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Anaesthesia and Intensive Care, Vol. 38, No. 6, November 2010

Antimicrobial resistance is a major concern inhospitals throughout the world. Resistant pathogensthat cause hospital-acquired infections havecontributed to increased morbidity and mortalityamong hospitalised patients1. Pseudomonas

aeruginosa is a leading cause of hospital-acquiredpneumonia worldwide2-4.

The incidence of imipenem-resistantPseudomonasaeruginosa (IRPA) is increasing. The NationalNosocomial Infections Surveillance Systemreported a 15% increase in the isolation of IRPAamong nosocomially-infected patients in 2003, incomparison to 1998 to 20025. In addition, we haveseen a high incidence of IRPA in hospitals in Brazil6.

Recent studies have suggested that the case-case-control design is the most suitable methodologyto determine risk factors for infection caused byresistant pathogens7-8. Thus, the aim of this study

was to identify risk factors for hospital-acquired

pneumonia caused by IRPA in critically ill patients,since, as far as we know, no previous study hasanalysed this subject utilising this methodology.

METHODS

Setting

The study was conducted at the Hospital SaoPaulo, 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 thehospital, including paediatric and neonatal ICUs. Thisstudy was undertaken in the anesthesiology ICU, a16-bed medical-surgical unit. This ICU has a stafng

comprised of full-time intensivists, nurses, assistantnurses and respiratory therapists. The nursing/patientratio was 1/4. The antibiotic policy was at thediscretion of the intensivists but restricted antibiotics

were discussed with the Antimicrobial Stewardshipgroup comprised of infectious disease physiciansand a pharmacist on a daily basis.

Study design

A case-case-control design was used for thisstudy. After approval by the Institutional EthicsCommittee, two retrospective case-control studies

were concurrently performed with patients admitted

* M.D., Physician and Researcher. M.D., Assistant Professor. R.N., Infection Control Nurse. B.S., Lab Researcher, Alerta Laboratory.

Address for correspondence: Dr G. H. Furtado, 690 Napoleao de Barrosst, 2nd floor, So Paulo/SP Brazil 04024-002. Email: [email protected]

Accepted for publication on June 15, 2010.

Anaesth Intensive Care 2010; 38: 994-1001

Original Papers

Risk factors for hospital-acquired pneumonia caused by

imipenem-resistant Pseudomonas aeruginosa in an intensivecare 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 todetermine 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-surgicalintensive care unit from a university-affiliated hospital with hospital-acquired pneumonia caused by imipenem-

resistant Pseudomonas aeruginosa strains and by imipenem-susceptible Pseudomonas aeruginosa strains werematched to control patients by time under risk and comorbidities. A total of 58 resistant cases, 47 susceptible casesand 237 controls were evaluated. The risk factors independently associated to hospital-acquired pneumonia causedby imipenem-resistant Pseudomonas aeruginosa were: duration of hospitalisation, Acute Physiological and ChronicHealth 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

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995ImIpenem-resIstantpseudomonasaeruginosapneumonIa


to the anaesthesiology ICU between 1 January 2006and 31 December 2008. The rst group of casepatients included patients with age 18 years

who had hospital-acquired pneumonia caused byIRPA. The second group included patients who had

hospital-acquired pneumonia caused by imipenem-susceptiblePseudomonas aeruginosa (ISPA). Patientsin the control group were selected from a groupreceiving care from the same ICU where casepatients were receiving care matched by period ofhospitalisation (six-month interval), time under riskand comorbidity. Time under risk was dened as thelength of time from the date of ICU admission tothe date of the positive culture for case patients andthe length of time from the date of ICU admissionto the discharge for controls.

