The Perfidious Effect of Topical Placebo: Calibration of Staphylococcus aureus Ventilator-Associated Pneumonia Incidence within Selective Digestive Decontamination Studies versus the Broader Evidence Base

Abstract

Among various methods for preventing ventilator-associated pneumonia (VAP), the evidence base for selective digestive decontamination (SDD) appears most compelling. However, the extent of Staphylococcus aureus emergence with SDD use remains uncertain. Groups from 37 observational studies and component (control and intervention) groups from 58 studies of SDD and other methods of VAP prevention were sourced exclusively from 10 systematic reviews. S. aureus as a proportion of VAP isolates (S. aureus isolate proportion [S. aureus IP]) among component groups was calibrated versus that among observational groups (the benchmark). The influence of topical placebo used for blinding purposes and other group-level factors was estimated using generalized estimating equation methods (GEE). The mean S. aureus IP is 22% (95% confidence interval [CI], 19 to 25) for 37 observational groups versus 32% (24 to 41) and 20% (15 to 25) for 22 control groups from the SDD evidence base which did versus did not receive topical placebo, respectively. In GEE models including all 148 observational and component groups, membership of a control (P ‫؍‬ 0.03) or intervention (P < 0.001) group of an SDD study that used topical placebo was associated with higher S. aureus IP, whereas, in contrast, membership of these groups was without effect on Pseudomonas aeruginosa. Topical placebo is implicated as a vehicle for selective cross-infection with S. aureus within the specific context of the SDD evidence base. This effect of topical placebo is perfidious; it could contribute to the higher VAP incidence and inflate the apparent "effectiveness" of SDD. The SDD evidence base requires reappraisal. Selective digestive decontamination (SDD), an extensively studied method for VAP prevention (9, 10), achieves decreased colonization with aerobic Gram-negative bacilli at the oropharynx (11) through the use of topical antibiotic paste. However, SDD may increase colonization with Gram-positive bacteria (12, 13), including staphylococci (14, 15).The SDD evidence base is unusual in four respects. The mean VAP incidence in the concurrent control groups of SDD studies is more than 10 percentage points higher, and the dispersion is greater, than a benchmark of VAP incidence proportion (VAP-IP) derived from observational studies and also versus control groups of studies of other strategies of VAP prevention using nonantibiotic methods (16). Strikingly, the disparity versus this benchmark is even greater for control groups from SDD studies rated as higher in study quality as a consequence of observer blinding achieved by the use of topical placebo (17). Paradoxically, the VAP incidence of the intervention groups within the SDD evidence base is more homogeneous, and the mean is within less than 10 percentage points of the VAP incidence benchmark (17). Finally, the explanation for the profound difference in VAP incidence seen between intervention and control groups of SDD studies is unclear. Specifically, an antipseudomonal activity of SDD is not evident within the lis...

Incidences of Pseudomonas aeruginosa-Associated Ventilator-Associated Pneumonia within Studies of Respiratory Tract Applications of Polymyxin: Testing the Stoutenbeek Concurrency Postulates

“…First, the use of a topical placebo to achieve observer blinding is a key marker of a high-quality study, especially where the endpoint is somewhat subjective, as is the case for VAP. However, approximately half of the studies of topical polymyxin used a topical placebo to achieve observer blinding (27). The PsVAP incidences derived from CC studies that were or were not observer blinded were similar.…”

“…The disparity in the incidence of PsVAP among studies of topical polymyxin versus the respective benchmarks recapitulates similar observations for various endpoints among studies of SOD/SDD versus externally derived benchmarks from populations of MV patients. For example, with respect to Staphylococcus aureus as a VAP isolate (27), Staphylococcus aureus bacteremia (36), Candida as a respiratory tract isolate (37), and candidemia incidence (35), in each case, the endpoint is higher among control groups of SOD/SDD studies than the respective benchmarks.…”

“…Fourth, is a topical placebo used within a randomized double-blind placebocontrolled evaluation of topical antibiotics as prophylaxis without effect within the ICU context? Such studies require careful consideration of any potential perfidious effect of a topical placebo (27) contributing to herd peril (38) within this context.…”

ICU-acquired candidemia within selective digestive decontamination studies: a meta-analysis

“…The effect of observer . Note that studies that used candidemia risk factors as a basis for patient selection are not shown and the y-axis is a logit scale blinding may be confounded by the separate effect of topical placebo in this context [28].…”

Structural equation modeling the “control of gut overgrowth” in the prevention of ICU-acquired Gram-negative infection

“…In each case, the increased incidence within control groups of CC design studies of topical antibiotics remains apparent in meta-regression models adjusting for other recognized associations. The influence of topical placebo use, concurrent colonization with Candida, and other influences may also have influences in this process [45][46][47].…”