Anaesth Intensive Care 2010; 38: 994-1001

Original Papers
Risk factors for hospital-acquired pneumonia caused by imipenem-resistant Pseudomonas aeruginosa in an intensive care unit
G. H. FURTADO*, A. C. GALES, L. B. PERDIZ, A. F. SANTOS, S. B. WEY**, E. A. MEDEIROS
Division of Infectious Diseases, Federal University of So Paulo, So Paulo, Brazil

SUMMARY Imipenem-resistant Pseudomonas aeruginosa is a leading cause of hospital-acquired pneumonia. Aiming to determine the risk factors associated for hospital-acquired pneumonia due to imipenem-resistant Pseudomonas aeruginosa, we undertook a retrospective case-case-control study. Patients admitted to a 14-bed medical-surgical intensive care unit from a university-affiliated hospital with hospital-acquired pneumonia caused by imipenemresistant Pseudomonas aeruginosa strains and by imipenem-susceptible Pseudomonas aeruginosa strains were matched to control patients by time under risk and comorbidities. A total of 58 resistant cases, 47 susceptible cases and 237 controls were evaluated. The risk factors independently associated to hospital-acquired pneumonia caused by imipenem-resistant Pseudomonas aeruginosa were: duration of hospitalisation, Acute Physiological and Chronic Health Evaluation II score, male gender, receipt of haemodialysis, receipt of piperacillin-tazobactam and receipt of third-generation cephalosporins.
Key Words: hospital-acquired pneumonia, risk factors, Pseudomonas aeruginosa, intensive care

Antimicrobial resistance is a major concern in hospitals throughout the world. Resistant pathogens that cause hospital-acquired infections have contributed to increased morbidity and mortality among hospitalised patients1. Pseudomonas aeruginosa is a leading cause of hospital-acquired pneumonia worldwide2-4. The incidence of imipenem-resistant Pseudomonas aeruginosa (IRPA) is increasing. The National Nosocomial Infections Surveillance System reported a 15% increase in the isolation of IRPA among nosocomially-infected patients in 2003, in comparison to 1998 to 20025. In addition, we have seen a high incidence of IRPA in hospitals in Brazil6. Recent studies have suggested that the case-casecontrol design is the most suitable methodology to determine risk factors for infection caused by resistant pathogens7-8. Thus, the aim of this study was to identify risk factors for hospital-acquired
* M.D., Physician and Researcher. M.D., Assistant Professor. R.N., Infection Control Nurse. B.S., Lab Researcher, Alerta Laboratory.

pneumonia caused by IRPA in critically ill patients, since, as far as we know, no previous study has analysed this subject utilising this methodology. METHODS Setting The study was conducted at the Hospital Sao Paulo, So Paulo, Brazil, a 750-bed teaching hospital with an average of 180,000 patient days per year. There are nine intensive care units (ICU) in the hospital, including paediatric and neonatal ICUs. This study was undertaken in the anesthesiology ICU, a 16-bed medical-surgical unit. This ICU has a staffing comprised of full-time intensivists, nurses, assistant nurses and respiratory therapists. The nursing/patient ratio was 1/4. The antibiotic policy was at the discretion of the intensivists but restricted antibiotics were discussed with the Antimicrobial Stewardship group comprised of infectious disease physicians and a pharmacist on a daily basis. Study design A case-case-control design was used for this study. After approval by the Institutional Ethics Committee, two retrospective case-control studies were concurrently performed with patients admitted
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Address for correspondence: Dr G. H. Furtado, 690 Napoleao de Barros st, 2nd floor, So Paulo/SP Brazil 04024-002. Email: ghfurtado@uol.com.br Accepted for publication on June 15, 2010.

