Eur J Pediatr DOI 10.1007/s00431-014-2459-3
ORIGINAL ARTICLE
Pathogens causing urinary tract infections in infants: a European overview by the ESCAPE study group Irene Alberici & Aysun Karabay Bayazit & Dorota Drozdz & Sevinç Emre & Michel Fischbach & Jérôme Harambat & Augustina Jankauskiene & Mieczyslaw Litwin & Sevgi Mir & William Morello & Amira Peco-Antic & Peter Sallay & Lale Sever & Giacomo D. Simonetti & Przemyslaw Szczesniak & Ana Teixeira & Enrico Vidal & Elke Wuehl & Otto Mehls & Lutz T. Weber & Franz Schaefer & Giovanni Montini & for the ESCAPE study group and the PREDICT trial
Received: 26 August 2014 / Revised: 9 October 2014 / Accepted: 12 November 2014 # Springer-Verlag Berlin Heidelberg 2014
Abstract Knowledge of the distribution spectrum of causative organisms and their resistance patterns has become a core requirement for the rational and effective management of
urinary tract infections. In the context of a prospective trial on the use of antibiotic prophylaxis in infants with underling kidney malformations, we conducted an online survey among
Communicated by Jaan Toelen I. Alberici : W. Morello : G. Montini (*) Nephrology and Dialysis Unit, Department of Pediatrics, Azienda Ospedaliera Universitaria Sant’Orsola-Malpighi Bologna, Via Massarenti 11, 40138 Bologna, Italy e-mail: [email protected] I. Alberici e-mail: [email protected] W. Morello e-mail: [email protected] A. K. Bayazit Division of Pediatric Nephrology, School of Medicine, Cukurova University, Adana, Turkey e-mail: [email protected]
e-mail: [email protected] A. Jankauskiene Vilnius University Children Hospital, Vilnius, Lithuania e-mail: [email protected] M. Litwin Department of Nephrology, The Children’s Memorial Health Institute, Warsaw, Poland e-mail: [email protected] S. Mir Faculty of Medicine, Ege University, Izmir, Turkey e-mail: [email protected]
D. Drozdz Dialysis Unit, Jagielloniam University, Krakow, Poland e-mail: [email protected]
A. Peco-Antic Division of Pediatric Nephrology, University Children’s Hospital, Belgrade, Serbia e-mail: [email protected]
S. Emre Pediatric Nephrology Department, Istanbul Medical Faculty, Istanbul University, Istanbul, Turkey e-mail: [email protected]
P. Sallay Department of Pediatrics, Semmelweis University, Budapest, Hungary e-mail: [email protected]
M. Fischbach Service de Pédiatrie, Centre Hospitalier Universitaire Hautepierre, Strasbourg, France e-mail: [email protected]
L. Sever Cerrahpasa School of Medicine, Istanbul University, Istanbul, Turkey e-mail: [email protected]
J. Harambat Service de Pédiatrie, Centre de Reference Maladies Rénales Rares du Sud Ouest, Centre Hospitalier Universitaire de Bordeaux, Bordeaux, France
G. D. Simonetti Pediatric Nephrology, University Children’s Hospital, Bern, Switzerland e-mail: [email protected]
Eur J Pediatr
paediatric nephrologists on positive urine cultures (July 2010– June 2012) from both hospitalized and non-hospitalized infants under 24 months of age. We collected 4745 urine cultures (UCs) at 18 units in 10 European countries. Escherichia coli was the most frequent bacterium isolated from UCs; however, in 10/16 hospitals and in 6/15 community settings, E. coli was isolated in less than 50 % of the total positive UCs. Other bacterial strains were Klebsiella, Enterococcus, Proteus and Pseudomonas not only from hospital settings. E. coli showed a high resistance to amoxicillin and trimethoprim and variable to cephalosporin. Nitrofurantoin had a good rate of efficacy, with 11/16 hospitals and 11/14 community settings reporting a resistance lower than 5 %. Conclusion: E. coli is the most common organism causing UTIs in infants; however, other bacterial strains are frequently isolated. As a result, antibiotic prophylaxis should be more elastic and adaptable over time in order to guarantee maximum efficacy. Keywords Urinary tract infection . Antibiotic resistance . Infants . Escherichia coli . Urine culture Abbreviations CLSI Clinical and Laboratory Standards Institute EUCAST European Committee for Antimicrobial Susceptibility Testing P. Szczesniak Department Paediatrics, Nephrology and Hypertension, Medical University Gdansk, Gdansk, Poland e-mail: [email protected] A. Teixeira Pediatric Nephrology, University Children’s Hospital, Porto, Portugal e-mail: [email protected] E. Vidal Pediatric Nephrology, Dialysis and Transplantation Unit, Department of Pediatrics, University of Padova, Padova, Italy e-mail: [email protected] E. Wuehl : O. Mehls : F. Schaefer Division of Pediatric Nephrology, Center for Pediatrics and Adolescent Medicine, University of Heidelberg, Heidelberg, Germany E. Wuehl e-mail: [email protected] O. Mehls e-mail: [email protected] F. Schaefer e-mail: [email protected] L. T. Weber Pediatric Nephrology, Children’s and Adolescent’s Hospital, University Hospital of Cologne, Cologne, Germany e-mail: [email protected]
UCs UTI VUR
Urine cultures Urinary tract infection Vesico-ureteral reflux
Introduction Approximately 8 % of girls and 2 % of boys experience at least one urinary tract infection (UTI) during their first 8 years of life [20]. Some children are at increased UTI risk due to predisposing congenital factors favouring urine stasis, such as vesicoureteral reflux (VUR), neurogenic bladder and bladder instability [19, 26]. Most clinical practice guidelines recommend antibiotic prophylaxis for all children with reflux grades III–V and/ or relapsing infections [2, 31, 33] and reserve VUR surgery for patients with breakthrough UTIs while on prophylaxis. The NICE [27] and American Academy of Pediatrics guidelines [1] on the management of children with UTIs recommend choosing antibiotics with the lowest resistance profiles for treatment regimes, and this line of reasoning is also routinely followed as regards the choice of drug for prophylaxis. Antibiotic resistance of bacteria causing paediatric infections has reportedly increased dramatically in recent years [9]. Whereas the problem of antibiotic resistance used to be confined to hospital settings, it has become common also in community settings [16]. Furthermore, resistance patterns may vary regionally and nationally [5] for both nosocomial and community-acquired infections [32] and for both adults and children [14, 35]. The Escape Study [34] group has designed and initiated a randomized controlled study (PREDICT [11]: Antibiotic Prophylaxis and Renal Damage in Congenital abnormalities of the Kidney and Urinary Tract) in order to study and define the role of antibiotic prophylaxis in children with high grade VUR. As up-to-date knowledge of the distribution spectrum of causative organisms and their resistance patterns has become a core requirement for rational and effective management of UTI, we conducted a detailed online survey among European paediatric nephrologists with the aim of discovering the best antibiotic(s) for UTI prevention in children.
Materials and methods European Paediatric Nephrology units participating in the ESCAPE study group, with the support of their referral hospital microbiology units, were invited to complete a questionnaire on the web site www.surveymonkey.com. The survey focused on positive urine cultures (UCs) analyzed by the hospital microbiology laboratories, between 1 July 2010 and 30 June 2012, in infants under the age of 24 months. UCs from inpatients and from outpatients were analyzed separately. We considered inpatients to be children who were already
Eur J Pediatr
hospitalized at the moment of urine collection. As inpatient UTIs include not only nosocomial infections but also those that acquired less than 72 h prior to admission, we also refer to inpatient UTIs as “hospital setting” infections. We considered outpatients to be children who were not hospitalized at the moment of urine collection; therefore, outpatient infections are also referred to as community setting-acquired infections. Six laboratories (Bern, Belgrade, Adana, both hospitals from Istanbul and Izmir) determined Escherichia coli antimicrobial susceptibility using the Clinical and Laboratory Standards Institute (CLSI) standardized disk diffusion method, whereas 12 laboratories used the European Committee for Antimicrobial Susceptibility Testing (EUCAST) methodology. The topics discussed in the survey were the following: demographic characteristics, the spectrum of uropathogens isolated from UCs and E. coli patterns of resistance to the most frequently prescribed antibiotics. The information was reviewed, and queries were made in the case of implausibility.
