Can Daptomycin Have An Impact With Skin And Skin Structure Infections?
Podiatrists commonly encounter and treat skin and skin-structure infections (SSSIs), ranging from cellulitis to more complicated surgical site infections and infected diabetic foot ulcers. Aerobic gram-positive cocci, such as Staphylococcus aureus and streptococci, are the most common causative agents of skin infections.1
While the treatment of simple and superficial infections is relatively straightforward with brief courses of oral antibiotics, many skin infections of the foot are complicated by diabetes.1,2 Foot ulceration, usually secondary to peripheral neuropathy or peripheral vascular disease, often leads to infection in the diabetic foot.2 Gram-positive aerobic bacteria are the most commonly isolated pathogens as S. aureus constitute almost half of all isolates, according to one study.3 However, chronic wounds and more severe infections are usually polymicrobial and may also involve anaerobes and gram-negative bacilli (see “An Overview Of Common Organisms In Chronic Foot Wounds”).1,2
The increasing prevalence of methicillin-resistant S. aureus (MRSA) infections in both the hospital and community setting is well documented. Bear in mind that MRSA is now involved in almost 60 percent of intensive care unit (ICU) infections in hospitals in the United States.4 Authors of a British study found that MRSA was isolated from 30 percent of outpatients with diabetic foot ulcers during 2001. This was twice the rate of MRSA found in patients three years earlier.3
Vancomycin And MRSA: Why Treatment Alternatives Are Needed
Since the emergence of MRSA in U.S. hospitals during the 1980s, vancomycin has been the standard of care for the majority of infections caused by MRSA. Vancomycin helped fill the clinical need for an agent that could consistently cure the growing number of MRSA infections. However, when it comes to patients receiving vancomycin, one must monitor drug serum peaks and troughs in order to achieve the drug levels required to eradicate MRSA.5 One study of 95 patients, most of whom had MRSA pneumonia or bacteremia, found that those who had reached target serum trough levels were significantly more likely to have positive clinical responses to vancomycin than patients who had serum troughs below target levels.6 However, the study also found significantly more nephrotoxicity (12 percent) in the group of patients who achieved the target trough levels in comparison with the low level group.6
In the last several years, clinicians have detected MRSA isolates with reduced susceptibility and outright resistance to vancomycin after decades of successful clinical application. Although still very rare, the first documented case of vancomycin-resistant S. aureus (VRSA) in the U.S. involved a patient who had a polymicrobial diabetic foot infection in which vancomycin-resistant enterococci (VRE), containing the vancomycin resistance gene vanA, transferred resistance to MRSA.7 In addition, S. aureus strains with reduced susceptibility to vancomycin — so-called vancomycin-intermediate S. aureus (VISA) — also exist and may be linked to clinical failures.8,9
Perhaps of even greater concern are reports that strains of MRSA that appear to be susceptible to vancomycin (based on susceptibility testing (minimum inhibitory concentration [MIC] ≤ 2 µg/mL)) may not actually respond to vancomycin therapy. For example, one study showed that among patients with MRSA bacteremia, those patients who had MIC levels 8
Given that vancomycin can no longer be considered a universally effective drug against MRSA, safe and effective anti-MRSA drugs are needed. However, there are only a few alternatives for patients who cannot tolerate vancomycin or fail vancomycin therapy.
Podiatrists commonly use linezolid (Zyvox, Pfizer) as it is effective against MRSA in complicated SSSIs. However, one may need to limit the duration of therapy due to hematologic adverse events (suppression of blood cell counts).1 Newer options approved for use against MRSA in complicated SSSIs include tigecycline (Tygacil, Wyeth) and daptomycin (Cubicin, Cubist Pharmaceuticals). With this in mind, let us take a closer look at daptomycin.
Spectrum Of Activity: What Does Daptomycin Offer?
