Cubicin® (Daptomycin): Treatment of S. Aureus Bacteremia/Endocarditis
By Erica Tam, Yanina Goykhman, Jessica C. Song, and Paul Hsiao, Erica Tam and Yanina Goykhman are PharmD Candidates, University of the Pacific, Paul Hsiao, PharmD, is Pharmacist Specialist, Santa Clara Valley Medical Center, Jessica C. Song is Pharmacy Residency Coordinator, Assistant Professor, Pharmacy Practice, University of the Pacific, Stockton, CA, Pharmacy Clerkship and Coordinator, Santa Clara Valley Medical Center, Section Editor, Managed Care, is Associate Editor for Infectious Disease Alert.
Erica Tam, Yanina Goykhman, Jessica C. Song, and Paul Hsiao report no financial relationships relevant to this field of study.
In recent years, S. aureus has been identified as the most common cause of infective endocarditis (IE). Risk factors for S. aureus IE include the presence of indwelling prosthetic devices and intravascular catheters.1
S. aureus-induced IE is a major problem in hospitals and communities alike. With the overuse of traditional antibiotic therapy such as nafcillin and oxacillin, there has been a surge of drug-resistant bacteria emerging for which β-lactam antibiotics are no longer effective.1 Vancomycin is generally regarded as the mainstay of treatment for methicillin-resistant S. aureus (MRSA),2 but cases of vancomycin-resistant or intermediate-resistant S. aureus strains have been reported.3,4 In light of the recent emergence of reduced vancomycin susceptibility in S. aureus, the need for new antimicrobial agents with expanded indications is greater than ever.
Daptomycin, a cyclic lipopeptide produced by Streptomyces roseosporus has been of particular interest due to its activity against MRSA, MSSA (methicillin-susceptible S. aureus), vancomycin-resistant Enterococci (VRE), and linezolid-resistant E. faecium strains.5,6 Its unique mechanism of action sets it apart from other antibiotics currently on the market, as its bactericidal action appears to be through inhibition of amino acid transport and membrane disruption.5 Unlike other available agents, such as vancomycin, quinupristin/dalfopristin, and linezolid, daptomycin offers once daily dosing and rapid in vitro bactericidal activity against VRE and MRSA.7
At present, daptomycin is indicated for use in the treatment of complicated skin/skin structure infections caused by susceptible strains of S. aureus (including MRSA), Streptococcus pyogenes, Streptococcus agalactiae, Streptococcus dysgalactiae subsp. Equisimilis, and Enterococcus faecalis (vancomycin-susceptible strains only).8 Cubist Pharmaceuticals Inc. received an Approvable Letter for the supplemental New Drug Application (label expansion to include S. aureus bacteremia, including those with known or suspected IE) on March 24, 2006.9 This article will review daptomycin's: 1) spectrum of activity, pharmacological and pharmacokinetic properties; 2) safety profile; 3) dosage, interaction, and resistance patterns; and 4) clinical efficacy in IE patients.
Pharmacology/In Vitro Studies
A summary of the pharmacologic, pharmacokinetic, and clinical properties of daptomycin can be found in Table 1.
Studies assessing the effectiveness of daptomycin in animal model S. aureus IE suggest that it is as effective or better than vancomycin, penicillin, and semi-synthetic penicillins, such as nafcillin and cloxacillin.12,13 Cantoni and colleagues compared daptomycin to cloxacillin in the treatment of rats with S. aureus IE,13 and found that daptomycin was as effective in low-bacterial count infections, but more effective against high-bacterial count infections. Also, Cantoni et al demonstrated that earlier treatment resulted in a faster recovery.
Of particular importance is the finding that daptomycin is effective against glycopeptide-intermediate-resistant-S. aureus (GISA) infections.3,4 This finding is clinically significant because vancomycin, a glycopeptide, has been used excessively since the development of methicillin-resistant strains. Due to this overuse, vancomycin-resistant strains have developed.
