Prevalence,Resistance Mechanisms,and Susceptibility of Multidrug-Resistant Bloodstream Isolates of Pseudomonas aeruginosa

Pseudomonas aeruginosa is an important pathogen commonly implicated in nosocomial infections. The occurrence of multidrug-resistant (MDR) P. aeruginosa strains is increasing worldwide and limiting our therapeutic options. The MDR phenotype can be mediated by a variety of resistance mechanisms, and the corresponding relative biofitness is not well established. We examined the prevalence, resistance mechanisms, and susceptibility of MDR P. aeruginosa isolates (resistant to ≥3 classes of antipseudomonal agents [penicillins/cephalosporins, carbapenems, quinolones, and aminoglycosides]) obtained from a large, university-affiliated hospital. Among 235 nonrepeat bloodstream isolates screened between 2005 and 2007, 33 isolates (from 20 unique patients) were found to be MDR (crude prevalence rate, 14%). All isolates were resistant to carbapenems and quinolones, 91% were resistant to penicillins/cephalosporins, and 21% were resistant to the aminoglycosides. By using the first available isolate for each bacteremia episode (n = 18), 13 distinct clones were revealed by repetitive-element-based PCR. Western blotting revealed eight isolates (44%) to have MexB overexpression. Production of a carbapenemase (VIM-2) was found in one isolate, and mutations in gyrA (T83I) and parC (S87L) were commonly found. Growth rates of most MDR isolates were similar to that of the wild type, and two isolates (11%) were found to be hypermutable. All available isolates were susceptible to polymyxin B, and only one isolate was nonsusceptible to colistin (MIC, 3 mg/liter), but all isolates were nonsusceptible to doripenem (MIC, >2 mg/liter). Understanding and continuous monitoring of the prevalence and resistance mechanisms of MDR P. aeruginosa would enable us to formulate rational treatment strategies to combat nosocomial infections.Pseudomonas aeruginosa is an important pathogen commonly implicated in serious nosocomial infections such as pneumonia and sepsis. The occurrence of multidrug-resistant P. aeruginosa strains is increasing worldwide and limiting our therapeutic options. Resistance in P. aeruginosa may be mediated via several distinct mechanisms (3, 13). In multidrug-resistant isolates, the relative contributions of different molecular mechanisms toward phenotypic multidrug resistance are not well established. While there are multiple surveillance studies tracking the resistance of P. aeruginosa to various antimicrobial agents over the years (6, 7), studies reporting trends in concomitant resistance to multiple agents over time are scarce.A hypermutable state is often observed in multidrug-resistant pathogens causing chronic infections in cystic fibrosis patients. It is often related to defects in genes involved in the mismatch repair system (e.g., mutS and mutL). It is also commonly believed that in multidrug-resistant P. aeruginosa isolates, reduced virulence may result due to decreased biofitness. However, recent data suggest otherwise, and multidrug-resistant P. aeruginosa may remain fully pathogenic (8).Many first-line agents are ineffective if used alone against multidrug-resistant P. aeruginosa isolates. Consequently, unconventional agents or those that are less preferred (due to toxicity concerns) may have to be used. The objectives of this study were to examine (i) the prevalence of multidrug-resistant P. aeruginosa, (ii) the mechanism and biofitness cost of multidrug resistance, and (iii) the susceptibilities of multidrug-resistant P. aeruginosa isolates to polymyxin antibiotics and a newer carbapenem (doripenem). These investigations are expected to provide a rationale for effective treatment strategies to combat nosocomial infections.(This study was presented in part at the 48th Interscience Conference on Antimicrobial Agents and Chemotherapy-Infectious Diseases Society of America 46th Annual Meeting, Washington, DC, 25 to 28 October 2008 [26].)