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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:
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.
Full description
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 /
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:
Once the patient is consented, the antibiotic therapy will be started. The combination regimen will include the following drugs in standard approved dosing.
Gram negative bacteria: Aztreonam or ciprofloxacin / + aminoglycosides*
Anaerobic bacteria: Metronidzole
Gram positive bacteria: Daptomycin For all patients the recommended dose of Daptomycin will be 6 mgm/kg/day administered over 30 minutes. A pharmacokinetic study performed in obese patients demonstrated that daptomycin could be dosed based on total body weight. No adjustment in daptomycin dose should be required based solely on obesity (12). Any patient who develops a decrease in renal function during the study to the point where his/her creatinine clearance (CrCl) falls below 30 mL/min would have their dose adjusted to 6 mg/kg every 48 hours, the interval recommended by the package insert. This includes patients who go on to require conventional hemodialysis. Since there are no data available on the pharmacokinetics (PK) of daptomycin in patients receiving continuous renal replacement therapy (CRRT), and therefore no recommendation for dosage adjustment, these patients would be removed from the study and initiated on a standard of care regimen . Treatment duration will be 7-14 days.
At various intervals, the following information will be collected or procedures will be followed: (See attached study schedule) Baseline
At various intervals, the following procedures will be followed:.
The End points of the study are as follows:
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 pre-infection baseline, the infectious process has been controlled) and no additional gram-positive antibiotic therapy is needed until the end of treatment visit.
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
Microbiological Response at End of Treatment and Test of Cure Visit:
Patients will also be monitored for 3 - 28 days post therapy.
Analysis Because of the small sample size (25 patients) stated above, this study will serve as a preliminary study to obtain data to evaluate the presence of positive trends in terms of outcome in the patients treated with Daptomycin. If favorable, this would warrant a larger prospective controlled study in which a larger sample size would allow for a more robust statistical analysis. Variables in the initial analysis will include antibiotic days, intensive care unit and hospital length of stay and mortality.
Enrollment
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Inclusion and exclusion criteria
Inclusion/Exclusion Criteria
Inclusion criteria :
Read and sign the consent form. If patient is unable to sign, the consent will be obtained from a legally authorized representative.
Male or female > 18 years of age
If female of child bearing potential, negative pregnancy test
Surgical diagnosis of severe necrotizing fasciitis, severe necrotizing skin and soft tissue infections (e.g. Fournier's gangrene)
A) At least three of the following clinical signs and symptoms of local infection should be present:
B) At least 1 of the two systemic conditions should be present:
Positive gram stain or wound culture obtained within 3 calendar days prior to the first dose of Daptomycin.
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:
Criteria for withdrawal from the study:
Primary purpose
Allocation
Interventional model
Masking
25 participants in 1 patient group
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Data sourced from clinicaltrials.gov
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