Generally accepted risk factors towards the acquisition of AGNB in the ICU include LOS > 7 days, exposure to invasive devices such as MV, and exposure to antibiotics together with acquisition by cross infection within the ICU environment [10]. The COGO concepts are used as a framework in which to evaluate these risk factors versus other group level exposures within a GSEM model. This framework enables the component groups of studies of the various infection prevention methods to be considered as a natural experiment with various group wide exposures among a large number of ICU populations in the literature. This enables a novel perspective on the COGO concept that would not be possible within any one study or systematic review examined in isolation [20].
The data used here to confront the COGO model is drawn mostly from studies located in systematic reviews. In this regard, the summary effect sizes here for each of the three broad categories of TAP, anti-septic and non-decontamination methods, against both overall VAP and against overall bacteremia are similar to prior published estimates [1–10]. TAP (moreso when in combination with PPAP [21]) appears to be have the strongest prevention effect as previously noted.
In confronting the COGO model with the Pseudomonas and Acinetobacter infection data, the COGO model is robust with several factors remaining consistent over the evolution through seven versions of the GSEM. There are several expected observations. Length of stay and admission to a trauma ICU are strong positive factors and non-decontamination interventions appear not to mediate significant effects on either Pseudomonas GO or Acinetobacter GO. TAP exposure is associated with a negative coefficient towards Pseudomonas GO, albeit weaker than that associated with anti-septic interventions. This association with TAP exposure is consistent with the generally lower Pseudomonas VAP among the intervention groups of these studies.
On the other hand, the various components of the SOD/SDD regimens, TAP, EAP and PPAP have mixed effects. Neither TAP nor EAP have negative coefficient towards Acinetobacter GO. This is surprising as in nearly all instances these contain polymyxin and or an aminoglycoside. PPAP is associated with a strong positive correlation with Pseudomonas bacteremia.
Finally, patient groups exposed to the full SDD regimen (i.e. TAP, EAP and PPAP) have Pseudomonas and Acinetobacter bacteremia incidences that are either higher or else not lower than patient groups receiving TAP alone. This is possibly not paradoxical as antibiotics used for PPAP typically lack activity against Pseudomonas and Acinetobacter and the cumulative days of exposure to antibiotics without activity against Pseudomonas is a risk factor for acquiring P aeruginosa and Acinetobacter in the ICU [22–24]. Moreover, concomitant systemic antibiotic therapy (CSAT) fails to prevent the acquisition of respiratory tract colonization with Gram negative bacteria [25] and more than triples the risk of subsequent infection among ICU patients receiving an enteral decolonization regimen with gentamicin against KPC-producing Klebsiella pneumonia [26] and CRE producing Acinetobacter [27].
The exact relationship between gut colonization, PPAP use and subsequent bacteremia remains controversial amid conflicting reports that this may or may not be important for some Gram negative bacteremias versus others [28–31]. In studying the relative prevention effects of SDD versus SOD each versus standard care in the prevention of gram-negative bacteremias (i.e. not limited to Pseudomonas bacteremia), the majority of bacteremias occur after 4 days in the ICU (the typical duration of PPAP) and indeed the daily risk peaks after day 30 [11, 30]. Moreover, among patients receiving SDD or SOD, Pseudomonas accounts for one third of GN bacteremia episodes with most episodes not preceded by enteral colonization.
Defining the separate effects of EAP, TAP and PPAP is difficult as these are variably confounded with each other as constituent of different SDD regimens in different studies. Also, the duration of application of the regimens varied among the studies. In this regard, a non-significant increase in hospital acquired infections post discharge from the ICU as great as 50% was noted in a small SDD sub-study [32].
Limitations.
There are four key limitations to this analysis, the first being that this analysis is a group level modelling of two latent variables, Pseudomonas GO and Acinetobacter GO, within the COGO construct. These latent variables and the coefficients derived in the GSEM are indicative and intended for internal reference only. They have no counterpart at the level of any one patient or study and cannot be directly measured. There was no ability nor purpose to adjust for the underlying patient level risk. There was considerable heterogeneity in the interventions, populations, and study designs among the studies here as the inclusion criteria for the various studies have been intentionally broadly specified. In this regard, a strength of the analysis is that the heterogeneity among the studies here generally resembles that expected among ICU populations to which these interventions might be targeted.
The second limitation is that the analysis is inherently observational. Only a limited number of key group level factors were entered into the GSEM models. Moreover, the GSEM modelling is deliberately simplistic with exposures entered as only binary variables and no use of interaction terms. In reality, the relationships between expoures and outcomes will likely be complex and expoure interactions could have great importance.
Thirdly, the analysis is likely underpowered to examine the Acinetobacter infection data, being such a rare end point.
Fourthly, only those studies for which Pseudomonas and Acinetobacter infection data were available were able to be included in this analysis. However, the effect of the interventions on overall VAP and bacteremia incidences (Figure S2-S7) resembles that in the broader literature.
Finally, it should be noted that the various interventions among the studies here targeted a range of sites which may or may not have included the oropharynx and gastrointestinal tract. In this regard, it is surprising that the TAP and EAP interventions, which most directly targeted the oropharynx and gastrointestinal tract had weaker effects than did anti-septic interventions several of which, such as chlorhexidine body washes, target other sites.
Can the paradoxical findings of the GSEM model be reconciled with the apparent summary effects of TAP versus overall VAP and bacteremia? TAP exposure and control group concurrency have associations with Pseudomonas GO that are similar in size but contrary in direction. In this regard, the incidence of overall VAP and bacteremia among the concurrent control groups within studies of SDD/SOD are as much as ten percentage points higher than control groups within studies of equivalent ICU populations. This higher VAP incidence can partly be accounted for by incidences of VAP with Acinetobacter [33], Pseudomonas [34] and Staphlococcus aureus [35] being each 3 to 5 percentage points higher among CC (but not NCC) control groups and each up to 2 percentage points higher for intervention groups.
Likewise, the higher bacteremia incidence can partly be accounted for incidences of bacteremia with specific bacteria being each 1 to 4 percentage points higher among CC (but not NCC) control groups and up to 3 percentage points higher for intervention groups for Acinetobacter (Fig. 2), Pseudomonas (Fig. 2) [36], Staphlococcus aureus [37], Enterococci [38] and coagulase negative Staphlococci [39].
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 is yet to be considered in this process [40–42].