Results Sample size Clinicians from 18 paediatric nephrology centres in 10 European countries (Bordeaux and Strasbourg in France; Heidelberg and Munich in Germany; Budapest from Hungary; Bologna and Padua in Italy; Vilnius in Lithuania; Gdansk, Krakow and Warsaw in Poland; Porto in Portugal; Bern in Switzerland; and Adana, 2 hospitals from Istanbul and Izmir in Turkey) completed the questionnaire. Information from 4745 positive UCs was obtained, of which, 60 % were from inpatients. Spectrum of microorganisms isolated from urine cultures Data for in- and for outpatients are summarized in Tables 1 and 2 which show the spectrum of bacteria isolated from UCs in 16 European hospitals. Data refer to the number
of centres reporting positive UCs for the ranges indicated for in- and outpatients. E. coli E. coli is the most frequent bacterium isolated from UCs in both hospital and community settings. In two hospitals (Belgrade and Izmir) and in four community settings (Bordeaux, Budapest, Izmir and Porto), E. coli was isolated in more than 80 % of the positive UCs, whereas in 10/16 hospitals and in 6/15 community settings, E. coli comprised less than 50 % of organisms in the positive UCs. Fractions of E. coli-positive UCs were more similar within than between countries (France 51–80 %, Italy 35–39 % and Poland 31– 45 %), except for Turkey (Istanbul 31 %, Adana 46 % and Izmir 81–100 %) (Fig. 1). Enterococcus spp. Most laboratories can differentiate between Enterococcus faecalis and Enterococcus faecium (14/ 18); however, no differences in distribution between E. faecalis and E. faecium were observed, with the majority of hospitals reporting less than 10 % of UCs positive for Enterococci. There were higher percentages of Enterococci in Istanbul and Vilnius (inpatients), Izmir and Gdansk (outpatients) and Heidelberg and Bologna (both in- and outpatients). Klebsiella spp. Klebsiella spp. were isolated in more than 10 % of UCs in all the Turkish hospitals, both for in (one centre >50 %) and outpatients. As regards the rest of Europe, the majority of countries reported lower, but variable, percentages of UCs positive for Klebsiella. Proteus spp. In hospitalized patients, UCs positive for Proteus spp. were reported to be between 1 and 10 % in almost all centres, except for Porto (23 % of UCs). Similar results were noted for non-hospitalized patients, with the highest percentage of Proteus being seen in Belgrade, Gdansk and Warsaw.
Table 1 The spectrum of bacteria isolated from UCs in 16 European hospitals. Data refer to the number of centres reporting positive UCs for the ranges indicated for inpatients IN
% Range of positive UC
No. of responders
0 1–5 6–10 11–30 31–50 51–80 81–100
E.coli
Enterococcus faecalis
Enterococcus faecium
Klebsiella
Proteus
Pseudomonas
Staph. coag. neg.
0 0 0 0 10 4 2 16
2 4 6 4 0 0 0 16
2 8 2 0 0 0 0 12
1 4 4 6 0 1 0 16
1 9 5 1 0 0 0 16
0 6 5 5 0 0 0 16
7 8 1 0 0 0 0 16
Eur J Pediatr Table 2 The spectrum of bacteria isolated from UCs in 16 European hospitals. Data refer to the number of centres reporting positive UCs for the ranges indicated for outpatients OUT
% Range of positive UC
No. of responders
0 1–5 6–10 11–30 31–50 51–80 81–100
E.coli
Enterococcus faecalis
Enterococcus faecium
Klebsiella
Proteus
Pseudomonas
Staph. coag. neg.
0 0 0 1 5 5 4 15
0 6 5 4 0 0 0 15
4 7 1 0 0 0 0 12
0 6 4 4 1 0 0 15
0 7 5 3 0 0 0 15
2 6 5 2 0 0 0 15
5 9 1 0 0 0 0 15
Pseudomonas spp. Five hospitals reported over 10 % of UCs of hospitalized children positive for Pseudomonas spp., while Budapest and Porto reported more than 10 % of UCs positive for Pseudomonas spp. in outpatients. Pseudomonas spp. were isolated in less than 5 % of UCs by 6/16 of the responders for inpatients and 8/15 for outpatients. E. coli resistance pattern Focusing on E. coli-positive urine cultures, our survey was designed to collect data regarding susceptibility of the germ to the most commonly used antibiotics. E. coli resistance patterns from in- and outpatient UCs are summarized in Figs. 2 and 3 . Amoxicillin and trimethoprim showed a very high resistance in all hospitals participating in the survey. More than 50 % of isolated E. coli were resistant to amoxicillin in 14/16 centres for inpatients and in 8/ 15 for outpatients. Similarly, trimethoprim has a percentage of resistance greater than 20 % in all centres for inpatients and 8/ 15 centres for outpatients. We analyzed sensitivity to group II and group III oral cephalosporins; however, 3/18 laboratories were not able to test the group III cephalosporin. Data showed a wide distribution of resistance percentages, with a slightly worse profile for group II cephalosporin and for hospitalized
children vs outpatients and for all children from Turkey, irrespective of hospitalization. There is also a very wide variability in resistance to co-amoxiclavulanate among the centres, with two hospitals reporting an E. coli resistance rate of more than 50 % for inpatients. As regards outpatients, the E. coli resistance rate to co-amoxiclavulanate ranges between 20 and 50 % in six centres. Lithuania, Poland and Switzerland reported the best profile towards this antimicrobial agent. Nitrofurantoin has a good rate of efficacy, with 11/16 hospitals reporting a resistance lower than 5 %. In contrast, a higher rate of resistance was found in Poland (11–20 %), one Italian hospital (25 %) and one Turkish centre (>50 %).
Discussion The size of the problem Monitoring of the microbial agents involved and local antibiotic resistance patterns has recently been recognized as a key element in guiding antimicrobial prescription [22] and is now
Fig. 1 Percentages of UC positive for E. coli from in- and outpatients for each city
Eur J Pediatr Fig. 2 Inpatient UCs: prevalence of E. coli resistance rates to the listed antibiotics
considered essential in combatting the growing problem of increasing resistance rates [3, 8, 29], particularly in the context of relapsing UTIs and prophylactic antibiotic therapy. A recent attempt to standardize a surveillance method for antimicrobial use in children hospitalized in Europe was made through a point prevalence survey, but data are not yet available [36]. In Europe, there exists a well-established pan European surveillance network of antibiotic resistance (EARS-NET) which includes national data from around 900 public health laboratories [15]. Unfortunately, it does not focus on either children 0–2 years old or bacteria isolated from urine cultures. Focusing on the area of paediatric nephrology, national reports on antimicrobial resistance trends, including age-specific trends, are currently available for almost every country in Europe [24, 30, 37] as well as for large cohorts in America [17, 23]. With a collection of 4745 positive UCs from 10 different European nations, this survey allows for a more global understanding of European practices.
