The Pediatric Infectious Disease Journal Volume 32, Number 4, April 2013

Pyelonephritis With ESBLs

TREATMENT OF PYELONEPHRITIS CAUSED BY EXTENDED-SPECTRUM -LACTAMASE PRODUCING ENTEROBACTERIACEAE IN CHILDREN Tomohiro Katsuta, MD, PhD,* Kensuke Shoji, MD, Yasushi Watanabe, MS, and Akihiko Saitoh, MD, PhD
Abstract: Fifty-four children were diagnosed as pyelonephritis caused by extended-spectrum -lactamaseproducing Enterobacteriaceae at the largest childrens hospital in Japan. Although 32 (59%) patients were treated with antimicrobials that are ineffective against the organisms, 39 (72%) patients became afebrile 2 days and clinical outcome was excellent. Children with pyelonephritis caused by extended-spectrum -lactamase producing Enterobacteriaceae can be successfully treated with noncarbapenem antimicrobials. Key Words: pyelonephritis, extended-spectrum -lactamase, child, treatment
From the *Department of Pediatrics, Division of Infectious Diseases, St. Marianna University School of Medicine, Kanagawa; Department of Medical Specialties, Division of Infectious Diseases, National Center for Child Health and Development; Department of Clinical laboratory, National Center for Child Health and Development, Tokyo; and Department of Pediatrics, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan. Presented, in part, at the 5th Asian Congress of Pediatric Infectious Diseases, Taipei, Taiwan, September, 2010. This study was supported by a Grant from the National Center for Child Health and Development (21A-2 to A.S.). The authors have no other funding or conflicts of interest to disclose. Address for correspondence: Akihiko Saitoh, MD, PhD, FAAP, 1757 Asahimachi, Chuo-ku Niigata, 9518510, Japan. E-mail: asaitoh@med.niigata-u. ac.jp. Copyright 2013 by Lippincott Williams & Wilkins DOI: 10.1097/INF.0b013e318284b1e8

2009 and December 2010. All urine specimens were obtained by bladder catheterization (for younger children who could not urinate by themselves) or by the midstream or clean-catch method (without the use of a diaper for children >3 years). Pyelonephritis was defined as the presence of a positive urine culture (5104 colony forming unit/mL of pathogens), pyuria (>5 white blood cells/ high-power field on centrifuged specimen) and fever (38C), in the absence of signs of an alternative cause of fever. The hospital course and clinical outcomes of the children were monitored for 4 weeks after the episode. We excluded patients with bacteremia. Assessment of antimicrobial susceptibilities and identification of ESBL organisms were done according to the 2009 Clinical and Laboratory Standards Institute guidelines.4 The following information was extracted from the medical records database: age, sex, baseline diseases, previous history of urinary tract infection (UTI) and causative organisms, antimicrobials for UTI prophylaxis, previous urinary culture results, duration of fever, antimicrobial therapy (empirical and definitive therapy) and its duration and clinical outcomes (resolution of fever [37C], infection relapse within 4 weeks after completion of therapy). Patient outcome was classified using established definitions: cure was defined as absence of symptoms and no recurrence of the same isolates, and relapse was defined as recurrence of symptoms in combination with isolation of the same organisms. We used the SPSS 15.0 software package (SPSS, Inc., Chicago, IL) for the analyses. The chi-square test and Fishers exact test were used to compare categorical variables between 2 groups. The MannWhitney U test and KruskalWallis test were used to compare continuous variables between 2 groups and among 3 or more groups, respectively. All P values were 2-tailed and were considered significant if P < 0.05.

RESULTS
xtended-spectrum -lactamase (ESBL)-producing Enterobacteriaceae have spread throughout the world, and a significant increase in related infections and diseases has been observed worldwide, including in children.1 Treatment options for ESBLproducing Enterobacteriaceae are limited because these bacteria are resistant to a number of classes of antimicrobials. Carbapenems are the treatment of choice for serious infections caused by ESBLproducing Enterobacteriaceae;2,3 however, empirical carbapenem treatment of infections believed to be due to ESBL-producing Enterobacteriaceae has substantially increased because of the number of carbapenem-resistant isolates. Recently, several reports have discussed the clinical significance and treatment of infections caused by ESBL-producing Enterobacteriaceae.1,2 Pyelonephritis is the most common infection caused by the organism; however, there are few data on treatment options and clinical outcomes for pyelonephritis in children, especially those who were treated with noncarbapenem antimicrobials, which have been used with considerable clinical success to treat such infections in adults.2 Therefore, we investigated treatment regimens and clinical outcomes of children who were treated with noncarbapenem antimicrobials for pyelonephritis caused by ESBL-producing Enterobacteriaceae.