Data from 2 studies revealed the superior efficacy of daptomycin in combination with gentamicin, compared with daptomycin monotherapy, for the treatment of in vitro pharmacodynamic models of S. aureus IE.14,15 LaPlante et al14 showed that the time-to-achieve bactericidal activity against MSSA and MRSA was 3-fold faster with combination therapy (daptomycin 6 mg/kg + gentamicin 1.3 mg/kg q 12h) compared with daptomycin monotherapy. Synergistic activity against GISA was attained within 48 hours of starting combination therapy. Tsuji and colleagues15 reported that a combination regimen of daptomycin 6 mg/kg and a single-dose of gentamicin 5 mg/kg reduced the time-to-kill by 6- to 8-fold, compared with daptomycin monotherapy, with less toxicity.
Current Endocarditis Guidelines
Current American Heart Association (AHA) guidelines for the treatment of S. aureus IE highlight the therapeutic options for patients lacking prosthetic valves and for prosthetic valve patients.1 In addition, therapeutic regimens were further subdivided according to the causative pathogen (MSSA or MRSA). Table 2 summarizes the AHA recommendations for the treatment of S. aureus IE.
A review of published literature showed that most reports of daptomycin use for the treatment of IE patients have been presented as retrospective analyses or as case reports.16-18 Segreti and colleagues conducted a retrospective analysis of 31 daptomycin-treated patients with bacteremia ± IE, most of whom failed previous antimicrobial therapy.16 Of the 30 bacteremic patients, 9 were classified as IE patients. MRSA, VRE, and MSSA represented the most commonly implicated pathogens in this study. Clinical cure rates for patients infected with MRSA, MSSA, and VRE were 100% (11/11), 86% (6/7), and 45% (5/11), respectively. Six of the 9 IE patients were successfully treated with daptomycin. Six of the 7 deaths were attributed to incurable VRE infection. Daptomycin was generally well-tolerated, but 3 of 31 patients experienced elevations in creatine kinase (CK) levels in excess of 10 times the baseline level. However, CK elevations were attributed to recent surgical procedures.
Veligandla and colleagues described the case of a patient experiencing severe myalgia associated with daptomycin use.17 In this report, a 26-year-old African-American woman with MRSA IE was administered intravenous daptomycin due to intolerance to vancomycin and quinupristin/dalfopristin. Although her CK level was well below the level associated with significant myopathy symptoms, the patient nevertheless experienced significant muscle pain that subsided shortly (few days) after treatment discontinuation.
Rybak and colleagues assessed the efficacies of daptomycin (3 mg/kg IV q 12h) and vancomycin for the treatment of 12 intravenous (IV) drug users with Gram-positive bacteremia and right-sided IE.18 Clinical failures occurred with daptomycin therapy, and were most likely due to insufficient dosing regimens.
Phase III S. Aureus Bacteremia/Endocarditis Study
One multicenter, randomized, open-label, Phase III study has assessed the efficacy of daptomycin in patients with S. aureus bacteremia, including those with known or suspected S. aureus IE.11
Cubist Pharmaceuticals compared daptomycin to vancomycin and semi-synthetic penicillins in the treatment of 246 patients with S. aureus bacteremia. A summary of the therapeutic drug regimens and patient population characteristics can be found in Table 3.
The primary end point of clinical success was assessed 38-46 days after the final dose of study medication for patients who achieved a successful outcome at the end of therapy. The FDA efficacy analysis of the overall intent-to-treat patient population showed non-inferiority of daptomycin, compared with vancomycin/semi-synthetic penicillins, with identical success rates of 38.3% (95% CI for difference in success rates, 0.1% [-12.4, 12.5]; using a non-inferiority margin of -20.
Fifty-three of the 246 patients with S. aureus bacteremia comprised the subgroup patient population with IE. Of those, 50% (3/6) of uncomplicated right-sided IE were cured, compared with 25% (1/4) of those in the comparator arm. Clinical success rates achieved by daptomycin- and comparator drug-treated patients with complicated right-sided IE were 38.5% (5/13) and 50% (6/12), respectively. Only 11% (1/9) of daptomycin-treated patients and 22% (2/9) of comparator-treated patients with left-sided IE were cured. Since the study was not powered to detect statistical differences between the 2 treatment arms in patients with IE, descriptive statistics were used to report the data.
