Multicenter, double-blind, randomized, phase II trial to assess the safety and efficacy of ceftolozane-tazobactam plus metronidazole compared with meropenem in adult patients with complicated intra-abdominal infections.

Ceftolozane-tazobactam (TOL-TAZ) is a novel antibacterial with activity against Pseudomonas aeruginosa and other common Gram-negative pathogens, including extended-spectrum ß-lactamase (ESBL)-producing Enterobacteriaceae, that are associated with complicated intra-abdominal infections (cIAIs). This prospective, double-blind, randomized, multicenter, phase II trial assessed patient clinical and microbiological responses to and the safety of TOL-TAZ plus metronidazole compared with those of meropenem. Hospitalized adults with cIAIs that required surgical intervention were randomized (2:1) to receive intravenous (i.v.) TOL-TAZ (1.5 g [containing 1,000 mg TOL and 500 mg TAZ] every 8 h [q8h]) with or without i.v. metronidazole (500 mg q8h) or i.v. meropenem (1 g q8h) for 4 to 7 days. The primary endpoint was the clinical response at the test-of-cure visit in the microbiologically modified intent-to-treat (mMITT) and microbiologically evaluable (ME) populations. Secondary measures included the patients' microbiological response and safety. In total, 82 patients received TOL-TAZ (90.2% with metronidazole), and 39 received meropenem. For the mMITT population, clinical cure was seen in 83.6% of the patients (51/61; 95% confidence interval [CI], 71.9 to 91.8) who received TOL-TAZ and 96.0% of the patients (24/25; 95% CI, 79.6 to 99.9) who received meropenem (difference, -12.4%; 95% CI, -34.9% to 11.1%); in the ME population, clinical cure was seen in 88.7% and 95.8% of the patients (difference, -7.1%; 95% CI, -30.7% to 16.9%) who received TOL-TAZ and meropenem, respectively. TOL-TAZ demonstrated microbiological success against Escherichia coli (89.5%), Klebsiella pneumoniae (100%), and P. aeruginosa (100%). The adverse event rates were similar in the groups (50.0% with TOL-TAZ and 48.8% with meropenem). TOL-TAZ in combination with metronidazole was well tolerated and resulted in clinical and microbiological success rates supportive of further clinical development in patients with cIAIs. (This study has been registered at ClinicalTrials.gov under registration no. NCT01147640.).

Randomized controlled trial of the safety and efficacy of Daptomycin versus standard-of-care therapy for management of patients with osteomyelitis associated with prosthetic devices undergoing two-stage revision arthroplasty.

The prevalence of Staphylococcus aureus causing prosthetic joint infection (PJI) supports investigation of higher doses of daptomycin in the management of PJI. This was a prospective, randomized controlled trial studying safety and efficacy of daptomycin (6 and 8 mg/kg of body weight) compared with standard-of-care therapy for PJI. This open-label study randomized 75 patients undergoing 2-stage revision arthroplasty to daptomycin at 6 or 8 mg/kg or a comparator (vancomycin, teicoplanin, or semisynthetic penicillin). After prosthesis removal, patients received 6 weeks of antibiotic treatment and a 2- to 6-week antibiotic-free period before implantation of a new prosthesis. Test of cure (TOC) was within 1 to 2 weeks after reimplantation. The primary objective was evaluation of creatine phosphokinase (CPK) levels. Secondary objectives were clinical efficacy and microbiological assessments. Of 73 CPK safety population patients, CPK elevation of >500 U/liter occurred in 4 of 25 (16.0%) (daptomycin, 6 mg/kg) and 5 of 23 (21.7%) (daptomycin, 8 mg/kg) daptomycin-treated patients and 2 of 25 (8.0%) comparator patients. Adverse-event rates were similar among daptomycin and comparator groups. Among modified intent-to-treat patients at TOC, clinical success rates were 14 of 24 (58.3%) for 6 mg/kg daptomycin, 14 of 23 (60.9%) for 8 mg/kg daptomycin, and 8 of 21 (38.1%) for the comparator. Overall microbiological success at TOC was 12 of 24 (50.0%) for 6 mg/kg daptomycin, 12 of 23 (52.2%) for 8 mg/kg daptomycin, and 8 of 21 (38.1%) for comparator patients. In conclusion, daptomycin at 6 and 8 mg/kg given for up to 6 weeks was safe and appeared to be effective in managing staphylococcal PJI using a 2-stage revision arthroplasty technique in a total of 49 patients.

Prospective, non-comparative study of daptomycin for the treatment of superficial and deep incisional surgical site infections.

