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Daptomycin for the Treatment of Severe Necrotizing Soft-Tissue Infections

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
ClinicalTrials.gov Identifier: NCT00261807
Recruitment Status : Completed
First Posted : December 5, 2005
Last Update Posted : June 2, 2008
Cubist Pharmaceuticals LLC
Information provided by:
University of Maryland

Brief Summary:

Daptomycin is a new antimicrobial agent which has activity against resistant Gram positive cocci including MRSA. The phase 3 clinical trials for skin and soft tissue infections (SSTI) with Staphylococci and Streptococci have already demonstrated that daptomycin was noninferior to the comparator agent (vancomycin or beta-lactams) (10). Although this clinical trial did not include any patients with clostridial infection, there is in vitro data to support the activity of daptomycin against a variety of clostridial species(11) ( Clostridium perfringens) Therefore, for this trial we will include patients with clostridial infections with this species. Additionally, the patients in the SSTI study were not as ill as the proposed study population. Therefore for treatment of such severe infections, we would like to use a higher dose of daptomycin (6mg/kg/dose). The reasons for using a higher dose of daptomycin in this subgroup are as follows:

  1. Patients who are severely ill have an increased volume of distribution; and therefore have a lower serum concentration of daptomycin. These patients might require a higher dose of daptomycin to achieve the desired serum concentration.
  2. One of the organisms involved in necrotizing fasciitis is enterococcus (both-fecalis and faecium). E.faecium has higher MICs to daptomycin and would require a higher dose of the drug to achieve adequate free (unbound) serum concentration of the drug.
  3. Both necrotizing fasciitis and endocarditis are serious deep seated infections. The clinical trials for endocarditis are using 6mg/kg/dose of daptomycin.

Therefore for optimal treatment of necrotizing fasciitis, it is justifiable that we should use the higher dose of daptomycin.


To evaluate the clinical and microbiological efficacy and safety of higher dose daptomycin therapy in the treatment of patients with severe necrotizing skin and soft tissue infections.

Type of Study:

Open label, single center study.

Condition or disease Intervention/treatment
Fasciitis, Necrotizing Severe Necrotizing Skin and Soft Tissue Infections Fournier's Gangrene Drug: Daptomycin 6mg/kg/day

  Show Detailed Description

Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 25 participants
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Open Label, Single Center Study to Evaluate Higher Doses of Daptomycin in the Treatment of Patients With Severe Necrotizing Skin and Soft Tissue Infections.
Study Start Date : June 2005
Primary Completion Date : May 2008
Study Completion Date : May 2008

Resource links provided by the National Library of Medicine

Drug Information available for: Daptomycin
U.S. FDA Resources

Primary Outcome Measures :
  1. Clinical Response at the end of treatment (7-14 days) and test of cure (3-28 days) post end of treatment):
  2. Cure: Resolution of clinically significant signs and symptoms* associated with the infected wound present at the time of study entry and no additional gram-positive antibiotic therapy is needed until the end of treatment visit.
  3. Improved: Partial resolution of clinical signs and symptoms* of the wound (e.g., although the patient's clinical status has not completely returned to preinfection baseline, the infectious process has been controlled) and no additional gram-positive
  4. Failure: No response or worsening of clinical signs and symptoms of infection; or new signs and symptoms of infection are present; or additional gram-positive antibiotic therapy is needed until the end of treatment visit.
  5. Unable to Evaluate: Unable to determine response; e.g., no evaluation performed at the time point, or administration of non-study antibiotics effective against a study pathogen.
  6. * Clinically significant signs and symptoms are:
  7. - pain out of proportion to clinical findings
  8. - tenderness to palpation
  9. - elevated temps.[100.4] or reduced temps.[>96]
  10. - WBC counts > 12.000/cu.mm
  11. - swelling
  12. - erythema
  13. - induration
  14. - pus formation

Secondary Outcome Measures :
  1. Microbiological Response at End of Treatment and Test of Cure Visit:
  2. Documented Eradicated: The baseline infecting pathogen was absent at end of treatment as determined by a negative culture result.
  3. Presumed Eradicated: The baseline infection was presumed absent at the end of treatment as determined that there was "nothing to culture".
  4. Documented Persistent: The baseline infecting pathogen was present at the end of treatment.
  5. Patients will also be monitored for 3 - 28 days post therapy.

Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

Inclusion/Exclusion Criteria

Inclusion criteria :

  1. Read and sign the consent form. If patient is unable to sign, the consent will be obtained from a legally authorized representative.
  2. Male or female > 18 years of age
  3. If female of child bearing potential, negative pregnancy test
  4. Surgical diagnosis of severe necrotizing fasciitis, severe necrotizing skin and soft tissue infections (e.g. Fournier's gangrene)
  5. A) At least three of the following clinical signs and symptoms of local infection should be present:

    • pain out of proportion to clinical findings
    • tenderness to palpation
    • swelling
    • erythema
    • induration
    • pus formation

    B) At least 1 of the two systemic conditions should be present:

    • Elevated temps.[100.4] or reduced temps. [<96]
    • WBC counts > 12.00/cu.mm
  6. Positive gram stain or wound culture obtained within 3 calendar days prior to the first dose of Daptomycin.

