An international multicenter retrospective study of Pseudomonas aeruginosa nosocomial pneumonia: impact of multidrug resistance

This international investigation representing the largest cohort study of Pa-NP demonstrated high prevalence of MDR at 30.5%. Infection caused by MDR P. aeruginosa was found to be an important determinant of hospital mortality, thus, it is critical for clinicians to identify patients at risk of MDR from the onset of infection. Our analysis suggests that the patient’s age, comorbid conditions specifically diabetes, and the severity of infection as indicated by the need for ICU admission predicts infection with a MDR strain of P. aeruginosa.

The prevalence of MDR Pa-NP is variable depending on the type of study performed and the participating institutions. A recent large epidemiologic study from the United States identified 205,526 P. aeruginosa isolates (187,343 pneumonia; 18,183 bloodstream infection (BSI)) and 95,566 Enterobacteriaceae specimens (58,810 pneumonia; 36,756 BSI) associated with infection [1]. Prevalence of MDR P. aeruginosa (MDR Pa) was approximately 15-fold greater than carbapenem-resistant-Enterobacteriaceae in both infection types. A net rise in MDR Pa as a proportion of all P. aeruginosa infections occurred from 2000 to 2009. Likewise, data from the National Healthcare Safety Network (NHSN) in the United States revealed an increased prevalence of MDR Pa VAP from the period 2007 to 2008 to the period 2009 to 2010, but, it should be noted the overall prevalence of MDR Pa was 17.7% in the latter time period, markedly less than our study [3]. The international composition of the participants is the most likely explanation for the higher prevalence of MDR strains in our study.

The literature also varies with respect to the outcomes of patients with MDR Pa-NP. Peña et al. examined a Spanish cohort of 91 episodes of ventilator-associated pneumonia (VAP) in 83 patients, 31 caused by susceptible P. aeruginosa and 60 by MDR Pa strains [18]. These investigators found that susceptible P. aeruginosa infections were more likely than MDR Pa episodes to receive AIAT and definitive antimicrobial therapy, and in a logistic regression model IIAT was identified as an independent risk factor for early mortality. A recent meta-analysis supports these findings by demonstrating that MDR status is an important determinant of mortality due to nosocomial infections attributed to Gram-negative bacteria, where P. aeruginosa and Acinetobacter species were the most common isolates [19]. Di Pasquale et al. recently found MDR status was not associated with a higher rate of ICU or hospital mortality in patients with ICU-acquired pneumonia. However, unlike our study, the etiology of infection was a mix of Gram-positive and Gram-negative pathogens and there was a small number of MDR Pa cases (n = 18) [20].

Increasing antimicrobial resistance in P. aeruginosa infections seems to be the most important predictor of outcome. In a recent Brazilian study of P. aeruginosa bacteremia isolates from 120 patients [21], 45.8% were resistant to carbapenems, and 23.3% expressed a metallo-β-lactamase gene, blaSPM-1 (57%) or blaVIM-type (43%). Cefepime-resistance, MDR status and XDR isolates were independently associated with IIAT, which was an important predictor of mortality. These studies support the importance of appropriate and timely antibiotic therapy as a potential determinant of outcome for serious infections attributed to P. aeruginosa. Given the association of antibiotic resistance with increasing administration of IIAT and greater hospital mortality, several strategies have been developed to improve upon the appropriateness of empiric therapy in patients at risk of infection with P. aeruginosa and other antibiotic-resistant pathogens.

A number of investigations have identified risk factors and scoring systems for infection with MDR pathogens, including MDR Pa [22-25]. Major limitations of such approaches are that the potential for IIAT remains, although potentially diminished, and the resultant overuse of broad-spectrum antibiotics in many patients because of the non-specificity of the scoring systems. Novel methods to improve early identification of pathogens and antibiotic susceptibilities are also entering the diagnostic arena. Such diagnostic technology advances offer the potential to maximize administration of appropriate antibiotic therapy while minimizing unnecessary antibiotic exposure. These approaches include the use of molecular methods (for example, polymerase chain reaction electrospray ionization mass spectrometry and matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF), as well as advanced automated microscopy techniques that allow the identification of bacterial species, the presence of antibiotic resistance genes, and bacterial killing by specific antibiotics within 4 to 6 hours using direct specimen inoculation [26,27].

Our study has a number of limitations. As a retrospective cohort, it is prone to several forms of bias, most notably selection bias. We attempted to mitigate this by enroling consecutive patients fitting the predetermined enrolment criteria. Although we adjusted for known confounders, the possibility exists that some residual confounding remains, particularly confounding by indication. Another important limitation is the potential for patients to be enroled who did not have true pneumonia. Our use of clinical criteria along with microbiologic confirmation was an attempt to maximize the number of patients with Pa-NP in our cohort. Additionally, antimicrobial susceptibility testing was performed at the local hospital level. Therefore, the determination of MDR status may have varied more than if a single reference laboratory was used to determine the presence or absence of drug resistance. It is also important to note that although our results strongly suggest that the association of MDR status with increased risk of death is mechanistically related to the risk of receiving inappropriate empiric therapy, we cannot rule out that MDR Pa-NP may exert its lethal effect directly due to higher virulence, as has been suggested with other pathogens exhibiting higher minimum inhibitory concentration (MIC) to certain antimicrobials [28,29]. Because we examined hospital mortality rather than the more standard 28-day mortality as the primary outcome for our study, we may have overestimated the magnitude of this outcome. Last, individual antibiotics are commonly part of a regimen for the treatment of nosocomial pneumonia, therefore, independent analysis of the impact on AIAT may not represent the true prescribing practice at each site.