Candida–Acinetobacter–Pseudomonas Interaction Modelled within 286 ICU Infection Prevention Studies

Background: Whether Candida interacts to enhance the invasive potential of Acinetobacter and Pseudomonas bacteria cannot be resolved within individual studies. There are several anti-septic, antibiotic, anti-fungal, and non-decontamination-based interventions to prevent ICU acquired infection. These effective prevention interventions would be expected to variably impact Candida colonization. The collective observations within control and intervention groups from numerous ICU infection prevention studies simulates a multi-centre natural experiment with which to evaluate Candida, Acinetobacter and Pseudomonas interaction (CAPI). Methods: Eight Candidate-generalized structural equation models (GSEM), with Candida, Pseudomonas and Acinetobacter colonization as latent variables, were confronted with blood culture and respiratory tract isolate data derived from >400 groups derived from 286 infection prevention studies. Results: Introducing an interaction term between Candida colonization and each of Pseudomonas and Acinetobacter colonization improved model fit in each case. The size of the coefficients (and 95% confidence intervals) for these interaction terms in the optimal Pseudomonas (+0.33; 0.22 to 0.45) and Acinetobacter models (+0.32; 0.01 to 0.5) were similar to each other and similar in magnitude, but contrary in direction, to the coefficient for exposure to topical antibiotic prophylaxis (TAP) on Pseudomonas colonization (−0.45; −0.71 to −0.2). The coefficient for exposure to topical antibiotic prophylaxis on Acinetobacter colonization was not significant. Conclusions: GSEM modelling of published ICU infection prevention data supports the CAPI concept. The CAPI model could account for some paradoxically high Acinetobacter and Pseudomonas infection incidences, most apparent among the concurrent control groups of TAP studies.

Supplemental file contents: Table S1: Observational studies (Benchmark groups) 2 -6 Table S2: Groups of non-decontamination studies 7-10 Table S3: Groups of anti-septic studies 11 -12 Table S4: Groups of TAP studies 13 -18 Table S5: Groups from anti-fungal studies 19 Table S6: Development of Pseudomonas GSEM models (models 1-4) 20 -22  (Excluding studies with ICU-LOS<5 days) 52      Table S1 footnotes Notes; T = Data originating from a study for which the majority of ICU admission were for trauma; C = cardiothoracic ICU; I = Infection control intervention to entire ICU; crf = group wide candidemia risk factor MV = percentage of group receiving mechanical ventilation; NS -Not stated; LOS is mean or median length of ICU stay; The ICU-LOS is the ICU length of stay. This is based on surrogate measures including mean (or median) length of MV were taken if the length of ICU LOS was not available in order to generate broad categories of ICU stay of <5 days, 5 to 10 days and >10 days v_ps_n is the count of Pseudomonas VAP; v_sr_n is the count of Staphylococcus aureus VAP; v_ac_n is the count of Acinetobacter VAP and v_can_n is the count of Candida isolates from patients with VAP.
b_ps_n is the count of Pseudomonas bacteremia; b_sr_n is the count of Staphylococcus aureus bacteremia; and b_ac_n is the count of Acinetobacter bacteremia; b_can_n is the count of Candidemia; b_cns_n is the count of coagulative negative Staphylococcus bacteremia and b_ent_n is the count of Enterococcal bacteremia.
Several (n = 43) of these studies were cited in the following source systematic reviews.    Notes; T = Data originating from a study for which the majority of ICU admission were for trauma; C = cardiothoracic ICU; I = Infection control intervention to entire ICU; crf = group wide candidemia risk factor MV = percentage of group receiving mechanical ventilation; NS -Not stated; LOS is mean or median length of ICU stay, The ICU-LOS is the ICU length of stay. This is based on surrogate measures including mean (or median) length of MV were taken if the length of ICU LOS was not available in order to generate broad categories of ICU stay of <5 days, 5 to 10 days and >10 days v_ps_n is the count of Pseudomonas VAP; v_sr_n is the count of Staphylococcus aureus VAP; v_ac_n is the count of Acinetobacter VAP and v_can_n is the count of Candida isolates from patients with VAP.
b_ps_n is the count of Pseudomonas bacteremia; b_sr_n is the count of Staphylococcus aureus bacteremia; and b_ac_n is the count of Acinetobacter bacteremia; b_can_n is the count of Candidemia; b_cns_n is the count of coagulative negative Staphylococcus bacteremia and b_ent_n is the count of Enterococcal bacteremia.
