Clinical Trial: Daptomycin for the Treatment of Severe Necrotizing Soft-Tissue Infections

Study Status: Completed
Recruit Status: Completed
Study Type: Interventional

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.

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.

At the shock trauma center, the management of patients with NSTI is conducted in the following fashion: All new patients with NSTI are admitted to the trauma center through the 12-bed shock trauma admitting area. Full hemodynamic resuscitation is undertaken. The on-call soft-tissue and infection team is mobilized. Standard investigations, radiographic evaluations, and laboratory tests, including gram stain and culture specimens, are obtained. The University of Maryland Medical Systems/shock trauma laboratory is utilized for hematology, biochemical, and bacteriologic studies. Aggressive empiric broad-spectrum antibiotic therapy is instituted. The standard antibiotic therapy for NSTI's at shock trauma includes the following:

Gram negative rods: Piperacillin/Tazobactam or quinolones or aztreonam /

+ aminoglycosides Anaerobes: Piperacillin/Tazobactam or Metronidazole or Clindamycin Gram positive cocci (not MRSA/VRE): Piperacillin/Tazobactam or Clindamycin Gram positive cocci (MRSA): Vancomycin Gram positive cocci (VRE): Linezolid For purposes of this study, daptomycin would replace Vancomycin, Linezolid or clindamycin for gram positive coverage. Prior antibiotic therapy, culture data, comorbid conditions, allergy history and other variables may result in institution of a different antibiotic regimen.

The patient is taken to the shock trauma operating room for debulking of infected tissue (excision and debridement) and reculturing. Postoperatively, the patient is moved to a critical or intensive care unit for further management and monitoring. When the patient is stable, HBO is begun within 12 hours of arrival. Once the patient is enrolled in the study the following procedures will be followed:

Antibiotic Therapy:

  • 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


    • Original Primary Outcome: Same as current

    Current Secondary Outcome:

    • 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.


    Original Secondary Outcome: Same as current

    Information By: University of Maryland

    Dates:
    Date Received: December 1, 2005
    Date Started: June 2005
    Date Completion:
    Last Updated: May 30, 2008
    Last Verified: May 2008