Study of Daptomycin Safety and Efficacy for Complicated Skin and Skin Structure Infections (cSSSI) and Bacteremia in Renal Impairment (RENSE)

Inclusion Criteria:

• Written informed consent
• Male or female ≥ 18 years of age
• Diagnosis of cSSSI or S. aureus bacteremia
• Renal impairment of CLcr of 30 - 50 mL/min or CLcr <30 mL/min per Cockcroft-Gault equation using actual body weight;
• Functioning hemodialysis access and on stable regimen for those receiving dialysis;
• In appropriate health for the study with no acute or chronic illnesses that could adversely impact safety or ability to complete the study.

Specific inclusion criteria for cSSSI:

• Presence of a wound infection, major abscess, severe carbunculosis, infected ulcers, dialysis access site infection, or other type of infection in presence of complicating factor.
• At least 3 of the following symptoms, signs, or laboratory values of a skin infection: elevated temperature; elevated white blood cell (WBC) count; Pain; Tenderness; Swelling; Erythema greater than 1 cm beyond wound edge; Induration; Pus formation;
• Evidence of a Gram-positive infecting pathogen as indicated by positive Gram stain or culture obtained within 48 hours prior to study drug administration
• Infection of sufficient severity to require parenteral antimicrobial therapy.

Specific inclusion criteria for S. aureus bacteremia:

• Documented S. aureus bacteremia defined as at least one positive blood culture for S. aureus obtained within 96 hours prior to the first dose of study medication

Exclusion Criteria:

• Pregnant or lactating females, or unwilling to practice barrier methods of birth control
• Received an investigational drug (including experimental biologic agents) within 30 days of study entry;
• Unable to discontinue use of HMG-CoA reductase inhibitor therapy while on study;
• Known allergy or intolerance to daptomycin, penicillin, or vancomycin;
• Active I.V. drug abuse;
• Confirmed or suspected osteomyelitis, septic arthritis, meningitis, epidural abscess, intra-abdominal infection, pneumonia, or infective endocarditis;
• Required use of non-study systemic antibacterial agent with activity against target pathogen;
• History of muscular disease;
• Neurological disease except stroke >6 months prior to study entry;
• Intramuscular injection within 7 days of study drug administration;
• Moribund clinical condition (high likelihood of death during next 3 days);
• Shock or hypotension (supine systolic blood pressure <80 mmHg);
• Body mass index (BMI) <18 or >40 kg/m2 [BMI = weight (kg)/height (m2)]
• Known HIV infection with CD4 count ≤200 cells/mm3;
• Neutropenic subjects with an absolute neutrophil count ≤500 cells/mm3;
• Anticipated to develop neutropenia absolute neutrophil count ≤500 due to prior or planned chemotherapy;
• Alanine aminotransferase (ALT) value >3 × upper limit of normal (ULN);
• Aspartate aminotransferase (AST) value >3 × ULN;
• Total bilirubin values ≥ 1.5 x ULN associated with ALT values >3 x ULN;
• Creatine phosphokinase (CPK) value >2 × ULN;
• Hemoglobin <8 gm/dL;
• Unlikely to comply with study procedures or to return for evaluations;
• History of rhabdomyolysis;
• Prior enrollment into this study;
• Infections caused by Gram-positive pathogens known to be resistant to daptomycin or selected comparator agent.

Specific exclusion criteria for cSSSI:

• Minor or superficial skin infections as the primary site of infection;
• Cellulitis or erysipelas not associated with complicating factor as primary site of infection;
• Perirectal abscess, hidradenitis suppurativa, concomitant gangrene, myositis, multiple infected ulcers at distant sites, necrotizing fasciitis, or infected third-degree burn wounds;
• Infections requiring emergency surgery;
• Infections suspected or documented to be due exclusively to gram-negative, anaerobic, or fungal organism;
• Confirmed or suspected disorder that could interfere with the evaluations (e.g., primary skin disorders);
• Use of a topical antibiotic at the site of the infection;
• Use of systemic antibacterial therapy for the infection for >24 hours within 48 hours prior to start of study drug unless (a) infecting Gram-positive pathogen resistant to therapy or (b) therapy administered for 3 or more days with worsening or no improvement;
• Planned surgical treatment that is considered curative of the infection.

Specific exclusion criteria for S. aureus bacteremia:

• Has intravascular foreign material at the time the positive blood culture was drawn (e.g., intracardiac pacemaker wires, percutaneous or implanted venous catheters, vascular grafts) unless material removed within 4 days after first dose of study medication or approval of medical monitor (exceptions: vascular stents in place for > 6 months, permanent pacemaker attached via epicardial leads, or any dialysis access device unless this material is felt to be infected);
• Prosthetic heart valve;
• Cardiac decompensation or valve damage or both with high likelihood of valve surgery in the 3 days after randomization;
• Polymicrobial blood infection.