The American Journal of Medicine
Volume 120, Issue 10, Supplement 1 , Pages S1-S3, October 2007

Introduction

  • Kenneth V.I. Rolston, MD

      Affiliations

    • M. D. Anderson Cancer Center, University of Texas, Houston, Texas, USA
    • Corresponding Author InformationRequests for reprints should be addressed to Kenneth V. I. Rolston, MD, M. D. Anderson Cancer Center, University of Texas, 4032 Coleridge, Houston, Texas 77005.
    • ,
  • John Segreti, MD

      Affiliations

    • Rush University Medical Center, Chicago, Illinois, USA

Article Outline

 

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Daptomycin: An important addition to the management of gram-positive infections 

The growing problem of bacterial resistance has been recognized and documented for some time, and is global in its scope. The emergence of resistant microorganisms has considerably outpaced our ability to develop new antimicrobial agents to combat these pathogens. Reasons for this state of affairs include the inappropriate use of antimicrobial agents; the use of these agents in agriculture, animal husbandry, household products, and other nonmedical settings; the ability of microorganisms to mutate and develop multiple mechanisms of resistance that render several classes of antimicrobial agents ineffective; widespread and swift global travel that facilitates the spread of resistant clones; and the exorbitant costs associated with developing new pharmaceutical products. These issues have been highlighted in 2 recent publications from the Infectious Diseases Society of America (IDSA).1, 2

Gram-positive organisms cause many serious infections, especially in susceptible patient populations such as those undergoing extensive surgery, those with prosthetic devices, premature infants and elderly persons, and individuals with immunosuppression/neutropenia. Of particular concern are methicillin-resistant Staphylococcus aureus (MRSA), including community-acquired strains, and vancomycin-resistant enterococci (VRE). The infections encountered most often are bacteremias, catheter-related infections, skin and skin-structure infections (SSSIs), osteomyelitis, and endocarditis. For several decades, vancomycin has been the agent of choice for the treatment of infections caused by MRSA.3 In recent years, the efficacy of vancomycin appears to be declining owing to several mechanisms, including increasing minimum inhibitory concentrations, increasing tolerance (i.e., an inhibitory-to-bactericidal concentration ratio of ≥1:32), and dysfunctional accessory gene regulator mechanisms leading to loss of bactericidal activity.4, 5, 6 It also is noted increasingly that there are other explanations for vancomycin’s suboptimal performance, such as its poor penetration into various tissues, including the skin.7 Agents with activity against VRE (e.g., quinupristin-dalfopristin, linezolid) also are associated with problems such as substantial toxicity, poor bactericidal activity, and increasing levels of resistance.

Daptomycin (Cubicin; Cubist Pharmaceuticals, Inc., Lexington, MA) is a cyclic lipopeptide with potent bactericidal activity against most pathogenic gram-positive organisms including MRSA and VRE.8 It was approved by the US Food and Drug Administration (FDA) in late 2003 for the treatment of complicated SSSIs caused by S aureus (including MRSA), Streptococcus pyogenes, Streptococcus agalactiae, Streptococcus dysgalactiae subsp equisimilis, and vancomycin-susceptible Enterococcus faecalis, and, more recently, for the treatment of bacteremias and right-sided infective endocarditis (IE) caused by S aureus (including MRSA) in May 2006. Shortly after its initial approval, the Cubicin Outcomes Registry and Experience (CORE) was established with a multicenter, retrospective, observational study design in order to gather real-world postmarketing data on daptomycin usage. This supplement to The American Journal of Medicine features several reports based on the data gathered through the CORE program. Each article focuses on 1 of the more frequently reported conditions for which daptomycin usage was reported. In addition, the authors frame these experiences within the limitations experienced with single-agent, unblinded, nonrandomized, retrospective studies in patients with complicated antimicrobial histories.

In the first article, Dr. Kenneth V. I. Rolston and coworkers describe the CORE methodology used for data collection by all participating sites. The second article, by Dr. Robert C. Owens, Jr., and colleagues, recount the experience in 522 patients with SSSIs. Daptomycin was most frequently used for SSSIs due to S aureus—predominantly MRSA—in a population with reduced renal function in 25% of patients. The median dose and duration in this CORE report were similar to those in the registrational trial for SSSIs reported by Arbeit and associates in 2004.9 The success rates at the end of daptomycin treatment were 96% for complicated infections and 98% for uncomplicated infections.

