Multi-drug-resistant Gram-negative bacterial infection in surgical patients hospitalized in the ICU

Introduction. Mortality and prolonged hospitalization among patients who have beensubmitted to major surgical operations is often attributed to infections that occur in theearly postoperative period. During the last decade, there has been considerable change inthe epidemiology of hospital acquired infections; Gram-negative surpassed Gram-positivebacteria as leading pathogens. Furthermore, the emergence of Gram-negative bacteriaresistant to most of the commonly used antibiotics makes treatment of such infections aclinical challenge. Identification of the risk factors for the development of infections causedby multi-drug-resistant Gram-negative bacteria (MDR-GNB) may help clinicians preventnosocomial infection. This becomes even more important, if we consider the slow pace ofdevelopment of new effective antimicrobial agents and the constantly rising prevalencerates of MDR-GNB, especially in intensive care units (ICUs).Multi-drug-resistance (MDR) has received various definitions in regard to the number ofclasses of antimicrobial agents of pathogen’s resistance. MDR defined as resistance to allbut 3 classes of antibiotics has not been extensively investigated, especially in surgicalpatients. Based on the above, the aim of this study was to identify risk factors for thedevelopment of infections, caused by MDR-GNB, in a cohort of patients hospitalized in theICU for more than 5 days following general surgical operations. We sought to investigatenumerous factors that have been related, by previous studies, to the development ofresistance to antibiotics, both in vitro and in special patient populations. In addition, thiscohort study may permit to attribute mortality and length of hospital stay of patients withsuch infections to the resistance pattern of the pathogen or to the various other comorbidityconditions and complicating factors.Methods.Study designA retrospective cohort study at a general, 450-bed, tertiary-care hospital in Athens,Greece. The study was approved by the hospital's ethics review board.Cohort description Patients hospitalized in the ICU for more than 5 days following general surgical operationsduring a 7 year period from the first day of hospital operation, in November 2001, to May2007, were identified. The cohort included only patients without any infection on ICUadmission. All cases of infection included were clinically and microbiologicallydocumented. Patients who had a clinical infection that was not microbiologicallydocumented were eliminated from the study.Group comparisonPatients who had an infection, caused by MDR-GNB, were assigned to the case group(group A). The rest were included in the comparison group (group B). Moreover, therewere three comparison subgroups; patients who did not develop any microbiologicallydocumented infection (sub-group B1), patients who developed infection caused by aGram-positive pathogen during the hospital and ICU stay (sub-group B2), and patientswho developed infection caused by Gram-negative bacteria susceptible to more than 3 ofthe tested antibiotics (sub-group B3).It should be noted that only one infection per patient was taken into account for this study.Thus, only the first infection caused by MDR-GNB was studied as case. Respectively, forthe comparison group, only the first infection caused by pathogens other than MDR-GNBwas included. Furthermore, for cases of multi-microbial infection, patients were assignedto Group A if at least one of the isolated microbes was an MDR-GNB.Data analysisThe chi square and Fisher’s exact tests were used to compare groups for dichotomousvariables, as appropriate. The t-test and the Mann-Whitney signed-rank test were used tocompare groups for normally and non-normally distributed continuous variables,respectively. Variables found to be significantly associated with the development ofinfection caused by MDR-GNB, in the bi-variable analyses, were entered in a multivariableforward, stepwise, logistic regression model and the adjusted odds ratio (OR) and95% confidence intervals (CIs) were calculated. The probability for removal in the logisticregression model was set at p>0,1. For all tests, two-tailed p values lower than 0.05denoted statistical significance. Furthermore, variables’ colinearity was tested. Tolerance <0.1 indicated that the variable was redundant and highly correlated with other variablesthat were already in the model. Summary measures of goodness of fit were performedusing the Hosmer-Lemeshow test. Additional checks were performed by entering the samevariables in relevant backward, stepwise, logistic regression models.Results. During the study period, 100 patients (54 males) fulfilled the inclusion criteria.Patients were submitted to one or more operations, the mean total operative time was 278minutes (range 45-665) and 42% of patients were re-operated. The range of operationsincluded colorectal (38%), small bowel (19%), stomach (9%), liver (9%), pancreas (6%),and other general surgical operations (19%). Among the studied patients, 48 had clinicallyand microbiologically documented infections caused by MDR-GNB (32 cases ofAcinetobacter baumannii, 8 cases of Pseudomonas aeruginosa, and 8 cases of Klebsiellapneumoniae) (group A), 14 patients had infections caused by Gram-positive bacteria (5cases of Streptococcus faecalis, 3 cases of Staphylococcus aureus and 6 cases of otherGram-positive pathogens) (sub-group B2), and 6 had infections caused by Gram-negativebacteria susceptible to more than 3 of the tested antibiotics (5 cases of Pseudomonasaeruginosa and 1 case of Klebsiella pneumoniae) (sub-group B3). Furthermore, therewere 2 patients who had infection caused by Candida albicans. Finally, there were 30patients that did not have any clinically diagnosed nosocomial infection duringhospitalization (sub-group B1). It should be noted that there were 14 cases of multimicrobialinfections (23% of infections were multi-microbial).First, we compared patients that developed infection caused by MDR-GNB (n=48) (groupA) with patients that did not (n=52) (group B). In Table 2, we present the findings of themulti-variable logistic regression model for infection caused by MDR-GNB (dependentvariable). The adjusted odds ratios provided by the final model equation showed that everyminute of operative time, use of special treatments during hospitalization (anti-neoplastic,immunosuppressive or immunomodulating therapies), every day of metronidazole, andevery day of carbapenems use, increased patients’ odds to acquire an infection caused byMDR-GNB by 0.7%, 8.9 times, 9%, and 9%, respectively [OR (95% CIs): 1.007 (1.003-1.011); p=0.001, 8.9 (1.8-17.3); p=0.004, 1.09 (1.04-1.18); p=0.039, 1.09 (1.01-1.18);p=0.023, respectively). The above predictors were adjusted for admission in the first year of hospital operation [OR (95% CIs): 0.1 (0.03-0.43); p=0.002]. The overall test for themodel was statistically significant (p<0.001) and successfully measured for goodness of fit.Secondly, we compared patients that developed infection caused by MDR-GNB (n=48)(group A) with patients that did not develop any infection (n=30) (sub-group B1). In Table 3,we present the findings of the multi-variable logistic regression model for infection causedby MDR-GNB (dependent variable). The adjusted odds ratios provided by the final modelequation showed that every minute of operative time, and use of antibiotics, within3months prior to admission, increased patients’ odds to acquire an infection caused byMDR-GNB by 0.7% and 3.8 times, respectively [OR (95% CIs): 1.007 (1.003-1.011);p=0.001, 3.8 (1.07-13.2); p=0.002, respectively]. The above predictors were adjusted foradmission in the first year of hospital operation [OR (95% CIs): 0.07 (0.01-0.4); p=0.03].The overall test for the model was statistically significant (p