Increasing antibiotic arsenal against serious gram-positive infections

June 2003

Antibiotic resistance in gram-positive organisms is a growing, international concern. Serious infections caused by these pathogens have resulted in increased mortality, morbidity and treatment costs and have restricted current therapeutic options.

Unfortunately, the gold standard for many serious gram-positive infections — vancomycin — is threatened, particularly against serious infections caused by Enterococcus faecium. In addition, there are now clinical reports of eight cases of vancomycin-intermediate resistant Staphylococcus aureus (VISA) and two cases of vancomycin-resistant S. aureus (VRSA) in the United States.

The increasing prevalence of serious infections involving gram-positive cocci and an increasing concern about antimicrobial resistance has generated renewed interest in the development of novel antibiotics to combat serious infections involving these organisms. One novel compound in late-stage clinical development is the lipopeptide antibiotic, daptomycin.

After an apparent initial setback, the clinical development of daptomycin has re-emerged. Initially, Eli Lilly investigated the use of daptomycin as a multiple daily-dose drug and conducted several phase-1 and phase-2 clinical trials in the 1980s and early 1990s. Although daptomycin demonstrated promising efficacy in the treatment of skin and soft tissue infections and bacteremia, there were concerns about potential toxicities in the form of myopathy. As a consequence, Eli Lilly voluntarily halted clinical development of the product in 1991. However, because of the growing need for new, effective treatment options for serious gram-positive infections, there has been a renewal in activity and interest in the clinical development of daptomycin, which is now being pursued by Cubist Pharmaceuticals.

Daptomycin is a novel lipopeptide antibiotic that exhibits rapid, in vitro bactericidal activity against most clinically important gram-positive cocci, including methicillin-resistant S. aureus, VISA, VRSA, coagulase-negative staphylococci, vancomycin-resistant enterococci, and penicillin-resistant S. pneumoniae. Daptomycin is also active in vitro against other gram-positive bacteria, including Streptococcus pyogenes, groups C, E and F Streptococcus ssp., Peptostreptococcus spp., some Clostridium spp. and Listeria monocytogenes.

The drug binds to the cell membrane of gram-positive bacteria and inserts into the membrane by a calcium-dependent mechanism. Consequently, daptomycin is not active against gram-negative bacteria, and physiologic concentrations of calcium are required for full activity.

In vitro studies with 7,445 isolates of gram-positive cocci, including 2,789 clinical isolates from 11 North American medical centers using media supplemented with physiologic concentrations (50 mg/l) of free calcium ions, exhibited 90% minimal inhibitory concentration values of 0.5 µg/ml for 305 methicillin-resistant S. aureus isolates and 770 methicillin-resistant coagulase-negative staphylococci isolates, 2.0 to 4.0 µg/ml for 259 vancomycin-resistant enterococci isolates, and 0.12 µg/ml for 187 penicillin-resistant S. pneumoniae isolates. Among 2,740 strains of staphylococci, streptococci and enterococci, no isolates had minimal inhibitory concentration values >8 µg/ml in broth media containing physiologic concentrations of free calcium. In vitro studies have also demonstrated that daptomycin is a faster bactericidal against S. aureus compared with vancomycin, linezolid and quinupristin-dalfopristin.

Adverse reactions

The concern over myopathy appears to be related to dosing frequency and was clarified in animal studies. These studies showed the increased risk for skeletal muscle adverse events, as indicated by elevated serum creatinine phosphokinase levels, was caused by divided-dose daily administration of daptomycin and was not related to peak daptomycin plasma concentrations. Therefore, the risk for skeletal muscle adverse events was decreased by once-daily dosing of daptomycin compared with a divided-dose daily regimen. Because once-daily dosing minimized the potential for myopathy in this animal model, clinical trials were initiated using this dosing regimen.

