This was an open-label, randomized, active-control study conducted between August 28, 2002, and February 16, 2005, in 44 sites in the United States and Western Europe. Patients were considered for enrollment in the study if they were at least 18 years of age and had at least 1 blood culture that was positive for S. aureus within 2 calendar days of initiating the study medication. Exclusion criteria included creatinine clearance less than 30mL/min and known osteomyelitis, polymicrobial bacteremia, or pneumonia. For a full list of the exclusion criteria, please refer to the initial publication.17 In the initial phases of the trial, patients with left-sided endocarditis (LIE) were excluded.

Eligible patients were randomly assigned to receive either daptomycin (CUBICIN®, Cubist Pharmaceuticals) at 6mg/kg/day or standard therapy, with either 1g vancomycin every 12h (for MRSA isolates) or 2g antistaphylococcal penicillin every 4h (for methicillin-susceptible S. aureus [MSSA] isolates). The duration of treatment was determined by the investigators based on the working diagnosis. All patients who had a high likelihood of LIE at randomization were randomly assigned to receive daptomycin, and all patients randomly assigned to receive standard therapy, also received 1mg/kg gentamicin every 8h for the first 4 days. All patients underwent transesophageal echocardiography (TEE) within 5 days of enrollment, as well as any necessary follow-up echocardiography. Additionally, all patients underwent diagnostic evaluation for metastatic foci of infection.

The primary efficacy measure was the success rate in the modified intent-to-treat (MITT) population 6 weeks after the end of therapy. An independent external adjudication committee blinded to therapy, consisting of 5 infectious diseases experts, reviewed individual patient data to establish final diagnoses and outcomes. Overall success was defined as survival, clinical cure or improvement, and a documented clearance of bacteremia. In addition, patients who did not complete adequate therapy, who received potentially effective non-study antibiotics, or who did not have blood cultures taken 6 weeks after completion of therapy were considered “treatment failures.” In this analysis, we also describe clinical success based on the presence of all of the following criteria: survival, clinical outcome of cure or improvement, and resolution of S. aureus infection 6 weeks after the end of therapy.

Entry diagnoses were determined according to the modified Duke University criteria for IE.18 Final diagnoses were based on standard clinical definitions. Uncomplicated RIE (uRIE) was defined as definite or possible MSSA endocarditis in the absence of predisposing abnormalities or active infection of the mitral or aortic valve in a patient who actively uses injection drugs, has a serum creatinine level of less than 2.5mg/dL, and has no evidence of extrapulmonary sites of infection. Minimum duration of therapy for patients with uRIE ranged from 14 to 28 days. Complicated RIE (cRIE) was similarly defined, but patients also had extrapulmonary sites of infection, a serum creatinine level of at least 2.5mg/dL, or MRSA bacteremia, or did not use injection drugs. Patients with cRIE received a minimum of 28–42 days of therapy. Patients with LIE were treated for a minimum 28–42 days.

In order to evaluate differences in the genotypic profiles of S. aureus isolates causing infections of variable severity, we compared S. aureus isolates causing LIE (usually the most serious infection) with those causing uncomplicated bacteremia (least serious infection). Pulsed-field gel electrophoresis (PFGE) on these isolates was performed as previously described.19 In addition, and following previously reported methodology,19 DNA extraction and polymerase chain reaction (PCR) assays were used to examine 33 bacterial determinants, including toxins, adhesins, agr groups I–IV, staphylococcal cassette chromosome mec (SCCmec) types I–IV, as well as other virulence genes.

Because of the limited number of patients in each arm, only descriptive statistics were performed for this subgroup analysis.

Of the 235 patients included in the MITT population in the original study, 181 were thought to have definite or possible endocarditis on enrollment, according to the modified Duke criteria for IE. A total of 53 patients received a final diagnosis of IE. All 37 patients who fulfilled the Duke criteria for definite endocarditis at enrollment had IE as the final diagnosis. Of the 144 patients with possible endocarditis according to the Duke criteria, 15 (10%) had a final diagnosis of IE. An additional patient was initially classified in the group without endocarditis, but was subsequently found to have IE.

Of the 53 patients with a final diagnosis of endocarditis, 28 were randomly assigned to receive daptomycin and 25 were randomly assigned to standard therapy. There were no major differences between the study arms with regard to baseline patient characteristics, risk factors for endocarditis, entry diagnoses, or final diagnoses (Table 1). The most common type of IE in both groups was cRIE (25 patients, 47%), followed by LIE (18 patients, 34%) and uRIE (10 patients, 19%). The proportion of patients with MRSA IE was similar in both groups (46% for daptomycin vs 44% for the comparator). Clinical evidence of systemic inflammatory response syndrome was present in 22 patients treated with daptomycin (79%) and in 21 patients treated with standard therapy (84%). Sixteen patients randomly assigned to receive daptomycin completed the course of therapy and received a median of 27 days of treatment. In the comparator arm, 14 patients completed the course of therapy and received a median of 30 days of antibiotic treatment. Gentamicin was administered as study medication for 4 days to 1 patient in the daptomycin group and for a median of 5 days to all 25 patients in the comparator group. Twenty-two patients with IE (41%) received a diagnosis of septic pulmonary infarct during the first 5 days of the study (10 in the daptomycin arm and 12 in the comparator arm).

In the MITT population, the overall success rates for patients with RIE treated with daptomycin were similar to those of the comparator MITT population (42% vs 44%; Table 2). Clinical success rates in this group of patients were higher in both arms (63% vs 69%). No difference in outcome was observed between the treatment groups of patients with MRSA or MSSA infection, or in patients with septic pulmonary infarct. Mortality rates were comparable for daptomycin and standard therapy (0% vs 12%).

The overall success rates with LIE were poor in both arms (11% vs 22%; Table 2). None of the 9 patients with LIE with MRSA infection had a successful outcome. Mortality rates were 33% with daptomycin treatment and 56% with standard therapy. Only 3 patients with LIE underwent valve surgery (2 in the daptomycin arm, 1 in the comparator arm): 2 after treatment and 1 during treatment for IE.

The overall failure rates of daptomycin and standard therapy were comparable (54% vs 56%; Table 3). The most common reason for failure in both study groups was persisting or relapsing S. aureus infection or clinical failure (29% vs 28%). Patients receiving the comparator were more likely than those receiving daptomycin to experience treatment failure resulting from death, adverse events (AEs), or receipt of potentially effective non-study antibiotics.

Daptomycin was well tolerated. The overall incidence of drug-related AEs was lower in the daptomycin arm (32% vs 50%), but the difference was not statistically significant (P=0.27). The proportion of patients in whom treatment was discontinued because of AEs was slightly lower with daptomycin (21%) than with standard therapy (31%; P=0.54). Increases in creatine kinase levels (>500IU/L) were noted in 12% of patients taking daptomycin and in 4% of those who received standard therapy (P=0.61). Conversely, renal toxicity occurred in 21% of patients in the comparator arm and in 15% of patients in the daptomycin arm (P=0.73).

The minimum inhibitory concentrations (MICs) of vancomycin and daptomycin were determined at baseline. In both treatment arms, the vancomycin MICs ranged between 0.5 and 0.1μg/mL while the daptomycin MICs ranged between 0.12 and 0.5μg/mL.

Regarding molecular analysis, no significant differences were seen in the distribution of virulence genes between the 2 groups of isolates (those causing LIE and those causing uncomplicated bacteremia), including toxins, adhesins, and other genes, such as the agr gene complex. In addition, the S. aureus isolates were similar with respect to SCCmec types, PFGE types, and antimicrobial susceptibility patterns.