Impact of Extended-Spectrum Beta-Lactamase on Acute Pyelonephritis Treated with Empirical Ceftriaxone

Abstract

Background: Ceftriaxone is frequently administered empirically for hospitalized patients with acute pyelonephritis (APN) due to prevalent quinolone resistance in our hospital; however, its use is inappropriate for extended-spectrum beta-lactamase (ESBL)-producing Escherichia coli, an increasing problem. Methods: A retrospective, 1:2 matched cohort study was performed to evaluate the impact of ESBL on APN treated with empirical ceftriaxone. Each patient in ESBL group was matched with two patients in the non-ESBL group, using a 16-point scoring system, which included age, sex, bacteremia, simplified acute physiology score 2, Charlson comorbidity index and APN severity score. Results: From 2009 to 2011, among 1,322 community-onset cases of the E. coli bacteriuria with 212 (16%) ESBL producers, 261 patients with APN were treated empirically with ceftriaxone in a secondary care hospital. Among these 261 cases, twenty-six patients in the ESBL group and 52 matched patients in the non-ESBL group (1:2) were included. Mean time to defervescence was 4.6±2.2 days in the ESBL group and 2.6±1.3 days in the non-ESBL group (p<0.01). Rate of microbiological resolution within 5 days after antibiotic treatment was 77% (17/22) in the ESBL group and 100% (45/45) in the non-ESBL group (p=0.01). The duration of hospitalization was 13.3±8.2 days in the ESBL group and 7.3±3.5 days in the non-ESBL group (p<0.01). No patient died in either group. Conclusion: Empirical ceftriaxone therapy for APN caused by ESBL-producing E. coli is inappropriate, and consequently can delay recovery and result in longer hospitalization.

Introduction

Acute pyelonephritis (APN) is an important community-onset infection and a practice guideline recommends empirical ceftriaxone as one of the treatments for APN, where the prevalence of fluoroquinolone resistance exceeds 10%.⁶ Because Escherichia coli comprises 88%–92% of causative organisms and its resistant rate to ciprofloxacin is ∼15% in community-onset APN,¹⁰ ceftriaxone is recommended as one of the empirical antibiotics for this infection in South Korea.^21,30 From January 2009 to December 2011, ceftriaxone was administered empirically to 84% (261/312) of the patients with community-onset APN in our hospital (Fig. 1).

FIG. 1.

Flow diagram of the study. APN, acute pyelonephritis.

Antimicrobial resistance of E. coli, the predominant uropathogen, is problematic. Recently, extended-spectrum beta-lactamase (ESBL)-producing E. coli have spread globally even in the community.^22,24,25 Several studies evaluated the impact of ESBL on the outcomes of bloodstream infections derived from various primary sites and revealed that infection with ESBL-producing organisms delayed appropriate therapy and caused more fatal outcomes.^16,28,29 However, the impact of both ESBL and inappropriate antibiotics on the outcomes in APN has not been evaluated.

We performed this study to evaluate the impact of ESBL on the clinical outcomes of APN treated with empirical ceftriaxone, which was inappropriate for ESBL-producing organisms.

Materials and Methods

Study design

A retrospective, 1:2 matched cohort study was performed in a 750-bed secondary care hospital (Daegu, South Korea). All patients whose urine culture were requested on the first day of hospitalization and yielded E. coli between January 2009 and December 2011 were identified from microbiology records. Those that met the following criteria were included: (1) body temperature on admission >38°C, (2) imaging study consistent with APN and (3) the initial empirical antibiotic was ceftriaxone. The ESBL group included patients with APN due to ESBL-producing E. coli, while the non-ESBL group comprised those with APN due to non-ESBL-producing E. coli. Detection of ESBL producer was performed on the VITEK II, automated system (bioMérieux, Durham, NC).

Medical records, laboratory data, and image findings were reviewed retrospectively. The Charlson comorbidity index (CCI) was used to classify the severity of underlying diseases.² The simplified acute physiology score 2 (SAPS II) was used to classify acute physiologic status of the illness.⁴ The modified APN score was used to classify the anatomical findings and severity of pyelonephritis.¹⁵ A radiologist, who was blinded for diagnosis and clinical data, reviewed the CT findings and graded the severity of the pyelonephritis.