Patients in the control group did not have IRPA

or ISPA isolated during their hospital stay. Weutilised the same control group for both case-controlstudies. For each case patient with IRPA or ISPAselected, at least four control patients were chosen.Hospital-acquired pneumonia was diagnosed by theinfection control team according to the criteria ofthe Centers for Disease Control and Prevention9.Briey, the clinical diagnosis was made with thefollowing prerequisites: presence of fever (>38C);high leukocyte count (>12,000 /mm3) or lowleukocyte count (

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996 G. H. Furtado, a. C. Galesetal


table 1

Univariate analysis of risk factors associated to hospital-acquired pneumonia caused by IRPA

Variable Resistant cases (n=58) Controls (n=237) Pvalue

Age, y, mean 54 54 0.93

Length of hospital stay, median 36 17

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(23.4%). For the control group, the major diagnoseswere neurological diseases (17.3%) and gastro-intestinal diseases (15.2%). The minimum inhibitorycon-centrations, MIC

50and MIC

90for imipenem

among IRPA strains were 16 g/ml and 32 g/mlrespectively.

Results of univariate analysis of risk factors forIRPA and ISPA are shown in Tables 1 and 2respectively.

Multivariable logistic regression analysisdemonstrated that patients with HAP caused byIRPA were more likely to have been exposed to

table 1

Univariate analysis of risk factors associated to hospital-acquired pneumonia caused by IRPA (continued)

Variable Resistant cases (n=58) Controls (n=237) Pvalue

Fluoroquinolone 10 (17.2%) 23 (9.7%) 0.10

Piperacillin-tazobactam 9 (15.5%) 3 (1.3 %) 0.99

Chronic renal failure 2 (4.3%) 34 (14.3%) 0.06

Transplantation 0 (0%) 14 (5.9%) 0.13

AIDS 1 (2.1%) 4 (1.7%) >0.99

Cirrhosis 1 (2.1%) 15 (6.3%) 0.48

Trauma 5 (10.6%) 25 (10.5%) 0.98

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the following antibiotics: piperacillin-tazobactam(odds ratio [OR] 14.31, 95% condence 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 tohave been exposed to corticosteroids (OR 13.18,

95% CI 3.80 to 45.64, P

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years, with the lower respiratory tract being one ofthe major sites of isolation6.

We undertook this study using a case-case-controlmethodology. This methodology has been discussedin recent years7,8. It uses two separate case-control

studies in a single study as follows: the rst studycompares case patients infected by resistant bacteria(resistant cases) with control patients withoutinfection caused by the organism of study, and whoare representative of the source-population, whilethe second study compares case patients with asusceptible phenotype of the organism studied(susceptible cases) with the same controls. These twoanalyses supply risk models regarding 1) isolation ofa resistant phenotype of the organism of study and2) isolation of a susceptible phenotype of theorganism studied. When these two risk factor models

are compared and contrasted, the risk factorsespecially associated with the isolation of theresistant phenotype can be identied. The advantageof using this type of control group is that it allowsan adequate comparison of both risk factor models(e.g. resistant phenotype versus control andsusceptible phenotype versus control), because thetwo case groups are compared with the same controlgroup7.

In the IRPA group, we found independent riskfactors related to the duration of stay (time ofhospitalisation), gender of the patient, clinicalstatus (APACHE II score, haemodialysis, use ofcorticosteroids) and nally the administration ofantimicrobial drugs (piperacillin-tazobactam, third-generation cephalosporins).

Several studies in the last 10 years have analysedrisk factors related to infections caused bycarbapenem-resistant Pseudomonas aeruginosa1,3,12-19.Other studies have concomitantly assessed riskfactors and clinical outcomes20-22. However, fewstudies have assessed risk factors specically relatedto pneumonia23-25. In turn, few previous studieshave utilised case-case-control methodology aimingat analysing risk factors for IRPA infections14,15,19.

Only three studies have specically assessed riskfactors for pneumonia by carbapenem-resistant

Pseudomonas aeruginosa23-25. Two of them alsofound exposure to carbapenems as a risk factor24,25.However, none of these studies used the case-case-control methodology. Interestingly, in our study wedid not nd carbapenem exposure as a risk factorfor IRPA. This variable was only signicant in theunivariate analysis.

On the other hand, several antimicrobial drugshave also been identied as risk factors for IRPA inprevious studies, such as uoroquinolones1,18-20,23,25,

aminoglycosides15,21, cephalosporins21, piperacillin-tazobactam3,14 and polymyxin24. As such, in additionto carbapenems, uoroquinolones are the mostimplicated group related to carbapenem-resistantstrains. A potential explanation for this is that the

usage of uoroquinolones would select for strainswith hyperexpression of efux pumps18,19. Nonetheless,in our study, the use of uoroquinolones was notfound as a risk factor for these infections. It may bethat the reduced use of these antimicrobial drugsmight explain this fact, since only 17.2 and 10.6%of patients utilised these drugs in the resistant andsusceptible case groups respectively.

