Risk Factors for Mortality in Patientswith Pseudomonas aeruginosa Bacteremia:

Clinical Impact of Antimicrobial Resistance on Outcome

Eun-Jeong Joo,1 Cheol-In Kang,1 Young Eun Ha,1 Seung-Ji Kang,1 So Yeon Park,1

Doo Ryeon Chung,1 Kyong Ran Peck,1 Nam Yong Lee,2 and Jae-Hoon Song1

Despite the high prevalence of antimicrobial resistance among Pseudomonas aeruginosa bacteremia, the clinicalconsequence of resistance remains unclear. The purpose of this study was to identify predictors of mortality andevaluate the clinical impact of antimicrobial resistance on outcome in P. aeruginosa bacteremia. A retrospectivecohort study including patients with P. aeruginosa bacteremia was performed. The risk factors for antimicrobialresistances were evaluated, and the impact of the respective resistances on mortality was assessed. Of 202P. aeruginosa bacteremia cases, the resistance rates to ceftazidime, piperacillin, imipenem, fluoroquinolone, andaminoglycoside were 36.6%, 22.3%, 22.8%, 23.8%, and 17.8%, respectively. A prior use of fluoroquinolones andan indwelling urinary catheter were common risk factors for all types of antimicrobial resistance. The overall 30-day mortality rate was 25.2% (51/202), and the risk factors for mortality were corticosteroid use, nosocomialacquisition, polymicrobial infection, an increasing Charlson’s weighted co-morbidity index, and intensive careunit care ( p< 0.05). As compared with the susceptible group, ceftazidime-, piperacillin-, or imipenem-resistantgroups had a higher mortality ( p< 0.05). A multivariate analysis showed that resistance to ceftazidime orimipenem remained a significant factor associated with mortality (odds ratio, 2.96; 95% confidential interval,1.20–7.31; and odds ratio, 2.74; 95% confidential interval, 1.02–7.31, respectively). Antimicrobial resistance,especially to ceftazidime or imipenem, adversely affected outcome in patients with P. aeruginosa bacteremia.

Introduction

T he clinical impact of antimicrobial resistance on theoutcome of serious infections caused by Gram-negative

pathogens has been the subject of highly controversial de-bates over the past decade. Antimicrobial-resistant Gram-negative bacterial infections are associated with prolongedhospital stay and an increased mortality.10,23 Among Gram-negative pathogens, Pseudomonas aeruginosa remains a sig-nificant cause of morbidity and mortality in nosocomialinfections, and its antimicrobial resistance is closely relatedto difficulties in controlling and treating infection because ofintrinsic resistance and rapid acquisition of additional resis-tance.6 One possible explanation for the increased mortalityassociated with antimicrobial-resistant P. aeruginosa infec-tions is delayed administration of appropriate antimicrobialtherapy.9,10,13,17

It is presumed that infections caused by antimicrobial-resistant bacterial infections result in higher mortality, longer

hospitalizations, and greater costs than infections caused bysusceptible infections. Although carbapenem resistance inP. aeruginosa infections was associated with a longer durationof hospital stay and a greater hospital cost,15,20,25 the impactof antimicrobial resistance on treatment outcome might de-pend on the severity of the underlying disease and thepresence of comorbid conditions. Despite the high preva-lence of antimicrobial resistance among P. aeruginosa thatcause bacteremia, the clinical consequence of resistance re-mains unclear.24 Thus, this study was performed to identifythe predictors of mortality and evaluate the clinical impactof antimicrobial resistance on outcome in patients withP. aeruginosa bacteremia.

Materials and Methods

Patients and bacterial strains

The database at our Clinical Microbiology Laboratory wasreviewed to identify patients with P. aeruginosa bacteremia.

1Division of Infectious Diseases and 2Department of Laboratory Medicine, Samsung Medical Center, Sungkyunkwan University School ofMedicine, Seoul, Republic of Korea.

MICROBIAL DRUG RESISTANCEVolume 17, Number 2, 2011ª Mary Ann Liebert, Inc.DOI: 10.1089/mdr.2010.0170

305

Cases that were identified to have P. aeruginosa infectionwere screened, and isolates recovered from blood culturespecimens were reviewed. Patients older than 16 years withP. aeruginosa bacteremia were included in this study. Wereviewed the electronic medical records of individuals foundto have P. aeruginosa bacteremia from October 2006 to March2009 at Samsung Medical Center (Seoul, Republic of Korea),a 1,900-bed tertiary care university hospital. Patients whostayed in hospital more than 100 days before P. aeruginosabacteremia occurred and those who died within a day wereexcluded. Only the first bacteremic episode for each patientwas included in the analysis.

Microbiological identification was performed using astandard identification card, and antimicrobial susceptibilitytesting was performed on the VITEK II automated system(bioMerieux, Marcy l’Etoile, France) using the modifiedbroth microdilution method. Minimum inhibitory concen-tration breakpoints and quality-control protocols were usedaccording to standards established by the Clinical and La-boratory Standard Institute. Strains showing intermediateantimicrobial susceptibility testing were considered to beresistant.