The main outcome measures were time to defervescence, necessity of intensive care unit (ICU) stay, and mortality. Microbiological responses, clinical responses, and hospital stay of both groups were also compared.

The Institutional Review Board at Daegu Fatima Hospital approved the study protocol.

Definitions

The cases were considered to be healthcare associated infections if patients had been hospitalized for ≥2 days in the preceding 90 days, resided in a nursing home or extended care facility, received chronic hemodialysis or home wound care within 30 days.^5,7

The appropriate antibiotic treatment was defined as administering susceptible antibiotic on in vitro susceptibility test. The patients were considered to be microbiologically responded if their follow-up urine culture were converted to negative. To compare extent of infections and anatomical findings, we used the modified APN score. The APN score was a diagnostic score based on nine reproducible criteria (abscess, pyonephrosis, pelvicalyceal air, poor excretion of contrast, obliteration of renal sinus, global renal enlargement, tachycardia or hypotension, persistent fever or pyuria, and diabetes). Kim et al. weighted each factor which affected on severity of infection through a statistical model.¹⁵ We used six image variables derived from CT findings.

Matching process

Each patient with APN due to ESBL-producing E. coli (case) was matched to two patients with APN due to non-ESBL-producing E. coli (controls) on the following variables: bacteremia, age, sex, CCI for underlying illness, SAPS II, and modified APN score. To select the most closely matched controls, a 16-point scoring system was used, similar to that described elsewhere:^8,14 matching for presence or absence of bacteremia; for age (3 points if age difference was ≤5 years, 2 points if age difference was 6–10 years, and no point if age difference was >10 years); for sex (2 points if concordant, no point if discordant); for CCI (5 points if concordant, 4 points if CCI difference was 1, 3 points if CCI difference was 2, and no point if CCI difference was ≥3); for SAPS II (3 points if SAPS II difference was ≤5, 2 points if SAPS II difference was 6–10, and no point if SAPS II difference was >10); for APN score (3 points if APN score difference was ≤5, 2 points if the score difference was 6–10, and no point if the score difference was >10). If more than two control patients had the same point score, two of them were selected randomly without knowing patients outcomes.

Statistical analysis

SPSS software, version 18.0 (SPSS, Chicago, IL) was used for all statistical analyses. Multivariate logistic regression analysis was used to evaluate the risk factors for ESBL. Fisher's exact test or Pearson χ² test was used as appropriate to compare categorical variables, and continuous variables were compared using the Student's t test. For the matched case-control study, we used McNemar's test to compare categorical variables and the paired t-test for continuous variables. Time to defervescence was compared in survival analysis using a Kaplan-Meier curve. All the tests of significance were two-tailed; p<0.05 was considered to be significant.

Results

Clinical characteristics and risk factors for ESBL

From January 2009 to December 2011, 1,322 cases of community-onset E. coli bacteriuria were detected of which 212 (16%) were ESBL positive. Among the 1,322 cases of E. coli bacteriuria, 182 met the inclusion criteria (Fig. 1). The clinical characteristics of these 182 patients with APN, treated with empirical ceftriaxone are shown in Table 1. An ESBL-producing E. coli was isolated from the urine of the 26 (14.3%) cases. In univariate analysis, healthcare-association, high BUN, and high SAPS II score were significant risk factor for ESBL (Table 2). In the multivariable analysis, that included the variables, which were p-value≤0.2 in univariate analysis, healthcare-association was the only significant risk factor for ESBL (adjusted odds ratio [aOR] 5.1; 95% CI, 1.3–20.3; p=0.02, Table 2).

Table 1.