In the IRPA group, the use of piperacillin-tazobactam and the use of third-generationcephalosporins were independently associated withthe presence of IRPA pneumonia as previously

described

7,14,21

. These broad-spectrum antibioticsprovoke the eradication of competitive microbiotaand also ease the selection of multidrug-resistantstrains21. In addition, the selected Pseudomonas

aeruginosa strain with chromosomal derepressedbeta-lactamases by these two classes of antimicrobialsmay be more susceptible to the loss of the porinOprD, and become resistant to carbapenem drugs,mainly imipenem7,26,27.

Aside from the use of antimicrobial drugs, othervariables have been related to the presence ofcarbapenem-resistant Pseudomonas aeruginosa,such as the length of hospitalisation14,17, ICUhospitalisation3,21, transfer from another hospital15,severity of disease18, organ transplantation12 andinvasive procedures21-23,25. A important nding of ourstudy in contrast to previous studies is that invasiveprocedures, mainly mechanical ventilation, duringthe ICU stay was not associated with IRPAacquisition21-23,25.

As use of corticosteroid was found as the onlyindependent variable in both studies we suggestthat this variable may be related specically with

Pseudomonas aeruginosa infection regardless of itssusceptibility prole. Thus, only the other variablesfound as independently related to IRPA infectionshould be considered as risk factors for IRPApneumonia.

In addition, a recent study demonstrated that theuse of corticosteroids does not reduce mortalityrates in septic patients28. Furthermore, this studyshowed a greater incidence of superinfectionincluding new sepsis and septic shock in patients

who used corticosteroid therapy. Previous studieswith greater dosages of corticosteroids had alreadydemonstrated an increased incidence of superinfection in this population29,30.

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Corticosteroids yield several anti-inammatoryactivities, including the inhibition of lymphocytemigration and inhibition of transcription ofdependent cytokines from the nuclear factor ofactivation-kappa b. Furthermore, these drugs have

action on inammatory interleukins, such as IL-6,IL-8 and GM-CSF31. Prior studies alreadydemonstrated a possible association betweencorticosteroid use and development ofPseudomonas

aeruginosa infections32-34.

According to our ndings, most of the variablesfound as independently associated with IRPApneumonia are non-modiable (length of hospitalstay, APACHE II score, male gender, haemodialysis).Indeed, only antimicrobial utilisation (thirdgeneration cephalosporins and piperacillin-tazobactam) are preventable risk factors. We can

argue that the restriction of these two antibioticclasses would be a favourable measure aiming toreduce the prevalence of IRPA infections.

Our study has limitations. First, active surveillancecultures were not performed but this measure

would most likely identify colonisation insteadof infection which was not the objective of ourstudy. Second, we did not evaluate the molecularmechanisms of resistance among our isolates.However, regardless of the kind of acquiredresistance mechanism, our major goal was toevaluate which risk factors are more related to

acquisition of HAP caused by IRPA. Furthermore,no outbreak or newer kind of imipenemresistance was reported during the study period.Finally, our study was undertaken in a single unit,and these results may not be generalised to othersettings.

As the mechanism of carbapenem resistanceamong Pseudomonas aeruginosa isolates in oursetting is multiple (enzymatic, efux pumps, losingof porins)35, reinforcement of infection controlmeasures (e.g. handwashing, contact precautions)is very important to avoid the maintenance of

this resistant micro-organism in the ICUenvironment.

In conclusion, our data support a major role forvariables related to the duration of stay (time ofhospitalisation), gender of the patient, clinical status(APACHE II score, haemodialysis) and nally theadministration of antimicrobial drugs (piperacillin-tazobactam, third-generation cephalosporins) as riskfactors for hospital-acquired pneumonia caused byIRPA. To our knowledge, this is the rst studyutilising case-case-control methodology for this kindof infection.

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