Daptomycin is the first antibiotic in a new class called the cyclic lipopeptides. Daptomycin binds to and depolarizes the cytoplasmic membrane of gram-positive bacteria, ultimately causing rapid cell death.10 It was approved in 2003 in the U.S. for the treatment of complicated SSSIs caused by S. aureus, including MRSA, as well as Streptococcus pyogenes, Streptococcus agalactiae, Streptococcus dysgalactiae subsp. equisimilis, and Enterococcus faecalis (vancomycin-susceptible isolates only). Recently, the label for daptomycin was extended to include the treatment of bacteremia, including right-sided endocarditis caused by S. aureus.11
Daptomycin provides dose-dependent bactericidal activity against a wide range of aerobic and anaerobic gram-positive isolates (including multiresistant strains).12,13 In addition, it has demonstrated in vitro activity against methicillin-susceptible S. aureus (MSSA), MRSA and anaerobic gram-positive organisms (such as Finegoldia magna and Peptoniphilus asaccharolyticus) cultured from diabetic foot infections.13 Furthermore, an in vitro study demonstrated that 96 percent of 105 strains of S. aureus with reduced susceptibility to vancomycin, including VISA, were susceptible to daptomycin.14
What The Literature Reveals About Daptomycin
In two multicenter, randomized phase 3 clinical trials, researchers compared daptomycin with standard therapy (penicillinase-resistant penicillins or vancomycin) in 1,092 patients with complicated SSSI and most of these were caused by S. aureus.15 The treatment duration was seven to 14 days. Researchers defined clinical success as the resolution of signs and symptoms to the point where antibiotic therapy is no longer required. They assessed clinical success six to 20 days after the last dose. These studies showed that clinical success rates were statistically comparable (“noninferior”) between those patients clinically evaluable in the daptomycin and comparator groups (83 percent versus 84 percent respectively).15 In the MRSA subpopulation, clinical success rates were 75 percent and 69 percent respectively for patients treated with daptomycin and vancomycin.15
Daptomycin’s efficacy against other gram-positive pathogens (streptococci and enterococci) was also comparable to that of standard therapy.15 Patients receiving daptomycin had fewer days of therapy as 63 percent of these patients required four to seven days of therapy in comparison to 33 percent of patients in the comparator group.15 A post hoc analysis of the data from 103 clinically evaluable patients who had diabetic foot infections demonstrated that daptomycin was as effective as vancomycin or penicillinase-resistant penicillins in treating gram-positive infections.16 Bear in mind that the number of MRSA isolates in this subpopulation was modest with only one MRSA isolate in the daptomycin-treated group.
With all new antibiotics, there is concern about resistance but daptomycin resistance rates to S. aureus and other gram-positive cocci are low in vitro.17 In a few instances, MRSA isolates have been reported to have become nonsusceptible to daptomycin in vivo during treatment for bacteremia, endocarditis or osteomyelitis.18 Nonsusceptible isolates have not yet been reported in patients with complicated SSSI who received daptomycin treatment.18
Daptomycin was well tolerated in these trials of patients with complicated SSSIs, and the frequency, distribution and severity of adverse events were similar between daptomycin and comparator drugs.15 For example, 2.2 percent of patients treated with daptomycin experienced renal failure in comparison to 2.7 percent of patients in the comparator group.15 The prevalence of adverse events was similarly small and comparable between treatment groups among those patients who had diabetic ulcer infections.16 In contrast, a recent phase 3 trial of daptomycin 6 mg/kg for the treatment of S. aureus bacteremia found significantly more patients had renal impairment with standard therapy (antistaphylococcal penicillin or vancomycin) (18 percent) than with daptomycin (7 percent).19
In regard to patients who receive daptomycin, one should monitor for the development of muscle pain and weakness, and also test creatinine phosphokinase (CPK) levels weekly or more often if necessary.11 However, elevations in CPK levels were comparable between daptomycin and comparator groups in the aforementioned complicated SSSI trials, and only two of 534 patients receiving daptomycin developed CPK levels that necessitated discontinuation of the drug.15
The approved dose of daptomycin for complicated SSSI is 4 mg/kg once a day by intravenous infusion for seven to 14 days. When it comes to patients with insufficient renal function, the dosing should be once every 48 hours.11 Since many foot infections are caused or complicated by diabetes, parenteral therapy is often necessary at least initially.1,2
Since daptomycin is dosed once daily, it is a suitable modality for outpatient parenteral therapy. One study found that daptomycin is safe to use in a hospital-based outpatient setting. This provided the opportunity for patients to receive professional wound care in addition to drug administration.20
In summary, daptomycin has potent bactericidal activity against gram-positive bacteria, including MRSA. Given the currently available studies, it appears that this new antibiotic may provide a useful option for treating many skin infections of the foot.
1. Eron LJ, Lipsky BA, Low DE, et al. Managing skin and soft tissue infections: expert panel recommendations on key decision points. J Antimicrob Chemother 52 Suppl 1: i3-i17, 2003.
