Clinical and economic consequences of hospital-acquired resistant and multidrug-resistant Pseudomonas aeruginosa infections: a systematic review and meta-analysis

Pseudomonas aeruginosa is a frequent causative pathogen in healthcare associated infections [1]. P. aeruginosa is the most common Gram-negative pathogen causing nosocomial pneumonia in the United States, and it is frequently implicated in hospital-acquired urinary tract and bloodstream infections [2–4]. In a point prevalence study conducted in Western European ICUs, P. aeruginosa was one of the most common organisms, constituting nearly a third (29%) of all Gram-negative isolates, and was present in 17% of all positive cultures [5]. The Infectious Disease Society of America includes P. aeruginosa in its list of ‘ESKAPE’ pathogens that pose the greatest public health threat due to a combination of increasing prevalence and ineffectiveness of existing antibacterial agents [6].

Rates of antibiotic resistant Gram-negative infections continue to rise worldwide, and effective therapeutic options against these infections are severely limited [7–9]. Each year in Europe, approximately 400,000 patients with hospital-acquired infections present with a resistant strain [10]. Resistance is a particular problem with P. aeruginosa, because of the low permeability of its cell wall [11, 12] and its ability to acquire and express multiple resistance mechanisms including porin deletions and overexpression of efflux pumps [13–17].

Several studies have examined the impact of resistant Gram-negative bacilli generally and MDR P. aeruginosa specifically, but there has not been an in-depth, comparative analysis of the contemporary literature reporting on mortality, morbidity and costs associated with resistant versus susceptible infection. This report is a systematic review of the clinical and economic consequences of resistant and MDR P. aeruginosa compared to susceptible P. aeruginosa and control patients without P. aeruginosa infections. We also conducted a meta-analysis of all-cause mortality to quantify the impact of resistant and MDR P. aeruginosa on this clinical outcome.

The authors followed standard systematic review methods [43]. A systematic search was conducted in the Cochrane Library and MEDLINE. In addition, the authors manually reviewed citations from retrieved articles to ensure inclusion of all relevant literature. Appendix 1 lists the initial search strategy terms related to the pathogen (P. aeruginosa), mode of infection (nosocomial, hospital-acquired, healthcare-acquired, hospital-associated, healthcare-associated, and ventilator-associated), and outcomes (resource utilization including length of stay, antibiotic use/duration, procedures, inpatient costs, readmission, recurrence, and death).

Two researchers with training in evidence-based methods extracted relevant data for analysis. The extracted data included study design; participant characteristics; follow-up period; method of assessing resistant P. aeruginosa; association between resistance status and outcome; potential confounding variables adjusted for; method of ascertaining outcome; and statistical analyses. A web-based, automated data platform (Doctor Evidence, Santa Monica, CA) further cross-calculated the data to identify any numerical discrepancies (i.e., mismatches of sub-data to main population data, data reported in percentiles conflicting with unit data and vice versa). A third evidence-based review produced the final digital data repository. The web-based platform assessed identified studies for inclusion. Meta-analysis was conducted using the random effects method of weighting data for pooling [44]. The results are reported as summary relative risk (RR).

We considered the following outcomes for inclusion in a meta-analysis: all-cause mortality in hospital, length of stay (hospital and ICU), hospital costs or charges, microbiological infection clearance and readmissions. The random effects meta-analyses assessed any potential differential impact of resistant and MDR pathogens on the outcomes of interest using unadjusted and adjusted data, when available. All presented p-values were obtained from analysis within included studies. The Cochrane Q Chi-square test was used to test for heterogeneity of results across studies and quantified with I²[45]. In addition, we combined studies using logit transformation of individual proportions and calculated their confidence interval (CI) and then back transformed the combined value. For meta-analyses with at least 10 studies, we evaluated the potential for publication bias with funnel plots and Egger’s tests for small study effects [46]. We looked for differences across studies using stratified analyses to explain heterogeneity in association results. To assess study quality, we applied quality questions from the Newcastle-Ottawa Quality Assessment Scales for case–control and observational studies [47]. When feasible, sensitivity analyses were conducted by excluding studies of high risk of bias. All analyses were performed in Stata version 13 (StataCorp, College Station, Texas).

Studies that used hospital costs or charges as a defined primary or secondary endpoint were included in this analysis. Hospital costs and charges were inflated to 2012 US dollars using the Consumer Price Index (CPI) as reported by the Bureau of Labor Statistics [48]. In one study where the costs were reported in Euros [49], conversion to USD was performed according the exchange rate at the time of the original analysis.

This review was based on evaluation of data from published studies and was exempt from ethics committee approval. In addition, this review did not involve any direct research on patients, and no informed consent was required.

This systematic review of the literature identified some strengths and weaknesses in relation to published data on the impact of P. aeruginosa infections on clinical and economic outcomes. The meta-analysis of studies examining the impact of resistance or MDR infection indicates a significant increase in hospital all-cause mortality compared to infections due to susceptible pathogens. Patients with resistant and MDR P. aeruginosa infections versus those with susceptible P. aeruginosa infections had a relative risk of 1.24 and 2.31, respectively.