Clinical development

Phase-1 studies have demonstrated that once-daily daptomycin exhibits a favorable pharmacokinetic (PK) profile. Pharmacokinetic studies with once-daily 4 to 8 mg/kg daptomycin administered for up to 14 days demonstrated that daptomycin PK was linear through the clinical dose range (4 to 6 mg/kg). A slight (approximately 20%) nonlinearity was observed in the area under the curve and trough concentration as the dose was increased from 6 to 8 mg/kg. Daptomycin exhibited a median half-life of approximately 9 hours, with approximately 54% of daptomycin excreted intact in urine (0 to 24 hours). Daptomycin was well tolerated at a dose as high as 8 mg/kg for 14 consecutive days in healthy volunteers. Because of the favorable PK and safety profile, once-daily daptomycin has been investigated in patients with serious gram-positive infections.

Complicated skin structure infections

Two randomized, international, multicenter, noninferiority clinical trials enrolled 1,079 patients with complicated skin and soft tissue infections, including abscesses, wounds and diabetic ulcer infections. Once-daily daptomycin 4 mg/kg IV therapy was compared with standard IV therapy, administration of a semisynthetic penicillin or vancomycin, for seven to 14 days. Results showed that the safety and efficacy of daptomycin therapy were comparable with standard therapy. The most common infecting organism was S. aureus, occurring in 71% of daptomycin-treated patients and 69% of comparator-treated patients. Clinical success rates were 82% for daptomycin-treated patients and 83% for comparator-treated patients, but the duration of treatment was significantly shorter for daptomycin-treated patients (table 1). The frequency and type of adverse events were also similar between daptomycin- and comparator-treated patients.

Complicated urinary tract infections

A randomized, noninferiority, phase-3 trial in patients with complicated urinary tract infections caused primarily by gram-positive pathogens was recently conducted comparing once-daily daptomycin 4 mg/kg versus ciprofloxacin (Cipro, Bayer) for five to 14 days. Ciprofloxacin IV was used as a comparator agent because vancomycin is not approved for this indication by the FDA. Daptomycin and ciprofloxacin exhibited comparable clinical success rates in this patient population: 29 of 31 (94%) daptomycin-treated patients versus 28 of 30 (93%) ciprofloxacin-treated patients, but the adverse event profile of daptomycin was improved over that of ciprofloxacin.

Overall, these studies have demonstrated that daptomycin exhibits a safety profile comparable with standard therapy using vancomycin, a semisynthetic penicillin, or ciprofloxacin. The incidence of myopathy has occurred in only three of more than 1,300 patients, based on symptoms of myalgia or elevated serum creatinine phosphokinase levels. In these three cases, the onset of myopathy occurred after five or more days of treatment and was reversible.

Future directions

Both microbiologic and clinical data have supported the continued investigation of daptomycin for the treatment of serious gram-positive infections, including infections caused by antimicrobial-resistant gram-positive cocci. A randomized, noninferiority, phase-3 trial has recently been initiated in the United States to evaluate the safety and efficacy of once-daily daptomycin 6 mg/kg versus conventional therapy with IV vancomycin or nafcillin in patients with infective endocarditis or bacteremia caused by S. aureus. In addition, Cubist submitted a New Drug Application to the FDA at the end of 2002. It is anticipated that Cubist will initially seek indications for daptomycin in the treatment of complicated skin and soft tissue infections, serious staphylococcal infections and other serious infections involving gram-positive bacteria.

For more information:

• Fuchs PC, Barry AL, Brown SD. In vitro bactericidal activity of daptomycin against staphylococci. J Antimicrob Chemother. 2002;49(3):467-470.
• Thorne GM, Alder J. Daptomycin: a novel lipopeptide antibiotic. Clin Microbiol Newsletter. 2002;24:33-40.
• Barry AL, Fuchs PC, Brown SD. In vitro activities of daptomycin against 2,789 clinical isolates from 11 North American medical centers. Antimicrob Agents Chemother. 2001;45(6):1919-1922.
• Oleson FB, Berman CL, Kirkpatrick JB, et al. Once-daily dosing in dogs optimizes daptomycin safety. Antimicrob Agents Chemother. 2000;44(11):2948-2953.