Clinical Characteristics of the 182 Enrolled Patients

Characteristics	ESBL group (n=26)	Non-ESBL group (n=156)	p-Value
Age (years, mean±SD)	68±12	61±16	0.02
Male	4 (15)	9 (6)	0.10
Healthcare-associated infection	6 (23)	10 (6)	0.01
Previous UTI within 1 year	2 (8)	12 (8)	>0.99
SAPS II score (mean±SD)	26±7	22±9	0.06
Underlying diseases
Urologic abnormality	5 (19)	13 (8)	0.15
Diabetes	8 (31)	57 (37)	0.57
Solid tumor	2 (8)	3 (2)	0.15
Neurologic disorder	3 (12)	20 (13)	>0.99
Liver cirrhosis	0 (0)	3 (2)	>0.99
Cardiovascular disease	4 (15)	16 (10)	0.50
High CCI (≥3)	4 (15)	16 (10)	0.50
Bacteremia	6 (23)	40 (26)	0.78
Abnormality on CT scan^a
Abscess	5 (23)	17 (12)	0.17
Pyonephrosis	2 (11)	16 (11)	>0.99
Obliteration of renal sinus	1 (5)	27 (19)	0.13
Global renal enlargement	10 (48)	49 (35)	0.24
Poor excretion of contrast	2 (17)	9 (8)	0.30
Modified APN score (mean±SD)	10.48±12	8.91±13	0.59

Data are no. (%) of patients, unless otherwise indicated.

This analysis included 164 patients (22 in the ESBL group and 142 in the non-ESBL group); 18 patients who had an ultrasonogram image consistent with APN, but no CT results were excluded.

APN, acute pyelonephritis; ESBL, extended-spectrum beta-lactamase; CCI, Charlson comorbidity index; SAPS II, simplified acute physiology score 2.

Table 2.

Multivariable Logistic Regression Analysis of Risk Factors for ESBL

	Univariate analysis		Multivariate analysis
Risk factors	OR (95% CI)	p-Value	aOR (95% CI)	p-Value
Old age	2.4 (1.0–6.0)	0.06	1.2 (0.4–3.9)	0.80
Male	3.0 (0.8–10.8)	0.10	2.0 (0.3–13.3)	0.46
Healthcare-associated infection	4.4 (1.4–13.4)	<0.01	5.1 (1.3–20.3)	0.02
Urologic abnormality	2.6 (0.8–8.1)	0.15	1.1 (0.2–6.7)	0.92
Solid tumor	4.3 (0.7–26.8)	0.15	1.6 (0.1–34.7)	0.77
High BUN	3.6 (1.5–8.5)	<0.01	3.0 (0.9–10.3)	0.09
High SAPS II score	3.6 (1.5–8.4)	<0.01	1.3 (0.4–4.6)	0.64
High APN score	1.9 (0.8–4.3)	0.13	1.3 (0.2–6.9)	0.79

One hundred eighty-two patients (26 in the ESBL group and 156 in the non-ESBL group) were included in this analysis.

Bold values indicate statistically significant variables in multivariable analysis.

CI, confidence interval; OR, odds ratio; aOR, adjusted odds ratio.

Matched cohort study

On the 16-point matching scale, the 52 controls had a mean score of 15 (SD±1.1, range 12–16). The clinical characteristics of the 26 cases of the ESBL group were similar to those of the 52 matched controls of the non-ESBL group (Table 3). No emphysematous pyelonephritis case was included. Antimicrobial susceptibility to amikacin, fluoroquinolone, ceftriaxone, cefepime, piperacillin/tazobactam (TZP), and imipenem were 88.5%, 50%, 0%, 53.8%, 88.5%, and 100%, respectively, in the ESBL group; 100%, 94.2%, 100%, 100%, 96.2%, and 100%, respectively, in the non-ESBL group. The ESBL group was significantly more resistant to amikacin, fluoroquinolone, ceftriaxone, cefepime than was the non-ESBL group (Table 3). Empirical ceftriaxone was an appropriate antibiotic in all patients of non-ESBL group. In the ESBL group, empirical ceftriaxone was replaced with ertapenem (80.8%) or fluoroquinolone (19.2%) according to the antimicrobial susceptibility results. Mean time to the administration of an appropriate antibiotic was 4.58±1.03 days in the ESBL group. One patient in the ESBL group had a percutaneous nephrostomy due to obstruction. Mean time to defervescence was 4.6±2.2 days in the ESBL group and 2.6±1.3 days in the non-ESBL group (p<0.01). This is illustrated in Figure 2 by survival analysis using a Kaplan-Meier curve. The duration of hospital stay was 13.3±8.2 days in the ESBL group and 7.3±3.5 days in the non-ESBL group (p<0.01). Within 5 days after antibiotic treatment, 77.3% (17/22) of patients in the ESBL group and 100% (45/45) in the non-ESBL group achieved microbiological resolution (p=0.01). The frequency of ICU care was greater, 15% (4/26), in the ESBL group than in the non-ESBL group, 0% (0/52) (p=0.01, Table 3). No patient died.

