator (n = 152; mean age, 40 years, male, 57%).
There were no significant differences between the 2 groups in terms of patient demographic, comorbid conditions (systemic inflammatory response syndrome, history of diabetes, peripheral vascular disease, immunocompromised), or primary diagnoses (wound infection, major abscess, infected ulcer, nondiabetic, diabetic, other), with the exception of mean patient weight (daptomycin, 70 kg; comparator, 65 kg; P < .005).
The Gram-positive organisms cultured at baseline were mainly methicillin-susceptible Staphylococcus aureus (MSSA; 46% vs 45%, respectively) and Streptococcus pyogenes (33% vs 37%). Therefore, the great majority of patients in the comparator group had received semi-synthetic penicillin (96%) rather than vancomycin (4%).
Consideration of the overall clinical success rates between these daptomycin and comparator treatments showed no significant differences (93% vs 95%; P = .378). However, on the basis of assessment of the primary infection sites for 8 clinical signs and symptoms at each study visit, the daptomycin-treated patients did respond significantly earlier than the comparator-treated patients at the 3-4 day evaluation visit for induration (P = .027) and erythema (P = .048), with trends also seen for oedema (P = .096) and necrotic tissue (P = .097).
There were no significant differences seen for resolution of ulceration, fluctuance, and purulent drainage.
Overall, this result translated as a significantly shorter median duration of therapy for the daptomycin-treated patients, as 7 days versus 8 days for comparator treatment (P < .0001).
For treatment safety considerations, both daptomycin and comparator were well tolerated with no significant differences seen between their adverse events. The most common adverse events in both groups were headache (6.4%), injection site thrombosis (5.5%), constipation (3.1%) and increased blood creatine phosphokinase (2.5%).
Therefore, this subpopulation analysis from the combined data from 2 trials indicated the emergence of statistically significant differences in symptom severity at the day 3-4 evaluation, suggesting that daptomycin provides a more rapid resolution of the infection symptoms than comparator in this patient population with cSSSIs. This provided significantly shorter antibiotic therapy with daptomycin relative to comparator, suggesting further that shorter courses of daptomycin should be sufficient to achieve clinical efficacy in clinical practice, the researchers concluded.
This study was funded by Cubist Pharmaceuticals Inc.
[Presentation title: Daptomycin Is Clinically More Rapidly Effective Than Comparator for Treatment of Complicated Skin and Skin-Structure Infections. Abstract P839]
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