The FDA's Anti-Infective Drugs Advisory Committee expressed concern that increasing minimal inhibitory concentrations (MIC), a surrogate measure of resistance, were associated with treatment failures among the patients (overall group and IE group) enrolled in this study. The rate of persistent and relapsing bacteremia, as reported by the FDA, was higher for daptomycin-treated patients (21/120 overall, 8/28 IE), compared with the rates observed in the comparator group (11/115 overall, 5/25 IE). Of the 8 IE patients who developed daptomycin MICs 2 m/mL, 6 experienced persisting/relapsing bacteremia, with equal distribution of infections due to MRSA and MSSA.
While the incidence of adverse events was comparable between treatment groups, there was concern about higher CK levels in the daptomycin arm versus the comparator arm. In particular, of the subset of 44 patients who received concomitant or prior statin therapy, nearly 17% of daptomycin-treated patients developed CK levels in excess of 500 U/L, whereas none of the patients on comparator treatment achieved such levels. Despite the high frequency of CK elevation observed during daptomycin treatment, only one report of daptomycin-associated rhabdomyolysis was noted in this study.
Resistance Concerns and Safety
As previously reported, the development of reduced susceptibility to daptomycin (MIC 1 µ/mL) was observed in the Phase III study of bacteremic patients, including those with known or suspected IE.11 In addition, recently published case reports have described the emergence of daptomycin-resistant S. aureus isolates during treatment of vertebral osteomyelitis and MRSA bacteremia.19,20
Because of its distinct mechanism of action, daptomycin has a low propensity for cross-resistance with other antibiotics, and it has a low frequency of spontaneous development of in vitro resistance.11 Nevertheless, data included in the FDA briefing report for daptomycin highlighted numerous other resistance issues, including the development of diminished susceptibility during daptomycin treatment, evidence of a trend towards decreasing activity against Staphylococci over the past few years, and the increased likelihood of exhibiting isolates with higher daptomycin MICs among patients experiencing persistent/relapsing bacteremia.
Daptomycin has been reported to have the potential for inducing myositis (muscle pain + CK elevation) in various reports11,17 and, more recently, 2 published reports described cases of rhabdomyolysis occurring during treatment.21,22 Consequently, the manufacturer recommends weekly CK level monitoring during therapy.
Daptomycin appears to be an effective alternative to vancomycin and semi-synthetic penicillins against ID due to various strains of S. aureus. In light of the growing resistance to standard treatment options, future comparative clinical studies enrolling a large number of S. aureus IE patients are warranted, in order to verify the safety and efficacy of daptomycin use for the treatment of these patients. However, the acquisition cost of daptomycin is considerably higher than those of comparator agents, such as vancomycin, cefazolin, and semi-synthetic penicillins. Consequently, semi-synthetic penicillins and vancomycin should probably continue to be used as first-line agents for the treatment of S. aureus IE, unless there is known resistance to these agents.
Cubist Pharmaceuticals submitted its response to the FDA Approvable letter on March 27, 2006.7 The final FDA recommendation for label expansion is pending.
- Baddour LM, et al. Infective Endocarditis: Diagnosis, Antimicrobial Therapy, and Management of Complications: A Statement for Healthcare Professionals From the Committee on Rheumatic Fever, Endocarditis, and Kawasaki Disease, Council on Cardiovascular Disease in the Young, and the Councils on Clinical Cardiology, Stroke, and Cardiovascular Surgery and Anesthesia, American Heart Association: Endorsed by the Infectious Diseases Society of America. Circulation. 2005;111:e394-e434. Erratum in: Circulation. 2005;112:2373.
- Appelbaum PC. The Emergence of Vancomycin-Intermediate and Vancomycin-Resistant Staphylococcus aureus. Clin Microbiol Infect. 2006;12:16-23.
- Akins RL, Rybak MJ. Bactericidal Activities of 2 Daptomycin Regimens Against Clinical Strains of Glycopeptide Intermediate-Resistant Staphylococcus aureus, Vancomycin-Resistant Enterococcus faecium, and Methicillin-Resistant Staphylococcus aureus Isolates in an In Vitro Pharmacodynamic Model with Simulated Endocardial Vegetations. Antimicrob Agents Chemother. 2001;45:454-459.
