Impact of Multidrug-resistant Pseudomonas aeruginosa Infection on Patient Outcomes

Elizabeth B Hirsch; Vincent H Tam

Disclosures

Expert Rev Pharmacoeconomics Outcomes Res. 2010;10(4):441-451. 

In This Article

Impact on Patient Outcomes

Mortality

As mentioned earlier, mortality rates following P. aeruginosa bloodstream infections are high, particularly in patients given inappropriate empirical therapy. Several studies have found increased mortality rates with MDR in comparison with MDS P. aeruginosa infections (Table 3). Cao et al. found a significantly higher crude mortality rate in patients with MDR infections (n = 44) compared with MDS infections (n = 68; 54.5 vs 16.2%; p < 0.05).[37] The study patients had nosocomial infections caused by P. aeruginosa isolated from any clinical culture. The definition of multidrug resistance in this study included resistance to ceftazidime, ciprofloxacin, piperacillin and imipenem. Similarly, Aloush et al. conducted a retrospective matched-cohort study to examine the clinical outcomes of patients with P. aeruginosa isolated from any clinical culture during a 10-month period. They defined multidrug resistance as an organism resistant to all of the following agents: ceftazidime, cefepime, aztreonam, ciprofloxacin, piperacillin and gentamicin. They found a trend toward in-hospital mortality with MDR infection compared with matched control patients (21 vs 12%; OR: 2.3; p = 0.08), and isolation of MDR P. aeruginosa infection was significantly associated with mortality in a multivariate model (OR: 4.4; p = 0.04).[35]

While the following studies do not specifically address patients having MDR infections, the recovered isolates were commonly resistant to multiple antipseudomonal agents. As a result, these isolates could be inferred to exhibit a MDR phenotype. In a study comparing patients with fluoroquinolone-susceptible (n = 527) P. aeruginosa infections to those with fluoroquinolone-resistant (n = 320) infections, Gasink et al. found imipenem resistance to be the only factor significantly associated with mortality (aOR: 1.79; 95% CI: 1.13–2.84; p = 0.01).[56] Interestingly, 42.6% of these imipenem-resistant isolates were resistant to five or more unique classes (i.e., aminoglycosides, carbapenems, piperacillin, aztreonam and antipseudomonal cephalosporins) of drugs, implying a MDR phenotype. A limitation of this study was that the isolates were not determined to be true pathogens versus colonizers; this could impact outcomes as critically ill patients who have been hospitalized (and/or ventilated) for extended periods of time are often colonized with resistant organisms. In a second study, Laupland and colleagues studied patients treated within the Calgary Health Region with imipenem-resistant P. aeruginosa infections.[57] PCR was used to identify isolates producing MBLs, which are responsible for resistance to the carbapenems and a variety of penicillins and cephalosporins.[58] They found a significantly higher crude case–fatality rate for patients infected with MBL-producing strains compared with that in non-MBL-producing strains (23 out of 93 [25%] vs 10 out of 80 [13%] deaths; relative risk [RR]: 1.98; 95% CI: 1.00–3.90; p = 0.05). Again, the majority (87 out of 98 [89%]) of these MBL-producing strains were resistant to three classes or more of antibiotics in comparison to only 7% in non-MBL-producing strains (p < 0.0001). Two similar case–control studies conducted by the same group found mortality to be significantly higher among patients with imipenem-resistant P. aeruginosa infection/colonization than patients with imipenem-susceptible infection/colonization. In the first single-center study, patients with any clinical isolate positive for P. aeruginosa were evaluated. Mortality was higher among case patients (31.1 vs 16.7%; RR: 1.86; 95% CI: 1.38–2.51; p < 0.001) compared with control patients.[59] Infection with an imipenem-resistant isolate remained significantly associated with mortality in a multivariable analysis adjusted for confounders (aOR: 1.94; 95% CI: 1.22–3.10; p = 0.005). Similar to the previous studies, the imipenem-resistant isolates had significantly higher resistance rates to other tested antimicrobials, including amikacin, aztreonam, cefepime, ciprofloxacin, gentamicin, levofloxacin and piperacillin (p < 0.001 for all comparisons). In the second two-center study by the same group, mortality was found to be significantly higher in patients with imipenem-resistant isolates compared with imipenem-susceptible isolates in the bivariate analysis (17.4 vs 13.4%; RR: 1.39; 95% CI: 1.09–1.76; p = 0.01).[60] However, after controlling for confounders in the multivariable analysis, an independent association with mortality remained only for patients with imipenem-resistant isolates collected from the bloodstream (aOR: 5.43; 95% CI: 1.72–17.10; p = 0.004). This second study, however, did not address resistance to other tested antimicrobials. Lastly, Hirakata and colleagues conducted a case–control study of 69 inpatients with blaIMP-positive P. aeruginosa and 247 control patients with blaIMP-negative P. aeruginosa.[61] They found more frequent infection-related death among patients with blaIMP-positive P. aeruginosa isolates compared with the control patients (5.8 vs 1.2%; OR: 5.00; 95% CI: 1.09–22.9; p = 0.02).[61] Similar to the previous studies, bla IMP-positive isolates were more likely to be resistant to three classes of antibiotics than bla IMP-negative isolates (p = 0.01), also implying a MDR phenotype was exhibited

