Antibiotic Resistance of Uropathogens in Newborns and Young Children with Acute Pyelonephritis

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1 Sr Arh Celok Lek Mar-Ar;140(3-4): DOI: /SARH P ОРИГИНАЛНИ РАД / ORIGINAL ARTICLE UDC: Antibiotic Resistance of Uroathogens in Newborns and Young Children with Acute Pyelonehritis Amira Peco-Antić 1, Dušan Pariović 2, Svetlana Buljugić 2, Divna Kruščić 2, Brankica Sasojević 2, Mirjana Cvetković 2, Mirjana Kostić 2, Suzana Laban-Nestorović 2, Gordana Miloševski-Lomić 2 1 School of Medicine, University of Belgrade, Belgrade, Serbia; 2 University Children s Hosital, Belgrade, Serbia SUMMARY Introduction Urinary tract infection is common in childhood. Deending on the localization of the infection, severity of its clinical resentation and ossible acute and long-term comlications, it may be described as either acute cystitis or acute yelonehritis. Objective The aim of this study was to assess the resistance atterns of uroathogens during the last 5 years in newborns and young children with acute yelonehritis. Methods Uroathogens resistance to commonly usable anti-microbial agents (amicillin, a combination of sulhamethoxasole and trimethorim, cehalexin, ceftriaxone, cefotaxime, ceftazidime, gentamycin, amikacin, cirofloxacin, imienem and nalidixic acid) was retrosectively studied in newborns and young children treated during early () and late () study eriods. Anti-bacterial suscetibility testing of the urine isolates was erformed by the standard disc diffusion method. Results 117 newborns and 294 children aged 9.3±0.7 months were treated during early (n=136) or late (n=275) study eriod due to the first eisode of acute yelonehritis. Escherichia coli was the most common bacterial athogen (85.5%). Comared to children older than one month, newborns had higher degree of antibacterial resistance to 2 nd and 3 rd generation cehalosorins, aminoglycosides, and nalidixic acid during early, and to ceftazidime, aminoglycosides and nalidixic acid during late study eriod. Also, multidrug resistance was more common in newborns during the early study eriod. Conclusion Newborns had higher rate of antibacterial resistance than young children. The rogressive increase of anti-microbial resistance in children with acute yelonehritis is of great concern. Keywords: antimicrobial agents; urinary tract infection; Escherichia coli; bacterial resistance; children INTRODUCTION Urinary tract infection (UTI) is common in childhood, second only in frequency to that of the resiratory tract [1, 2, 3]. Deending on the localization of the infection, severity of its clinical resentation and ossible acute and longterm comlications, UTI may be described as either acute cystitis or as acute yelonehritis [4-7]. Promt treatment of childhood acute yelonehritis is likely to reduce the risk of ermanent renal scarring [7, 8]. However, increased anti-microbial resistance, esecially the emergence of uroathogen strains roducing extended sectrum β-lactamases (ESBLs) has threatened the antibiotic treatment of UTI in children [9, 10, 11]. OBJECTIVE The aim of this study was to assess the changing trend of local resistance atterns of urinary athogens to commonly usable anti-microbial agents during the last 5 years in newborns and young children with acute yelonehritis. METHODS The medical records from January 2005 to December 2009 of all children aged less than 18 years admitted at the Nehrology or Neonatology Deartment of the University Children s Hosital in Belgrade for their first UTI were reviewed. Two different eriods, early (from January 2005 to December 2007) and late (from January 2008 to December 2009), were studied to evaluate the trend of anti-microbial resistance in children with clinically susected acute yelonehritis. Data were analyzed searately for two age grous: newborns (grou I) and children older than one month (grou II). Clinical arameters including age, gender, aetiology of UTI and bacterial resistance of uroathogens and urinary tract imaging were recorded for each atient. The atients who met the following criteria were included in the study: fever greater than 38.5 C with no other recognized cause, leukocytosis, C reactive rotein (CRP) higher than 20 mg/l, ositive distick for leukocyte esterase and/or yuria (urine secimen with 10 white blood cells/hf), and isolation of more than 10 5 colony-forming units (CFUs)/ ml of a single secies of bacteria in a urine samle obtained by midstream clean catch, or sterile bags. Those receiving antibiotics and immunosuressed children as well as those with history of revious UTI were excluded from the study. Ultra-sonograhy erformed within 72 hours after admission into hosital was required for all articiants, while voiding cysto-urethrograhy and Tc-99m DMSA scin- Corresondence to: Amira PECO-ANTIĆ University Children's Hosital Tiršova 10, Belgrade Serbia amira@udk.bg.ac.rs