Fig. 3 Outpatient UCs: prevalence of E. coli resistance rates to the listed antibiotics
Spectrum of uropathogens Data on uropathogens isolated from UCs in children less than 2 years of age showed E. coli to be the most prevalent bacteria in every health-care setting, especially as regards outpatients. These results are in agreement with data reported in the literature [24], which demonstrate that E. coli is the main bacteria responsible for UTIs. However, its prevalence has decreased over the past decade [13]. In this survey, in 10 hospitals from Italy, Poland, Switzerland, Turkey and Germany, E. coli was responsible for less than 50 % of all the positive inpatient UCs. In the community setting, 6/16 centres reported E. coli isolated in less than 50 %. Hence, in the majority of hospitals participating in the survey, as in a third of the community settings, more than 50 % of UCs were positive for non-E. coli bacteria, in contrast with data from the literature which reported 60 to 80 % of UTI caused by E. coli [24, 28]. As regards inpatients, the loss of E. coli supremacy in our
Eur J Pediatr
survey could be partially explained by the supposed high percentage of children with underlying kidney problems that can be found in a hospital setting, especially considering the fact that the centres involved in the survey are tertiary care referral centres for nephrology. On the other hand, data from outpatients confirm the high non-E. coli rate isolated from UCs. Similar percentages of UCs positive for E. coli were found in the two centres from France; the same occurrence was also noted in the two Italian centres and those from Poland, while centres from Turkey reported wider ranges, probably because of the large geographical area covered. Klebsiella spp. were isolated in a consistent number of UCs (>11 %) in Turkey and Poland, following a recently reported trend [7]. Enterococcus spp. were often isolated, as expected considering the age of our cohort [17]. As reported in previous studies [25], non-E. coli pathogens are more resistant to most antimicrobial agents (amoxicillin-clavulanate, cephalosporin, nitrofurantoin and amikacin); thus, empirical antibiotic therapy may not always be appropriate. E. coli resistance pattern We chose to evaluate resistance patterns of E. coli, the dominant causative organism in paediatric UTI and the main target of antibiotic treatment. Our survey confirmed a universally very high resistance rate towards amoxicillin, exceeding 50 % for almost all centres. These data confirm that amoxicillin is not an option in any setting. Past studies demonstrated very high resistance of uropathogens (E. coli, Klebsiella) to penicillins, either ampicillin or amoxicillin, which are still increasing today [7] and even more so in children than in adults [6]. On the other hand, our findings suggest that the combination of amoxicillin and clavulanate appears as a good antimicrobial option in UTIs, with resistance rates below 20 % in many countries. This is particularly true for outpatients in whom a lower previous cumulative exposure to antibiotics can be assumed. Our data suggest a large geographic variability in the co-amoxiclavulanate resistance rate in keeping with previous studies [4] and pointing to the need to consider local resistance patterns in the choice of antimicrobial therapy. Trimethoprim was seen to be just as resistant as amoxicillin to E. coli isolated from hospitalized children. In the past, trimethoprim was the antibiotic of choice for UTI prophylaxis, and although data show a very marked increase in resistance rates, it remains the preferred prophylactic agent according to some authors [10]. Its widespread prophylactic use is the most likely explanation for the very high prevalence of trimethoprim-resistant E. coli spp. throughout Europe. Data regarding oral cephalosporin showed large variability among countries in accordance with the literature. Even within the same country, cephalosporin resistance rates could vary so markedly that this class of drug would be an appropriate antibiotic choice in some centres, but not in others. As regards
E. coli resistance rate to cephalosporin group 3, a north–south decreasing trend was observed throughout Europe. This could be explained by the more frequent prescription of antibiotics in southern European countries than in the northern European countries, where antibiotics are less likely to be inappropriately prescribed [18]. Nitrofurantoin had a remarkably good sensitivity in almost all countries, in particular towards E. coli isolated from outpatients. Adverse reactions to nitrofurantoin have been reported mainly in adults [21] and less often in children [12]. Limitations A limitation of our survey was that, as we were expecting a higher E. coli rate, we did not inquire into antibiotic resistance rate vs other uropathogens. Similarly, expecting lower antibiotic resistance rates, we provided ranges for multiple choice questions which were probably too wide, and as a result, we are not able to balance the reported data on the spectrum of uropathogens, as well as antibiotic resistance, compared to the number of urine cultures provided by each unit. Furthermore, many, but not all, countries participating in the PREDICT trial completed the survey. Another limitation of the study was that almost all the centres answering the questionnaire were referral hospitals for paediatric nephrology patients; consequently, a selection bias of children with congenital abnormalities of the kidney and urinary tract was a possibility. However, all these hospitals prevalently treat a large number of children from the general paediatric population from whom the data was obtained. A final limitation of the survey was that it was not possible to match our data with clinical information.
Conclusion In conclusion, our data confirm that E. coli is still the most common single organism causing UTIs in children under 2 years of age; however, other bacterial strains are now more frequently isolated from UCs than in the past. This variability has a direct effect on the therapeutic choices made by physicians. As regards antimicrobial prophylaxis, our data demonstrate that E. coli uropathogens have the lowest rate of resistance to nitrofurantoin throughout Europe, apart from some isolated but important exceptions. Nitrofurantoin should theoretically be considered, in the majority of settings, as the antibiotic of choice for prophylaxis, but it is not approved or recommended in all countries due to safety and tolerability concerns. The other antibiotics show a large variation in in vitro sensitivity rates, even within individual countries. As a result, antibiotic prophylaxis should be more flexible and adaptable over time in order to guarantee maximum efficacy; fixed schemes are no longer acceptable. This philosophy was
Eur J Pediatr
applied in the design of the PREDICT Trial protocol in which antibiotic prophylaxis will be given to children for a period of 2 years. Considering the wide geographical area and the long duration of the trial, it was essential not to be mandatory in the choice of antibiotic for the prophylaxis arm of the study. In fact, the PREDICT protocol suggests four different schemes for antibiotic prophylaxis, permitting clinicians to choose the best antibiotic for their patients based on local resistance patterns. Acknowledgments Thanks to all the microbiology departments for the support given to the authors in the selection of the data: Simone Ambretti (Bologna), Akgun Yaman (Adana), Joanna Klepacka (Krakow), Derya Aydin (Istanbul), Jaulhac Benoit (Strasbourg), Emilie Bessede (Bordeaux), Genovaite Bernatoniene (Vilnius), Suzana Laban-Nestorović (Belgrade), Eva Kenesei (Budapest), Nigar Çelik Özer (Istanbul), SC Droz (Bern), Anna Komarnicka (Gdansk), Lucia Rossi (Padova), Irene Burckhardt (Heidelberg) and Johannes Huebner (Munich).
14.
15.
16. 17.
18.
19. 20.
References
21.