Study design and data collection

A retrospective cohort study was conducted to identify thepredictors of mortality and evaluate the clinical impactof antimicrobial resistance on outcome in patients withP. aeruginosa bacteremia. The risk factors for antimicrobialresistance to piperacillin, ceftazidime, imipenem, fluor-oquinolones, and aminoglycosides were evaluated, and theimpact of the respective antimicrobial resistance on mortalitywas assessed. Data from patients with antimicrobial-resistantP. aeruginosa bacteremia were compared with those frompatients with susceptible bacteremia. The collected data in-cluded age, sex, the date of bacteremia, underlying diseases,category of infection, presence of healthcare-associated(HCA) risk factors, empirical antibiotic regimens, appropri-ateness of empirical antibiotics, patterns of antimicrobial re-sistance, severity of illness, primary sites of infection, portalof entry, and clinical outcomes. The presence of devices suchas central venous and urinary catheters was evaluated at thedate when index blood samples were obtained. Severity ofillness was calculated by the Pitt bacteremia score andCharlson’s weighted co-morbidity index (WCI). Admissionto intensive care units (ICUs) and use of a mechanical ven-tilator were also assessed at the time of acquisition of P.aeruginosa bloodstream infection. For comparison of out-comes, initial response to treatment was assessed at 72–96hours after the initiation of antimicrobial therapy and wasclassified as follows: ‘‘improvement’’, patients who had res-olution of fever, leukocytosis, and all signs of infection, and‘‘failure’’, patients who experienced no improvement or ex-perienced deterioration in any of their clinical parameters aswell as those who died. The main outcome measure was the30-day mortality rate.

To identify the risk factors for antimicrobial resistance, thefollowing data were also collected: recent operations, type ofoperation, history of solid organ transplantation, immuno-suppressant use, corticosteroid use, prior use of antibiotics,prior hospitalization, and duration of hospital stay beforebacteremia. The decision on the diagnosis and management of

the primary source of infection was made solely by the at-tending physicians without any intervention by investigators.

Definitions

P. aeruginosa bacteremia was defined as an infection withP. aeruginosa isolates from blood cultures. Antimicrobial re-sistance was defined as in vitro resistance to ceftazidime,piperacillin, imipenem, fluoroquinolones, or aminoglyco-sides. In vitro resistance to levofloxacin or ciprofloxacin re-presented fluoroquinolone resistance, and resistance toamikacin, tobramycin, or gentamicin represented aminogly-coside resistance. A multidrug-resistant strain was defined asa strain resistant to three or more of the five categorizedclasses.3,22 The initial empirical antimicrobial therapy wasconsidered appropriate if initial empiric antibiotics wereadministered within 24 hours after acquisition of blood cul-ture samples and included at least one antibiotic that wasactive in vitro against P. aeruginosa and when the dosage androute of administration conformed with current medicalstandards. The length of delay of appropriate antimicrobialtherapy was also defined as the interval with 48, 72, and 96hours between the time the blood culture samples were ob-tained and the time effective antibiotics were administered.Inappropriate initial antimicrobial therapy referred to theadministration of antimicrobial agents to which P. aeruginosawas resistant in vitro. Previous antimicrobial therapy wasdefined when any type of antimicrobial therapy has beenadministered for more than 48 hours within 90 days before P.aeruginosa bacteremia. Types of antibiotics previously usedwere categorized into five classes: cephalosporin, penicillin,carbapenem, fluoroquinolones, and aminoglycosides.

Community-onset bacteremia was defined when it oc-curred within 48 hour of admission and was classified intoHCA and community-associated bacteremia. Patients werecategorized as HCA if they fulfilled any of the followingcriteria4,19: received intravenous therapy at home or in anoutpatient clinic in the previous 30 days; received renal di-alysis in a hospital or clinic during the preceding 30 days;had been hospitalized for two or more days in the previous90 days; or resided in a nursing home or long-term carefacility for two or more days in the previous 90 days.Community-onset bacteremia without these HCA risk fac-tors was classified as community-associated. Nosocomialinfection was defined as an infection that occurred 48 hoursafter hospital admission.

Neutropenia was defined as an absolute neutrophil countbelow 500/mm3. Severe sepsis was defined as sepsis withorgan dysfunction, hypoperfusion, or hypotension, andseptic shock was defined as refractory arterial hypotensionor hypoperfusion in spite of adequate fluid resuscitation,with a systolic blood pressure <90 or >30 mmHg less thanthe baseline or a requirement for use of a vasopressor tomaintain the blood pressure.

Statistical analysis

The Student’s t test and Mann–Whitney test were used tocompare continuous variables, and the w2 test or Fisher’s exacttest was used to compare categorical variables. To identify theindependent risk factors for antimicrobial resistance andmortality, a stepwise backward multivariable logistic regres-sion analysis model was used to control for the effects of

306 JOO ET AL.

confounding variables. Variables with p< 0.05 in the univar-iate analyses were candidates for multivariate analysis andvariables for which p< 0.05 in the multivariate analysis wereretained in the final mode. Interactions between variableswere not introduced into the models. Odds ratios (ORs) andtheir 95% confidential intervals (CIs) were calculated. All p-values were two-tailed, and p-values <0.05 were consideredto be statistically significant. SPSS statistics for Windows,PASW version 17.0, was used for these analyses.