In keeping with previous literature [27, 28, 32], our review suggests that MDR and resistant P. aeruginosa infections are associated with higher hospital and ICU length of stay as an outcome compared to susceptible P. aeruginosa infections; however, there was a scarcity of studies examining length of stay in patients with resistant P. aeruginosa infections compared to control patients without infection. Further research is needed into the economic impact of resistant P. aeruginosa infections and future studies must take into account regional and national differences in standards of care, and other critical patient level factors including community versus hospital acquired infection, duration of hospitalization prior to the infection, severity of illness, the timeliness and appropriateness of therapy, time at risk of infection, and site of infection [73].

Among reviewed studies, only one study highlighted inadequate initial antibiotic therapy as a significant risk factor for in-hospital mortality [55]. The importance of appropriate treatment was recently confirmed in a study of P. aeruginosa bloodstream infections; although neither bloodstream infections with metallo-β-lactamase producing P. aeruginosa nor bloodstream infections with various resistance phenotypes of P. aeruginosa were independently associated with mortality or length of hospital stay [74]. Inadequate initial therapy that does not provide coverage for resistant P. aeruginosa is associated with poor clinical outcomes, longer hospital stays and higher costs [37, 75–78]. A prospective study examining patients with bloodstream infections due to P. aeruginosa found that inappropriate empirical antibiotic treatment was associated with a two-fold increased risk of mortality [79]. A retrospective study from a large tertiary hospital in the US also demonstrated that inappropriate initial antimicrobial treatment was an independent determinant of hospital mortality in patients with P. aeruginosa bloodstream infections and was associated with a doubling in the odds ratio for death [40]. The timing of initiation of therapy and site of infection were not considered within the meta-analysis due to a lack of comparable data, but should be an area for further research. Future analyses of the economic impact of resistance should also consider use of propensity scoring to reduce the impact of some these potential confounders [80].

This review and meta-analysis should be interpreted in light of a few limitations. Our inclusion criteria required that studies only consider nosocomial infection and were published in English [28–30]. Additionally, studies that were eligible for inclusion did not report on 30 day mortality. Finally, the literature is heterogeneous with respect to the definition of MDR and site of infection with P. aeruginosa. As a result, combined analysis may misrepresent the true picture within different diseases (e.g. ventilator-associated pneumonia versus complicated UTIs).

Confounding in observational studies reporting unadjusted data should be acknowledged. For example, patients with resistant P. aeruginosa represent a sicker population, who may have been treated with more antibiotics and may have had a longer length of stay. These factors may have influenced the outcome of in-hospital mortality rather than resistant organism, specifically. The choice of the control group (e.g. patients with infection with susceptible strains versus patients without any infection at all) may have also influenced the results of the meta-analyses. The review findings indicate that resistant P. aeruginosa can be a potential marker for increased in-hospital mortality. Analyzing the impact of resistance on length of stay and costs is difficult due to competing events of mortality and discharge or time dependent bias, which were not appropriately addressed in most of the included studies. With P. aeruginosa, the situation is further complicated by the emergence of resistance during therapy [12].

From a societal and policy perspective, several significant stakeholders who have a major role to play in combating the burgeoning public health threat of antimicrobial resistance include: legislators, regulatory authorities, payers, pharmaceutical companies, hospital systems and physicians. Hospitals will need to initiate surveillance programs, adopt progressive policies, and embrace antibiotic stewardship as not just a means to cut costs but improve individual patient outcomes and provide societal benefit. Payers will have to adopt policies that support use of new, appropriate and/or effective antibiotics. Finally physicians will need to develop and implement appropriate infection control measures and generate evidence to support clinical decision-making and enable a tailored approach to treating infections.

In conclusion, the findings of this analysis underscore the substantial clinical and economic costs associated with resistant and, particularly, MDR P. aeruginosa in hospitalized patients. Decision-makers must prioritize implementation of best practices, treatment pathways and incentive systems to improve outcomes in this patient population. Novel and evolving treatment strategies, such as increasing heterogeneity of antibiotics prescribing, should be further explored as a valuable strategy for minimizing the spread of resistance in P. aeruginosa in hospitals [81]. Additionally, this analysis emphasized the need to ensure consistency in the definition of resistance to allow for additional comparative analyses with outcomes other than mortality in the future.

The initial search strategy utilized was as follows: pseudomonas[tiab] AND (cross infection [82] OR nosocomial[tiab] OR hospital-acquired[tiab] OR healthcare-acquired[tiab] OR hospital-associated[tiab] OR healthcare-associated[tiab] OR ventilator-associated[tiab] OR hospital[tiab] OR hospitals[tiab] OR hospitalized[tiab] OR intensive care or critical care) AND eng[la] AND (prevalence [82] OR prevalence [tiab] OR rate[tiab] OR risk factors [82] OR mortality [82] OR mortality[tiab] OR economics[mesh subheading] OR economic[tiab] OR risk[tiab] OR “statistics and numerical data”[mesh subheading] OR mortality[mesh subheading] OR patterns[tiab] OR epidemiology[mesh subheading] OR Surveillance[tiab] OR “risk factors” OR epidemiology OR outcome* OR cost[tiab]) AND (resistant OR resistance OR MDR[tiab] OR susceptib*[tiab] OR nonsusceptib*[tiab]) NOT (pediatric OR child[tiab] OR children[tiab] OR neonate*[tiab] OR neonatal[tiab] OR infant[tiab] OR infants[tiab] OR inhalation[tiab] OR inhaled[tiab] OR burn[tiab] OR transplant*[tiab] NOT (review [83] OR letter [83] OR case reports [83] OR meta-analysis [83] OR editorial [83] OR comment [83]).