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to the anaesthesiology ICU between 1 January 2006 and 31 December 2008. The first group of case patients included patients with age 18 years who had hospital-acquired pneumonia caused by IRPA. The second group included patients who had hospital-acquired pneumonia caused by imipenemsusceptible Pseudomonas aeruginosa (ISPA). Patients in the control group were selected from a group receiving care from the same ICU where case patients were receiving care matched by period of hospitalisation (six-month interval), time under risk and comorbidity. Time under risk was defined as the length of time from the date of ICU admission to the date of the positive culture for case patients and the length of time from the date of ICU admission to the discharge for controls. Patients in the control group did not have IRPA or ISPA isolated during their hospital stay. We utilised the same control group for both case-control studies. For each case patient with IRPA or ISPA selected, at least four control patients were chosen. Hospital-acquired pneumonia was diagnosed by the infection control team according to the criteria of the Centers for Disease Control and Prevention9. Briefly, the clinical diagnosis was made with the following prerequisites: presence of fever (>38C); high leukocyte count (>12,000 /mm3) or low leukocyte count (<4000 /mm3), purulent bronchial secretions and a new and persistent infiltrate on chest radiography. A cut-off of 104 organisms/ml and 106 organisms/ml was used for bronchoscopic lavage specimen and endotracheal aspirate, respectively. In addition, all the doubtful diagnosis were revised and discussed by the entire study group in order to minimise inter-rater discrepancy. Data collection Variables analysed as possible risk factors included age, gender, days of hospitalisation, number and type of antibiotics used, duration of mechanical ventilation, Acute Physiology and Chronic Health Evaluation (APACHE) II score, McCabe score10, previous surgery, previous hospitalisation (3 months), previous ICU hospitalisation current hospitalisation), corticosteroid use, immunosuppressive drug use, neutropenia (<500 granulocytes units), acute renal failure and invasive procedures. With regard to antimicrobial drugs, for case patients only antimicrobial drugs administered during the three weeks before isolation of IRPA or ISPA were included in the analysis. For control patients, antimicrobial drug treatment administered during the three weeks before discharge from the ICU was included in the analysis. Patients were
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classified according to McCabe score with rapidly fatal, ultimately fatal and non-fatal disease. With regard to corticosteroid and immunosuppressive drugs, only drugs administered before the isolation of IRPA and ISPA were considered. Concerning the use of corticosteroids, only the daily dosing at least equivalent of 300 mg of hydrocortisone was considered. For controls, we considered the administration of these drugs during the period of hospitalisation in the ICU. Microbiology data The hospitals microbiology laboratory database was used to identify all cultures from the lower respiratory tract that were obtained from patients hospitalised in the anaesthesiology ICU between 1 January 2006 and 31 December 2008 that grew either IRPA or ISPA strains. All strains were isolated from clinical specimens. Patients who had either IRPA or ISPA isolates recovered within 48 hours of hospital admission were excluded from the study. Pseudomonas aeruginosa isolates were identified by conventional techniques and antibiotic susceptibility was made using the disk diffusion technique. In addition, agar dilution method was performed for IRPA strains in order to confirm imipenem resistance11. Statistical analysis All statistical analyses were undertaken using SPSS software, version 15.0. In the univariate analysis, continuous variables were compared using Students t-test or Wilcoxon rank-sum test. The chisquare test or Fischers exact test was performed for categorical variables. Variables for which the P value was <0.05 in univariable analysis were included in a logistic regression model for multivariable analysis. A step-forward selection process was used, and risk factors were checked for confounding and colinearity. Confounders were included in the multivariate analysis if inclusion of the covariate changed the coefficient of any statistically significant variable in the logistic regression model by 10%. All tests used were twotailed, and P values <0.05 were considered to be significant in the multivariable model. RESULTS During the study period, 58 patients with IRPA and 47 patients with ISPA were identified. A total of 237 control patients were included in the control group. The major diagnoses for the IRPA group were neurologic diseases (19%) and infectious diseases (17.2%). For the ISPA group, the major diagnoses were neurological diseases (29.8%) and cancer