It should be noted that common limitations in these studies include retrospective study design, possible bias from unadjusted confounding variables, such as baseline severity of illness/co-morbidities, and different timing of therapy initiation. The clonality of the isolates recovered was also not routinely investigated. Addressing as many of these limitations as possible, a clinical investigation is currently being undertaken by our research group.

Morbidity

Multidrug-resistant P. aeruginosa infection not only could increase mortality, but it may also be associated with increased patient morbidity. Aloush et al. demonstrated that isolation of MDR P. aeruginosa was associated with a higher incidence of surgery as compared with controls (27 vs 16%; OR: 2.5; p = 0.05).[35] The surgery objective was often to remove the source of infection (i.e., debridement, amputation and graft removal), when otherwise not controlled with medical therapy. In addition, patients with MDR infection in this study also had an increased number of invasive procedures (i.e., bronchoscopy, tracheostomy or catheter implantation; 38 vs 11%; OR: 5.4; p = 0.001). When patients were classified into groups based upon their destination after discharge (home, rehabilitation center or chronic care facility), more patients with MDR infection were discharged to a chronic care facility (55 vs 24%; OR: 6; p = 0.01) and were lacking full activity at discharge compared with matched controls (59 vs 34%; OR: 6.7; p = 0.002).

Length of hospital stay is another marker frequently used for morbidity.[62] Aloush et al. found isolation of MDR P. aeruginosa to be associated with increased length of stay (p = 0.001) when compared with matched controls.[35] Similarly, Micek et al. found that patients treated with inappropriate empirical therapy had a statistically longer length of stay than those who received appropriate empirical treatment (41.4 ± 47.4 [mean ± standard deviation] days vs 23.9 ± 25.2 days; p = 0.006) [47]

Microbiological outcomes, such as persistence of infection and emergence of resistance during antibiotic therapy, have been shown to negatively affect patient outcomes. In a study of bacteremic patients with P. aeruginosa, patients whose isolates overexpressed AmpC (n = 21), a class C β-lactamase mediating resistance to multiple antipseudomonal penicillins and cephalosporins, were compared with pan-susceptible (wild-type) control patients (n = 33).[63] In a multivariate analysis, AmpC overexpression was a significant predictor of persistent disease (OR: 12.2; 95% CI: 1.7–87.7; p = 0.013). Persistent disease was defined as a new positive culture for P. aeruginosa at least 24 h after the collection of the index culture. While these patients were not specifically infected with a MDR strain, resistance to multiple antimicrobials was common in the AmpC overexpressed group. Carmeli and colleagues demonstrated that emergence of resistance (defined as subsequent detection of P. aeruginosa with at least a fourfold increase in minimum inhibitory concentration [MIC] relative to baseline) had significant effects on both mortality (RR: 3.3; p = 0.01) and length of stay (multiplicative effect: 1.5; p = 0.005).[64] Their study population of patients with confirmed Pseudomonas infection using the CDC definitions for infection, had P. aeruginosa recovered from any clinical culture and were hospitalized for at least 2 days. They also estimated that emergence of resistance was associated with an average adjusted increase of 5.7 days in length of hospital stay.

In summary, the current literature demonstrates that patients infected with resistant P. aeruginosa commonly have increased mortality and morbidity. While direct comparison of these studies may be difficult owing to varied study designs and definitions of resistance, the overall significance of these data is apparent.

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