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.
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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)