Results

Study population

During the study period, a total of 244 patients with P.aeruginosa bacteremia were screened and 42 patients ex-cluded in the study. Sixteen isolates were identified to beobtained from other sites except bloodstream. Thirteenstayed in hospital more than 100 days before the bacteremiaand 10 died within a day. Four patients experienced recur-rent Gram-negative bacteremia at the time of acquisition ofP. aeruginosa. Finally, a total of 202 patients were included inthis study. The mean age (�standard deviation) of patientswas 55� 15 years, and 127 patients (62.9%) were men. Themost common underlying diseases were solid tumors(n¼ 103, 51.0%), followed by hematologic malignancy andliver disease. Of 202 patients, 123 (60.9%) had nosocomialinfections and the remaining 79 (39.1%) had community-onset infections, of which 61 (77.2%) were classified ascommunity-onset HCA infections. As for the primary sites ofinfection, intra-abdominal infection was the most common(n¼ 84, 41.6%), followed by primary bacteremia and pneu-monia. Demographic and clinical characteristics of the studypopulation are described in Table 1.

For the P. aeruginosa blood isolates, the resistance rates toceftazidime, piperacillin, imipenem, fluoroquinolone, andaminoglycoside were 36.6% (74/202), 22.3% (45/202), 22.8%(46/202), 23.8% (48/202), and 17.8% (36/202), respectively.The multidrug resistance rate was 20.8% (42/202).

Risk factors associated with antimicrobial resistance

The factors associated with antimicrobial resistance toceftazidime, piperacillin, imipenem, fluoroquinolones, oraminoglycosides were evaluated. From the univariate anal-ysis, the common risk factors for resistance to ceftazidime orpiperacillin were nosocomial acquisition, prior receipt ofextended-spectrum penicillin or fluoroquinolones within theprevious 90 days, indwelling urinary catheters, percutaneoustubes, and having had an invasive procedure within theprevious 72 hours. The risk factors for imipenem resistancewere prior use of carbapenems, fluoroquinolones, or ami-noglycosides, and an indwelling urinary catheter. Risk fac-tors associated with resistance to fluoroquinolone oraminoglycoside were prior use of fluoroquinolones, an in-dwelling urinary catheter or percutaneous tubes, and havinghad an invasive procedure within the previous 72 hours. Wenext performed a multivariate analysis using variables thatwere significantly associated with the respective antimicro-bial resistances in the univariate analysis ( p< 0.05). The in-dependent risk factors associated with the respectiveantimicrobial resistances are shown in Table 2. A prior use offluoroquinolones and indwelling urinary catheter were

found to be common risk factors significantly associated withall types of antimicrobial resistance.

Treatment outcome and predictors of mortality

When clinical outcomes of P. aeruginosa bacteremia wereevaluated, the initial clinical failure rate was 51.5% (104/

Table 1. Clinical Characteristics of Patients

with Pseudomonas aeruginosa Bacteremia

CharacteristicsNo. of patients (%)

(n¼ 202)

Age, years (mean� SD) 55� 15Male/female 127/75 (62.9/37.1)Underlying disease

Solid tumor 103 (51.0)Hematologic malignancy 72 (35.6)Liver disease 71 (35.1)Renal failure 37 (18.3)Lung disease 30 (14.9)Heart disease 29 (14.4)Diabetes mellitus 25 (12.4)Cerebrovascular disease 13 (6.4)

Comorbid conditionsPrior hospitalization within 90 days 128 (63.4)Immunosuppressants use 109 (54.0)Corticosteroid use 94 (46.5)Recent operation within a year 54 (26.7)Solid organ transplantation 28 (13.9)Neutropenia 81 (40.1)Polymicrobial infection 28 (13.9)Intubated state 13 (6.4)Indwelling urinary catheter 35 (17.3)Central venous catheterization 90 (44.6)Percutaneous catheterization 47 (23.3)Invasive procedure within previous

72 hours80 (39.6)

Category of infectionCommunity-associated infection 18 (8.9)Healthcare-associated infection 61 (30.2)Hospital-acquired infection 123 (60.9)

Prior receipt of antibiotics within 3 monthsbefore bacteremia

Any types of antibiotics 148 (73.3)Extended-spectrum cephalosporins 131 (64.9)Penicillins 54 (26.7)Carbapenems 36 (17.8)Fluoroquinolones 35 (17.3)Aminoglycosides 16 (7.9)Severity of illnessPitt bacteremia score (mean� SD) 2.03� 2.65Charlson’s weighted index of

co-morbidity (mean� SD)4.51� 2.71

ICU admission 50 (24.8)Septic shock 72 (35.6)Severe sepsis or septic shock 88 (43.6)

Site of infectionPrimary bacteremia 44 (21.8)Intra-abdominal infection 84 (41.6)Respiratory tract infection 30 (14.9)Catheter-related infection 19 (9.4)Urinary tract infection 18 (8.9)Skin and soft tissue infection 7 (3.5)

SD, standard deviation; IQR, interquartile rate; MDR, multidrugresistance; ICU, intensive care units.

ANTIMICROBIAL-RESISTANT P. AERUGINOSA BACTEREMIA 307

202), and the overall 30-day mortality rate was 25.2% (51/202). No significant difference was found between patientswho received initial inappropriate antimicrobial therapy andthose who received appropriate therapy (26.2% [32/122] vs.23.8% [19/80], p¼ 0.692). The 30-day mortality rates, whenstratified according to intervals of 24, 48, 72, and 96 hoursbetween the time of acquisition of blood samples and thetime of initiation of appropriate antimicrobial therapy, werenot significantly different between the respective intervals.By univariate analysis, the factors associated with mortalitywere corticosteroid use, nosocomial acquisition, poly-microbial infections, an increase in Pitt bacteremia score andCharlson’s WCI, ICU care, presentation with severe sepsis orseptic shock, having pneumonia, and having endotrachealtubes, urinary catheters, or central venous catheters (allp< 0.05; Table 3). Multivariate analysis using a logistic re-gression model that included the variables associated withmortality by univariate analysis ( p< 0.05) showed that thesignificant risk factors for mortality were corticosteroid use,nosocomial acquisition, polymicrobial infection, an increas-ing Charlson’s WCI, and ICU care (Table 3).