2 180 Peco-Antić A. et al. Antibiotic Resistance of Uroathogens in Newborns and Young Children with Acute Pyelonehritis tigrahy were otional at the treating hysician s request and arents decision. All urine samles were obtained in hosital by health care ersonnel. Contaminated secimens were discarded from the study. Standard methods for isolation and identification of the isolates were used. Anti-bacterial suscetibility testing of the isolates was erformed by the standard disc diffusion method as recommended by the Clinical and Laboratory Standards Institute (CLSI) [12]. ESBL henotyic confirmatory test with ceftazidime, ceftriaxone and cefotaxime was erformed for all isolates by disc diffusion method on Mueller-Hinton agar lates. A 5 mm increase in a zone diameter for antimicrobial agent tested in combination with clavulanic acid versus its zone when tested alone was considered indicative of ESBL roduction. The methods used did not vary throughout the study eriod. No tests were erformed to further characterize the clonal origin of isolates. The following anti-microbial agents were tested: amicillin (AMP), a combination of sulhamethoxasole and trimethorim (TMP-SMZ), cehalexin (CEP), ceftriaxone (CX), cefotaxime (CTX), ceftazidime (CEF), gentamycin (GN), amikacin (AM), cirofloxacin (CIP), imienem (IMP) and nalidixic acid (N). Multi-drug resistance was defined when resistance to at least 3 different grous of antibiotics was aarent. Statistical analysis SPSS 13.0 for Microsoft Windows was used for all statistical analyses. Results for continuous variables were resented as mean (±SEM). Fisher s exact test was used to comare categorical variables. The Mann-Whitney U test was used for continuous variables. A P value <0.05 was considered to be statistical significant. RESULTS Clinical characteristics A total of 598 children were hositalized in the Nehrology and Neonatal deartments of the University Children s Hosital in Belgrade due to the first UTI between the 1st of January 2005 and the 31st of December Of these, only 411 children (189 girls and 222 boys, median age of 4.0 months; range months) fulfilled inclusion criteria of the study. Their clinical characteristics are shown in Table 1. The atients were divided in 2 grous based on age. Grou I consisted of 117 newborns while grou II consisted of 294 older children with a mean age of 9.3±0.7 months. The atients were treated in early () or late () during the study eriod (136 and 275 atients, resectively). The early and late eriod of the research were comarable excet for CRP and ESBL (+) UTI which were higher in early than in late eriod and renal ultrasound abnormalities which were more common in the early than in the later eriod. The ercentage of urine secimen-obtaining methods for urine culture, midstream clean catch urine and sterile bags were 65 and 35% in the early and 67 and 33% in late study eriod, resectively. Microbiology Escherichia coli (E. coli) was the leading cause of UTI (85.5%), followed by Klebsiella neumoniae (8.1%), Enterococcus s. (3.6%), Proteus mirabilis (2.0%), Enterobacter (0.4%) and Psedomonas aeruginosa (0.4%). The distribution of uroathogens did not vary significantly between the two study eriods, but E. coli was more revalent in grou II while non-e. coli athogens, Klebsiella and Enterococcus, were more common in grou I (Table 2). Table 1. Clinical characteristics Parameter Grou I Grou II Gender, male/female (%) 84/ /22.4 NS 32.6/ /51.9 <0.05 Age (months) 0.5± ±0.2 NS 11.4± ±0.7 NS Temerature ( C) 38.5± ±0.4 NS 39.2± ±0.6 NS White blood cells (10 3 /mm 3 ) 18.2± ±1.1 NS 18.6± ±0.5 NS C-reactive rotein (mg/l) 45.4± ±8.0 NS 57.3± ±4.5 <0.01 Renal ultrasound abnormalities (%) < NS ESBL (+) UTI (%) < <0.01 n number of atients; ESBL (+) UTI urinary tract infections caused by ESBL-roducing microorganisms; NS not statistically significant Table 2. Frequency of urinary athogens Urinary athogens Grou I Grou II (Grou I vs Grou II) Escherichia coli NS NS <0.05 <0.01 Klebsiella NS NS <0.01 <0.01 Enterococcus NS NS NS <0.01 Other NS NS NS NS Total doi: /SARH P