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table 1 Univariate analysis of risk factors associated to hospital-acquired pneumonia caused by IRPA Variable Age, y, mean Length of hospital stay, median Time under risk, days, mean Number of antibiotic classes used Duration of mechanical ventilation, days, median APACHE II score, mean McCabe score Rapidly fatal Ultimately fatal Non-fatal Male gender Surgery Previous ICU hospitalisation Use of corticosteroid Use of immunossupressive drug Neutropenia Previous hospitalisation Acute renal failure Comorbidities Diabetes mellitus COPD Cancer Haematologic cancer Chronic renal failure Transplantation AIDS Cirrhosis Trauma Invasive procedures Indwelling urinary catheter Central venous catheter Parenteral nutrition Mechanical ventilation Haemodyalisis Antimicrobial drugs 3rd gen Ceph 4th gen Ceph Carbapenem Clindamycin Vancomycin Metronidazole Aminoglycoside 34 (58.6%) 20 (34.5%) 49 (84.5%) 16 (27.6%) 53 (91.4%) 7 (12.1%) 12 (20.7%) 99 (41.8%) 94 (39.7%) 107 (45.1%) 51 (21.5%) 129 (54.4%) 46 (19.4%) 28 (11.8%) 0.02 0.46 <0.001 0.32 <0.001 0.19 0.07 49 (84.5%) 52 (89.7%) 6 (10.3%) 58 (100%) 19 (32.8%) 220 (92.8%) 214 (90.3%) 7 (3%) 161 (67.9%) 26 (11%) 0.04 0.88 0.02 <0.001 <0.001 6 (10.3%) 9 (15.5%) 12 (20.7%) 1 (1.7%) 10 (17.2%) 7 (12.1%) 0 (0%) 7 (12.1%) 7 (12.1%) 44 (18.6%) 18 (7.6%) 40 (16.9%) 5 (2.1%) 34 (14.3%) 14 (5.9%) 4 (1.7%) 15 (6.3%) 25 (10.5%) 0.13 0.06 0.49 0.85 0.57 0.10 >0.99 0.16 0.73 28 (48.3%) 30 (51.7%) 0 (0%) 41 (70.7%) 37 (63.8%) 14 (24.1%) 35 (60.3%) 8 (13.8%) 0 (0%) 33 (56.9%) 16 (27.6%) 102 (43%) 113 (47.7%) 22 (9.3%) 134 (56.5%) 157 (66.2%) 39 (16.5%) 30 (12.7%) 16 (6.8%) 1 (0.4%) 119 (50.2%) 18 (7.6%) 0.1 0.1 0.1 0.01 0.72 0.17 <0.001 0.10 >0.99 0.36 <0.001 Resistant cases (n=58) Controls (n=237) 54 36 21 4 17 17 54 17 11 2 8 12 P value 0.93 <0.001 0.08 <0.001 <0.001 <0.001

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table 1 Univariate analysis of risk factors associated to hospital-acquired pneumonia caused by IRPA (continued) Variable Fluoroquinolone Piperacillin-tazobactam Resistant cases (n=58) 10 (17.2%) 9 (15.5%) Controls (n=237) 23 (9.7%) 3 (1.3 %) P value 0.10 <0.001

997

IRPA=imipenem-resistant Pseudomonas aeruginosa, APACHE=Acute Physiological and Chronic Health Evaluation, ICU=intensive care unit, COPD=chronic obstructive pulmonary diasease, AIDS=acute immunodeficiency syndrome, gen Ceph=generation cephalosporin.

(23.4%). For the control group, the major diagnoses were neurological diseases (17.3%) and gastrointestinal diseases (15.2%). The minimum inhibitory con-centrations, MIC50 and MIC90 for imipenem among IRPA strains were 16 g/ml and 32 g/ml respectively.

