Treatment of Urinary Tract Infections Caused by ESBL-Producing

- 10,11

10–12 5 - Entero 8 Risk factors for

12 Receipt of antibiot- 5,6 E. coli or Klebsiella patho- β-lactamases. 9 In a multicenter study from 4 , include prolonged include pneumoniae, K. Global trends for AmpC uropathogens AmpC uropathogens Global trends for Carbapenemase-producing Risk factors for ESBL uropathogens Klebsiella species. (Larissa, Greece) (Larissa, Greece) (Mannhein, Tenenbaum Tobias Germany) UK) (Southampton, Tebruegge Marc 5% among community-acquired UTIs and UTIs community-acquired among 5% 12% among healthcare-associated ones. - China, 2% of E. coli and 10% of K. pneu moniae strains isolated from children, mostly found to bear plasmid- from urine, were mediated AmpC carbapenemase-producing uropathogens, in uropathogens, carbapenemase-producing particular in intensive-care hospitalization, especially and travel medical devices settings, invasive ics during the previous 1–3 months, especially 1–3 months, especially ics during the previous has been increas- as continuous prophylaxis, as a major risk factor for the recognized ingly of resistant uropathogens. development AmpC uropathogens have been associated been have uropathogens AmpC to third specifically exposure with previous as under generation cephalosporins as well hospitalization. requiring conditions lying an by UTI children with an index Moreover, ESBL or AmpC gen are at increased risk for a subsequent with organism the same or different UTI by high resistance properties. are not available but surveillance programs are not available high ESBL with suggest high rates in regions prevalence. bacteriaceae are less common than ESBL AmpC producers but is of their spread or particular concern. frequencies of Global 4% for K. pneumoniae and approximately <1% for E. coli isolated from children have been reported. include recurrent reflux, UTIs, vesicoureteral age to antibiotics, younger exposure previous and Volume 38, Number 12, December 2019 Volume •

5 - eviews and coli E. Board Members Board β-lactamase R The first ESBL 4 and

, we summarize 1, we Table Cristiana Nascimento-Carvalho (Bahia, Brazil) Finland) (Turku, Peltola Ville Shah (Mumbai, India) Ira Syrogiannopoulos George In 3 -lactamases and B metallo- B and β-lactamases Until 2000, ESBL-producing A functional classification 6 eports 3 ST131 (a CTX-M-15 ST131 (a coli E. UROPATHOGENS

Despite the international surveillance The first transferrablefirst The COLI AND K. PNEUMONIAE EPIDEMIOLOGY OF ESBL E. 4,6,7 The Pediatric Infectious Disease Journal correlated the properties of a specific enzyme - with the resistance profile of a clinical iso late and included 3 major groups, 1, 2 and 3 with subgroups. caused mainly nosoco- caused mainly Enterobacteriaceae with the gradual mial infections. However, Munich of cefotaximase of predominance (CTX-M) producing strains and after intro- of duction spread to the commu- quickly strain), they nity. the clinically important β-lactamases pro- the clinically resistant E. coli and K. pneumoniae duced by uropathogens. -lactamases into 4 classes, A, and classified β-lactamases into 4 classes, serine D and C β-lactamases. programs, data on ESBL uropathogens in uropathogens data on ESBL programs, children remain limited. In a meta-analysis, found was 14% of prevalence ESBL an with isolates, urine 7374 among Klebsiella spp. being the most common. Rates were high in Africa (76%) and South- high in Rates were Asia (37%), intermediate in Europe East (12%) and Eastern Mediterranean (5%) and Americas. ESBL rate was the (2%) in lowest was named TEM, after the name of a patient named was 1960s with an E. in Greece in the early culture. blood coli–positive enzyme of sulphydryl variable type was iden- type was variable enzyme of sulphydryl tified in a Klebsiella strain isolated in Ger in 1983. many ESPID R ESPID independently by the Editorial Board of ESPID.