1. Academy of Pediatrics subcommittee on Urinary Tract Infection, Steering Committee on Quality Improvement and Management (2011) Urinary Tract Infection: clinical practice guideline for the diagnosis and management of the initial UTI in febrile infants and children 2 to 24 months. Pediatrics 128:595 2. Ammenti A, Cataldi L, Chimenz R, Fanos V, La Manna A, Marra G, Materassi M, Pecile P, Pennesi M, Pisanello L, Sica F, Toffolo A, Montini G, Italian Society of Pediatric Nephrology (2012) Febrile urinary tract infection in young children. Recommendations for the diagnosis, treatment and follow-up. Acta Paediatr 101(5):451–457 3. Ashkenazi S (2012) Beginning and possibility the end of the antibiotic era. J Paediatr Child Health 49:E179–E182 4. Beetz R, Westenfelder M (2011) Antimicrobial therapy of urinary tract infections in children. Int J Antimicrob Agents 38:42–50 5. Bertrand X, Dowzick MJ (2012) Antimicrobial susceptibility among gram-negative isolates collected from intensive care units in north America, Europe, the Asia-pacific rim, Latin America, the Middle East, and Africa between 2004 and 2009 as part of the tigecycline evaluation and surveillance trial. Clin Ther 34(1):124–137 6. Boggan J, Navar-Boggan A, Jhaveri R (2012) Pediatric-specific antimicrobial susceptibility data and empiric antibiotic selection. Pediatrics 130:e615–e622 7. Catal F, Bavbek N, Bayrak O, Karabel M, Karabel D, Odemis E, Uz E (2009) Antimicrobial resistance patterns of urinary tract pathogens and rationale for empirical therapy in Turkish children for the years 2000–2006. Int Urol Nephrol 41:953–957 8. CDC Antibiotic resistance threats in the United States 2013[http:// www.cdc.gov/drugresistance/threat-report-2013] 9. Chavez-Bueno S, Stull TL (2009) Antibacterial agents in pediatrics. Infect Dis Clin N Am 23:865–880 10. Cheng C, Tsai MH, Huang YC, Su LH, Tsau YK, Lin CJ, Chiu CH, Lin TY (2008) antibiotic resistance patterns of community-acquired urinary tract infections in children with vesicoureteral reflux receiving prophylactic antibiotic therapy. Pediatrics 122:1212–1217 11. ClinicalTrials.gov Identifier: NCT02021006 12. Coraggio MJ, Gross TP, Roscelli JD (1989) Nitrofurantoin toxicity in children. J Pediatr Infect Dis 8:163–168 13. Cullen IM, Manecksha RP, McCullagh E, Ahmad S, O’Kelly F, Flynn R, McDermott TE, Murphy P, Grainger R, Fennell JP, Thornhill JA (2013) An 11-year analysis of the prevalent
22.
23.
24. 25.
26.
27.
28.
29. 30.
31.
32.
uropathogens and the changing pattern of Escherichia coli antibiotic resistance in 38,530 community urinary tract infections, Dubllin 1999–2009. Ir J Med Sci 182:81–89 David MZ, Crawford SE, Boyle-Vavra S, Hostetler AM, Kim DC, Daum RS (2006) Contrasting pediatric and adult methicillin-resistant Staphylococcus aureus isolates. Emerg Infect Dis 12(4):631–637 ECDC Antimicrobial resistance interactive database [http://www. ecdc.europa.eu/en/healthtopics/antimicrobial_resistance/database/ Pages/database.aspx] Elliott SP (2008) Antimicrobial-resistant pathogens: an emerging pediatric threat. Adv Pediatr 55(1):329–348 Gaspari R, Dickson E, Karlowsky J, Doern G (2005) Antibiotic resistance trends in paediatric uropathogens. Int J Antimicrob Agents 26:267–271 Goossen H, Ferech M, Stichele RV, Elseviers M, for the ESAC Project Group (2005) Outpatient antibiotic use in Europe and association with resistance: a cross-national database study. Lancet 365: 379–387 Hellerstein S (1982) Recurrent urinary tract infection in children. Pediatr Infect Dis J 1:271–281 Hellström A, Hanson E, Hansson S, Hjälmås K, Jodal U (1991) Association between urinary symptoms at 7 years old and previous urinary tract infection. Arch Dis Child 66(2):232–234 Holmberg L, Boman G, Böttiger LE, Eriksson B, Spross R, Wessling A (1980) Adverse reactions to nitrofurantoin. Analysis of 921 reports. Am I Med 69:733–738 Hyun D, Hersh A, Namtu K, Palazzi D, Maples H, Newland J, Saiman L (2013) Antimicrobial stewardship in pediatrics: How every pediatrician can be a steward. JAMA Pediatr 167(9):859–866 Karlowsky J, Karlowsky JA, Lagacé-Wiens PRS, Simner PJ, DeCorby MR, Adam HJ, Walkty A, Hoban DJ, Zhanel GG (2011) Antimicrobial resistance in urinary tract pathogens in Canada from 2007 to 2009: CANWARD Surveillance Study. Antimicrob Agents Chemotherapy 55:3169–3175 Ladhani S, Gransden W (2003) Increasing antibiotic resistance among urinary tract isolates. Arch Dis Child 88:444–445 Marcus N, Ashkenazi S, Yaari A, Samra Z, Livni G (2005) NonEscherichia coli versus Escherichia coli community-acquired urinary tract infections in children hospitalized in a tertiary center. Pediatr Infect Dis J 24:581–585 Montini G, Rigon L, Zucchetta P, Fregonese F, Toffolo A, Gobber D, Cecchin D, Pavanello L, Molinari PP, Maschio F, Zanchetta S, Cassar W, Casadio L, Crivellaro C, Fortunati P, Corsini A, Calderan A, Comacchio S, Tommasi L, Hewitt IK, Da Dalt L, Zaccheelo G, Dall’Amico R, IRIS Group (2008) Prophylaxis after first febrile urinary tract infection in children? A multicenter, randomized, controlled, non inferiority trial. Pediatrics 122(5):1064–1071 National Institute for Health and Clinical Excellence. Urinary tract infection in children: diagnosis, treatment and long term management. August 2007. [www.nice.org.uk/guidance/CG54] Newman TB, Bernzweig JA, Takayama JI, Finch SA, Wasserman RC, Pantell RH (2002) Urine testing and urinary tract infections in febrile infants seen in office settings: the Pediatric Research in Office Settings’ Febrile Infant Study. Arch Pediatr Adolesc Med 156:44–54 O’Brien TF (2011) What has kept the antibiotic miracle alive? N Engl J Med 365:953–955 Peco-Antic A, Paripovic D, Buljugic S, Kruscic D, Spasojevic B, Cvetkovic M, Kostic M, Laban-Nestorovic S, Milosevski-Lomic G (2012) Antibiotic resistance of uropathogens in newborn and young children with acute pyelonephritis. Srp Arh Celok Lek 140:179–183 Peters CA, Skoog SJ, Arant BS Jr, Coppo HL, Elder JS, Hudson RG, Khoury AE, Lorenzo AJ, Pohl HG, Shapiro E, Snodgrass WT, Diaz M (2010) Summary of the AUA Guidelines on management of primary vesicoureteral reflux in children. J Urol 184:1134–1144 Smith SP, Manges AR, Riley LW (2008) Temporal changes in the prevalence of community-acquired antimicrobial-resistant urinary
Eur J Pediatr tract infection affected by Escherichia coli clonal group composition. Clin Infect Dis 46(5):689–695 33. Tekgül S, Riedmiller H, Hoebeke P, Kocvara R, Nijman RJ, Radmayr C, Stein R, Dogan HS, European Association of Urology (2012) EAU Guidelines on vesicoureteral reflux in children. Eur Urol 62:534–542 34. The ESCAPE Trial Group (2009) Strict blood-pressure control and progression of renal failure in children. N Engl J Med 361:1639–1650 35. Tonkic M, Barisk IG, Punda-Polic V (2005) Prevalence and antimicrobial resistance of extended-spectrum beta-lactamases-producing Escherichia coli and Klebsiella pneumoniae strains isolated in a university hospital in Split, Croatia. Int Microbiol 8(2):119–124
36. Versporten A, Sharland M, Bielicki J, Drapier N, Vankerckhoven V, Goossens H (2012) The antibiotic resistance and prescribing in European Children project: a neonatal and pediatric antimicrobial web-based point prevalence survey in 73 hospitals worldwide. Pediatr Infect Dis J 32: e242–e253 37. Yuksel S, Oztürk B, Kavaz A, Ozçakar ZB, Acar B, Güriz H, Aysev D, Ekim M, Yalçinkaya F (2006) Antibiotic resistance of urinary tract pathogens and evaluation of empirical treatment in Turkish children with urinary tract infectious. Int J Antimicrob Agents 28:413–416
ORIGINAL ARTICLE
Pathogens causing urinary tract infections in infants: a European overview by the ESCAPE study group Irene Alberici & Aysun Karabay Bayazit & Dorota Drozdz & Sevinç Emre & Michel Fischbach & Jérôme Harambat & Augustina Jankauskiene & Mieczyslaw Litwin & Sevgi Mir & William Morello & Amira Peco-Antic & Peter Sallay & Lale Sever & Giacomo D. Simonetti & Przemyslaw Szczesniak & Ana Teixeira & Enrico Vidal & Elke Wuehl & Otto Mehls & Lutz T. Weber & Franz Schaefer & Giovanni Montini & for the ESCAPE study group and the PREDICT trial