FIG. 2.

Kaplan-Meyer curve of the time to defervescence between the extended-spectrum beta-lactamase (ESBL) and non-ESBL groups.

Table 3.

Comparison of Clinical Characteristics and Outcomes Between the ESBL Group and the Non-ESBL Group in the Matched Cohort Study

Characteristics	ESBL group (n=26)	Non-ESBL group (n=52)	p-Value
Age (years, mean±SD)	68±12	62±11	0.63
Male	4 (15)	5 (10)	0.25
Healthcare-associated infection	6 (23)	4 (8)	0.06
Previous UTI within 1 year	2 (8)	4 (8)	>0.99
SAPS II score (mean±SD)	26±7	26±7	0.42
High CCI (≥3)	4 (15)	5 (10)	0.45
Bacteremia	6 (23)	12 (23)	>0.99
Modified APN score (mean±SD)	10.48±12	9.29±12	0.22
Rresistance to amikacin	3 (12)	0 (0)	0.03
Resistance to fluoroquinolone	13 (50)	3 (6)	<0.01
Resistance to ceftriaxone	26 (100)	0 (0)	<0.01
Resistance to cefepime	12 (46)	0 (0)	<0.01
Outcomes
Time to defervescence (days, mean±SD)	4.6±2.2	2.6±1.3	<0.01
Hospital stay (days, mean±SD)	13.3±8.2	7.3±3.5	<0.01
ICU care during hospitalization	4 (15)	0 (0)	0.01
Microbiological response (5 days)	17/22 (77)	45/45 (100)	0.01
Mortality (2 weeks)	0 (0)	0 (0)	>0.99
Relapse (3 months)	0/16 (0)	2/32 (6)	>0.99

Data are no. (%) of patients, unless otherwise indicated.

ICU, intensive care unit.

Discussion

Studies concerning of clinical outcomes of blood stream infections due to ESBL-producing organisms demonstrated that ESBL-producing organisms were associated with poor clinical outcome;^16,29,31 however, other studies failed to demonstrate this association.^11,18 One study found that administration of inappropriate antibiotics for blood stream infections caused by ESBL-producing organisms could cause grave outcomes.²² Other studies reported use of inappropriate antibiotics for ESBL-producing organisms had no clinical implications for the outcome of community-acquired infections, such as urinary tract infections (mainly lower urinary tract infections) and wound infections.^17,25 In our opinion, these conflicts derived from the fact that previous studies included diverse clinical syndromes, underlying conditions, and levels of severity.

This study evaluated the clinical impact of ESBL on APN, one of the most frequent community-onset infections. Prior studies found that inappropriate antibiotics against ESBL-producing organisms had no clinical implications in urinary tract infections.^17,19,25 In our opinion, however, the results of these studies might be due to analyses of heterogeneous infections or because most cases were cystitis, the mildest form of urinary tract infection. Differences between the ESBL and non-ESBL groups in the severity of illness, comorbidity, virulence of organism, and anatomical complications may have distorted prior comparisons of outcomes in urinary tract infections. Our study was designed to minimize these potential confounding factors. First, we enrolled only hospitalized cases in APN caused by E. coli, thereby controlled by restriction. Second, we controlled severity of illness, comorbidity, and anatomical complications with a matched cohort design. A recent study identified image findings and clinical findings that were independently associated with treatment deterioration in patients with serious APN, weighted them according to level of association with severity, then developed and validated a scoring system, the APN score.¹⁵ To measure anatomical severity and to match the ESBL group with the non-ESBL group, we used the image components of the APN score in our matching procedure. Third, only the patients who empirically received ceftriaxone were included in this study; hence, using restriction we controlled potential confounding due variation in antibiotics.