Patient Characteristics
During the observation period, 55 patients received a diagnosis of pyelonephritis caused by ESBL-producing Enterobacteriaceae; 1 patient with bacteremia was excluded from the study. Median age of the study population was 28 months (interquartile range: 92 months), and 38 of the 54 (70%) patients were female. Regarding past medical history related to UTI, pyelonephritis was noted in 38 (70%), anatomic anomalies in 20 (37%), neurogenic bladder dysfunction in 18 (33%) and vesicoureteral reflux in 14 (26%). Twenty (37%) children were immunocompromised, which was defined as presence of neutropenia or immunosuppressant treatmentie, prednisone (2mg/kg per day for >14 days), cyclosporine, tacrolimus hydrate or other chemotherapeutic agents during the past 3months.

Treatments
Mean duration of therapy was 13.7 days (range: 724 days). Mean durations of empirical and definitive therapy were 4.5 days (range: 211) and 9.2 days (range: 221), respectively. Table 1 shows the details of the treatment regimens. Initially, 32 (59%) children were treated with antimicrobials that are ineffective against ESBLproducing organisms. After identification of ESBL-producing isolates, 52 children (96%) were switched to antimicrobials that are effective against such isolates, and only 2 (4%) children continued treatment with the same antimicrobials.

Methods
We retrospectively reviewed the treatment options and clinical outcomes of children who developed pyelonephritis caused by ESBL-producing Enterobacteriaceae. All children were patients at the largest pediatric tertiary care hospital in Japan, the National Center for Child Health and Development in Tokyo, between April 2013 Lippincott Williams & Wilkins

Clinical Outcomes
Most patients (72%) became afebrile within 2 days (average: 2.1 days; range: 15 days). Duration of fever after initiating antimicrobial treatment did not differ by sex (P = 0.33), past history
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The Pediatric Infectious Disease Journal Volume 32, Number 4, April 2013

TABLE 1. Details of Treatments Received by Study Subjects

Empirical Therapy* Antibiotics Susceptible Parenteral Cefmetazole Cefazolin Cefotiam Ceftazidime Cefotaxime Cefepime Ampicillin/sulbactam Piperacillin/azobactam Gentamicin Ciprofloxacin Meropenem Oral Cefaclor Sulfamethoxazole/ trimethoprim Fosfomycin Ciprofloxacin Levofloxacin Total Intermediate or Resistant 1 1 2 1 14 8 1 1 1 0 0 1 0 0 1 0 32 21 0 0 0 0 0 1 3 3 2 2 0 13 (+3) 6 (+1) 2 (+2) 1 54 (+6) Definitive Therapy

10 0 0 0 0 0 0 5 0 0 7 0 0 0 0 0 22

*All of 54 patients, 16 (30%) were introduced antimicrobial prophylaxis before the empiric therapy with sulfamethoxazole/trimethoprim: 10 (19%) and cefaclor: 6 (11%). Isolated organisms were Escherichia coli: 33 (61%), Klebsiella pneumoniae: 20 (37%) and Citrobacter freundii: 1 (2%). Two patients received the same antibiotics for empirical and definitive therapy, namely, cefmetazole (n = 1; 2%) and ampicillin/sulbactam (n = 1; 2%). Six patients were switched to definitive oral therapy from definitive parenteral therapy (+X).

of pyelonephritis (P = 0.44) or prior prophylactic treatment with sulfamethoxazole/trimethoprim (P = 0.27) or cefaclor (P = 0.71). Among 32 patients treated with antimicrobials that were resistant to the isolates, 24 (75%) became afebrile before the antimicrobials were switched to appropriate antimicrobials. The mean duration of antimicrobial therapy that were resistant to the isolates was 4.4 days. In addition, duration of fever after initiating antimicrobial treatment did not differ between those who received susceptible agents and those who received nonsusceptible antimicrobials (2.0 days versus 2.2 days, respectively; P = 0.62). However, immunocompromised patients had a longer duration of fever after initiation of therapy than did immunocompetent patients (2.5 days versus 1.9 days; P = 0.01). All patients cured of infection and no relapse was observed.