Results of univariate analysis of risk factors for IRPA and ISPA are shown in Tables 1 and 2 respectively. Multivariable logistic regression analysis demonstrated that patients with HAP caused by IRPA were more likely to have been exposed to

table 2 Univariate analysis of risk factors associated to hospital-acquired pneumonia caused by ISPA Variables Age, y, mean Length of hospital stay, median Time under risk, days, mean Number of antibiotic classes used Duration of mechanical ventilation, days, median APACHE II score, mean McCabe score Rapidly fatal Ultimately fatal Non-fatal Male gender Surgery Previous ICU hospitalisation Use of corticosteroid Use of immunossupressive drug Previous hospitalisation Neutropenia Acute renal failure Comorbidities Diabetes mellitus COPD Cancer Haematologic cancer Chronic renal failure Transplantation AIDS Cirrhosis Trauma
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Susceptible cases (n=47) 58 22 13 3 11 12 19 (40.4%) 28 (59.6%) 0 (0%) 27 (57.4%) 32 (68.1%) 12 (25.5%) 19 (40.4%) 1 (2.1%) 24 (51.1%) 0 (0%) 6 (12.8%) 11 (23.4%) 5 (10.6%) 11 (23.4%) 1 (2.1%) 2 (4.3%) 0 (0%) 1 (2.1%) 1 (2.1%) 5 (10.6%)

Controls (n=237) 54 17 11 2 8 12 102 (43%) 113 (47.7%) 22 (9.3%) 134 (56.5%) 157 (66.2%) 39 (16.5%) 30 (12.7%) 16 (6.8%) 119 (50.2) 1 (0.4%) 18 (7.6%) 44 (18.6%) 18 (7.6%) 40 (16.9%) 5 (2.1%) 34 (14.3%) 14 (5.9%) 4 (1.7%) 15 (6.3%) 25 (10.5%)

P value 0.74 0.24 0.10 0.06 0.03 0.53 0.12 0.12 0.12 0.90 0.80 0.13 <0.001 0.32 0.91 >0.99 0.25 0.44 0.55 0.28 >0.99 0.06 0.13 >0.99 0.48 0.98

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table 2 Univariate analysis of risk factors associated to hospital-acquired pneumonia caused by ISPA (continued) Variables Invasive procedures Indwelling urinary catheter Central venous catheter Parenteral nutrition Haemodialysis Mechanical ventilation Antimicrobial drugs 3rd gen Ceph 4th gen Ceph Carbapenem Clindamycin Vancomycin Metronidazole Aminoglycosides Fluoroquinolones Piperacillin-tazobactam 25 (53.2%) 23 (48.9%) 18 (38.3%) 14 (29.8%) 30 (63.8%) 7 (14.9%) 10 (21.3%) 5 (10.6%) 2 (4.3%) 99 (41.8%) 94 (39.7%) 107 (45.1%) 51 (21.5%) 129 (54.4%) 46 (19.4%) 28 (11.8%) 23 (9.7%) 3 (1.3%) 0.14 0.23 0.38 0.21 0.23 0.46 0.08 0.79 0.19 41 (87.2%) 39 (83%) 1 (2.1%) 4 (8.5%) 47 (100%) 220 (92.8%) 214 (90.3%) 7 (3%) 26 (11%) 161 (67.9%) 0.23 0.14 >0.99 0.79 <0.001 Susceptible cases (n=47) Controls (n=237) P value

ISPA=imipenem-susceptible Pseudomonas aeruginosa, APACHE=Acute Physiological and Chronic Health Evaluation, ICU=intensive care unit, COPD=chronic obstructive pulmonary diasease, AIDS=Acute immunodeficiency syndrome, ggen Ceph=generation cephalosporin.

the following antibiotics: piperacillin-tazobactam (odds ratio [OR] 14.31, 95% confidence interval [CI] 1.02 to 200.16, P=0.04) and third-generation cephalosporins (OR 7.45, 95% CI 1.80 to 30.86, P=0.006). These patients were also more likely to have been exposed to corticosteroids (OR 13.18,
table 3 Multivariable analysis with comparative adjusted odds ratio between the two groups Variable Length of hospital stay APACHE II score Male gender Haemodialysis Use of corticosteroid Use of piperacillintazobactam Use of 3rd-gen cephalosporin IRPA 1.19 (1.12-1.26, P <0.001) 1.11 (1.01-1.22, P=0.003) 8.01 (1.66-38.51, P=0.009) 6.85 (1.33-35.2, P=0.02) 13.18 (3.80-45.64, P <0.001) 14.31 (1.02-200.16, P=0.04) 7.45 (1.80-30.86, P=0.006) 12.32 (5.81-26.10, P=0.001) ISPA

