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

Background Conceptually, the “control of gut overgrowth” (COGO) is key in mediating prevention against infection with Gram-negative bacilli by topical antibiotic prophylaxis, a common constituent of selective digestive decontamination (SDD) regimens. However, the relative importance of the other SDD components, enteral and protocolized parenteral antibiotic prophylaxis, versus other methods of infection prevention and versus other contextual exposures cannot be resolved within individual studies. Methods Seven candidate generalized structural equation models founded on COGO concepts were confronted with Pseudomonas and Acinetobacter bacteremia as well as ventilator-associated pneumonia data derived from > 200 infection prevention studies. The following group-level exposures were included in the models: use and mode of antibiotic prophylaxis, anti-septic and non-decontamination methods of infection prevention; proportion receiving mechanical ventilation; trauma ICU; mean length of ICU stay; and concurrency versus non-concurrency of topical antibiotic prophylaxis study control groups. Results In modeling Pseudomonas and Acinetobacter gut overgrowth as latent variables, anti-septic interventions had the strongest negative effect against Pseudomonas gut overgrowth but no intervention was significantly negative against Acinetobacter gut overgrowth. Strikingly, protocolized parenteral antibiotic prophylaxis and concurrency each have positive effects in the model, enteral antibiotic prophylaxis is neutral, and Acinetobacter bacteremia incidences are high within topical antibiotic prophylaxis studies, moreso with protocolized parenteral antibiotic prophylaxis exposure. Paradoxically, topical antibiotic prophylaxis (moreso with protocolized parenteral antibiotic prophylaxis) appears to provide the strongest summary prevention effects against overall bacteremia and overall VAP. Conclusions Structural equation modeling of published Gram-negative bacillus infection data enables a test of the COGO concept. Paradoxically, Acinetobacter and Pseudomonas bacteremia incidences are unusually high among studies of topical antibiotic prophylaxis.

Supplemental file contents: Table S1: Pseudomonas and Acinetobacter data: observational studies (Benchmark groups) 2 -5 Table S2: Pseudomonas and Acinetobacter data: Groups of non-decontamination studies 6 -9 Table S3: Pseudomonas and Acinetobacter data: Groups of anti-septic studies 10 -11 Table S4: Pseudomonas and Acinetobacter data: Groups of TAP studies 12 -15 Table S5: Development of GSEM model 16-17 Table S6: VAP count data 18      Table S1 footnotes T -Data originating from a study for which the majority of ICU admission were for trauma I -Infection control intervention to entire ICU NS -Not stated; LOS is mean or median length of ICU stay v_ps_n is the count of Pseudomonas VAP and v_ac_n is the count of Acinetobacter VAP b_ps_n is the count of Pseudomonas bacteremia and b_ac_n is the count of Acinetobacter bacteremia Several (n = 43) of these studies were cited in the following source systematic reviews.     Table S2 footnotes T -Data originating from a study for which the majority of ICU admission were for trauma NS -Not stated; LOS is mean or median length of ICU stay v_ps_n is the count of Pseudomonas VAP and v_ac_n is the count of Acinetobacter VAP b_ps_n is the count of Pseudomonas bacteremia and b_ac_n is the count of Acinetobacter bacteremia Several (n = 47) of these studies were cited in the following source systematic reviews.   Intervention regimens abbreviations Chlx = chlorhexidine; Chlx BW = chlorhexidine body wash; ChC = chlorhexidine and colisitn; TD = targetted decolonization; UD = universal decolonization; PVI = povidone iodine; CC = concurrent control; SC = saline control; iseganan, is a synthetic variant of a porcine protegrin, which is a natural antibiotic peptide released by neutrophils in response to invasion by microbes [Kollef 2006, 162].    The control group in one study by Stoutenbeek [176] appears also as the control group in another study by this author [177] and is used only once in the analysis here.
Several (n = 24) of these studies were cited in the following source systematic reviews.      e. The counts of Pseudomonas VAP among the three categories of intervention groups and the category of observation groups among studies after excluding those with length of stay <7 days was differed marginally (p = 0.05; Fisher's exact test)

Benchmarking: visual
Caterpillar plots were generated to facilitate a visual benchmark of the Pseudomonas bacteremia and Acinetobacter bacteremia incidence proportion and these were generated as follows.
The data for each bacteremia incidence proportion were logit transformed to generate caterpillar plots using the 'metan' command in STATA ( Dot plots were used to provide an 'at a glance' summary of the entire evidence base. These were derived as above for caterpillar plots but without the confidence limits. In dot plots, any group with a zero event rate (N=0) was arbitrarily assigned a low finite value (either 0.1%, 0.02% or 0.01%, depending on the spread of values). In the dot plots, a benchmark derived from the caterpillar plot as described above is used.

Meta-analysis: Effect sizes
The study specific and overall summary effect sizes and associated 95% confidence interval for each of the antibiotic, antiseptic and non-decontamination based interventions against either VAP overall or bacteremia overall were calculated using the Der Simonian-Laird random-effect methods of meta-analysis using the 'metan' command in Stata 14.2 (Stata Corp., College Station, TX, USA). (1) An electronic search for systematic reviews or meta-analysis (SR/MA) containing potentially eligible studies using search terms; "ventilator associated pneumonia", "mechanical ventilation", "intensive care unit", each combined with either "meta-analysis" or "systematic review" up to December 2018; (2) The systematic reviews were then searched for studies of patient populations requiring prolonged (> 24 hours) ICU admission (3) The studies were triaged from the systematic reviews into one of four categories; studies in which there was no intervention (observational studies), studies of various non-decontamination methods such as methods delivered either via the gastric route, the airway route or via the oral care route, studies of antiseptic methods and studies with a TAP (in any formulation) based intervention.
(4) All studies were reviewed for potentially eligible studies and screened against inclusion and exclusion criteria. Any duplicate or ineligible studies were removed and (5) Studies identified outside of systematic reviews were included; (6) The component groups were decanted from each study being control (rectangles), intervention (ovals) and observation (diamond) groups.
Note; the total numbers do not tally as some systematic reviews provided studies in more than one category and some studies provided groups in more than one category and some studies have unequal numbers of control and interventions groups.  Table S2.  Table S3.  Table S4.  Table S2.  Table S3.