2. Lipsky BA, Berendt AR, Deery HG, et al. Diagnosis and treatment of diabetic foot infections. Clin Infect Dis 39: 885-910, 2004.
3. Dang CN, Prasad YD, Boulton AJ, Jude EB. Methicillin-resistant Staphylococcus aureus in the diabetic foot clinic: a worsening problem. Diabet Med 20(2): 159-161, 2003.
4. National Nosocomial Infections Surveillance (NNIS) System Report, data summary from January 1992 through June 2004, issued October 2004. Am J Infect Control 32(8): 470-485, 2004.
5. Stevens DL. The role of vancomycin in the treatment paradigm. Clin Infect Dis 42 Suppl 1: S51-S57, 2006.
6. Hidayat LK, Hsu DI, Quist R, Shriner KA, Wong-Beringer A. High-dose vancomycin therapy for methicillin-resistant Staphylococcus aureus infections: efficacy and toxicity. Arch Intern Med 166(19): 2138-2144, 2006.
7. Centers for Disease Control and Prevention. Staphylococcus aureus resistant to vancomycin--United States, 2002. MMWR Morb Mortal Wkly Rep 51(26): 565-567, 2002.
8. Sakoulas G, Moise-Broder PA, Schentag J, et al. Relationship of MIC and bactericidal activity to efficacy of vancomycin for treatment of methicillin-resistant Staphylococcus aureus bacteremia. J Clin Microbiol 42(6): 2398-2402, 2004.
9. Howden BP, Ward PB, Charles PG, et al. Treatment outcomes for serious infections caused by methicillin-resistant Staphylococcus aureus with reduced vancomycin susceptibility. Clin Infect Dis 38(4): 521-528, 2004.
10. Silverman JA, Perlmutter NG, Shapiro HM. Correlation of daptomycin bactericidal activity and membrane depolarization in Staphylococcus aureus. Antimicrob Agents Chemother 47(8): 2538-2544, 2003.
11. Cubist Pharmaceuticals. Cubicin® (daptomycin for injection) prescribing information. 2006. Lexington, MA.
12. Rybak MJ, Hershberger E, Moldovan T, Grucz RG. In vitro activities of daptomycin, vancomycin, linezolid, and quinupristin-dalfopristin against staphylococci and enterococci, including vancomycin-intermediate and -resistant strains. Antimicrob Agents Chemother 44(4): 1062-1066, 2000.
13. Goldstein EJ, Citron DM, Warren YA, et al. In vitro activities of dalbavancin and 12 other agents against 329 aerobic and anaerobic gram-positive isolates recovered from diabetic foot infections. Antimicrob Agents Chemother 50(8): 2875-2879, 2006.
14. Sader HS, Fritsche TR, Jones RN. Daptomycin bactericidal activity and correlation between disk and broth microdilution method results in testing of Staphylococcus aureus strains with decreased susceptibility to vancomycin. Antimicrob Agents Chemother 50(7): 2330-2336, 2006.
15. Arbeit RD, Maki D, Tally FP, Campanaro E, Eisenstein BI. The safety and efficacy of daptomycin for the treatment of complicated skin and skin-structure infections. Clin Infect Dis 38(12): 1673-1681, 2004.
16. Lipsky BA, Stoutenburgh U. Daptomycin for treating infected diabetic foot ulcers: evidence from a randomized, controlled trial comparing daptomycin with vancomycin or semi-synthetic penicillins for complicated skin and skin-structure infections. J Antimicrob Chemother 55(2): 240-245, 2005.
17. Silverman JA, Oliver N, Andrew T, Li T. Resistance studies with daptomycin. Antimicrob Agents Chemother 45(6):1799-1802, 2001.
18. Garau J. Management of cSSTIs: the role of daptomycin. Curr Med Res Opin 22(11): 2079-2087, 2006.
19. Fowler VG, Jr., Boucher HW, Corey R, et al. Daptomycin versus standard therapy for bacteremia and endocarditis caused by Staphylococcus aureus. N Engl J Med 355(7): 653-665, 2006.
20. Nguyen HH, Hoze MD. Hospital-based Oupatient Parenteral Antimicrobiol Therapy (OPAT) at a University Hospital. Presented at Infectious Diseases Society of America (IDSA) 44th Annual Meeting, held October 12-15, in Toronto, Ontario, Canada. Abstract # 221.