When the impact of the respective antimicrobial resis-tances on mortality was assessed, ceftazidime, piperacillin,and imipenem resistances were associated with mortality inthe univariate analysis (Table 4). A multivariate analysisshowed that ceftazidime and imipenem resistances remainedsignificant factors associated with mortality after adjustment

for other variables that were found to be risk factors formortality (OR, 2.96; 95% CI, 1.20–7.31; and OR, 2.74; 95% CI,1.02–7.31, respectively) (Table 4).

Clinical outcome of antimicrobial-resistantP. aeruginosa bacteremia

When the initial clinical response to treatment was as-sessed, patients with antimicrobial-resistant bacteremia hadhigher clinical failure rates than those with antimicrobial-susceptible bacteremia, regardless of the type of antimicro-bial resistance (all p< 0.05; Table 5). With the exception offluoroquinolone resistance and aminoglycoside resistance,the 30-day mortality rate was higher, and the duration ofhospital stay was longer in the resistant group than in thesusceptible group (Table 5).

Discussion

Our study has provided a comprehensive evaluation ofthe clinical impact of antimicrobial resistance on the outcomeof patients with P. aeruginosa bacteremia. The mortality as-sociated with P. aeruginosa bacteremia with reduced sus-ceptibility to ceftazidime, piperacillin, or imipenem wassignificantly higher than that associated with susceptiblebacteremia in this study. As the underlying illness in theresistant group was more severe than in the susceptiblegroup, it may be presumed that bacteremia by antimicrobial-resistant bacteremia has a worse prognosis because of themore severe underlying illness. However, after adjusting forother prognostic factors associated with mortality, ceftazi-dime resistance and imipenem resistance were identified asindependent risk factors for mortality in our study of pa-tients with P. aeruginosa bacteremia. Our findings were alsoin accordance with a previous study which reported thatfluoroquinolone resistance was not an independent riskfactor for mortality even though fluoroquinolone-resistant P.aeruginosa was associated with increased hospital charges;rather, other resistance patterns, such as imipenem resis-tance, had a more significant impact on mortality.5

It is presumed that infection with antimicrobial-resistantP. aeruginosa results in higher mortality, longer hospitaliza-tions, and greater costs than infection with susceptiblestrains. Although several studies have described highermortality rates in infections caused by antimicrobial-resistantGram-negative bacilli, the causal link between antimicrobialresistance and fatal bacteremia remains unclear. In previousstudies that focused on clinical impact of antimicrobial re-sistance of P. aeruginosa, it was found that resistance to imi-penem, multidrug or piperacillin/tazobactam, adverselyaffected the outcome in patient with P. aeruginosa bacteremiaalike with our findings.1,15,23,27 Even though well-designed,large-population studies have already addressed the riskfactors associated with P. aeruginosa bloodstream infection,the main purpos of these studies was identification of factorsfor development of P. aeruginosa bacteremia or the evaluationof the adverse impact of inappropriate therapy on outcomein P. aeruginosa infection, rather than focusing on impact ofantimicrobial resistance.9,21 In our study, we aimed to eval-uate the impact of respective antimicrobial resistance onmortality in P. aeruginosa infection, and identified that cef-tazidime and imipenem resistance adversely affects theoutcome in patients with P. aeruginosa bacteremia. One

Table 2. Independent Risk Factors Associated

with the Respective Antimicrobial Resistances

in Pseudomonas aeruginosa Bacteremia

VariablesAdjusted OR

(95% CI) p

Resistance to ceftazidime (n¼ 74)Prior receipt of penicillins 2.25 (1.06–4.75) 0.034Prior receipt of fluoroquinolones 3.13 (1.32–7.38) 0.009Indwelling urinary catheter 2.52 (1.06–6.00) 0.037Percutaneous catheterization 2.99 (1.32–6.78) 0.009Invasive procedure within

previous 72 hours2.56 (1.21–5.42) 0.014

Resistance to piperacillin (n¼ 45)Prior receipt fluoroquinolones 2.16 (0.87–5.36) 0.096Indwelling urinary catheter 2.43 (1.02–5.77) 0.045

Resistance to imipenem (n¼ 46)Prior receipt carbapenems 2.87 (1.26–6.56) 0.012Prior receipt of fluoroquinolones 2.54 (1.08–5.96) 0.033Prior receipt of aminoglycosides 3.60 (1.39–7.31) 0.025Indwelling urinary catheter 3.19 (1.39–7.31) 0.006

Multidrug resistance (n¼ 42)Prior receipt of fluoroquinolones 3.01 (1.29–7.01) 0.011Indwelling urinary catheter 4.28 (1.14–5.53) 0.001Percutaneous catheterization 2.51 (1.14–5.53) 0.023

Resistance to fluoroquinolones (n¼ 48)Prior receipt of fluoroquinolones 4.45 (1.95–10.14) <0.001Indwelling urinary catheter 2.68 (1.19–6.06) 0.018Invasive procedure within

previous 72 hours2.12 (1.02–4.38) 0.043

Resistance to aminoglycosides (n¼ 36)Prior receipt of fluoroquinolones 3.40 (1.42–8.13) 0.006Indwelling urinary catheter 4.09 (1.74–9.60) 0.001Percutaneous catheterization 2.56 (1.12–5.87) 0.026

OR, odds ratio, CI, confidential interval.