- Cha R, Rybak MJ. Daptomycin Against Multiple Drug-Resistant Staphylococcus and Enterococcus Isolates in an In Vitro Pharmacodynamic Model with Simulated Endocardial Vegetations. Diagn Microbiol Infect Dis. 2003;47:539-546.
- Lamp KC, et al. In Vitro Pharmacodynamic Effects of Concentration, pH, and Growth Phase on Serum Bactericidal Activities of Daptomycin and Vancomycin. Antimicrob Agents Chemother. 1992;36:2709-2714. Erratum in: Antimicrob Agents Chemother. 1993;37:930.
- Piper KE, et al. In Vitro Activity of Daptomycin Against Clinical Isolates of Gram-Positive Bacteria. J Infect Chemother. 2005;11:207-209.
- Furuya EY, Lowy FD. Antimicrobial Strategies for the Prevention and Treatment of Cardiovascular Infections. Curr Opin Pharmacol. 2003;3:464-469.
- Daptomycin (Cubicin®) Prescribing Information. Lexington, MA: Cubicin Pharmaceuticals Inc.: June 2005.
- Pharmaceuticals has Submitted Response to FDA Approvable Letter Received on Friday: Action Anticipated by late May. Website accessed on June 1, 2006. www.salesandmarketingnetwork.com/news_release.php?D=2010582
- 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. 2005;55:240-245.
- Cubicin (Daptomycin for Injection) for the Treatment of Staphylococcus aureus Bacteremia, Including Those with Known or Suspected Infective Endocarditis. FDA Briefing Document for Anti-Infective Drugs Advisory Committee Meeting. March 6, 2006.
- Kennedy S, Chambers HF. Daptomycin (LY146032) for Prevention and Treatment of Experimental Aortic Valve Endocarditis in Rabbits. Antimicrob Agents Chemother. 1989;33:1522-1525.
- Cantoni L, et al. Comparative Efficacy of Daptomycin, Vancomycin, and Cloxacillin for the Treatment of Staphylococcus aureus Endocarditis in Rats and Role of Test Conditions in this Determination. Antimicrob Agents Chemother. 1990;34:2348-2353.
- LaPlante KL, Rybak MJ. Impact of High-Inoculum Staphylococcus aureus on the Activities of Nafcillin, Vancomycin, Linezolid, and Daptomycin, Alone and in Combination with Gentamicin, in an In Vitro Pharmacodynamic Model. Antimicrob Agents Chemother. 2004;48:4665-4672.
- Tsuji BT, Rybak MJ. Short-Course Gentamicin in Combination with Daptomycin or Vancomycin Against Staphylococcus aureus in an In Vitro Pharmacodynamic Model with Simulated Endocardial Vegetations. Antimicrob Agents Chemother. 2005;49:2735-2745.
- Segreti JA, et al. Daptomycin for the Treatment of Gram-Positive Bacteremia and Infective Endocarditis: A Retrospective Case Series of 31 Patients. Pharmacotherapy. 2006;26:347-352.
- Veligandla SR, et al. Muscle Pain Associated with Daptomycin. Ann Pharmacother. 2004;38:1860-1862.
- Rybak MJ, et al. Pharmacokinetics and Bactericidal Rates of Daptomycin and Vancomycin in Intravenous Drug Abusers Being Treated for Gram-Positive Endocarditis and Bacteremia. Antimicrob Agents Chemother. 1992;36:1109-1114.
- Marty FM, et al. Emergence of a Clinical Daptomycin-Resistant Staphylococcus aureus Isolate During Treatment of Methicillin-Resistant Staphylococcus aureus Bacteremia and Osteomyelitis. J Clin Microbiol. 2006;44:595-597.
- Skiest DJ. Treatment Failure Resulting from Resistance of Staphylococcus aureus to Daptomycin. J Clin Microbiol. 2006;44:655-656.
- Papadopoulos S, et al. Rhabdomyolysis During Therapy with Daptomycin. Clin Infect Dis. 2006;42:e108-e110.
- Kazory A, et al. Rhabdomyolysis and Acute Renal Failure in a Patient Treated with Daptomycin. J Antimicrob Chemother. 2006;57:578-579.