    • positive gram stain would include gram positive cocci or gram positive rods
    • positive wound culture would include growth of staphylococci and/or streptococci and/or enterococcus and/or clostridia (Clostridium perfringens ).
  7. If the patient is on HMG-CoA reductase inhibitors then these agents will be discontinued at the study initiation and resumed after discontinuation of daptomycin.

Exclusion criteria:

  1. If female, pregnant, or lactating and breast-feeding
  2. Previous antibiotic therapy exceeding 72 hours duration, unless patient is worsening clinically or has gram positive pathogens cultured from wound that are resistant to current antibiotic therapy.
  3. Sites of infection other than skin i.e., osteomyelitis, meningitis, bacteremia, etc.
  4. Known to be allergic or intolerant to study medications
  5. Expected to die in < 5 days
  6. Significant renal impairment - creatinine clearance < 30m/min
  7. A primary diagnosis of uncomplicated skin infections, such as cellulitis, minor post-op. wound infection, small decubitus ulcer etc.
  8. Patients with baseline CPKs equal to or greater than 10 times upper limit of normal without myopathy and CPK elevation of greater than or equal to 5 times upper limit of normal with symptoms of myopathy
  9. Documentation of myoglobinuria at onset of the study. The study will be conducted over a one-year period. We are anticipating enrollment of 25 patients on the study.

Criteria for withdrawal from the study:

  1. If the patient complains of myalgias and has high CPK values as specified below.
  2. If the patient develops myoglobinuria, CPKs equal to or 10 times upper limit of normal without myopathy and CPK elevation of greater than 5 times upper limit of normal with symptoms of myopathy.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT00261807

United States, Maryland
R Adams Cowley Shock Trauma Center, U. of Maryland Medical Center
Baltimore, Maryland, United States, 21201
Sponsors and Collaborators
University of Maryland
Cubist Pharmaceuticals LLC
Principal Investigator: Manjari G Joshi, MD University of Maryland, School of Medicine - Shock Trauma

References 1. Wang K, Shin C. Necrotizing fasciitis of the extremities. J Trauma 1992; 32:19-182. 2. Swartz MN. Cellulitis and subcutaneous tissue infections. In Mandell AL, Dolin R, Bennett JE (eds). Principles and Practice of Infectious Diseases. New York, Churchill Livingstone, 1995, p 909-929. 3. Stone HH, Martin JD. Synergistic necrotizing cellulitis. Ann. Surg. 1972; 175: 702-710. 4. Stevens DL, Tanner MH, Winship J, et al. Severe group A streptococcal infections associated with a toxic shock-like syndrome and a scarlet fever toxin. N Engl J Med 1989; 1: 321. 5. Elliott DC, Kufera JA, Myers RAM. Necrotizing soft tissue infections; risk factors for mortality and strategies for management. Ann. Surg 1966; 224: 672-683. 6. Asfar SK. Necrotizing fasciitis. Br. J. Surg. 1991; 7-8, 828-840. 7. Rotstein OD, Pruett TL, Simmons RL. Mechanisms of microbial synergy in polymicrobial surgical infections. Rev Infect Dis. 1985; 7: 151-170. 8. Naimi, TS, LeDell RH, Como-Sabelth K, et al. Comparison of community-and health care associated MRSA infection. JAMA 2003; 290: 2976. 9. Herold, BC, Immerglick LC, Maranana MC, et al. Community-acquired methicillin-resistant S. aureus in children with no identified predisposing risk. JAMA 1998; 279: 593. 10. Arbeit RD, Maki D, Tally FP, Campanaro E, Eisenstein BI. Daptomycin 98-01 and 99-01 Investigators. The safety and efficacy of daptomycin for the treatment of complicated skin skin-structure infection.. Clin. Infect. Dis. 2004 June 15: 38 (12): 1673-81, Epub 2004 May 11. Ellie J.C.Goldstein, Diane M.Citron, C.Vreni Merriam, et al. In Vitro Activities of daptomycin, Vancomycin, Quinupristin-Dalfopristin, Linezolid, and Five Other Antimicrobials against 307 Gram-Positive Anaerobic and 31 Corynebacterium Clinical Isolates. Antimicrobial agents and chemoterapy,2003 June: 47(1) 337-341 12. Barry H.Dvorchik, PhD, FCP, and David Damphousse,MS. Pharmacokinetics of daptomycin in Moderately Obese, Morbidly obese, and Matched Nonobese Subjects.J Clin Pharmacol 2005; 45:48-56 13. Package insert for CUBICIN (daptomycin for injection)

ClinicalTrials.gov Identifier: NCT00261807     History of Changes
Other Study ID Numbers: H-26386
First Posted: December 5, 2005    Key Record Dates
Last Update Posted: June 2, 2008
Last Verified: May 2008

Keywords provided by University of Maryland:

Additional relevant MeSH terms:
Communicable Diseases
Soft Tissue Infections
Musculoskeletal Diseases
Bacterial Infections
Genital Diseases, Male
Skin Diseases, Bacterial
Fournier Gangrene
Fasciitis, Necrotizing
Pathologic Processes
Anti-Bacterial Agents
Anti-Infective Agents