308 JOO ET AL.

challenge in our study was how to adjust adequately for theseverity of underlying illness in quantifying the difference inoutcomes between patients with infections caused by sus-ceptible versus resistant organisms. To control for the in-herent biases due to clinical heterogeneity between patientsin the resistant and susceptible groups, we used multivariatelogistic regression analysis to determine the factors associ-ated with 30-day mortality. As expected, we found signifi-cant differences between patients with resistant andsusceptible infections when the resistance was stratified ac-cording to the respective type of antimicrobials, and showed

that antimicrobial-resistant P. aeruginosa infection itself wasindependently associated with poorer outcome than wassusceptible one. For more comprehensive evaluation of exactimpact of antimicrobial resistance on the outcome in patientswith P. aeruginosa infection, further large-scale case–controlstudy is needed by matching with similar severity of illness.

Inappropriateness of empirical therapy has been found tobe the strong prognostic factor for mortality in P. aeruginosabacteremia, even after adjustment for severity of illness andunderlying conditions, emphasizing the importance of ap-propriate antimicrobial therapy.9,10,26 Contrary to findings of

Table 3. Factors Associated with 30-day Mortality in Patients with Pseudomonas aeruginosa Bacteremia

Univariate analysis Multivariate analysis

Survivor(n¼ 151)

Nonsurvivor(n¼ 51)

OR(95% CI) p

AdjustedOR (95% CI) p-value

Age (mean years� SD) 56� 16 56� 16 56� 16 0.210Male/female 99/52 28/23 0.64 (0.34–1.22) 0.173Comorbid conditions

Prior hospitalization within 90 days 96 (63.6) 32 (62.7) 0.97 (0.50–1.96) 0.915Receipt of immunosuppressants 78 (51.7) 31 (60.8) 1.45 (0.76–2.77) 0.258Receipt of corticosteroid 58 (38.4) 36 (70.6) 3.85 (1.94–7.64) <0.001 4.01 (1.15–13.94) 0.029Recent operation within a year 38 (25.2) 16 (31.4) 1.36 (0.68–2.73) 0.387Solid organ transplantation 19 (12.6) 9 (17.6) 1.49 (0.63–3.54) 0.366Intubation 3 (2.0) 10 (19.6) 12.03 (3.16–45.76) <0.001Indwelling urinary catheter 19 (12.6) 16 (31.4) 3.18 (1.48–6.81) 0.002Central venous catheterization 60 (39.7) 30 (58.8) 2.17 (1.14–4.13) 0.018Percutaneous catheterizations 32 (21.2) 15 (29.4) 1.55 (0.76–3.18) 0.230Invasive procedure within 72 hours 62 (41.1) 18 (35.3) 0.78 (0.41–1.51) 0.467Neutropenia 61 (40.4) 20 (39.2) 0.95 (0.50–1.82) 0.882Polymicrobial infection 13 (8.6) 15 (29.4) 4.42 (1.93–10.13) <0.001 3.52 (1.13–11.01) 0.030Nosocomial acquisition 81 (53.6) 42 (82.4) 4.03 (1.83–8.87) <0.001 5.01 (1.39–17.99) 0.014Appropriateness of empirical therapy 90 (59.4) 32 (62.7) 0.88 (0.46–1.69) 0.692

Severity of illnessPitt bacteremia score (mean� SD) 1.18� 1.46 4.55� 3.63 1.69 (1.42–2.00) <0.001Charlson’s WIC (mean� SD) 4.23� 2.58 5.33� 2.92 1.16 (1.03–1.30) 0.013 1.31 (1.04–1.65) 0.023ICU admission 17 (11.3) 33 (64.7) 14.45 (6.73–31.04) <0.001 3.84 (1.17–12.60) 0.027Severe sepsis or septic shock 45 (29.4) 43 (84.3) 12.66 (5.51–29.08) <0.001

Site of infectionPrimary bacteremia 34 (22.5) 10 (19.6) 0.84 (0.38–1.85) 0.663Intra-abdominal infection 67 (44.4) 17 (33.3) 0.63 (0.32–1.22) 0.167Respiratory tract infection 14 (9.3) 16 (31.4) 4.47 (2.00–10.03) <0.001Catheter-related infection 16 (10.6) 3 (5.9) 0.53 (0.14–1.89) 0.413Urinary tract infection 17 (11.3) 1 (2.0) 0.16 (0.02–1.22) 0.048Skin and soft tissue infection 3 (2.0) 4 (7.8) 4.20 (0.91–19.44) 0.069

WIC, weighted index of co-morbidity.

Table 4. Impact of the Respective Antimicrobial Resistances on Mortality

in Pseudomonas aeruginosa Bacteremia

R to Ceftazidime(n¼ 74)

R to Piperacillin(n¼ 45)

R to Imipenem(n¼ 46)

MDR(n¼ 42)

R to FQ(n¼ 48)

OR (95% CI) p OR (95% CI) p OR (95% CI) p OR (95% CI) p OR (95% CI) p

Overall 2.78 (1.45–5.33) 0.002 2.20 (1.08–4.48) 0.028 2.40 (1.18–4.86) 0.014 2.20 (1.06–4.55) 0.031 1.94 (0.96–3.91) 0.063Adjusteda 3.35 (1.38–8.10) 0.007 1.77 (0.66–4.74) 0.257 2.74 (1.02–7.37) 0.046 2.24 (0.80–6.29) 0.126 1.76 (0.65–4.74) 0.263

aAdjusted for corticosteroid use, nosocomial acquisition, polymicrobial infection, Charlson’s weighted index of co-morbidity, andadmission to ICUs.

