Impact of Multidrug-resistant Pseudomonas aeruginosa Infection on Patient Outcomes

Elizabeth B Hirsch; Vincent H Tam


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

In This Article

Impact of Antimicrobial Therapy

Importance of Appropriate Empirical Therapy

Multiple studies have demonstrated that inappropriate empirical antimicrobial therapy is associated with poorer outcomes in patients with varied types of infections. Specifically, delays in appropriate therapy are linked to increased mortality, morbidity and hospital length of stay.[39–43] One rational strategy is to initiate therapy with broad-spectrum antimicrobials until full culture and susceptibility results are available.[44,45] Once the pathogen(s) and susceptibility profile are known, therapy may be de-escalated or streamlined to the most appropriate patient-specific regimen. However, treatment of infections caused by P. aeruginosa may be particularly difficult owing to the limited number of antipseudomonal agents available.

Four retrospective cohort studies have shown trends toward increased mortality after inappropriate empirical therapy for P. aeruginosa bloodstream infections (Table 2). In a retrospective cohort study of 136 patients, both inappropriate empirical and inappropriate definitive antibiotic treatment were independent risk factors for mortality (odds ratio [OR]: 4.61; 95% confidence interval [CI]: 1.18–18.09; p = 0.028 and OR: 11.68; 95% CI: 2.51–54.38; p = 0.002, respectively).[46] Appropriate empirical therapy was defined as agent(s) administered within 24 h after blood cultures were obtained and found subsequently to be active in in vitro susceptibility testing. The mean duration of delay in appropriate antimicrobial therapy was 3.5 ± 1.28 days. After excluding those who did not receive appropriate definitive therapy, there was a trend toward a higher 30-day mortality rate compared with the appropriate empirical treatment group (43.4 vs 27.7%; p = 0.079). Similarly, a second retrospective cohort study of 305 patients also identified administration of inappropriate empirical antimicrobial treatment (defined as absence of an agent given with in vitro activity as determined by susceptibility testing) as an independent determinant of hospital mortality.[47] Hospital mortality rate was statistically higher for patients given inappropriate empirical antimicrobial treatment compared with appropriate empirical treatment (30.7 vs 17.8%; p = 0.018). Lastly, a retrospective cohort study of 167 patients evaluated the impact of empirical therapy in three distinct time windows: 8 h before the time the culture was obtained to 24 h afterward, between 24 and 48 h after the culture was obtained; and from 48 h after the culture was obtained to 4 h after antibiotic susceptibility results were available.[48] Empirical antibiotic therapy was considered appropriate if it included antibiotics to which the specific bacterial isolate exhibited in vitro susceptibility (with the exclusion of aztreonam and aminoglycoside monotherapy). The authors found a trend toward a protective effect of appropriate antibiotics at 24 h (OR: 0.93; 95% CI: 0.45–1.92), at 48 h (OR: 0.66; 95% CI: 0.29–1.49), and at the time susceptibility results were available (OR: 0.96; 95% CI: 0.31–2.93), after adjustment for mean modified acute physiology score at time of culture and age in the multivariable logistic regression analysis.

In an effort to further investigate the length of delay in appropriate therapy associated with increased mortality, Lodise and colleagues analyzed a cohort of 100 patients with P. aeruginosa bloodstream infections.[49] Using classification and regression tree analysis, the most significant delay breakpoint to define the risk of 30-day mortality was 52 h. Patients with delay in appropriate therapy of over 52 h had a greater than twofold increase in 30-day mortality compared with those receiving timely appropriate therapy within 52 h (43.8 vs 19.2%; p = 0.008). Delayed appropriate therapy for 52 h was also independently associated with a 30-day mortality in the multivariate analysis. Antibiotic resistance to multiple (≥3) drug classes was the most important determinant of delayed appropriate therapy (adjusted odds ratio [aOR]: 4.6; 95% CI: 1.9–11.2; p = 0.001).

Collectively, these studies demonstrate the importance of timely initiation of appropriate empirical therapy in relation to mortality associated with P. aeruginosa bloodstream infections. In MDR infections, the likelihood of patients receiving appropriate empirical antibiotics is decreased owing to resistance to multiple antibiotic classes. Therefore, these data provide an additional mechanistic framework as to why MDR infections would be associated with worse clinical outcomes, regardless of their intrinsic biofitness/virulence.