BACKGROUND: Skin infections, including surgical site infections (SSIs), usually involve gram-positive pathogens and continue to be a leading cause of morbidity and death among hospital patients. The increasing prevalence of methicillin-resistant Staphylococcus aureus and other resistant strains accentuates the need for effective and safe therapies for such infections. This exploratory study evaluated the efficacy and safety of daptomycin in patients with gram-positive SSI according to wound classification. METHODS: Eligible patients had an SSI with onset < 30 days after surgery, positive gram stain or culture at least three days before daptomycin therapy began, and three or more clinical signs and symptoms of infection. The incisional SSI was classified as superficial or deep according to the U.S. Centers for Disease Control and Prevention criteria. Patients with organ-space infections were excluded, as were those with major concomitant infections, foreign material in the incision that could not be removed, previous systemic antimicrobial therapy, or creatinine clearance < 30 mL/min. Daptomycin 4 mg/kg was administered intravenously once daily for 7-14 days. The primary efficacy endpoint was clinical response at the end of daptomycin therapy, and the safety assessment was based on adverse events (AEs). RESULTS: Sixty-nine patients were enrolled, 60 of whom were evaluable for efficacy. Extremity wounds predominated among superficial incisional SSIs (n = 30), whereas abdominal wounds predominated among deep SSIs (n = 30). Patients with deep incisional SSI were more likely to be young, male, white, and febrile and to weigh more than patients with superficial SSIs. The overall clinical success rate was 92% (95% confidence interval [CI] 82-97%); the success rate was 100% in superficial incisional SSI and 83% in deep SSI (17% difference; 95% CI 0-33%). Staphylococcus aureus (28/36 methicillin-resistant) was the pathogen isolated most frequently. In 10 patients who were febrile at baseline, the median time to defervescence was five days, and the mean duration of treatment in the series was 11.2 days. Daptomycin was well tolerated. In most patients, AEs were mild or moderate in intensity; in two patients (one superficial, one deep), daptomycin was discontinued because of AEs. CONCLUSIONS: The results of this exploratory study of SSI are consistent with those of previous studies of daptomycin in the treatment of diverse complicated skin and skin-structure infections, and suggest that wound classification should be treated as an important covariate in future studies of daptomycin and other antibiotics.

A retrospective review of clinical experience with daptomycin for a variety of wound types in a burn and wound care facility.

OBJECTIVE: Daptomycin is a novel antibiotic with activity against many Gram-positive organisms that has demonstrated efficacy in the management of skin and soft tissue infections (SSTIs). However, data regarding the use of daptomycin for the management of burn wound infections are lacking. We assessed the efficacy and safety of daptomycin in the treatment of complicated skin and soft tissue infections (cSSTIs), including burn wound infections. METHODS: We performed a retrospective review of patients receiving daptomycin for burn wound infections and other cSSTIs in a referral burn and wound treatment center. RESULTS: Our review revealed an overall success rate (microbiological cure + clinically improved) of 99.5%, with an overall success rate of 98.5% among burn patients, specifically. The overall success rate was 100% among patients in the three other diagnosis groups (cSSTIs, chronic wounds, and other infections). A success rate of 98% was noted among the subset of patients with wounds associated with bacteremia. CONCLUSIONS: Our study suggests that daptomycin is a safe and effective agent for the management of burn wound infections, although further study is warranted to confirm these results.

Daptomycin for the treatment of enterococcal bacteraemia: results from the Cubicin Outcomes Registry and Experience (CORE).

Enterococcal infections are a common cause of nosocomial bloodstream infections. Vancomycin resistance and the emergence of linezolid resistance necessitate alternative therapies. Studies in vitro as well as animal and case studies suggest that daptomycin may be effective in enterococcal infections. Patients with positive blood cultures for enterococci in the Cubicin((R)) Outcomes Registry and Experience (CORE) 2005-2006 were identified. Patients with endocarditis, intracardiac foreign body infections or non-speciated enterococci were excluded. Outcome was assessed using protocol-defined criteria. Of 159 patients included in the efficacy population, Enterococcus faecium and Enterococcus faecalis were isolated in 120 (75.5%) and 39 (24.5%) patients, respectively. Vancomycin resistance was detected in 91% and 23% of patients with E. faecium and E. faecalis infections, respectively. Prior to daptomycin, 94/159 (59.1%) and 35/159 (22.0%) patients had received vancomycin and linezolid, respectively. Daptomycin was first-line therapy in 27/159 cases (17%). Success was observed in 139/159 patients (87%) and in 104/120 (87%) and 35/39 (90%) patients with E. faecium and E. faecalis infections, respectively. Among the safety population (n=211), 20 (9.5%) experienced 28 adverse events possibly related to daptomycin, 8 of which were considered serious. Daptomycin may be a useful agent for treating enterococcal bacteraemia caused by E. faecium or E. faecalis. Further studies are warranted.

Pharmacokinetics and tolerability of daptomycin at doses up to 12 milligrams per kilogram of body weight once daily in healthy volunteers.

Daptomycin, a novel lipopeptide, is bactericidal against a broad range of gram-positive strains, including methicillin- (MRSA) and vancomycin-resistant Staphylococcus aureus. Daptomycin is approved at 4 mg/kg of body weight given intravenously once daily for the treatment of complicated skin and skin structure infections and at 6 mg/kg for the treatment of S. aureus bloodstream infections (bacteremia), including right-sided endocarditis caused by methicillin-susceptible S. aureus and MRSA. The present study was designed to evaluate the multiple-dose pharmacokinetics and safety of daptomycin at doses of 6 to 12 mg/kg in healthy volunteers. Three cohorts of 12 subjects each were given daptomycin (10 mg/kg) or placebo once daily for 14 days, daptomycin (12 mg/kg) or placebo once daily for 14 days, or daptomycin (6 or 8 mg/kg) once daily for 4 days. Daptomycin produced dose-proportional increases in the area under the plasma concentration-time curve and in trough daptomycin levels and nearly dose-proportional increases in peak daptomycin concentrations. Other pharmacokinetic parameters measured on day 1 and at steady state were independent of the dose, including the half-life (approximately 8 h), weight-normalized plasma clearance (9 to 10 ml/h/kg), and volume of distribution (approximately 100 ml/kg). Plasma protein binding was 90% to 93% and was independent of the daptomycin concentration. Daptomycin did not produce electrocardiographic abnormalities or electrophysiological evidence of muscle or nerve toxicity. Daptomycin was well tolerated in subjects dosed with up to 12 mg/kg intravenously for 14 days. Doses of daptomycin higher than 6 mg/kg once daily may be considered in further studies to evaluate the safety and efficacy of daptomycin in difficult-to-treat infections.