Now Available for Public Comment: Notice of Proposed Rulemaking (NPRM) for FDAAA 801 and NIH Draft Reporting Policy for NIH-Funded Trials

Daptomycin for the Treatment of Severe Necrotizing Soft-Tissue Infections

This study has been completed.
Sponsor:
Collaborator:
Cubist Pharmaceuticals
Information provided by:
University of Maryland
ClinicalTrials.gov Identifier:
NCT00261807
First received: December 1, 2005
Last updated: May 30, 2008
Last verified: May 2008
  Purpose

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.

Objective:

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

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Bio-equivalence Study
Intervention Model: Single Group Assignment
Masking: 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.

Resource links provided by NLM:


Further study details as provided by University of Maryland:

Primary Outcome Measures:
  • Clinical Response at the end of treatment (7-14 days) and test of cure (3-28 days) post end of treatment):
  • 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.
  • 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
  • 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.
  • 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.
  • * Clinically significant signs and symptoms are:
  • - pain out of proportion to clinical findings
  • - tenderness to palpation
  • - elevated temps.[100.4] or reduced temps.[>96]
  • - WBC counts > 12.000/cu.mm
  • - swelling
  • - erythema
  • - induration
  • - pus formation

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

Estimated Enrollment: 25
Study Start Date: June 2005
Study Completion Date: May 2008
Primary Completion Date: May 2008 (Final data collection date for primary outcome measure)
  Show Detailed Description

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00261807

Locations
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
Investigators
Principal Investigator: Manjari G Joshi, MD University of Maryland, School of Medicine - Shock Trauma
  More Information

Publications:
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
Study First Received: December 1, 2005
Last Updated: May 30, 2008
Health Authority: United States: Food and Drug Administration

Keywords provided by University of Maryland:
severe
skin
infections

Additional relevant MeSH terms:
Communicable Diseases
Fasciitis, Necrotizing
Fournier Gangrene
Infection
Soft Tissue Infections
Bacterial Infections
Fasciitis
Genital Diseases, Male
Musculoskeletal Diseases
Skin Diseases, Bacterial
Daptomycin
Anti-Bacterial Agents
Anti-Infective Agents
Pharmacologic Actions
Therapeutic Uses

ClinicalTrials.gov processed this record on November 27, 2014