Combination Therapy versus Monotherapy

Resistance to multiple antimicrobial classes further limits treatment options and decreases the likelihood of appropriate empirical therapy. It is not clearly established whether or not combination therapy for P. aeruginosa bacteremia is associated with more favorable outcomes than monotherapy.[43,50] A potential advantage of combination therapy is the higher probability that a MDR isolate will be susceptible to at least one agent in the combination regimen. In addition, synergistic combination of antimicrobials could also result in enhanced bacterial killing, which may be important for the reduction in bacterial burden at the onset of infection and limiting disease progression.[51]

A retrospective cohort analysis of 115 patients who received empirical therapy for P. aeruginosa bacteremia sought to determine whether combination antipseudomonal therapy was superior to monotherapy.[52] Patients were categorized into six treatment groups: appropriate empirical combination therapy, appropriate empirical monotherapy, inappropriate empirical therapy, appropriate definitive combination therapy, appropriate definitive monotherapy and inappropriate definitive therapy. Empirical therapy was defined as treatment that included at least one antipseudomonal agent that was initiated no later than 24 h after the index positive blood culture. Monotherapy consisted of treatment with one antipseudomonal agent (excluding aminoglycoside monotherapy) while combination therapy consisted of piperacillin, ceftazidime, imipenem, or cefepime together with either an aminoglycoside (gentamicin or amikacin) or ciprofloxacin or an aminoglycoside with ciprofloxacin. The risk of death before receipt of the final susceptibility results was similar for the appropriate empirical monotherapy (adjusted hazard ratio [aHR]: 0.81; 95% CI: 0.31–2.1; p = 0.66) and inappropriate empirical therapy (aHR: 1.2; 95% CI: 0.29–5.2; p = 0.79) groups compared with that for the appropriate empirical combination therapy group. However, the risk of death after receipt of final susceptibility results varied according to empirical therapy. The results of a stratified Cox proportional hazard model revealed that patients in the appropriate empirical monotherapy group were 3.7-times more likely (95% CI: 1.0–14.1; p = 0.05) and patients in the inappropriate empirical therapy group were five-times more likely (95% CI: 1.2–20.4; p = 0.02) to have died within 30 days after receipt of the final susceptibility results than patients who received appropriate empirical combination therapy. Likewise, Micek et al. reported that inappropriate empirical antimicrobial therapy (prior to receipt of final susceptibility results) was statistically more likely to occur among patients receiving monotherapy compared with those receiving combination therapy (34.5 vs 20.6%; p = 0.011).[47] However, there was no statistical difference in hospital mortality (p = 0.214) among patients who received treatment with a single β-lactam (n = 95; mortality: 12.5%), a single aminoglycoside (n = 29; mortality: 10.3%), the combination of a β-lactam and an aminoglycoside (n = 59; mortality: 22%) or ciprofloxacin alone (n = 15; mortality: 6.7%).

Several meta-analyses evaluating combination therapy versus monotherapy for Gram-negative infections have shown conflicting results.[53–55] These pooled results, often derived from subgroup analyses of pseudomonal infections, may be difficult to interpret owing to varied definitions used for 'combination therapy' patient populations, and varied study designs (i.e., retrospective versus prospective). The meta-analysis by Safdar and colleagues included five studies of patients with P. aeruginosa bacteremia. A significant mortality benefit was seen with the use of combination therapy (summary OR: 0.5; 95% CI: 0.3–0.79). However, the underlying patient populations in the five studies varied considerably.[53] Three studies included general medical patients (with a large proportion of immunocompromised patients), one study primarily included HIV-infected patients and one study consisted of patients with underlying malignancies. Conversely, a mortality benefit was not seen with the use of combination therapy in septic patients in the meta-analysis by Paul and colleagues.[55] They analyzed patients with P. aeruginosa infections from all anatomic locations and noted a lack of data to specifically study bacteremias. While meta-analyses can provide large numbers of patients with rare conditions/infections on which to draw conclusions, they are not without limitations and should not be solely relied on. Hence, it appears that more clinical data are needed to make an accurate assessment on the use of combination therapy.