No., number; R, resistance; FQ, fluoroquinolones.

ANTIMICROBIAL-RESISTANT P. AERUGINOSA BACTEREMIA 309

previous studies, we could not find the adverse impact ofinappropriate therapy on mortality in P. aeruginosa bacter-emia. It might result from the fact that the outcomes of in-fections may be dependent on the primary site of infection,and the virulence of the pathogens.7,12 Similarly, the impactof antimicrobial resistance on outcome might depend onthe severity of underlying disease and the primary site ofinfection.

Our data showed that prior receipt of fluoroquinolonesand an indwelling urinary catheter were significant risk fac-tors for antimicrobial resistance to various anti-pseudomonalantibiotics. Several studies have already provided the riskfactors for antimicrobial-resistant P. aeruginosa infection, butmainly focused on imipenem resistance or multidrug resis-tance.2,8,15,20,28 In our study, we evaluated the risk factors forrespective antimicrobial resistance and found the associationof fluoroquinolone and indwelling urinary catheters with alltypes of antimicrobial resistance. Alike with our findings, aprevious study also showed that P. aeruginosa bacteremicisolates from patients who have been exposed to ciproflox-acin during the 30 days before the development of bacter-emia had an increased risk of being resistant to ceftazidime,imipenem, meropenem, piperacillin-tazobactam, or cipro-floxacin.18 This result, regarding risk factors associated withantimicrobial resistance, has significant clinical implicationsfor the utility of fluoroquinolone, which might result in highlevels of cross-resistance to other antibiotics. To reduce thefrequency of P. aeruginosa bacteremia due to antimicrobial-resistant organisms, it would be important to administerfluoroquinolone prudently and minimize invasive proce-dures, including the insertion of urinary catheters or percu-taneous catheterization if possible.11

It is known that ceftazidime and piperacillin share thesame resistance mechanisms of P. aeruginosa carrying an in-ducible AmpC cephalosporinase. The resistance rate of cef-tazidime (36.6%) in our study, however, was much higherthan that of piperacillin (22.3%), suggesting the existence ofdifferent resistance mechanisms. Whereas resistance to the b-lactams emerges as a result of AmpC overproduction, a de-finitive relationship between P. aeruginosa AmpC and certainb-lactams remains unknown. It is notable that our studypopulation has received cephalosporin more frequentlywithin 90 days before P. aeruginosa bacteremia than havepenicillin (65% vs. 26.7%). Given the ability of resistant P.aeruginosa to emerge during the course of therapy, the pre-vious prolonged exposure to cephalosporin could play a roleof higher resistance of ceftazidime than that of piperacillin,combined with the variability in the hydrolytic activity ofAmpC from P. aeruginosa to both antibiotics.16 Interestingly,the resistance of fluoroquinolone (23.8%) was quite lowerthan that of ceftazidime in our data. It might result frommore frequent use of cephalosporin than that of fluor-oquinolone.

Our study had several limitations. First, the retrospectivenature of this study may preclude accurate comparisons. Theresults of clear-up of P. aeruginosa from the blood were notavailable in many patients, which would be a very helpfulclinical factor on mortality. Further, any hidden bias that wasnot adjusted for in our cohort may lead to underestimation oroverestimation of the true relationship between antimicrobialresistance and mortality, even though we performed multi-variate logistic analysis to control for other confoundingfactors. Second, although information concerning in-hospitalantibiotic use was available from the medical records, the

Table 5. Clinical Outcome of Antimicrobial-Resistant Pseudomonas aeruginosa Bacteremia

Resistant group Susceptible group p

CeftazidimeClinical failure 52/74 (70.3) 52/128 (40.6) 0.00030-day mortality 28/74 (37.8) 23/128 (18.0) 0.002Hospital stay, median day (IQR)a 23 (14–41) 15 (9–30) 0.023

PiperacillinClinical failure 33/45 (73.3) 71/157 (45.2) 0.00130-day mortality 17/45 (37.8) 34/157 (21.7) 0.028Hospital stay, median day (IQR)a 25 (14–48) 16 (10–30) 0.018

ImipenemClinical failure 37/46 (80.4) 67/156 (42.9) 0.00030-day mortality 18/46 (39.1) 33/156 (21.2) 0.014Hospital stay, median day (IQR)a 26 (14–42) 16 (9–29) 0.016

MDRClinical failure 32/42 (76.2) 72/160 (45.0) 0.00030-day mortality 16/42 (38.1) 35/160 (21.9) 0.031Hospital stay, median day (IQR)a 25 (13–38) 16 (10–31) 0.102

FluoroquinoloneClinical failure 33/48 (68.8) 71/154 (46.1) 0.00630-day mortality 17/48 (35.4) 34/154 (22.1) 0.063Hospital stay, median day (IQR)a 21 (14–35) 16 (9–22) 0.106

AminoglycosidesClinical failure 25/36 (69.4) 79/166 (47.6) 0.01730-day mortality 9/36 (25.0) 42/166 (25.3) 0.970Hospital stay, median day (IQR)a 21 (11–36) 17 (10–31) 0.457

Data are presented as no. of events/no. of patients (%), unless otherwise indicated.aThe patients who died within 30 days after bacteremia were excluded in the calculation of hospital stay, and Mann–Whitney test was used

for the comparison.

