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

 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.

 -  Aminoglycosides will be added if there is suspicion or documentation of resistant
 gram negative rods.

 At various intervals, the following information will be collected or procedures will be
 followed: (See attached study schedule) Baseline

 1. Demographic data - age, gender, weight, height, nursing home residence

 2. Number and length of previous hospitalizations in last six months

 3. Nature and duration of symptoms

 4. Admission status including vital signs, GCS, APACHE, SIRS scores, CBC with diff, CPK,
 lactate, BUN, creatinine, liver function tests, blood gases if on ventilator, cultures
 of wound-aerobic and anaerobic.

 5. Prior surgery for NSTI - number and dates

 6. Comorbid conditions - diabetes, peripheral vascular disease, immunocompromised, etc.

 7. Prior antibiotics over last six months - dose/route/type

 8. Prior cultures of NSTI, presence of resistant bacteria.

 9. Wound size - length, depth in cm.

 10. Use of drugs such as HMG-CoA reductase inhibitors

 At various intervals, the following procedures will be followed:.

 -  GCS, vital signs, CBC, CPK, BUN, creatinine, liver functions, blood gases if ventilated

 -  Wound size in cm

 -  Surgical intervention

 -  Cultures of wound, (both aerobic and anaerobic), blood, super infections. Preferably
 cultures of the debrided tissue or purulent material will be obtained. If there is no
 tissue or pus available, only then a deep culture of the wound will be obtained. The
 culture will be evaluated in the microbiologic lab for gram stain, culture (aerobic and
 anaerobic if already indicated) and antimicrobiological sensitivity (by standard CLSI
 (NCCLS) techniques. The organisms in the study will be identified at the genus and
 species level.

 -  LOS - hospital, ICU

 -  Wound dressing - type

 -  Use of vacuum assisted dressing

 -  Duration of antibiotic therapy

 -  Adverse events

 -  Mortality

 -  Patient will be evaluated clinically on a daily basis by several clinical services
 (surgery, infectious diseases, critical care, hyperbaric medicine)and safety labs will
 be obtained every 3-5days. If a patient is failing therapy then based on available
 microbiological determinants, patient will be changed to an appropriate antibiotic
 regimen.

 The End points of the study are as follows:

 -  clinical cure at 7-14 days

 -  clinical failure at any point after 72 hours of treatment

 -  if the patient is clinically cured and there is persistence of initial infective
 organism in the wound culture, the study would be terminated. However, if the patient is
 worse then appropriate treatment will be initiated and study drug will be discontinued.

 -  if the patient experiences a serious adverse event related to the study drug, the study
 drug will be terminated.

 -  if the patient decides to withdraw consent.

 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:

 -  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.

 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.
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.