3 Sr Arh Celok Lek. 2012;140(3-4): Resistance atterns Resistance to anti-microbial agents for overall athogens both in the early and late study eriods is resented in Table 3. When early and late study eriods were comared increasing trends in bacterial resistance atterns were observed towards TMP-SMX, 2 nd and 3 rd generation cehalosorins and gentamicin as well as in multidrug resistance, while a decreasing trend was seen towards AM and unchanged towards CIP, IMP and to N (Table 3). Comared to children older than 1 month, newborns had similar (AMP; TMP-SMZ, CIP, IMP and N) or higher degree of antibacterial resistance (CEP, CX, CTX and multidrug resistance during early, and CEF, GN and AM during whole study eriod) (Table 3). ESBL (+) was more common in the late than in early eriod (Table 1). DISCUSSION The revalence of the resistance to secific antibiotics is highly variable in different oulations and in different countries [13-28]. In general, in oor and undeveloed countries overall revalence of antimicrobial resistance is notably high, reflecting irrational and inordinate use of anti-microbial agents [29, 30]. Bacterial resistance of uroathogens in the aediatric oulation in Serbia has been regularly monitored [31, 32, 33]. Herein, we comared the trend of the bacterial resistance revalence over a recent 5-year eriod in newborns comared to that in young children with the first acute yelonehritis. The increased number of young children with acute yelonehritis during the later study eriod may be exlained by its better diagnosis due to the imroved education of aediatricians [32], as well as by an enlarged bed caacity of nehrology service from The redominance of E. coli among uroathogens in our study is in agreement with many other aediatric studies [28-31, 33-38]. Also, a high resistance to amicillin (>80%) is not surrising based on eidemiological studies from elsewhere [10, 15, 31-34]. According to these results, amicillin should not be used alone for the emirical treatment of aediatric UTIs. The resistance towards TMP/ SMX (about 50%) is similar to that in Turkey [37], Greece [26], England [38], Belgium [36] and Taiwan [30], but less common than in Cambodia [33], Central African Reublic [34] and Pakistan [39]. Thus, the use of TMP-SMZ as a single agent for emiric treatment of aediatric UTI would not cover half of the uroathogens. The resistance to gentamicin and amikacin was higher in newborns than in young children to whom amikacin remained suitable for emiric treatment of acute yelonehritis. None of the isolates was found to be resistant to imienem. However, this drug should be reserved only in the most severe forms of illness caused by multi-drug resistant uroathogens. In general, we observed a strikingly increasing trend for ESBL (+) and for multi-drug-resistant uroathogens during the late study eriod comared to the early eriod. These findings were even worse in the newborns than in older children. Multi-drug-resistance was most common among ESBL (+) uroathogens. This can be exlained by the fact that the resistance towards beta lactam drugs usually extends to other classes of antibiotics through resistance genes carried on the same lasmids. The increased resistance rate found in our study cannot be attributed to either more sensitive methods of detection of resistant strains (as identification methods remained the same throughout the study eriod), to incidental sread of hosital-resistant organisms at a certain time (as UTI in our atients was mainly community acquired) or to a greater frequency of urinary tract anomalies reorted by other authors [13, 15]. The increased uroathogen resistance trend demonstrated by our current study could be linked to non-restricted use of antibiotics in Serbia by hysicians as well as to high degree of self medication in oulation. Our analysis has some limitations. The first one is the retrosective design of the study. Also, sterile bags or midstream clean catch urine is not the method of choice to obtain sterile urine in infants and children. Nevertheless, urine samles were obtained in hosital by health care ersonnel and the collections of data as well as the laboratory methods were consistent through the study eriod. Therefore, the increasing evolution of the antibacterial resistance over this five-year eriod should reresent the Table 3. Antibiotic in vitro resistance Antibacterial drugs Grou I (n=136) Grou II Grou I (n=275) Grou II (n=136) (n=275) ( vs ) Amicillin NS NS NS TMP-SMZ NS NS <0.001 Cehalexin < NS <0.001 Cehrtiaxone < NS <0.001 Cefotaxime < NS <0.001 Ceftazidime < < <0.05 Gentamicin < < <0.001 Amikacin < < <0.05 Cirofloxacin NS NS NS Imienem 0 0 NS NS 0 0 NS Nalidixic acid < < NS Multidrug resistance < NS <0.01

