Meta-Analysis of Trials Evaluating Parenteral Antimicrobial Therapy for Skin and Soft Tissue Infections
Rebecca J. McClaine
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Thomas L. Husted
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Renee S. Hebbeler-Clark
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Joseph S. Solomkin
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Received 24 September 2009; accepted 1 December 2009; electronically published 8 March 2010. Care, Dept of Surgery, University of Cincinnati College of Medicine
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231 Albert Sabin Way, ML0558, Cincinnati, OH 45267-0558
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Medicine, University of Cincinnati Medical Center
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Cincinnati, Ohio
Background. Many trials have been carried out to determine the effectiveness of antimicrobial agents in treating skin and soft tissue infections. The results of these studies are often utilized to make determinations about the use of these antimicrobials against other types of infections. Despite the importance of these trials in determining clinical care, we hypothesized that many of these studies failed to include a variety of infections of significant enough severity to effectively draw objective conclusions about antimicrobial efficacy. Methods. We conducted a modified PubMed search to identify studies of antimicrobial agents in treating soft tissue infections that were published from 1998 through 2008. We then evaluated these trials for specific recommended study criteria, which were based on published US Food and Drug Administration guidelines for the conduct of trials of antimicrobials for soft tissue infection. Results. Seventeen studies were identified for inclusion in the trial. Upon review, only 30% of trials required both local and systemic signs of infection for inclusion in the trial. One trial stratified results on the basis of operative intervention, less than half reported patient comorbidities, and only 53% provided a specific definition for cure. Conclusions. Our meta-analysis of current trials evaluating antimicrobial therapy for skin and soft tissue infections revealed substantial shortcomings in the design of most of these trials. These data provide evidence for the importance of designing specialist panels to objectively evaluate studies and photographs of included infections to ensure that conclusions drawn from these trials concerning clinical practice are justified. Many trials have been designed to compare the efficacy of antimicrobial agents in the treatment of skin and soft tissue infections. Complicated skin and skin-structure infections have been the initial indication for regulatory approval for all agents active against methicillinresistant Staphylococcus aureus (MRSA). Although these study designs often incorporate blinded and randomized assignment and prespecified outcome criteria, their failure to address other clinically relevant variables that independently predict outcome may significantly weaken their validity.
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(FDA) completed an industry guidance document to
steer the development of antimicrobial drugs for the
treatment of uncomplicated and complicated skin and
skin-structure infections [1]. The recommendations
from this document, summarized in Table 1, provide
definitions of uncomplicated and complicated skin and
soft tissue infections, suggest inclusion and exclusion
criteria, address specific details concerning study
conduct, and provide definitions of outcomes.
In evaluating the relevance of a studys results to
clinical practice, clinicians strive to determine whether
the trials conclusions or recommendations would
apply to their patient population. Specifically, information
concerning the severity of enrolled patients illnesses,
the anatomy of the infections of the patients enrolled,
and the agreement between the trials recommendations
and current practice guidelines all contribute to this
evaluative process. For surgeons, information
addressing the drainage or debridement procedures performed
during the management of such infections is important.
Studies that provide this information as clearly and
Include ulcers, burns, major abscesses, deep soft tissue infections, patients with infections concurrent with
significant comorbidities, and minor infections in anatomic areas predisposed to be polymicrobial (gram-negative
rods and anaerobes)
Provide clear inclusion, exclusion, and outcome definitions
Provide information about included patients (description of infected site, including severity and anatomic location;
cause of infection; underlying medical conditions; previous medical and/or surgical therapy for the infection;
picture of infected site [optional])
Consider primary measure of effectiveness to be clinical cure
70% of patients microbiologically evaluable
Analysis of treatment outcomes stratified by presence of surgical intervention
Analysis of outcomes for clinically evaluable and clinically and microbiologically evaluable subsets of patients (ie,
confirm coincidence of clinical cure and bacterial eradication)
objectively as possible facilitate clinicians abilities to apply
study conclusions to ongoing patient care. Also, a means of
explicitly assuring readers that adequate source control
procedures were employed is considered to be of great importance.
With this background (...truncated)