Most patients in the ESBL group received ertapenem as their definite antibiotic. According to expert's reviews, carbapenem is the drug of choice for treating infection caused by ESBL-producing organisms.^20,22,23 Many clinicians rely on meropenem or imipenem for severe infections caused by ESBL-producing organisms.²⁷ However, ertapenem was usually used as the definite antibiotics in our hospital when causative organisms were susceptible to meropenem or imipenem. Ertapenem, which has no antimicrobial activity against Pseudomonas aeruginosa and Acinetobacter baumannii, has been shown to have good in vitro activity against ESBL-producing organisms.³ Some observational studies reported that ertapenem had appreciable efficacy for treating urinary tract infection and blood stream infection caused by ESBL-producing organisms.^1,9,27

Our study is the first to demonstrate the impact of ESBL on the clinical outcomes of APN. It could be postulated that the combination of inappropriate empirical ceftriaxone and infection with ESBL-producing E. coli resulted in persistent fever, progressions of diseases, and longer hospital stays, by this study. Therefore, we suggest that early use of appropriate antibiotics, such as carbapenem be considered if APN dose not respond to empirical antibiotics. TZP or amikacin could also be considered for clinically unresponsive cases pending the results of susceptibility testing.^12,26

Our study also showed that health care association was the risk factor of infections caused by ESBL-producing organisms in community-onset APN and it was consistent with previous studies.^7,13 Therefore, clinicians should monitor the APN patients with caution if the patients are healthcare-associated.

This study had some limitations. First, the patients were excluded if they could not afford image studies or received empirical carbapenem because of the serious conditions, such as severe sepsis or septic shock, limiting the generalizability of our study. Therefore, the impact of infection with ESBL-producing organisms on the full spectrum of APN was not evaluated because we excluded cases that were not hospitalized, those without image studies and more severe cases treated with carbapenem. Exclusion of severe cases may have limited this study's ability to detect the worst consequences, such as death, of this type of antibiotic resistance. Second, only the patients who empirically received ceftriaxone were included. Therefore, our study should be cautiously generalized to other antibiotics, such as fluoroquinlone and other β-lactams. Third, our study was a single center study and performed with retrospectively available data. Therefore, selection bias should be considered when interpreting our data.

In conclusion, empirical ceftriaxone therapy for APN caused by ESBL-producing E. coli can delay recovery and result in longer hospital stay. Therefore, when the response to empirical ceftriaxone is delayed in APN, infection with an ESBL-producing organism is likely and early use of more appropriate antibiotics should be considered.

Footnotes

Disclosure Statement

There were no conflicts of interest and no financial support for this study.

References

Bazaz

, Chapman

A.L.

, and Winstanley

T.G.

. 2010. Ertapenem administered as outpatient parenteral antibiotic therapy for urinary tract infections caused by extended-spectrum-beta-lactamase-producing Gram-negative organisms. J. Antimicrob. Chemother., 65:1510–1513.

Charlson

M.E.

, Pompei

, Ales

K.L.

, and MacKenzie

C.R.

. 1987. A new method of classifying prognostic comorbidity in longitudinal studies: development and validation. J. Chronic Dis., 40:373–383.

Collins

V.L.

, Marchaim

, Pogue

J.M.

, Moshos

, Bheemreddy

, Sunkara

, Shallal

, Chugh

, Eiseler

, Bhargava

, et al. 2012. Efficacy of ertapenem for treatment of bloodstream infections caused by extended-spectrum-beta-lactamase-producing Enterobacteriaceae. Antimicrob. Agents. Chemother., 56:2173–2177.

Cosentini

, Folli

, Cazzaniga

, Aliberti

, Piffer

, Grazioli

, Milani

, Pappalettera

, Arioli

, Tardini

, et al. 2009. Usefulness of simplified acute physiology score II in predicting mortality in patients admitted to an emergency medicine ward. Intern. Emerg. Med., 4:241–247.

Friedman

N.D.

, Kaye

K.S.

, Stout

J.E.

, McGarry

S.A.

, Trivette

S.L.

, Briggs

J.P.

, Lamm

, Clark

, MacFarquhar

, Walton

A.L.

, et al. 2002. Health care—associated bloodstream infections in adults: a reason to change the accepted definition of community-acquired infections. Ann. Intern. Med., 137:791–797.

Gupta

, Hooton

T.M.

, Naber

K.G.

, Wullt

, Colgan

, Miller

L.G.

, Moran

G.J.