4 182 Peco-Antić A. et al. Antibiotic Resistance of Uroathogens in Newborns and Young Children with Acute Pyelonehritis general trend among urinary tract athogens in children with first UTI treated at a key aediatric centre in Serbia. CONCLUSION Our study has demonstrated the rogressive increase in anti-microbial resistance in children with first UTI in Serbia during the eriod High revalence rate of ESBL (+) uroathogens and multi-drug-resistance in children, esecially in the newborns is of great concern. Further studies are needed to follow regional and time trends as well as to develo effective methods to limit increasing multi-drug resistance. ACKNOWLEDGEMENT The study was suorted by the Ministry of Education and Science, Government of Serbia, grant no REFERENCES 1. Winberg J, Anderson HJ, Bergström T, Jacobsson B, Learson H, Lincoin K. Eidemiology of symtomatic urinary tract infection in childhood. 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5 Sr Arh Celok Lek. 2012;140(3-4): Ismaili K, Lolin K, Damry N, Alexander M, Leage O, Hall M. Febrile urinary tract infections in 0- to 3-month old infants: A rosective follow-u study. J Pediatr. 2011; 158(1): Catal F, Bavbek N, Bayrak O, Odemis E, Uz E. Antimicrobial resistance atterns of urinary tract athogens and rationale for emiric theray in Turkish children for the years Int Urol Nehrol. 2009; 42: Bean DC, Krahe D, Wareham DW. Antimicrobial resistance in community and nosocomial Escherichia coli urinary isolates, London Ann Clin Antimicrob. 2008; 7: Thaver D, Ali SA, Zaidi AK. Antimicrobial resistance among neonatal athogens in develoing countries. Pediatr Infect Dis J. 2009; 28:S Антибактеријска резистенција уринарних бактерија код новорођенчади и мале деце оболеле од акутног пијелонефритиса Амира Пецо-Антић 1, Душан Париповић 2, Светлана Буљугић 2, Дивна Крушчић 2, Бранкица Спасојевић 2, Мирјана Цветковић 2, Мирјана Костић 2, Сузана Лабан-Несторовић 2, Гордана Милошевски-Ломић 2 1 Медицински факултет, Универзитет у Београду, Београд, Србија; 2 Универзитетска дечја клиника, Београд, Србија КРАТАК САДРЖАЈ Увод Инфекција уринарног тракта је честа у детињству. У зав и сн о с т и од м е с т а ин ф е к ц и је, ја чи н е њ е н е к ли нич ке с ли ке и могућих акутних и дугорочних компликација, она се описује као акут ни ци сти тис или акут ни пи је ло не фри тис. Циљ ра дац и љ р ад аб и ој ед аи сп ит ар ез ис т е нц ија у р ин ар - них бак те ри ја то ком пет го ди на код но во ро ђен ча ди и ма ле де це обо ле ле од акут ног пи је ло не фри ти са. М ет од е р ад а Ре т р о сп е к т ив н о је анализ ир а на р ез и с те н ц и ја уропатогених бак те ри ја на ан ти бак те риј ске ле ко ве (ам пи ци - лин, ком би на ци ју сулфометоксазола и триметопри ма, це фа - л е к си н а, ц еф т р иаксон а, ц еф от аксим а, ц е ф т аз ид им а, ге н т а - м и ц и н а, а м ик ац ин а, ц ип р оф л о кс ац ин а, и м ип ен ем а и н а л и - дик сич не ки се ли не) код но во ро ђен ча ди и ма ле де це то ком ра ног () и ка сни јег () сту диј ског пе ри о- да. За од ре ђи ва ње ан ти бак те риј ске сен зи тив но сти у ури ну ко р и шћ ен а ј е с т а нд ар дн а д и ск-д ифу з ион а м е т о д а. Ре зул та ти Ук у п н о 117 н ов ор ођ е н ч ад и и 29 4 м ал а д ет ет а у з - ра ста 9,3±0,7 ме се ци ле че но је то ком ра ног (136 бо ле сни ка) и ка сног (275 бо ле сни ка) сту диј ског пе ри о да. Esche ric hia co li је била најчешћи узрочник инфекције у оба периода (85,5%). У од но су на де цу ста ри ју од ме сец да на, код но во ро ђен чад и ј е у т в р ђ е н в е ћ и с т е п е н ан т и б ак т е р иј ске р е з и с т е н ц и ј е н а ц е ф а л о сп о р и н е д ру ге и т р е ћ е ге не ра ци је, ами но гли ко зи де и на ли дик сич ну ки се ли ну за вре ме ра ног сту диј ског пери - о да, а на цеф та зи дим, ами но гли ко з и д е и н а л и д и к сич н у к и - сел и н у т око м к асн иј е г п ер иод а и с п и т и в а њ а. Ре з и с т е н ц и ја на не колико лекова била је такође чешћа код новорођен - ча ди у ра ном сту диј ском пе ри о ду. За кљу чак Код н о в о р о ђ е н ча д и је в е ћи с те п е н ан т и б ак те р иј - ске ре зи стен ци је не го код де це ста ри је од ме сец да на. За - б р и њ а в а, м е ђу т и м, п о в е ћа њ е у ч е с т а л о с т и ан т и б ак т е р ијске ре зи стен ци је код де це с пр вим акут ним пи је ло не фри ти сом. Кључ не ре чи: а н т и м и к р о б н и л е ко в и; и н ф е к ц и ја у р и н ар - ног трак та; Esche ric hia co li; бак те риј ска ре зи стен ци ја; де ца Примљен Received: 24/01/2011 Прихваћен Acceted: 20/06/2011