DISCUSSION
To our knowledge, this study enrolled the largest number of children treated with noncarbapenem antimicrobials for pyelonephritis caused by ESBL-producing Enterobacteriaceae without bacteremia. Treatment with noncarbapenem antimicrobials was successful, and there was no case of treatment failure during the observation period. Some evidence indicates that carbapenems are the drugs of choice for infections caused by ESBL-producing Enterobacteriaceae.2 Inappropriate antimicrobial choice might have a deleterious impact if noncarbapenem antimicrobials are selected for patients with serious infections such as bacteremia.5 For this reason, antimicrobials must be carefully selected in seriously ill patients with suspected bacteremia caused by ESBL-producing Enterobacteriaceae. Nevertheless, physicians should avoid overuse

of carbapenems, as it could lead to development and worsening of infections and diseases caused by carbapenem-resistant isolates. Thus, knowledge of the risk factors for infections caused by ESBLproducing organisms in children could aid in identifying high-risk patients and enable initiation of appropriate empirical therapy for such patients. These risk factors include female sex, infection with Klebsiella spp, steroid use, exposure to extended-spectrum cephalosporin within the previous 30 days, underlying diseases, hospitalization within the previous 3 months and history of positive culture for ESBL-producing organisms.68 If any of these risk factors are present, and patients are believed to be seriously ill, carbapenems remain the best treatment option. To ensure appropriate antimicrobial use, noncarbapenem treatment options should be considered for infections caused by ESBL-producing organisms. The cephamycins (eg, cefmetazole) are stable against the hydrolytic effects of ESBL, and several studies found that they are effective for treating infections caused by ESBL-producing organisms.2 In our study, high proportions of isolates of ESBL-producing Escherichia coli (97%) and Klebsiella pneumoniae (85%) were susceptible to cefmetazole. Cefmetazole was used as a first-line therapy in 11 patients, and clinical outcomes were excellent. Because cephamycins have a narrower spectrum and are less expensive than carbapenems, they could be an excellent alternative for children without bacteremia who have pyelonephritis caused by ESBL-producing Enterobacteriaceae. Third-generation cephalosporins are the most common antimicrobials used for treating UTI, but susceptibility tests show that ESBL-producing organisms are resistant to drugs in this class. However, because of their high urinary concentrations, they have been successfully used to treat pyelonephritis caused by ESBL-producing organisms.9 In the current study, most children received third-generation cephalosporins as empirical therapy and did well during the treatment period. Other antimicrobials that are potentially effective in treating pyelonephritis caused by ESBLproducing organisms are -lactams combined with -lactamase inhibitors, aminoglycosides, fluoroquinolones and fosfomycin.2,10 Unfortunately, there are few clinical data on the effectiveness of these agents against ESBL-producing isolates. Additional clinical data on the use of these agents in children are needed. The current study has some limitations. First, due to the study design, the study population was drawn from a single pediatric hospital in Japan and was small. Second, this was a retrospective study that lacked a control group, and choice of antimicrobials was mainly at the discretion of individual physicians; therefore, choice and change of antimicrobials were not controlled. Third, a follow-up urine culture was not obtained in all patients; thus, the sterility of urine culture was not confirmed. Finally, the secondary outcome of the current study was determined on the basis of medical records, which may have lacked relevant information. In conclusion, noncarbapenem antimicrobial treatment of pyelonephritis caused by ESBL-producing Enterobacteriaceae was successful in children. A further prospective study is warranted in order to confirm that this treatment is effective for treating pyelonephritis caused by ESBL-producing Enterobacteriaceae in children. REFERENCES
1. Blaschke AJ, Korgenski EK, Daly JA, et al. Extended-spectrum beta-lactamase-producing pathogens in a childrens hospital: a 5-year experience. Am J Infect Control. 2009;37:435441. 2. Paterson DL, Bonomo RA. Extended-spectrum beta-lactamases: a clinical update. Clin Microbiol Rev. 2005;18:657686. 3. Paterson DL, Ko WC, Von Gottberg A, et al. Antibiotic therapy for Klebsiella pneumoniae bacteremia: implications of production of extended- spectrum beta-lactamases. Clin Infect Dis. 2004;39:3137.