Several (n = 47) of these studies were cited in the following source systematic reviews.   Notes; T = Data originating from a study for which the majority of ICU admission were for trauma; C = cardiothoracic ICU; I = Infection control intervention to entire ICU; crf = group wide candidemia risk factor MV = percentage of group receiving mechanical ventilation; NS -Not stated; LOS is mean or median length of ICU stay; The ICU-LOS is the ICU length of stay. This is based on surrogate measures including mean (or median) length of MV were taken if the length of ICU LOS was not available in order to generate broad categories of ICU stay of <5 days, 5 to 10 days and >10 days v_ps_n is the count of Pseudomonas VAP; v_sr_n is the count of Staphylococcus aureus VAP; v_ac_n is the count of Acinetobacter VAP and v_can_n is the count of Candida isolates from patients with VAP.
b_ps_n is the count of Pseudomonas bacteremia; b_sr_n is the count of Staphylococcus aureus bacteremia; and b_ac_n is the count of Acinetobacter bacteremia; b_can_n is the count of Candidemia; b_cns_n is the count of coagulative negative Staphylococcus bacteremia and b_ent_n is the count of Enterococcal bacteremia. Several (n = 5) of these studies were cited in the following source meta-analyses.       The control group in one study by Stoutenbeek [1987] appears also as the control group in another study by this Author [1984] and is used only once in the analysis here.
Several (n = 24) of these studies were cited in the following source systematic reviews.   Notes; T = Data originating from a study for which the majority of ICU admission were for trauma; C = cardio-thoracic ICU; I = Infection control intervention to entire ICU; crf = group wide candidemia risk factor MV = percentage of group receiving mechanical ventilation; NS -Not stated; LOS is mean or median length of ICU stay; The ICU-LOS is the ICU length of stay. This is based on surrogate measures including mean (or median) length of MV were taken if the length of ICU LOS was not available in order to generate broad categories of ICU stay of <5 days, 5 to 10 days and >10 days RT Candida is respiratory tract candida. v_can_n is the count of Candida isolates from patients with VAP; b_can_n is the count of Candidemia;    c. v_ps_n is the count of Pseudomonas VAP; v_ac_n is the count of Acinetobacter VAP; v_can_n is the count of RT Candida; b_ps_n is the count of Pseudomonas bacteremia and b_ac_n is the count of Acinetobacter bacteremia; b_can_n is the count of Candidemia.
d. PPAP is the group wide use of protocolized parenteral antibiotic prophylaxis; tap is topical antibiotic prophylaxis; non-D is a non-decontamination intervention; year = year of study publication in units of ten (decade) e. MVP90 is use of mechanical ventilation by more than 90% of the group f. Crf is group wide exposure to a candidemia risk factor.
g. LOS5 is a mean or median length of ICU stay for the group of less than 5 days h. LOS10 is a mean or median length of ICU stay for the group of more than 10 days i. Trauma ICU arbitrarily defined as an ICU for which >50% of admissions were for trauma  _cons -8.14*** -8.08*** -9.2 to -6.9 -7.60*** -7.42*** -9.2 to -6.9    c. v_ps_n is the count of Pseudomonas VAP; v_ac_n is the count of Acinetobacter VAP; v_can_n is the count of RT Candida; b_ps_n is the count of Pseudomonas bacteremia and b_ac_n is the count of Acinetobacter bacteremia; b_can_n is the count of Candidemia.
d. PPAP is the group wide use of protocolized parenteral antibiotic prophylaxis; tap is topical antibiotic prophylaxis; non-D is a non-decontamination intervention; year = year of study publication in units of ten (decade) e. MVP90 is use of mechanical ventilation by more than 90% of the group f. Crf is group wide exposure to a candidemia risk factor.
g. LOS5 is a mean or median length of ICU stay for the group of less than 5 days h. LOS10 is a mean or median length of ICU stay for the group of more than 10 days i. Trauma ICU arbitrarily defined as an ICU for which >50% of admissions were for trauma j. Acinetobacter colonization (Acinteobacter col) is a latent variable k. Candida colonization (Candida col) is a latent variable l. Model fit; AIC is Akaike's information criteria. This indicates model fit taking into account the statistical goodness of fit and the number of parameters in the model. Lower values of AIC indicate a better model fit. Groups is the number of patient groups; clusters is the number of studies; N is the number of parameters in the model. (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 five 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, studies with a TAP (in any formulation) based intervention, and studies of antifungal prophylaxis as a single agent.
(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 S6 for abbreviations) Table S6 for abbreviations)