310 JOO ET AL.

assessment of the use of antibiotics outside the hospital maynot be accurate. Third, we reported susceptibility as a cate-gorical variable, based on medical records provided byVITEK II automated system. Since P. aeruginosa blood iso-lates were not available at the time of initiation of our study,it was impossible to perform confirmative tests for identifi-cation and susceptibility of P. aeruginosa to antimicrobialagents. Similarly, the presence of resistance mechanismswas not able to be investigated either, especially in imipe-nem-resistant pathogens, which were usually mediated withmetallo-b-Lactamase production.14 Finally, our study wasconducted in a large referral center. Thus, many of our pa-tients had serious underlying illnesses, and these data mightnot be generalizable to other institutes, particularly com-munity hospitals.

In conclusion, antimicrobial resistance, especially ceftazi-dime resistance and imipenem resistance, adversely affectedoutcome in patients with P. aeruginosa bacteremia, althoughfluoroquinolone resistance was not associated with adverseoutcome. To our knowledge, this is the largest study to as-sess the impact of antimicrobial resistance on outcome inpatients with P. aeruginosa bacteremia after adjustment forhost variables.

Acknowledgments

This study was supported by a grant from the KoreanHealth 21 R&D Project Ministry of Health, Welfare, & FamilyAffairs, Republic of Korea (Grant No. A084063).

Disclosure Statement

No competing financial interests exit.

References

1. Aloush, V., S. Navon-Venezia, Y. Seigman-Igra, S. Cabili,

and Y. Carmeli. 2006. Multidrug-resistant Pseudomonas aer-uginosa: risk factors and clinical impact. Antimicrob. AgentsChemother. 50:43–48.

2. Cao, B., H. Wang, H. Sun, Y. Zhu, and M. Chen. 2004. Riskfactors and clinical outcomes of nosocomial multi-drug re-sistant Pseudomonas aeruginosa infections. J. Hosp. Infect.57:112–118.

3. Falagas, M.E., and D.E. Karageorgopoulos. 2008. Pandrugresistance (PDR), extensive drug resistance (XDR), andmultidrug resistance (MDR) among Gram-negative bacilli:need for international harmonization in terminology. Clin.Infect. Dis. 46:1121–1122; author reply 1122.

4. Friedman, N.D., K.S. Kaye, J.E. Stout, S.A. McGarry, S.L.

Trivette, J.P. Briggs, W. Lamm, C. Clark, J. MacFarquhar,

A.L. Walton, L.B. Reller, and D.J. Sexton. 2002. Healthcare—associated bloodstream infections in adults: a reasonto change the accepted definition of community-acquiredinfections. Ann. Intern. Med. 137:791–797.

5. Gasink, L.B., N.O. Fishman, M.G. Weiner, I. Nachamkin,

W.B. Bilker, and E. Lautenbach. 2006. Fluoroquinolone-resistant Pseudomonas aeruginosa: assessment of risk factorsand clinical impact. Am. J. Med. 119:526.e519–525.

6. Gaynes, R., and J.R. Edwards. 2005. Overview of nosoco-mial infections caused by gram-negative bacilli. Clin. Infect.Dis. 41:848–854.

7. Harbarth, S., V. Nobre, and D. Pittet. 2007. Does antibioticselection impact patient outcome? Clin. Infect. Dis. 44:87–93.

8. Harris, A.D., D. Smith, J.A. Johnson, D.D. Bradham, and

M.C. Roghmann. 2002. Risk factors for imipenem-resistantPseudomonas aeruginosa among hospitalized patients. Clin.Infect. Dis. 34:340–345.

9. Kang, C.I., S.H. Kim, H.B. Kim, S.W. Park, Y.J. Choe, M.D.

Oh, E.C. Kim, and K.W. Choe. 2003. Pseudomonas aeruginosabacteremia: risk factors for mortality and influence of de-layed receipt of effective antimicrobial therapy on clinicaloutcome. Clin. Infect. Dis. 37:745–751.

10. Kang, C.I., S.H. Kim, W.B. Park, K.D. Lee, H.B. Kim, E.C.

Kim, M.D. Oh, and K.W. Choe. 2005. Bloodstream infec-tions caused by antibiotic-resistant gram-negative bacilli:risk factors for mortality and impact of inappropriate initialantimicrobial therapy on outcome. Antimicrob. AgentsChemother. 49:760–766.

11. Kang, C.I., S.H. Kim, W.B. Park, K.D. Lee, H.B. Kim, E.C.

Kim, M.D. Oh, and K.W. Choe. 2005. Risk factors for an-timicrobial resistance and influence of resistance on mor-tality in patients with bloodstream infection caused byPseudomonas aeruginosa. Microb. Drug Resist. 11:68–74.

12. Kim, S.H., W.B. Park, K.D. Lee, C.I. Kang, H.B. Kim,

M.D. Oh, E.C. Kim, and K.W. Choe. 2003. Outcome ofStaphylococcus aureus bacteremia in patients with eradica-ble foci versus noneradicable foci. Clin. Infect. Dis. 37:794–799.

