Ignite Creation Date:
2024-05-05 @ 4:34 PM
Last Modification Date:
2024-10-26 @ 9:21 AM
Study NCT ID:
NCT00261807
Status:
COMPLETED
Last Update Posted:
2022-01-27
First Post:
2005-12-01
Brief Title:
Daptomycin for the Treatment of Severe Necrotizing Soft-Tissue Infections
Sponsor:
University of Maryland Baltimore
Organization:
University of Maryland Baltimore
Study Overview
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
Status:
COMPLETED
Status Verified Date:
2022-01
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
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 species11 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 6mgkgdose 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 Efaecium 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 6mgkgdose 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
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 Efaecium 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 6mgkgdose 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
Detailed 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 Systemsshock trauma laboratory is utilized for hematology biochemical and bacteriologic studies Aggressive empiric broad-spectrum antibiotic therapy is instituted The standard antibiotic therapy for NSTIs at shock trauma includes the following
Gram negative rods PiperacillinTazobactam or quinolones or aztreonam
aminoglycosides Anaerobes PiperacillinTazobactam or Metronidazole or Clindamycin Gram positive cocci not MRSAVRE PiperacillinTazobactam 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 mgmkgday 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 hisher creatinine clearance CrCl falls below 30 mLmin would have their dose adjusted to 6 mgkg 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 - doseroutetype
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 medicineand 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 eg although the patients 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 eg 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 temps1004 or reduced temps96
WBC counts 12000cumm
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
Gram negative rods PiperacillinTazobactam or quinolones or aztreonam
aminoglycosides Anaerobes PiperacillinTazobactam or Metronidazole or Clindamycin Gram positive cocci not MRSAVRE PiperacillinTazobactam 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 mgmkgday 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 hisher creatinine clearance CrCl falls below 30 mLmin would have their dose adjusted to 6 mgkg 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 - doseroutetype
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 medicineand 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 eg although the patients 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 eg 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 temps1004 or reduced temps96
WBC counts 12000cumm
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
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
None
Is a FDA Regulated Device?:
None
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None