For nonhospitalized patients with SSSIs, drainage or debridement alone may be sufficient. In this setting many antibiotics may be effective (e.g., minocycline, trimethoprim-sulfamethoxazole, or clindamycin) for uncomplicated MRSA infections. The most cost-effective and patient-friendly therapy should be chosen, but susceptibilities should be checked. For patients hospitalized with SSSIs, data exist primarily for treatment with vancomycin, daptomycin, tigecycline, and linezolid. Telavancin, dalbavancin, oritavancin, and ceftobiprole are currently in development. Because of its long half-life, dalbavancin may be an important therapeutic option once approved, and the new cephalosporins (ceftobiprole and ceftaroline) appear promising as well.

In the third article, Dr. Kenneth C. Lamp and colleagues describe their experience in 67 patients with predominantly MRSA and methicillin-susceptible S aureus osteomyelitis treated primarily with daptomycin. The success rate at the last follow-up visit was 82%. Patients with orthopedic devices or bacteremia had outcomes similar to those seen in the overall study. Success rates at follow-up were significantly higher for daptomycin at doses >4 mg/kg compared with lower doses. Unfortunately, there is a critical lack of data on the optimal role of antibiotics in the treatment of osteomyelitis. Prospective randomized studies of osteomyelitis are extremely difficult to perform. Vancomycin has generally been regarded as the drug of choice for MRSA. However, just as with pneumonia and bacteremia, there are growing concerns as to its true efficacy. Clearly, new therapies are needed, but it is unlikely that we will have any new clinical studies other than case series in the foreseeable future. A phase 2 randomized study investigating the safety, efficacy, and pharmacokinetics of daptomycin versus vancomycin in the treatment of patients with osteomyelitis associated with an infected prosthetic hip or knee joint caused by MRSA is set to begin. However, the results are likely years away.

The fourth article, by Dr. George Sakoulas and colleagues, presents details of 126 patients with catheter-related or cathether-unrelated bacteremias. The most common pathogens were MRSA, VRE, and coagulase-negative staphylococci. The success rate was 89% overall for evaluable patients and was similar for all pathogens. Approximately 33% of patients were receiving dialysis, almost all receiving daptomycin every 48 hours or 3 times per week, and the success rates of patients on dialysis were similar to those of patients not receiving dialysis. Agents that are not FDA approved for the indication of bacteremia and IE but are sometimes used include trimethoprim-sulfamethoxazole, linezolid, and quinupristin-dalfopristin. Based on results from a recently completed study for the treatment of catheter-related bacteremia, there is an increased mortality rate in patients treated with linezolid. Thus, the linezolid prescribing information has been revised to inform the medical community that linezolid is not approved and should not be used for the treatment of patients with catheter-related bloodstream infections or catheter-site infections.10 The efficacy of dalbavancin in a randomized open-label study was compared with vancomycin for the treatment of catheter-related bloodstream infections.11 Although the clinical cure rate was 87% (20 of 23) for patients receiving dalbavancin, and only 50% (14 of 28) for patients receiving vancomycin, these results should be interpreted with caution because these efficacy results were combined for all patients with gram-positive infections (including coagulase-negative staphylococci, coagulase-positive staphylococci, streptococci, and S aureus, including MRSA). Most important, the patient population studied was very heterogeneous (i.e., patients with α-streptococcal bacteremia are quite different from patients with S aureus bacteremia), making it difficult to draw conclusions about the efficacy of dalbavancin in bloodstream infections. Other agents that are under development for this indication include telavancin, and oritavancin.

In the final article, Dr. Donald P. Levine and Dr. Lamp describe the CORE experience in 49 patients with a diagnosis of endocarditis who received daptomycin as part of their therapy. Both right- and left-sided endocarditis are described. Approximately 50% of patients had a creatinine clearance of <30 mL/min, and approximately 33% were on dialysis—patients typically excluded from clinical studies. Therapy was successful in 63% of patients, 8% failed, and 29% of the cases were nonevaluable. Although vancomycin is often considered the “gold standard” for the treatment of MRSA IE, it is not necessarily the ideal choice for a variety of reasons.7 There are reports of relapses and poor outcomes with the use of vancomycin for persistent bacteremia, especially when it is caused by MRSA. There may be a variety of reasons for this, including inadequate dosing, poor tissue penetration, slow killing, and reduced susceptibility of S aureus to vancomycin (heteroresistance, intermediate resistance, and complete resistance). In a review of the available literature of the use of linezolid for IE, 21 of 33 patients achieved a cure.12 The cure rate for left-sided endocarditis due to MRSA was 50% (in 10 patients). Although these data suggest that linezolid may be useful in the treatment of bacteremia and endocarditis due to MRSA, additional data will be required for confirmation. In addition, the duration of therapy required to treat MRSA IE with linezolid raises concerns about significant toxicity, including bone marrow suppression, optic neuropathy, peripheral neuropathy, and lactic acidosis.13