13. Kollef, M.H. 2000. Inadequate antimicrobial treatment: animportant determinant of outcome for hospitalized patients.Clin. Infect. Dis. 31 Suppl 4:S131–S138.

14. Laupland, K.B., M.D. Parkins, D.L. Church, D.B. Gregson,

T.J. Louie, J.M. Conly, S. Elsayed, and J.D. Pitout. 2005.Population-based epidemiological study of infections causedby carbapenem-resistant Pseudomonas aeruginosa in the Cal-gary Health Region: importance of metallo-beta-lactamase(MBL)-producing strains. J. Infect. Dis. 192:1606–1612.

15. Lautenbach, E., M. Synnestvedt, M.G. Weiner, W.B. Bilk-

er, L. Vo, J. Schein, and M. Kim. 2010. Imipenem resistancein Pseudomonas aeruginosa: emergence, epidemiology, andimpact on clinical and economic outcomes. Infect. ControlHosp. Epidemiol. 31:47–53.

16. Lister, P.D., D.J. Wolter, and N.D. Hanson. 2009. Anti-bacterial-resistant Pseudomonas aeruginosa: clinical impactand complex regulation of chromosomally encoded resis-tance mechanisms. Clin. Microbiol. Rev. 22:582–610.

17. Lodise, T.P., Jr., N. Patel, A. Kwa, J. Graves, J.P. Furuno, E.

Graffunder, B. Lomaestro, and J.C. McGregor. 2007. Pre-dictors of 30-day mortality among patients with Pseudomo-nas aeruginosa bloodstream infections: impact of delayedappropriate antibiotic selection. Antimicrob. Agents Che-mother. 51:3510–3515.

18. Lopez-Dupla, M., J.A. Martinez, F. Vidal, M. Almela, A.

Soriano, F. Marco, J. Lopez, M. Olona, and J. Mensa. 2009.Previous ciprofloxacin exposure is associated with resistanceto beta-lactam antibiotics in subsequent Pseudomonas aeru-ginosa bacteremic isolates. Am. J. Infect. Control 37:753–758.

19. McDonald, J.R., N.D. Friedman, J.E. Stout, D.J. Sexton, and

K.S. Kaye. 2005. Risk factors for ineffective therapy in pa-tients with bloodstream infection. Arch. Intern. Med.165:308–313.

20. Onguru, P., A. Erbay, H. Bodur, G. Baran, E. Akinci, N.

Balaban, and M.A. Cevik. 2008. Imipenem-resistant Pseu-domonas aeruginosa: risk factors for nosocomial infections.J. Korean Med. Sci. 23:982–987.

21. Parkins, M.D., D.B. Gregson, J.D. Pitout, T. Ross, and K.B.

Laupland. 2010. Population-based study of the epidemiology

ANTIMICROBIAL-RESISTANT P. AERUGINOSA BACTEREMIA 311

and the risk factors for Pseudomonas aeruginosa bloodstreaminfection. Infection 38:25–32.

22. Paterson, D.L., and Y. Doi. 2007. A step closer to extremedrug resistance (XDR) in gram-negative bacilli. Clin. Infect.Dis. 45:1179–1181.

23. Raymond, D.P., S.J. Pelletier, T.D. Crabtree, H.L. Evans,

T.L. Pruett, and R.G. Sawyer. 2003. Impact of antibiotic-resistant Gram-negative bacilli infections on outcome inhospitalized patients. Crit. Care Med. 31:1035–1041.

24. Suarez, C., C. Pena, L. Gavalda, F. Tubau, A. Manzur, M.A.

Dominguez, M. Pujol, F. Gudiol, and J. Ariza. 2010. In-fluence of carbapenem resistance on mortality and the dy-namics of mortality in Pseudomonas aeruginosa bloodstreaminfection. Int. J. Infect. Dis. 14 Suppl 3:e73–e78.

25. Suarez, C., C. Pena, F. Tubau, L. Gavalda, A. Manzur, M.A.

Dominguez, M. Pujol, F. Gudiol, and J. Ariza. 2009. Clin-ical impact of imipenem-resistant Pseudomonas aeruginosabloodstream infections. J. Infect. 58:285–290.

26. Tam, V.H., E.A. Gamez, J.S. Weston, L.N. Gerard, M.T.

Larocco, J.P. Caeiro, L.O. Gentry, and K.W. Garey. 2008.Outcomes of bacteremia due to Pseudomonas aeruginosa withreduced susceptibility to piperacillin-tazobactam: implications

on the appropriateness of the resistance breakpoint. Clin.Infect. Dis. 46:862–867.

27. Tam, V.H., C.A. Rogers, K.T. Chang, J.S. Weston, J.P.

Caeiro, and K.W. Garey. 2010. Impact of multidrug-resistant Pseudomonas aeruginosa bacteremia on patient out-comes. Antimicrob. Agents Chemother. 54:3717–3722.

28. Troillet, N., M.H. Samore, and Y. Carmeli. 1997. Imipenem-resistant Pseudomonas aeruginosa: risk factors and antibioticsusceptibility patterns. Clin. Infect. Dis. 25:1094–1098.

Address correspondence to:Cheol-In Kang, M.D.

Division of Infectious DiseasesSamsung Medical Center

Sungkyunkwan University School of Medicine50 Irwon-dong

Gangnam-guSeoul 135-710

Republic of Korea

E-mail: cikang@skku.edu; collacin@hotmail.com

312 JOO ET AL.

Reproduced with permission of the copyright owner. Further reproduction prohibited without permission.