Risk Factors for Carbapenem-resistant Pseudomonas Aeruginosa Infection in a Tertiary Care Hospital in Serbia

Introduction Pseudomonas aeruginosa is well-known cause of hospital infections with high morbidity and mortality rates [1]. According to the National Nosocomial Infections Surveillance System (NNISS), P. aeruginosa is responsible for approximately 8% of all hospital infections. It was the most frequent cause of ventilator-associated pneumonias (VAP), the fourth-rated on the list of causes of hospital urinary infections, and fifth cause of surgical site infections according to frequency of occurence (2). Infections caused by P. aeruginosa are difficult to control and treat due to its high rate of resistance to antibiotics and to the limited number of available antibiotics with efficacy against P. aeruginosa. During the last decade, an increase in resistance to imipenem and meropenem was observed among many strains of Gram-negative bacteria, and especially among isolates of P. aeruginosa [3,4,5]. Numerous studies have also shown that carbapenem-resistant P. aeruginosa (CRPA) is frequently simultaneously resistant to other anti-pseudomonal antibiotics, making the treatment very difficult [6]. A number of risk factors for the emergence of CRPA-caused hospital infections was identified, including spending time in an intensive care unit and/or prior use of certain antibiotics [7,8,9,10]; however, for the majority of factors, the strength of the association was either low or equivocal. Sound knowledge of the risk factors and quantification of their influence on hospital infections are important for


Introduction
Pseudomonas aeruginosa is well-known cause of hospital infections with high morbidity and mortality rates [1].According to the National Nosocomial Infections Surveillance System (NNISS), P. aeruginosa is responsible for approximately 8% of all hospital infections.It was the most frequent cause of ventilator-associated pneumonias (VAP), the fourthrated on the list of causes of hospital urinary infections, and fifth cause of surgical site infections according to frequency of occurence (2).Infections caused by P. aeruginosa are difficult to control and treat due to its high rate of resistance to antibiotics and to the limited number of available antibiotics with efficacy against P. aeruginosa.During the last decade, an increase in resistance to imipenem and meropenem was observed among many strains of Gram-negative bacteria, and especially among isolates of P. aeruginosa [3,4,5].Numerous studies have also shown that carbapenem-resistant P. aeruginosa (CRPA) is frequently simultaneously resistant to other antipseudomonal antibiotics, making the treatment very difficult [6].
A number of risk factors for the emergence of CRPA-caused hospital infections was identified, including spending time in an intensive care unit and/or prior use of certain antibiotics [7,8,9,10]; however, for the majority of factors, the strength of the association was either low or equivocal.Sound knowledge of the risk factors and quantification of their influence on hospital infections are important for proper prevention and treatment of the CRPA-caused nosocomial infections.
The aim of this study was to identify risk factors associated with the CRPA-caused hospital infections.

The study
The prospective cohort study was conducted in a large tertiary-care hospital (1,183 beds, 50,000 inpatients per year) in Kragujevac, Serbia, from January 2009 to December 2011.There were two study cohorts: a group of patients with CRPA-caused intrahospital infections and a group of patients with intrahospital infections caused by carbapenemsensitive P. aeruginosa (CSPA).
All patients hospitalized during the study period were enrolled if they fulfilled the following inclusion criteria: CRPA or CSPA-caused hospital infection and age over 18.The hospital infections were diagnosed according to standard criteria established by the Centers for Disease Control and Prevention, Atlanta.United States [11].Sources of the study data were patient files and interviews with clinicians and patients.Each of the cases was analyzed by the Department for Prevention and Control of Hospital Infections (DPCHI), and more complex cases were evaluated by a special study group, composed of three independent experts for infectious diseases.All patients just colonized with P. aeruginosa without any overt sign of infection were excluded from the study.
Isolation and identification of P. aeruginosa was performed in the hospital microbiology laboratory by conventional biochemical methods [12], and testing of resistance to antibiotics was made by disk-diffusion method and interpreted according to the guidelines of the Clinical and Laboratory Standards Institute, formerly the National Committee for Clinical Laboratory [13].
The following study variables were measured: age; gender; prior hospitalization; admission diagnosis; comorbidity (diabetes mellitus, cancer, injury, chronic heart failure, chronic obstructive pulmonary disease [COPD], hypertension and kidney diseases); prior administration of antibiotics (at least 24 hours of treatment during 14 days before hospitalization); admission and release dates; stay in intensive care unit; applied diagnostic and therapeutic procedures (e.g., stay in intensive care unit, existence of central venous catheter, urinary catheter, mechanical ventilation, surgical intervention, transfusion); length of hospitalization; and treatment outcomes.
The study was approved by the local Ethics Committee.
Primary analysis of collected data was made by descriptive statistics, using measures of central tendency (mean and median) and dispersion (standard deviation and range).Significance of differences among the study groups was tested by the Student's ttest for continual variables, and by the Chi-square test for categorical variables.The variables which turned out to be significant predictors of nosocomial During the study period there were 267 hospital infections caused by the P. aeruginosa.Six cases were excluded because the data on resistance of the isolates to antibiotics were not available to the investigators.There were 167 patients classified as cases who had nosocomial infections caused by CRPA, while the 94 control patients were matched to the cases, and selected from the remaining patients with CSPA infections.
The majority of the studied patients were from the intensive care unit (51.7%), followed by the patients from the surgery (17.6%) and neurology (11.9%) wards, while the rest of the patients were from various other hospital wards.

Conclusion
The results of our study pointed to male gender, stay in intensive care unit (ICU), urinary bladder catheterization more than seven days long, and prior use of imipenem as important risk factors associated with CRPA infections, which bear higher mortality than those caused by CSPA strains.Early removal of urinary catheter from male patients (after no more than five days) and avoidance of unjustified utilization of imipenem in patients from ICU could contribute to a decrease in the rate of potentially deadly CRPA infections.

Table 2 .
Multivariate analysis (logistic regression) of risk factors for carbapenem-resistant P. aeruginosa infections univariant logistic analysis were included in a multivariant binary logistic regression analysis.The level of significance was set at 0.05 probability of null hypothesis.The statistical software SPSS version 18 for Windows (IBM SPSS, Inc, Chicago, Ill, USA), was used for all calculations.
*significant difference; B -coefficient of logistic regression analysis; OR -Odds Ratio; CI -confidence interval infections after