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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
Results First Posted : March 26, 2021
Last Update Posted : January 27, 2022
Sponsor:
Collaborator:
Cubist Pharmaceuticals LLC
Information provided by (Responsible Party):
Denise Rudell, University of Maryland, Baltimore

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.

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 or disease Intervention/treatment Phase
Fasciitis, Necrotizing Severe Necrotizing Skin and Soft Tissue Infections Fournier's Gangrene Drug: Daptomycin 6mg/kg/day Not Applicable

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 25 participants
Allocation: N/A
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
Actual Primary Completion Date : May 2008
Actual Study Completion Date : May 2008

Resource links provided by the National Library of Medicine

Drug Information available for: Daptomycin

Arm Intervention/treatment
Single ARM Study
It was a single arm study with higher dose of daptomycin used for patients with severe skin and soft tissue infections.
Drug: Daptomycin 6mg/kg/day



Primary Outcome Measures :
  1. Clinical Response to High Dose Daptomycin Therapy at End of Treatment (EOT) [ Time Frame: The clinical response was measured at the end of treatment (7-14 days) ]

    Clinical response was assessed by measuring impact of therapy on certain wound parameters. Specifically Erythema, Induration/Swelling, Suppuration, were recorded visually and WBC Counts were considered improved if <12,000/cu mm.

    The clinical response was documented as:

    1. CURE (resolution of clinical signs and symptoms and no additional need for gram-positive antibiotic therapy.
    2. IMPROVED (partial resolution of clinical signs and symptoms (although patient's clinical status had not completely returned to preinfection baseline but infectious process had been controlled , no additional gram-positive antibiotic therapy was needed;
    3. FAILURE (no response, worsening of clinical signs and symptoms of infection; or additional gram-positive antibiotic therapy was needed );
    4. UNABLE TO EVALUATE (unable to determine response; e.g., no evaluation performed at specified time points, or administration of non-study antibiotics effective against study pathogen).

  2. Clinical Response to High Dose Daptomycin Therapy at Test of Cure (TOC) [ Time Frame: The clinical response was measured at Test of Cure (3-28 days post end of treatment) ]

    Clinical response was assessed by measuring impact of therapy on certain wound parameters. Specifically Erythema, Induration/Swelling, Suppuration, were recorded visually and WBC Counts were considered improved if <12,000/cu mm.

    The clinical response was documented as:

    1. CURE (resolution of clinical signs and symptoms and no additional need for gram-positive antibiotic therapy.
    2. IMPROVED (partial resolution of clinical signs and symptoms (although patient's clinical status had not completely returned to preinfection baseline but infectious process had been controlled , no additional gram-positive antibiotic therapy was needed;
    3. FAILURE (no response, worsening of clinical signs and symptoms of infection; or additional gram-positive antibiotic therapy was needed );
    4. UNABLE TO EVALUATE (unable to determine response; e.g., no evaluation performed at specified time points, or administration of non-study antibiotics effective against study pathogen).


Secondary Outcome Measures :
  1. Microbiological Response to High Dose Daptomycin Therapy at End of Treatment (EOT) and Test of Cure (TOC) [ Time Frame: The microbiologicall response will be measured at the end of treatment (7-14 days) and Test of Cure (TOC) (3-28 days) ]

    Bacterial cultures were obtained in all patients and repeated if the patient had a second surgical intervention.

    The microbiological responses were documented as follows:

    1. DOCUMENTED ERADICATED: the baseline infecting pathogen was absent at end of treatment as determined by a negative culture.
    2. PRESUMED ERADICATED: The baseline infection was presumed absent at the end of treatment as determined that there was "nothing to culture".
    3. DOCUMENTED PERSISTENT: The baseline infecting pathogen was present at the end of treatment.



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
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.

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


Locations
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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, Baltimore
Cubist Pharmaceuticals LLC
Investigators
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Principal Investigator: Manjari G Joshi, MD University of Maryland, School of Medicine - Shock Trauma
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Responsible Party: Denise Rudell, Program Manager for Dr. Manjari Joshi, University of Maryland, Baltimore
ClinicalTrials.gov Identifier: NCT00261807    
Other Study ID Numbers: H-26386
First Posted: December 5, 2005    Key Record Dates
Results First Posted: March 26, 2021
Last Update Posted: January 27, 2022
Last Verified: January 2022
Keywords provided by Denise Rudell, University of Maryland, Baltimore:
severe
skin
infections
Additional relevant MeSH terms:
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Infections
Communicable Diseases
Soft Tissue Infections
Fournier Gangrene
Fasciitis
Fasciitis, Necrotizing
Gangrene
Disease Attributes
Pathologic Processes
Musculoskeletal Diseases
Necrosis
Bacterial Infections
Bacterial Infections and Mycoses
Daptomycin
Anti-Bacterial Agents
Anti-Infective Agents