Received: 26 August 2014 / Revised: 9 October 2014 / Accepted: 12 November 2014 # Springer-Verlag Berlin Heidelberg 2014
Abstract Knowledge of the distribution spectrum of causative organisms and their resistance patterns has become a core requirement for the rational and effective management of
urinary tract infections. In the context of a prospective trial on the use of antibiotic prophylaxis in infants with underling kidney malformations, we conducted an online survey among
Communicated by Jaan Toelen I. Alberici : W. Morello : G. Montini (*) Nephrology and Dialysis Unit, Department of Pediatrics, Azienda Ospedaliera Universitaria Sant’Orsola-Malpighi Bologna, Via Massarenti 11, 40138 Bologna, Italy e-mail: [email protected] I. Alberici e-mail: [email protected] W. Morello e-mail: [email protected] A. K. Bayazit Division of Pediatric Nephrology, School of Medicine, Cukurova University, Adana, Turkey e-mail: [email protected]
e-mail: [email protected] A. Jankauskiene Vilnius University Children Hospital, Vilnius, Lithuania e-mail: [email protected] M. Litwin Department of Nephrology, The Children’s Memorial Health Institute, Warsaw, Poland e-mail: [email protected] S. Mir Faculty of Medicine, Ege University, Izmir, Turkey e-mail: [email protected]
D. Drozdz Dialysis Unit, Jagielloniam University, Krakow, Poland e-mail: [email protected]
A. Peco-Antic Division of Pediatric Nephrology, University Children’s Hospital, Belgrade, Serbia e-mail: [email protected]
S. Emre Pediatric Nephrology Department, Istanbul Medical Faculty, Istanbul University, Istanbul, Turkey e-mail: [email protected]
P. Sallay Department of Pediatrics, Semmelweis University, Budapest, Hungary e-mail: [email protected]
M. Fischbach Service de Pédiatrie, Centre Hospitalier Universitaire Hautepierre, Strasbourg, France e-mail: [email protected]
L. Sever Cerrahpasa School of Medicine, Istanbul University, Istanbul, Turkey e-mail: [email protected]
J. Harambat Service de Pédiatrie, Centre de Reference Maladies Rénales Rares du Sud Ouest, Centre Hospitalier Universitaire de Bordeaux, Bordeaux, France
G. D. Simonetti Pediatric Nephrology, University Children’s Hospital, Bern, Switzerland e-mail: [email protected]
Eur J Pediatr
paediatric nephrologists on positive urine cultures (July 2010– June 2012) from both hospitalized and non-hospitalized infants under 24 months of age. We collected 4745 urine cultures (UCs) at 18 units in 10 European countries. Escherichia coli was the most frequent bacterium isolated from UCs; however, in 10/16 hospitals and in 6/15 community settings, E. coli was isolated in less than 50 % of the total positive UCs. Other bacterial strains were Klebsiella, Enterococcus, Proteus and Pseudomonas not only from hospital settings. E. coli showed a high resistance to amoxicillin and trimethoprim and variable to cephalosporin. Nitrofurantoin had a good rate of efficacy, with 11/16 hospitals and 11/14 community settings reporting a resistance lower than 5 %. Conclusion: E. coli is the most common organism causing UTIs in infants; however, other bacterial strains are frequently isolated. As a result, antibiotic prophylaxis should be more elastic and adaptable over time in order to guarantee maximum efficacy. Keywords Urinary tract infection . Antibiotic resistance . Infants . Escherichia coli . Urine culture Abbreviations CLSI Clinical and Laboratory Standards Institute EUCAST European Committee for Antimicrobial Susceptibility Testing P. Szczesniak Department Paediatrics, Nephrology and Hypertension, Medical University Gdansk, Gdansk, Poland e-mail: [email protected] A. Teixeira Pediatric Nephrology, University Children’s Hospital, Porto, Portugal e-mail: [email protected] E. Vidal Pediatric Nephrology, Dialysis and Transplantation Unit, Department of Pediatrics, University of Padova, Padova, Italy e-mail: [email protected] E. Wuehl : O. Mehls : F. Schaefer Division of Pediatric Nephrology, Center for Pediatrics and Adolescent Medicine, University of Heidelberg, Heidelberg, Germany E. Wuehl e-mail: [email protected] O. Mehls e-mail: [email protected] F. Schaefer e-mail: [email protected] L. T. Weber Pediatric Nephrology, Children’s and Adolescent’s Hospital, University Hospital of Cologne, Cologne, Germany e-mail: [email protected]
UCs UTI VUR
Urine cultures Urinary tract infection Vesico-ureteral reflux
Introduction Approximately 8 % of girls and 2 % of boys experience at least one urinary tract infection (UTI) during their first 8 years of life [20]. Some children are at increased UTI risk due to predisposing congenital factors favouring urine stasis, such as vesicoureteral reflux (VUR), neurogenic bladder and bladder instability [19, 26]. Most clinical practice guidelines recommend antibiotic prophylaxis for all children with reflux grades III–V and/ or relapsing infections [2, 31, 33] and reserve VUR surgery for patients with breakthrough UTIs while on prophylaxis. The NICE [27] and American Academy of Pediatrics guidelines [1] on the management of children with UTIs recommend choosing antibiotics with the lowest resistance profiles for treatment regimes, and this line of reasoning is also routinely followed as regards the choice of drug for prophylaxis. Antibiotic resistance of bacteria causing paediatric infections has reportedly increased dramatically in recent years [9]. Whereas the problem of antibiotic resistance used to be confined to hospital settings, it has become common also in community settings [16]. Furthermore, resistance patterns may vary regionally and nationally [5] for both nosocomial and community-acquired infections [32] and for both adults and children [14, 35]. The Escape Study [34] group has designed and initiated a randomized controlled study (PREDICT [11]: Antibiotic Prophylaxis and Renal Damage in Congenital abnormalities of the Kidney and Urinary Tract) in order to study and define the role of antibiotic prophylaxis in children with high grade VUR. As up-to-date knowledge of the distribution spectrum of causative organisms and their resistance patterns has become a core requirement for rational and effective management of UTI, we conducted a detailed online survey among European paediatric nephrologists with the aim of discovering the best antibiotic(s) for UTI prevention in children.
Materials and methods European Paediatric Nephrology units participating in the ESCAPE study group, with the support of their referral hospital microbiology units, were invited to complete a questionnaire on the web site www.surveymonkey.com. The survey focused on positive urine cultures (UCs) analyzed by the hospital microbiology laboratories, between 1 July 2010 and 30 June 2012, in infants under the age of 24 months. UCs from inpatients and from outpatients were analyzed separately. We considered inpatients to be children who were already
Eur J Pediatr
hospitalized at the moment of urine collection. As inpatient UTIs include not only nosocomial infections but also those that acquired less than 72 h prior to admission, we also refer to inpatient UTIs as “hospital setting” infections. We considered outpatients to be children who were not hospitalized at the moment of urine collection; therefore, outpatient infections are also referred to as community setting-acquired infections. Six laboratories (Bern, Belgrade, Adana, both hospitals from Istanbul and Izmir) determined Escherichia coli antimicrobial susceptibility using the Clinical and Laboratory Standards Institute (CLSI) standardized disk diffusion method, whereas 12 laboratories used the European Committee for Antimicrobial Susceptibility Testing (EUCAST) methodology. The topics discussed in the survey were the following: demographic characteristics, the spectrum of uropathogens isolated from UCs and E. coli patterns of resistance to the most frequently prescribed antibiotics. The information was reviewed, and queries were made in the case of implausibility.
