Source Control Review in Clinical Trials of Anti-Infective Agents in Complicated Intra-Abdominal Infections

Clinical Infectious Diseases, Jun 2013

In clinical trials of complicated intra-abdominal infections, assessment of adequacy of the initial surgical approach to the management of the infection is of considerable importance in determining outcome. Antibiotic therapy would not be expected to adequately treat the infection if the surgical procedure was inadequate with respect to source control. Inclusion of such cases in an efficacy analysis of a particular therapeutic antibiotic may confound the results. We analyzed the source control review process used in double-blind clinical trials of antibiotics in complicated intra-abdominal infections identified through systematic review. We searched MEDLINE (PubMed) and ClinicalTrials.gov databases to identify relevant articles reporting results from double-blind clinical trials that used a source control review process. Eight prospective, randomized, double-blind, multicenter, clinical trials of 5 anti-infective agents in complicated intra-abdominal infections used a source control review process. We provide recommendations for an independent, adjudicated source control review process applicable to future clinical trials.

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Source Control Review in Clinical Trials of Anti-Infective Agents in Complicated Intra-Abdominal Infections

Joseph S. Solomkin 1 Ross L. Ristagno 1 2 Anita F. Das 0 1 John B. Cone 1 6 Samuel E. Wilson 1 5 Ori D. Rotstein 1 4 Brian S. Murphy 1 3 Kimberley S. Severin 1 3 Jon B. Bruss 1 3 0 AxiStat, San Francisco, California 1 Received 28 September 2012; accepted 3 January 2013; electronically published 5 March 2013. nati College of Medicine , 231 Albert B Sabin Way, Cincinnati, OH 45267-0558 2 Radiology, University of Cincinnati College of Medicine , Ohio 3 Medpace, Cincinnati, Ohio 4 Department of Surgery, St Michael's Hospital, and University of Toronto , Ontario, Canada 5 Department of Surgery, University of California, Irvine Medical Center , Orange 6 Department of Surgery, University of Arkansas Medical School , Little Rock In clinical trials of complicated intra-abdominal infections, assessment of adequacy of the initial surgical approach to the management of the infection is of considerable importance in determining outcome. Antibiotic therapy would not be expected to adequately treat the infection if the surgical procedure was inadequate with respect to source control. Inclusion of such cases in an efficacy analysis of a particular therapeutic antibiotic may confound the results. We analyzed the source control review process used in double-blind clinical trials of antibiotics in complicated intra-abdominal infections identified through systematic review. We searched MEDLINE (PubMed) and ClinicalTrials.gov databases to identify relevant articles reporting results from double-blind clinical trials that used a source control review process. Eight prospective, randomized, doubleblind, multicenter, clinical trials of 5 anti-infective agents in complicated intra-abdominal infections used a source control review process. We provide recommendations for an independent, adjudicated source control review process applicable to future clinical trials. - Randomized clinical trials are routinely used to assess various therapeutic interventions for complicated intraabdominal infections (cIAIs). As compared with other infections that are studied in randomized trials, cIAIs are further defined by a requirement for some form of intervention, either operative or percutaneous [1]. At a minimum, intervention is needed to drain fluid collections and decrease the bacterial burden. Additional elements of source control that may be required in the individual case include management of the underlying pathological process (eg, bowel perforation), debridement of devitalized tissue, drainage, and appropriate wound management. It is widely accepted that systemic antibiotic therapy improves outcome results. Under certain circumstances, the procedure performed may not be adequate to control the source of infection. This may occur due to incomplete diagnosis, anatomic conditions not allowing the procedure of choice to be performed, hemodynamic instability in the operating room, judgment error, or technical error. Because the clinical outcome is dependent on both the procedure and the effect of the antimicrobial agent, inadequate procedures diminish the likelihood of clinical cure [2, 3]. Inclusion of such cases in an efficacy analysis of a particular antimicrobial agent under study may confound the results and distort the assessment of the effect of the antimicrobial agent. Given the wide variations in patient comorbidities, pre-operative diagnostic studies, anatomy, and pathology encountered, firm a priori decision rules for source control applicable to individual patients for inclusion in clinical trials become difficult and may introduce selection bias. A less biased approach to the assessment of adequacy of source control is a blinded consensus review process [4]. We performed a systematic review and identified 8 prospective, randomized, double-blind clinical trials of anti-infective agents in cIAI that used some form of source control review. On the basis of this review and our experiences, we then provide recommendations for an independent, adjudicated source control review process applicable to future clinical trials. METHODS Literature Search We searched MEDLINE (PubMed) and ClinicalTrials.gov databases to identify relevant articles, using the keywords [antibiotic name] AND intra-abdominal NOT urinary NOT pneumonia with the following limits: humans, clinical trial, randomized controlled trial, English, and all adults 19 years. The antibiotic names used were metronidazole, tinidazole, clindamycin, imipenem, ertapenem, biapenem, doripenem, piperacillin (returns all piperacillin and tazobactam studies), cefazolin, cefamandole, cephaloridine, cefoxitin, cefmetazole, cefotaxime, ceftriaxone, cefepime, ceftazidime, ceftizoxime, cefoperazone, moxalactam, aztreonam, ciprofloxacin, moxifloxacin, levofloxacin, trovafloxacin, gentamicin, tobramycin, amikacin, netilmicin, tigecycline, minocycline, tetracycline, doxycycline, ampicillin, amoxicillin, ticarcillin, mezlocillin, and carbenicillin. Data Extraction This search returned in a (...truncated)


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Joseph S. Solomkin, Ross L. Ristagno, Anita F. Das, John B. Cone, Samuel E. Wilson, Ori D. Rotstein, Brian S. Murphy, Kimberley S. Severin, Jon B. Bruss. Source Control Review in Clinical Trials of Anti-Infective Agents in Complicated Intra-Abdominal Infections, Clinical Infectious Diseases, 2013, pp. 1765-1773, 56/12, DOI: 10.1093/cid/cit128