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The Pediatric Infectious Disease Journal Volume 32, Number 4, April 2013

Pleural Effusions in Taiwanese Children

4. Clinical and Laboratory Standards Institute. 2009 Performance Standards for Antimicrobial Susceptibility Testing: Nineteenth Information Supplement (M100-S19). Wayne, PA: Clinical and Laboratory Standards Institute; 2009. 5. Lautenbach E, Patel JB, Bilker WB, et al. Extended-spectrum beta- lactamase-producing Escherichia coli and Klebsiella pneumoniae: risk factors for infection and impact of resistance on outcomes. Clin Infect Dis. 2001;32:11621171. 6. Zaoutis TE, Goyal M, Chu JH, et al. Risk factors for and outcomes of bloodstream infection caused by extended-spectrum beta-lactamaseproducing Escherichia coli and Klebsiella species in children. Pediatrics. 2005;115:942949. 7. Kuo KC, Shen YH, Hwang KP. Clinical implications and risk factors of extended-spectrum beta-lactamase-producing Klebsiella pneumoniae infection in children: a case-control retrospective study in a medical center in southern Taiwan. J Microbiol Immunol Infect. 2007;40: 248254. 8. Topaloglu R, Er I, Dogan BG, et al. Risk factors in community-acquired urinary tract infections caused by ESBL-producing bacteria in children. Pediatr Nephrol. 2010;25:919925. 9. Tratselas A, Iosifidis E, Ioannidou M, et al. Outcome of urinary tract infections caused by extended spectrum -lactamase-producing Enterobacteriaceae in children. Pediatr Infect Dis J. 2011;30:707710. 10. Falagas ME, Kastoris AC, Kapaskelis AM, et al. Fosfomycin for the treat ment of multidrug-resistant, including extended-spectrum beta-lactamase producing, Enterobacteriaceae infections: a systematic review. Lancet Infect Dis. 2010;10:4350.

received institutional grants for the present work and payments for development of educational presentations from the GlaxoSmithKline group of companies; K.P.H. declares no conflict of interest; C-C.L. declares no conflict of interest; R.B.T. declares no conflict of interest; C.Y.L. has received funding from the GlaxoSmithKline group of companies for research on which the present article is based; G.L.G. has received grants from the GlaxoSmithKline group of companies for performance of laboratory tests for the present project as well as for a similar project in Australia; K.T. declares no conflict of interest; J.S.M. was an employee of the GlaxoSmithKline group of companies; J-Y.P. is an employee of the GlaxoSmithKline group of companies; M.K.V.D. is an employee of the GlaxoSmithKline group of companies and declares stock ownership; Y.F.L. was an employee of the GlaxoSmithKline group of companies and had stock ownership; L-M.H. has received institutional grants for the present work from the National Taiwan University Hospital (Taipei, Taiwan). He also received from the GlaxoSmithKline group of companies fees for participation in advisory board on a HPV vaccine project, for consultancy (clinical trial protocol) and for giving lectures on vaccines. He has received institutional grants from the GlaxoSmithKline group of companies for detection of organisms in Empyema; W.P.H. is an employee of the GlaxoSmithKline group of companies and declares stock ownership. He is coholder of the patent for Prevnar 13 (Wyeth, New York, NY). The authors have no other funding or conflicts of interest to disclose. Address for correspondence: Li-Min Huang, PhD, Department of Pediatrics, National Taiwan University Hospital, 7 Chung-Shan South Road, Taipei, Taiwan 100. E-mail: lmhuang@ntu.edu.tw. Copyright 2013 by Lippincott Williams & Wilkins DOI: 10.1097/INF.0b013e31828637b1