95% CI 3.80 to 45.64, P <0.001). Other significant risk factors were male gender (OR 8.01, 95% CI 1.66 to 38.51, P=0.009), APACHE II score (OR 1.11, 95% CI 1.01 to 1.22, P=0.03) and haemodialysis (OR 6.85, 95% CI 1.33 to 35.2, P=0.02). The duration of hospitalisation was also a significant risk factor (OR 1.19, 95% CI 1.12 to 1.26, P <0.001). Patients with HAP caused by ISPA were more likely to have been exposed to corticosteroids (OR 12.32, 95% CI 5.81 to 26.10, P=0.001). In this multivariable analysis, no significant differences were found between ISPA patients and controls related to antimicrobial drug use. The sole variable that remained as statistically significant in both multivariable analyses was use of corticosteroid. Table 3 displays the comparative adjusted OR for the two groups. DISCUSSION Currently, healthcare professionals face a serious problem in hospitals with regard to the dissemination of multidrug-resistant pathogens. Countless hospitals worldwide have presented high incidence rates of these pathogens. At Hospital Sao Paulo, the isolation of imipenem-resistant Pseudomonas aeruginosa has been maintained at endemic levels of approximately 50% in recent
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IRPA=imipenem-resistant Pseudomonas aeruginosa, imipenemsusceptible Pseudomonas aeruginosa, APACHE=Acute Physiological and Chronic Health Evaluation, gen=generation.

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years, with the lower respiratory tract being one of the major sites of isolation6. We undertook this study using a case-case-control methodology. This methodology has been discussed in recent years7,8. It uses two separate case-control studies in a single study as follows: the first study compares case patients infected by resistant bacteria (resistant cases) with control patients without infection caused by the organism of study, and who are representative of the source-population, while the second study compares case patients with a susceptible phenotype of the organism studied (susceptible cases) with the same controls. These two analyses supply risk models regarding 1) isolation of a resistant phenotype of the organism of study and 2) isolation of a susceptible phenotype of the organism studied. When these two risk factor models are compared and contrasted, the risk factors especially associated with the isolation of the resistant phenotype can be identified. The advantage of using this type of control group is that it allows an adequate comparison of both risk factor models (e.g. resistant phenotype versus control and susceptible phenotype versus control), because the two case groups are compared with the same control group7. In the IRPA group, we found independent risk factors related to the duration of stay (time of hospitalisation), gender of the patient, clinical status (APACHE II score, haemodialysis, use of corticosteroids) and finally the administration of antimicrobial drugs (piperacillin-tazobactam, thirdgeneration cephalosporins). Several studies in the last 10 years have analysed risk factors related to infections caused by carbapenem-resistant Pseudomonas aeruginosa1,3,12-19. Other studies have concomitantly assessed risk factors and clinical outcomes20-22. However, few studies have assessed risk factors specifically related to pneumonia23-25. In turn, few previous studies have utilised case-case-control methodology aiming at analysing risk factors for IRPA infections14,15,19. Only three studies have specifically assessed risk factors for pneumonia by carbapenem-resistant Pseudomonas aeruginosa23-25. Two of them also found exposure to carbapenems as a risk factor24,25. However, none of these studies used the case-casecontrol methodology. Interestingly, in our study we did not find carbapenem exposure as a risk factor for IRPA. This variable was only significant in the univariate analysis. On the other hand, several antimicrobial drugs have also been identified as risk factors for IRPA in previous studies, such as fluoroquinolones1,18-20,23,25,
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aminoglycosides15,21, cephalosporins21, piperacillintazobactam3,14 and polymyxin24. As such, in addition to carbapenems, fluoroquinolones are the most implicated group related to carbapenem-resistant strains. A potential explanation for this is that the usage of fluoroquinolones would select for strains with hyperexpression of efflux pumps18,19. Nonetheless, in our study, the use of fluoroquinolones was not found as a risk factor for these infections. It may be that the reduced use of these antimicrobial drugs might explain this fact, since only 17.2 and 10.6% of patients utilised these drugs in the resistant and susceptible case groups respectively. In the IRPA group, the use of piperacillintazobactam and the use of third-generation cephalosporins were independently associated with the presence of IRPA pneumonia as previously described7,14,21. These broad-spectrum antibiotics provoke the eradication of competitive microbiota and also ease the selection of multidrug-resistant strains21. In addition, the selected Pseudomonas aeruginosa strain with chromosomal derepressed beta-lactamases by these two classes of antimicrobials may be more susceptible to the loss of the porin OprD, and become resistant to carbapenem drugs, mainly imipenem7,26,27. Aside from the use of antimicrobial drugs, other variables have been related to the presence of carbapenem-resistant Pseudomonas aeruginosa, such as the length of hospitalisation14,17, ICU hospitalisation3,21, transfer from another hospital15, severity of disease18, organ transplantation12 and invasive procedures21-23,25. A important finding of our study in contrast to previous studies is that invasive procedures, mainly mechanical ventilation, during the ICU stay was not associated with IRPA acquisition21-23,25. As use of corticosteroid was found as the only independent variable in both studies we suggest that this variable may be related specifically with Pseudomonas aeruginosa infection regardless of its susceptibility profile. Thus, only the other variables found as independently related to IRPA infection should be considered as risk factors for IRPA pneumonia. In addition, a recent study demonstrated that the use of corticosteroids does not reduce mortality rates in septic patients28. Furthermore, this study showed a greater incidence of superinfection including new sepsis and septic shock in patients who used corticosteroid therapy. Previous studies with greater dosages of corticosteroids had already demonstrated an increased incidence of super infection in this population29,30.