, Nicolle

L.E.

, Raz

, Schaeffer

A.J.

, et al. 2011. International clinical practice guidelines for the treatment of acute uncomplicated cystitis and pyelonephritis in women: A 2010 update by the Infectious Diseases Society of America and the European Society for Microbiology and Infectious Diseases. Clin. Infect. Dis., 52:e103–e120.

Y.E.

, Kang

C.I.

, Joo

E.J.

, Park

S.Y.

, Kang

S.J.

, Wi

Y.M.

, Chung

D.R.

, Peck

K.R.

, Lee

N.Y.

, and Song

J.H.

. 2011. Clinical implications of healthcare-associated infection in patients with community-onset acute pyelonephritis. Scand. J. Infect. Dis., 43:587–595.

Harbarth

, Rutschmann

, Sudre

, and Pittet

. 1998. Impact of methicillin resistance on the outcome of patients with bacteremia caused by Staphylococcus aureus. Arch. Intern. Med., 158:182–189.

Jacoby

, Han

, and Tran

. 1997. Comparative in vitro activities of carbapenem L-749,345 and other antimicrobials against multiresistant gram-negative clinical pathogens. Antimicrob. Agents. Chemother., 41:1830–1831.

10.

Jeon

J.H.

, Kim

, Han

W.D.

, Song

S.H.

, Park

K.U.

, Rhee

J.E.

, Song

K.H.

, Park

W.B.

, Kim

E.S.

, Park

S.W.

, et al. 2012. Empirical use of ciprofloxacin for acute uncomplicated pyelonephritis caused by Escherichia coli in communities where the prevalence of fluoroquinolone resistance is high. Antimicrob. Agents. Chemother., 56:3043–3046.

11.

Kang

C.I.

, Kim

S.H.

, Kim

D.M.

, Park

W.B.

, Lee

K.D.

, Kim

H.B.

, Oh

M.D.

, Kim

E.C.

, and Choe

K.W.

. 2004. Risk factors for and clinical outcomes of bloodstream infections caused by extended-spectrum beta-lactamase-producing Klebsiella pneumoniae. Infect. Control Hosp. Epidemiol., 25:860–867.

12.

Kang

C.I.

, Park

S.Y.

, Chung

D.R.

, Peck

K.R.

, and Song

J.H.

. 2012. Piperacillin-tazobactam as an initial empirical therapy of bacteremia caused by extended-spectrum beta-lactamase-producing Escherichia coli and Klebsiella pneumoniae. J. Infect., 64:533–534.

13.

Kim

, Kim

, Seo

M.R.

, Wie

S.H.

, Cho

Y.K.

, Lim

S.K.

, Lee

J.S.

, Kwon

K.T.

, Lee

, Cheong

H.J.

, et al. 2013. Clinical characteristics of community-acquired acute pyelonephritis caused by ESBL-producing pathogens in South Korea. Infection, 41:603–612.

14.

Kim

S.H.

, Kim

K.H.

, Kim

H.B.

, Kim

N.J.

, Kim

E.C.

, Oh

M.D.

, and Choe

K.W.

. 2008. Outcome of vancomycin treatment in patients with methicillin-susceptible Staphylococcus aureus bacteremia. Antimicrob. Agents. Chemother., 52:192–197.

15.

Kim

S.H.

, Kim

Y.W.

, and Lee

H.J.

. 2012. Serious acute pyelonephritis: a predictive score for evaluation of deterioration of treatment based on clinical and radiologic findings using CT. Acta. Radiol., 53:233–238.

16.

Kim

Y.K.

, Pai

, Lee

H.J.

, Park

S.E.

, Choi

E.H.

, Kim

J.H.

, and Kim

E.C.

. 2002. Bloodstream infections by extended-spectrum beta-lactamase-producing Escherichia coli and Klebsiella pneumoniae in children: epidemiology and clinical outcome. Antimicrob. Agents. Chemother., 46:1481–1491.

17.

Kola

, Maciejewski

, Sohr

, Ziesing

, and Gastmeier

. 2007. Clinical impact of infections caused by ESBL-producing E. coli and K. pneumoniae. Scand. J. Infect. Dis., 39:975–982.

18.