These reports provide us with insight as to how daptomycin is being used by clinicians in the community, as well as data on infections not within the approved indications and complement data already published. Additionally, outcomes are reported in patients with limited accrual in controlled clinical studies, such as renal insufficiency/hemodialysis patients. Information on higher daptomycin doses and longer treatment durations is also presented. The CORE database has identified that some clinicians may be using daptomycin at lower-than-recommended doses. Studies completed after initiation of CORE 2004 have better defined the appropriate dosing for daptomycin for various indications. Additional educational efforts, such as the publication of this supplement, are needed to disseminate the most current recommendations. Overall, the data are useful for evaluating daptomycin’s contribution to therapy despite the aforementioned limitations. The CORE program will continue to collect data as clinical experience with daptomycin accumulates.

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References 

  1. Bad Bugs, No Drugs. Infectious Diseases Society of America, July 2004. Available at: http://www.idsociety.org/pa/IDSA_ Paper4_ final_ web.pdf. Accessed August 20, 2007.
  2. Talbot GH, Bradley J, Edwards JE, Gilbert D, Scheld M, Bartlett JG Antimicrobial Availability Task Force of the Infectious Diseases Society of America. Bad bugs need drugs: an update on the development pipeline from the Antimicrobial Availability Task Force of the Infectious Diseases Society of America. Clin Infect Dis. 2006;42:657–668
  3. Moellering RC. Vancomycin: a 50-year reassessment. Clin Infect Dis. 2006;42(suppl 1):S3–S4
  4. Kapadia M, Coyle E, Prince R, Rolston K. Declining in vitro activity of vancomycin against Staphylococcus aureus isolates from cancer patients. Presented at the 45th Annual Meeting of Interscience Conference of Antimicrobial Agents and Chemotherapy (ICAAC) In: Washington DC: Ameican Society for Microbiology; 2005;p. 168;Abstract E–807.
  5. Safdar A, Rolston KV. Vancomycin tolerance, a potential mechanism for refractory gram-positive bacteremia observational study in patients with cancer. Cancer. 2006;106:1815–1820
  6. Fowler VG, Sakoulas G, McIntyre LM, et al. Persistent bacteremia due to methicillin-resistant Staphylococcus aureus: infection is associated with agr dysfunction and low-level in vitro resistance to thrombin-induced platelet microbicidal protein. J Infect Dis. 2004;190:1140–1149
  7. Deresinski S. Counterpoint: vancomycin and Staphylococcus aureus—an antibiotic enters obsolescence. Clin Infect Dis. 2007;44:1543–1548
  8. Carpenter CF, Chambers HF. Daptomycin: another novel agent for treating infections due to drug-resistant gram-positive pathogens. Clin Infect Dis. 2004;38:994–1000
  9. Arbeit RD, Maki D, Tally FP, Campanaro E Eisenstein BI, and the Daptomycin 98–01 and 99–01 Investigators. The safety and efficacy of daptomycin for the treatment of complicated skin and skin-structure infections. Clin Infect Dis. 2004;38:1673–1681
  10. Zyvox. [prescribing information] New York, NY: Pfizer Inc; 2007;
  11. Raad I, Darouiche R, Vazquez J, et al. Efficacy and safety of weekly dalbavancin therapy for catheter-related bloodstream infection caused by gram-positive pathogens. Clin Infect Dis. 2005;40:374–380
  12. Birmingham MC, Rayner CR, Meagher AK, Flavin SM, Batts DH, Schentag JJ. Linezolid for the treatment of multidrug-resistant, gram-positive infections: experience from a compassionate-use program. Clin Infect Dis. 2003;36:159–168
  13. Bishop E, Melvani S, Howden BP, Charles PG, Grayson ML. Good clinical outcomes but high rates of adverse reactions during linezolid therapy for serious infections: a proposed protocol for monitoring therapy in complex patients. Antimicrob Agents Chemother. 2006;50:1599–1602

 Statement of conflict of interest: Dr. Kenneth V. I. Rolston, MD, and Dr. John Segreti, MD report no conflict of interest with the sponsor of this supplement article or products discussed in this article.

PII: S0002-9343(07)00657-2

doi:10.1016/j.amjmed.2007.07.007

The American Journal of Medicine
Volume 120, Issue 10, Supplement 1 , Pages S1-S3, October 2007

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