Results Sample size Clinicians from 18 paediatric nephrology centres in 10 European countries (Bordeaux and Strasbourg in France; Heidelberg and Munich in Germany; Budapest from Hungary; Bologna and Padua in Italy; Vilnius in Lithuania; Gdansk, Krakow and Warsaw in Poland; Porto in Portugal; Bern in Switzerland; and Adana, 2 hospitals from Istanbul and Izmir in Turkey) completed the questionnaire. Information from 4745 positive UCs was obtained, of which, 60 % were from inpatients. Spectrum of microorganisms isolated from urine cultures Data for in- and for outpatients are summarized in Tables 1 and 2 which show the spectrum of bacteria isolated from UCs in 16 European hospitals. Data refer to the number
of centres reporting positive UCs for the ranges indicated for in- and outpatients. E. coli E. coli is the most frequent bacterium isolated from UCs in both hospital and community settings. In two hospitals (Belgrade and Izmir) and in four community settings (Bordeaux, Budapest, Izmir and Porto), E. coli was isolated in more than 80 % of the positive UCs, whereas in 10/16 hospitals and in 6/15 community settings, E. coli comprised less than 50 % of organisms in the positive UCs. Fractions of E. coli-positive UCs were more similar within than between countries (France 51–80 %, Italy 35–39 % and Poland 31– 45 %), except for Turkey (Istanbul 31 %, Adana 46 % and Izmir 81–100 %) (Fig. 1). Enterococcus spp. Most laboratories can differentiate between Enterococcus faecalis and Enterococcus faecium (14/ 18); however, no differences in distribution between E. faecalis and E. faecium were observed, with the majority of hospitals reporting less than 10 % of UCs positive for Enterococci. There were higher percentages of Enterococci in Istanbul and Vilnius (inpatients), Izmir and Gdansk (outpatients) and Heidelberg and Bologna (both in- and outpatients). Klebsiella spp. Klebsiella spp. were isolated in more than 10 % of UCs in all the Turkish hospitals, both for in (one centre >50 %) and outpatients. As regards the rest of Europe, the majority of countries reported lower, but variable, percentages of UCs positive for Klebsiella. Proteus spp. In hospitalized patients, UCs positive for Proteus spp. were reported to be between 1 and 10 % in almost all centres, except for Porto (23 % of UCs). Similar results were noted for non-hospitalized patients, with the highest percentage of Proteus being seen in Belgrade, Gdansk and Warsaw.
Table 1 The spectrum of bacteria isolated from UCs in 16 European hospitals. Data refer to the number of centres reporting positive UCs for the ranges indicated for inpatients IN
% Range of positive UC
No. of responders
0 1–5 6–10 11–30 31–50 51–80 81–100
E.coli
Enterococcus faecalis
Enterococcus faecium
Klebsiella
Proteus
Pseudomonas
Staph. coag. neg.
0 0 0 0 10 4 2 16
2 4 6 4 0 0 0 16
2 8 2 0 0 0 0 12
1 4 4 6 0 1 0 16
1 9 5 1 0 0 0 16
0 6 5 5 0 0 0 16
7 8 1 0 0 0 0 16
Eur J Pediatr Table 2 The spectrum of bacteria isolated from UCs in 16 European hospitals. Data refer to the number of centres reporting positive UCs for the ranges indicated for outpatients OUT
% Range of positive UC
No. of responders
0 1–5 6–10 11–30 31–50 51–80 81–100
E.coli
Enterococcus faecalis
Enterococcus faecium
Klebsiella
Proteus
Pseudomonas
Staph. coag. neg.
0 0 0 1 5 5 4 15
0 6 5 4 0 0 0 15
4 7 1 0 0 0 0 12
0 6 4 4 1 0 0 15
0 7 5 3 0 0 0 15
2 6 5 2 0 0 0 15
5 9 1 0 0 0 0 15
Pseudomonas spp. Five hospitals reported over 10 % of UCs of hospitalized children positive for Pseudomonas spp., while Budapest and Porto reported more than 10 % of UCs positive for Pseudomonas spp. in outpatients. Pseudomonas spp. were isolated in less than 5 % of UCs by 6/16 of the responders for inpatients and 8/15 for outpatients. E. coli resistance pattern Focusing on E. coli-positive urine cultures, our survey was designed to collect data regarding susceptibility of the germ to the most commonly used antibiotics. E. coli resistance patterns from in- and outpatient UCs are summarized in Figs. 2 and 3 . Amoxicillin and trimethoprim showed a very high resistance in all hospitals participating in the survey. More than 50 % of isolated E. coli were resistant to amoxicillin in 14/16 centres for inpatients and in 8/ 15 for outpatients. Similarly, trimethoprim has a percentage of resistance greater than 20 % in all centres for inpatients and 8/ 15 centres for outpatients. We analyzed sensitivity to group II and group III oral cephalosporins; however, 3/18 laboratories were not able to test the group III cephalosporin. Data showed a wide distribution of resistance percentages, with a slightly worse profile for group II cephalosporin and for hospitalized
children vs outpatients and for all children from Turkey, irrespective of hospitalization. There is also a very wide variability in resistance to co-amoxiclavulanate among the centres, with two hospitals reporting an E. coli resistance rate of more than 50 % for inpatients. As regards outpatients, the E. coli resistance rate to co-amoxiclavulanate ranges between 20 and 50 % in six centres. Lithuania, Poland and Switzerland reported the best profile towards this antimicrobial agent. Nitrofurantoin has a good rate of efficacy, with 11/16 hospitals reporting a resistance lower than 5 %. In contrast, a higher rate of resistance was found in Poland (11–20 %), one Italian hospital (25 %) and one Turkish centre (>50 %).
Discussion The size of the problem Monitoring of the microbial agents involved and local antibiotic resistance patterns has recently been recognized as a key element in guiding antimicrobial prescription [22] and is now
Fig. 1 Percentages of UC positive for E. coli from in- and outpatients for each city
Eur J Pediatr Fig. 2 Inpatient UCs: prevalence of E. coli resistance rates to the listed antibiotics
considered essential in combatting the growing problem of increasing resistance rates [3, 8, 29], particularly in the context of relapsing UTIs and prophylactic antibiotic therapy. A recent attempt to standardize a surveillance method for antimicrobial use in children hospitalized in Europe was made through a point prevalence survey, but data are not yet available [36]. In Europe, there exists a well-established pan European surveillance network of antibiotic resistance (EARS-NET) which includes national data from around 900 public health laboratories [15]. Unfortunately, it does not focus on either children 0–2 years old or bacteria isolated from urine cultures. Focusing on the area of paediatric nephrology, national reports on antimicrobial resistance trends, including age-specific trends, are currently available for almost every country in Europe [24, 30, 37] as well as for large cohorts in America [17, 23]. With a collection of 4745 positive UCs from 10 different European nations, this survey allows for a more global understanding of European practices.