Menashe

, Borer

, Yagupsky

, Peled

, Gilad

, Fraser

, Riesenberg

, and Schlaeffer

. 2001. Clinical significance and impact on mortality of extended-spectrum beta lactamase-producing Enterobacteriaceae isolates in nosocomial bacteremia. Scand. J. Infect. Dis., 33:188–193.

19.

Meyer

K.S.

, Urban

, Eagan

J.A.

, Berger

B.J.

, and Rahal

J.J.

. 1993. Nosocomial outbreak of Klebsiella infection resistant to late-generation cephalosporins. Ann. Intern. Med., 119:353–358.

20.

Naumovski

, Quinn

J.P.

, Miyashiro

, Patel

, Bush

, Singer

S.B.

, Graves

, Palzkill

, and Arvin

A.M.

. 1992. Outbreak of ceftazidime resistance due to a novel extended-spectrum beta-lactamase in isolates from cancer patients. Antimicrob. Agents. Chemother., 36:1991–1996.

21.

Pai

. 2011. Treatment of community-acquired uncomplicated urinary tract infection. Korean J. Med., 81:685–689.

22.

Paterson

D.L.

, and Bonomo

R.A.

. 2005. Extended-spectrum beta-lactamases: a clinical update. Clin. Microbiol. Rev., 18:657–686.

23.

Pitout

J.D.

, and Laupland

K.B.

. 2008. Extended-spectrum beta-lactamase-producing Enterobacteriaceae: an emerging public-health concern. Lancet Infect. Dis., 8:159–166.

24.

Pitout

J.D.

, Nordmann

, Laupland

K.B.

, and Poirel

. 2005. Emergence of Enterobacteriaceae producing extended-spectrum beta-lactamases (ESBLs) in the community. J. Antimicrob. Chemother., 56:52–59.

25.

Rodriguez-Bano

, Alcala

J.C.

, Cisneros

J.M.

, Grill

, Oliver

, Horcajada

J.P.

, Tortola

, Mirelis

, Navarro

, Cuenca

, et al. 2008. Community infections caused by extended-spectrum beta-lactamase-producing Escherichia coli. Arch. Intern. Med., 168:1897–1902.

26.

Rodriguez-Bano

, Navarro

M.D.

, Retamar

, Picon

, and Pascual

. 2012. beta-Lactam/beta-lactam inhibitor combinations for the treatment of bacteremia due to extended-spectrum beta-lactamase-producing Escherichia coli: a post hoc analysis of prospective cohorts. Clin. Infect. Dis., 54:167–174.

27.

Rodriguez-Bano

, and Pascual

. 2008. Clinical significance of extended-spectrum beta-lactamases. Expert Rev. Anti. Infect. Ther., 6:671–683.

28.

Rodriguez-Bano

, Picon

, Gijon

, Hernandez

J.R.

, Ruiz

, Pena

, Almela

, Almirante

, Grill

, Colomina

, et al. 2010. Community-onset bacteremia due to extended-spectrum beta-lactamase-producing Escherichia coli: risk factors and prognosis. Clin. Infect. Dis., 50:40–48.

29.

Schwaber

M.J.

, Navon-Venezia

, Kaye

K.S.

, Ben-Ami

, Schwartz

, and Carmeli

. 2006. Clinical and economic impact of bacteremia with extended-spectrum-beta-lactamase-producing Enterobacteriaceae. Antimicrob. Agents. Chemother., 50:1257–1262.

30.

The Korean Society of Infectious Diseases, The Korean Society for Chemotherapy, Korean Association of Urogenital Tract Infection and Inflammation, The Korean Society of Clinical Microbiology. 2011. Clinical Guideline for the Diagnosis and Treatment of Urinary Tract Infections: Asymptomatic Bacteriuria, Uncomplicated & Complicated Urinary Tract Infections, Bacterial Prostatitis. Infect. Chemother., 43:1–25.

31.

Tumbarello

, Spanu

, Sanguinetti

, Citton

, Montuori

, Leone

, Fadda

, and Cauda

. 2006. Bloodstream infections caused by extended-spectrum-beta-lactamase-producing Klebsiella pneumoniae: risk factors, molecular epidemiology, and clinical outcome. Antimicrob. Agents. Chemother., 50:498–504.