ETIOLOGY OF EMPYEMA THORACIS AND PARAPNEUMONIC PLEURAL EFFUSION IN TAIWANESE CHILDREN AND ADOLESCENTS YOUNGER THAN 18 YEARS OF AGE Tzou-Yien Lin, MD,* Kao Pin Hwang, MD, PhD, Ching-Chuan Liu, MD, MPH, Ren Bin Tang, MD, Ching Yuang Lin, MD, Gwendolyn L. Gilbert, MD, Kiran Thapa, MSc, Javier Sawchik Monegal, PhD, Jean-Yves Piron, PhD, Melissa K. Van Dyke, PhD, Yan Fang Liu, MD,** Li-Min Huang, PhD, and William P. Hausdorff, PhD
Abstract: We analyzed blood and pleural fluid samples from 89 Taiwanese children with empyema thoracis and parapneumonic pleural effusion. Streptococcus pneumoniae was the major pathogen, identified in 12 children by bacterial culture and 53 children by molecular techniques, and serotype 19A was the dominant serotype. Also noteworthy was the detection of pneumococcal serotype 1, Haemophilus influenzae and Mycoplasma pneumoniae in these children. Key Words: empyema thoracis, pleural effusion, molecular techniques, bacterial cultures, Taiwan
Accepted for publication January 4, 2013. From the *Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Taoyuan; China Medical University School of Medicine, China Medical University Hospital, Taichung; National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan; Taipei Veterans General Hospital, Taipei, Taiwan; Centre for Infectious Diseases and Microbiology, Westmead Hospital, University of Sydney, New South Wales, Australia; GlaxoSmithKline Vaccines, Rixensart, Belgium; **GlaxoSmithKline Vaccines, Tuas, Singapore (former affiliation); and National Taiwan University Hospital, Taipei, Taiwan. Javier Sawchik Monegal, PhD is currently at the Federal Agency for Medicines and Health Products, Brussels, Belgium. T-Y. L. and K.P.H. contributed equally to this work. GlaxoSmithKline Biologicals SA (Rixensart, Belgium) was the funding source and was involved in all stages of the study conduct and analysis. GlaxoSmithKline Biologicals SA also funded all costs associated with the development and the publishing of the present manuscript. All authors contributed to the study, were involved in writing and reviewing the paper and approved the final version. All authors had full access to the data and the corresponding author had final responsibility for submission of the manuscript. T-Y.L. has

acterial pneumonia may result in parapneumonic pleural effusion (PPE) or empyema thoracis (ET), 2 conditions that can cause significant morbidity. Between 1997 and 2004, the population-based annual ET incidence was estimated at 10.5 episodes per 100,000 children who were younger than 5 years of age in Taiwan and, as elsewhere, appeared to be increasing.1 Previous analyses of pleural fluid (PF) samples by bacterial cultures suggested Streptococcus pneumoniae (Spn) as the predominant etiologic agent in Taiwanese children,2 with the major serogroups being 14, 23, 6 and 19.3 However, most samples were culture negative, likely a result of antibiotic pretreatment, and it has been observed elsewhere that molecular techniques can uncover a broader range of pathogens and serotypes.46 This study used polymerase chain reaction (PCR)-based techniques to better characterize the etiology of ET and PPE in Taiwanese children.

MATERIALS AND METHODS

This observational, prospective, hospital-based surveillance study was conducted in 6 centers in Taiwan between April 2008 and October 2009 according to Good Clinical Practice guidelines and the Declaration of Helsinki. Before enrollment, informed consent was obtained from the parents/guardians of each participant and informed assent from each child aged more than 7 years. The protocol and consent form were approved by local ethics committees. The study targeted enrollment of ~100 children younger than 18 years of age, admitted to study hospitals with ET or PPE, whose clinical condition necessitated a diagnostic thoracocentesis or a thoracostomy for PF drainage and whose PF sample was available for laboratory testing. Major exclusion criteria included participation in another clinical study or known malignancy, collagen vascular disease or melioidosis. For each enrolled child, demographic characteristics, general signs and symptoms, medical history, biochemical compositions of PF and blood samples, treatment given, duration of hospitalization and outcome at discharge were recorded. At local hospital laboratories, PF and blood samples were cultured for facultative bacteria (Fig. 1).7 The macroscopic presence of pus in PF samples was taken to identify children with ET. A fraction of the PF samples also underwent standard bacterial culture and molecular analyses at the Centre for Infectious Diseases and Microbiology (New South
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