Fig. 3 Outpatient UCs: prevalence of E. coli resistance rates to the listed antibiotics
Spectrum of uropathogens Data on uropathogens isolated from UCs in children less than 2 years of age showed E. coli to be the most prevalent bacteria in every health-care setting, especially as regards outpatients. These results are in agreement with data reported in the literature [24], which demonstrate that E. coli is the main bacteria responsible for UTIs. However, its prevalence has decreased over the past decade [13]. In this survey, in 10 hospitals from Italy, Poland, Switzerland, Turkey and Germany, E. coli was responsible for less than 50 % of all the positive inpatient UCs. In the community setting, 6/16 centres reported E. coli isolated in less than 50 %. Hence, in the majority of hospitals participating in the survey, as in a third of the community settings, more than 50 % of UCs were positive for non-E. coli bacteria, in contrast with data from the literature which reported 60 to 80 % of UTI caused by E. coli [24, 28]. As regards inpatients, the loss of E. coli supremacy in our
Eur J Pediatr
survey could be partially explained by the supposed high percentage of children with underlying kidney problems that can be found in a hospital setting, especially considering the fact that the centres involved in the survey are tertiary care referral centres for nephrology. On the other hand, data from outpatients confirm the high non-E. coli rate isolated from UCs. Similar percentages of UCs positive for E. coli were found in the two centres from France; the same occurrence was also noted in the two Italian centres and those from Poland, while centres from Turkey reported wider ranges, probably because of the large geographical area covered. Klebsiella spp. were isolated in a consistent number of UCs (>11 %) in Turkey and Poland, following a recently reported trend [7]. Enterococcus spp. were often isolated, as expected considering the age of our cohort [17]. As reported in previous studies [25], non-E. coli pathogens are more resistant to most antimicrobial agents (amoxicillin-clavulanate, cephalosporin, nitrofurantoin and amikacin); thus, empirical antibiotic therapy may not always be appropriate. E. coli resistance pattern We chose to evaluate resistance patterns of E. coli, the dominant causative organism in paediatric UTI and the main target of antibiotic treatment. Our survey confirmed a universally very high resistance rate towards amoxicillin, exceeding 50 % for almost all centres. These data confirm that amoxicillin is not an option in any setting. Past studies demonstrated very high resistance of uropathogens (E. coli, Klebsiella) to penicillins, either ampicillin or amoxicillin, which are still increasing today [7] and even more so in children than in adults [6]. On the other hand, our findings suggest that the combination of amoxicillin and clavulanate appears as a good antimicrobial option in UTIs, with resistance rates below 20 % in many countries. This is particularly true for outpatients in whom a lower previous cumulative exposure to antibiotics can be assumed. Our data suggest a large geographic variability in the co-amoxiclavulanate resistance rate in keeping with previous studies [4] and pointing to the need to consider local resistance patterns in the choice of antimicrobial therapy. Trimethoprim was seen to be just as resistant as amoxicillin to E. coli isolated from hospitalized children. In the past, trimethoprim was the antibiotic of choice for UTI prophylaxis, and although data show a very marked increase in resistance rates, it remains the preferred prophylactic agent according to some authors [10]. Its widespread prophylactic use is the most likely explanation for the very high prevalence of trimethoprim-resistant E. coli spp. throughout Europe. Data regarding oral cephalosporin showed large variability among countries in accordance with the literature. Even within the same country, cephalosporin resistance rates could vary so markedly that this class of drug would be an appropriate antibiotic choice in some centres, but not in others. As regards
E. coli resistance rate to cephalosporin group 3, a north–south decreasing trend was observed throughout Europe. This could be explained by the more frequent prescription of antibiotics in southern European countries than in the northern European countries, where antibiotics are less likely to be inappropriately prescribed [18]. Nitrofurantoin had a remarkably good sensitivity in almost all countries, in particular towards E. coli isolated from outpatients. Adverse reactions to nitrofurantoin have been reported mainly in adults [21] and less often in children [12]. Limitations A limitation of our survey was that, as we were expecting a higher E. coli rate, we did not inquire into antibiotic resistance rate vs other uropathogens. Similarly, expecting lower antibiotic resistance rates, we provided ranges for multiple choice questions which were probably too wide, and as a result, we are not able to balance the reported data on the spectrum of uropathogens, as well as antibiotic resistance, compared to the number of urine cultures provided by each unit. Furthermore, many, but not all, countries participating in the PREDICT trial completed the survey. Another limitation of the study was that almost all the centres answering the questionnaire were referral hospitals for paediatric nephrology patients; consequently, a selection bias of children with congenital abnormalities of the kidney and urinary tract was a possibility. However, all these hospitals prevalently treat a large number of children from the general paediatric population from whom the data was obtained. A final limitation of the survey was that it was not possible to match our data with clinical information.
Conclusion In conclusion, our data confirm that E. coli is still the most common single organism causing UTIs in children under 2 years of age; however, other bacterial strains are now more frequently isolated from UCs than in the past. This variability has a direct effect on the therapeutic choices made by physicians. As regards antimicrobial prophylaxis, our data demonstrate that E. coli uropathogens have the lowest rate of resistance to nitrofurantoin throughout Europe, apart from some isolated but important exceptions. Nitrofurantoin should theoretically be considered, in the majority of settings, as the antibiotic of choice for prophylaxis, but it is not approved or recommended in all countries due to safety and tolerability concerns. The other antibiotics show a large variation in in vitro sensitivity rates, even within individual countries. As a result, antibiotic prophylaxis should be more flexible and adaptable over time in order to guarantee maximum efficacy; fixed schemes are no longer acceptable. This philosophy was
Eur J Pediatr
applied in the design of the PREDICT Trial protocol in which antibiotic prophylaxis will be given to children for a period of 2 years. Considering the wide geographical area and the long duration of the trial, it was essential not to be mandatory in the choice of antibiotic for the prophylaxis arm of the study. In fact, the PREDICT protocol suggests four different schemes for antibiotic prophylaxis, permitting clinicians to choose the best antibiotic for their patients based on local resistance patterns. Acknowledgments Thanks to all the microbiology departments for the support given to the authors in the selection of the data: Simone Ambretti (Bologna), Akgun Yaman (Adana), Joanna Klepacka (Krakow), Derya Aydin (Istanbul), Jaulhac Benoit (Strasbourg), Emilie Bessede (Bordeaux), Genovaite Bernatoniene (Vilnius), Suzana Laban-Nestorović (Belgrade), Eva Kenesei (Budapest), Nigar Çelik Özer (Istanbul), SC Droz (Bern), Anna Komarnicka (Gdansk), Lucia Rossi (Padova), Irene Burckhardt (Heidelberg) and Johannes Huebner (Munich).
14.
15.
16. 17.
18.
19. 20.
References
21.