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Corticosteroids yield several anti-inflammatory activities, including the inhibition of lymphocyte migration and inhibition of transcription of dependent cytokines from the nuclear factor of activation-kappa b. Furthermore, these drugs have action on inflammatory interleukins, such as IL-6, IL-8 and GM-CSF31. Prior studies already demonstrated a possible association between corticosteroid use and development of Pseudomonas aeruginosa infections32-34. According to our findings, most of the variables found as independently associated with IRPA pneumonia are non-modifiable (length of hospital stay, APACHE II score, male gender, haemodialysis). Indeed, only antimicrobial utilisation (third generation cephalosporins and piperacillintazobactam) are preventable risk factors. We can argue that the restriction of these two antibiotic classes would be a favourable measure aiming to reduce the prevalence of IRPA infections. Our study has limitations. First, active surveillance cultures were not performed but this measure would most likely identify colonisation instead of infection which was not the objective of our study. Second, we did not evaluate the molecular mechanisms of resistance among our isolates. However, regardless of the kind of acquired resistance mechanism, our major goal was to evaluate which risk factors are more related to acquisition of HAP caused by IRPA. Furthermore, no outbreak or newer kind of imipenem resistance was reported during the study period. Finally, our study was undertaken in a single unit, and these results may not be generalised to other settings. As the mechanism of carbapenem resistance among Pseudomonas aeruginosa isolates in our setting is multiple (enzymatic, efflux pumps, losing of porins)35, reinforcement of infection control measures (e.g. handwashing, contact precautions) is very important to avoid the maintenance of this resistant micro-organism in the ICU environment. In conclusion, our data support a major role for variables related to the duration of stay (time of hospitalisation), gender of the patient, clinical status (APACHE II score, haemodialysis) and finally the administration of antimicrobial drugs (piperacillintazobactam, third-generation cephalosporins) as risk factors for hospital-acquired pneumonia caused by IRPA. To our knowledge, this is the first study utilising case-case-control methodology for this kind of infection.

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