1. Academy of Pediatrics subcommittee on Urinary Tract Infection, Steering Committee on Quality Improvement and Management (2011) Urinary Tract Infection: clinical practice guideline for the diagnosis and management of the initial UTI in febrile infants and children 2 to 24 months. Pediatrics 128:595 2. Ammenti A, Cataldi L, Chimenz R, Fanos V, La Manna A, Marra G, Materassi M, Pecile P, Pennesi M, Pisanello L, Sica F, Toffolo A, Montini G, Italian Society of Pediatric Nephrology (2012) Febrile urinary tract infection in young children. Recommendations for the diagnosis, treatment and follow-up. Acta Paediatr 101(5):451–457 3. Ashkenazi S (2012) Beginning and possibility the end of the antibiotic era. J Paediatr Child Health 49:E179–E182 4. Beetz R, Westenfelder M (2011) Antimicrobial therapy of urinary tract infections in children. Int J Antimicrob Agents 38:42–50 5. Bertrand X, Dowzick MJ (2012) Antimicrobial susceptibility among gram-negative isolates collected from intensive care units in north America, Europe, the Asia-pacific rim, Latin America, the Middle East, and Africa between 2004 and 2009 as part of the tigecycline evaluation and surveillance trial. Clin Ther 34(1):124–137 6. Boggan J, Navar-Boggan A, Jhaveri R (2012) Pediatric-specific antimicrobial susceptibility data and empiric antibiotic selection. Pediatrics 130:e615–e622 7. Catal F, Bavbek N, Bayrak O, Karabel M, Karabel D, Odemis E, Uz E (2009) Antimicrobial resistance patterns of urinary tract pathogens and rationale for empirical therapy in Turkish children for the years 2000–2006. Int Urol Nephrol 41:953–957 8. CDC Antibiotic resistance threats in the United States 2013[http:// www.cdc.gov/drugresistance/threat-report-2013] 9. Chavez-Bueno S, Stull TL (2009) Antibacterial agents in pediatrics. Infect Dis Clin N Am 23:865–880 10. Cheng C, Tsai MH, Huang YC, Su LH, Tsau YK, Lin CJ, Chiu CH, Lin TY (2008) antibiotic resistance patterns of community-acquired urinary tract infections in children with vesicoureteral reflux receiving prophylactic antibiotic therapy. Pediatrics 122:1212–1217 11. ClinicalTrials.gov Identifier: NCT02021006 12. Coraggio MJ, Gross TP, Roscelli JD (1989) Nitrofurantoin toxicity in children. J Pediatr Infect Dis 8:163–168 13. Cullen IM, Manecksha RP, McCullagh E, Ahmad S, O’Kelly F, Flynn R, McDermott TE, Murphy P, Grainger R, Fennell JP, Thornhill JA (2013) An 11-year analysis of the prevalent
22.
23.
24. 25.
26.
27.
28.
29. 30.
31.
32.
uropathogens and the changing pattern of Escherichia coli antibiotic resistance in 38,530 community urinary tract infections, Dubllin 1999–2009. Ir J Med Sci 182:81–89 David MZ, Crawford SE, Boyle-Vavra S, Hostetler AM, Kim DC, Daum RS (2006) Contrasting pediatric and adult methicillin-resistant Staphylococcus aureus isolates. Emerg Infect Dis 12(4):631–637 ECDC Antimicrobial resistance interactive database [http://www. ecdc.europa.eu/en/healthtopics/antimicrobial_resistance/database/ Pages/database.aspx] Elliott SP (2008) Antimicrobial-resistant pathogens: an emerging pediatric threat. Adv Pediatr 55(1):329–348 Gaspari R, Dickson E, Karlowsky J, Doern G (2005) Antibiotic resistance trends in paediatric uropathogens. Int J Antimicrob Agents 26:267–271 Goossen H, Ferech M, Stichele RV, Elseviers M, for the ESAC Project Group (2005) Outpatient antibiotic use in Europe and association with resistance: a cross-national database study. Lancet 365: 379–387 Hellerstein S (1982) Recurrent urinary tract infection in children. Pediatr Infect Dis J 1:271–281 Hellström A, Hanson E, Hansson S, Hjälmås K, Jodal U (1991) Association between urinary symptoms at 7 years old and previous urinary tract infection. Arch Dis Child 66(2):232–234 Holmberg L, Boman G, Böttiger LE, Eriksson B, Spross R, Wessling A (1980) Adverse reactions to nitrofurantoin. Analysis of 921 reports. Am I Med 69:733–738 Hyun D, Hersh A, Namtu K, Palazzi D, Maples H, Newland J, Saiman L (2013) Antimicrobial stewardship in pediatrics: How every pediatrician can be a steward. JAMA Pediatr 167(9):859–866 Karlowsky J, Karlowsky JA, Lagacé-Wiens PRS, Simner PJ, DeCorby MR, Adam HJ, Walkty A, Hoban DJ, Zhanel GG (2011) Antimicrobial resistance in urinary tract pathogens in Canada from 2007 to 2009: CANWARD Surveillance Study. Antimicrob Agents Chemotherapy 55:3169–3175 Ladhani S, Gransden W (2003) Increasing antibiotic resistance among urinary tract isolates. Arch Dis Child 88:444–445 Marcus N, Ashkenazi S, Yaari A, Samra Z, Livni G (2005) NonEscherichia coli versus Escherichia coli community-acquired urinary tract infections in children hospitalized in a tertiary center. Pediatr Infect Dis J 24:581–585 Montini G, Rigon L, Zucchetta P, Fregonese F, Toffolo A, Gobber D, Cecchin D, Pavanello L, Molinari PP, Maschio F, Zanchetta S, Cassar W, Casadio L, Crivellaro C, Fortunati P, Corsini A, Calderan A, Comacchio S, Tommasi L, Hewitt IK, Da Dalt L, Zaccheelo G, Dall’Amico R, IRIS Group (2008) Prophylaxis after first febrile urinary tract infection in children? A multicenter, randomized, controlled, non inferiority trial. Pediatrics 122(5):1064–1071 National Institute for Health and Clinical Excellence. Urinary tract infection in children: diagnosis, treatment and long term management. August 2007. [www.nice.org.uk/guidance/CG54] Newman TB, Bernzweig JA, Takayama JI, Finch SA, Wasserman RC, Pantell RH (2002) Urine testing and urinary tract infections in febrile infants seen in office settings: the Pediatric Research in Office Settings’ Febrile Infant Study. Arch Pediatr Adolesc Med 156:44–54 O’Brien TF (2011) What has kept the antibiotic miracle alive? N Engl J Med 365:953–955 Peco-Antic A, Paripovic D, Buljugic S, Kruscic D, Spasojevic B, Cvetkovic M, Kostic M, Laban-Nestorovic S, Milosevski-Lomic G (2012) Antibiotic resistance of uropathogens in newborn and young children with acute pyelonephritis. Srp Arh Celok Lek 140:179–183 Peters CA, Skoog SJ, Arant BS Jr, Coppo HL, Elder JS, Hudson RG, Khoury AE, Lorenzo AJ, Pohl HG, Shapiro E, Snodgrass WT, Diaz M (2010) Summary of the AUA Guidelines on management of primary vesicoureteral reflux in children. J Urol 184:1134–1144 Smith SP, Manges AR, Riley LW (2008) Temporal changes in the prevalence of community-acquired antimicrobial-resistant urinary
Eur J Pediatr tract infection affected by Escherichia coli clonal group composition. Clin Infect Dis 46(5):689–695 33. Tekgül S, Riedmiller H, Hoebeke P, Kocvara R, Nijman RJ, Radmayr C, Stein R, Dogan HS, European Association of Urology (2012) EAU Guidelines on vesicoureteral reflux in children. Eur Urol 62:534–542 34. The ESCAPE Trial Group (2009) Strict blood-pressure control and progression of renal failure in children. N Engl J Med 361:1639–1650 35. Tonkic M, Barisk IG, Punda-Polic V (2005) Prevalence and antimicrobial resistance of extended-spectrum beta-lactamases-producing Escherichia coli and Klebsiella pneumoniae strains isolated in a university hospital in Split, Croatia. Int Microbiol 8(2):119–124
36. Versporten A, Sharland M, Bielicki J, Drapier N, Vankerckhoven V, Goossens H (2012) The antibiotic resistance and prescribing in European Children project: a neonatal and pediatric antimicrobial web-based point prevalence survey in 73 hospitals worldwide. Pediatr Infect Dis J 32: e242–e253 37. Yuksel S, Oztürk B, Kavaz A, Ozçakar ZB, Acar B, Güriz H, Aysev D, Ekim M, Yalçinkaya F (2006) Antibiotic resistance of urinary tract pathogens and evaluation of empirical treatment in Turkish children with urinary tract infectious. Int J Antimicrob Agents 28:413–416