Shamez N. Ladhani and Emmanuel J. Roilides J. Ladhani and Emmanuel Shamez N. 3,4

approved independently by the Editorial Board of ESPID. David Burgner (Melbourne, David Burgner Australia) Chen (Tainan,Taiwan) Kow-Tong Italy) Luisa Galli (Florence, (Melbourne, Graham Steve Australia) Klebsiella pneumoniae E. Coli or Klebsiella by UTI Caused BOARD EDITORIAL Editors: CONTENTS Maria Bitsori, MD, PhD, and Emmanouil Galanakis, MD, PhD Galanakis, MD, and Emmanouil PhD, Maria Bitsori, MD, Herein, we Herein, we lactamases 5 coli or Klebsiella pneumoniae Escherichia -lactams, including Klebsiella pneumo- Klebsiella

CLASSIFICATION www.pidj.com Copyright © 2019 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited. Copyright © 2019 Wolters UTIs caused by ESBL-producing E. UTIs caused by Beta-lactamases are classified either classified are Beta-lactamases Antimicrobial resistance is increasingis resistance Antimicrobial | 3,4

Extended spectrum β 3 rinary usually are (UTIs) infections tract - Enterobacte Gram-negative caused by 1,2

versity Hospital, Crete, Greece. Hospital, Crete, versity to disclose. of Department University of Paediatrics, PhD, MD, Crete, Crete, Greece. E-mail: [email protected]. rights reserved. The ESPID Reports and Reviews of Pediatric Infectious Disease Journal series topics, authors and contents are chosen and BETA-LACTAMASES AND ESBL BETA-LACTAMASES

-lactamases is a major resistance mecha-

The ESPID Reports and Reviews of Pediatric Infectious Diseases series topics, authors and contents are chosen and approved Treatment of Urinary Tract Infections Caused by ESBL-producing by ESBL-producing Infections Caused of Urinary Tract Treatment ISSN: 0891-3668/19/3812-e332 DOI: 10.1097/INF.0000000000002487 ance not only to newer β to newer ance not only tams, but classes of antibiotics. also to other (ESBLs) producing pathogens exhibit resist- exhibit (ESBLs) producing pathogens monobac- and cephalosporins generation third β nism. among uropathogens and the production of among uropathogens ESBL infections in childhood. coli and K. pneumoniae are the most common issues. thus posing considerable infection controlinfection considerable posing thus mids which are transferrable strains,to other which mids - ESBL resistance genes are located on plas e332 The authors have no funding or conflicts of interest The authors have Address for correspondence: Emmanouil Galanakis, All Inc. Health, Kluwer Wolters 2019 © Copyright Accepted for publication September 4, 2019. Accepted for publication the Department Heraklion Uni- From of Paediatrics, U and coli Escherichia niae. , the most common pathogens being riaceae, the most common pathogens with a focus on treatment choices. summarize available data on these pathogens data on these pathogens summarize available tein sequence and active site of the enzymes tein sequence and active erties. The structural way was based on pro- was The structural way erties. by their structure or by their functional prop- their structure or by by

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have retained their activity against ESBL E. TABLE 1. Clinically Important β-lactamases Produced by Resistant coli and K. pneumoniae and re-emerged as Escherichia coli and Klebsiella pneumoniae Uropathogens options for UTIs.3,4,16 Data for children are limited, but these agents seem worth of con- Ambler Bush-Jacoby-Medei- Mechanism of Representative Classification ros Classification Resistance enzymes sideration especially for non–life-threatening infections.3,4 The oral formulation of fosfo- Class A 2be, 2br, 2ber ESBLs TEM, SHV, CTX-M mycin is particularly appealing for treatment 2f Carbapenemases K. pneumoniae carbapen- continuation after initial improvement. Nitro- emase (KPC) Class B 3a, 3b Carbapenemases (metallo-β VIM, IMP, NDM furantoin could only be an option for cysti- lactamases) tis, given its insufficient serum levels and Class C 1 Plasmid-mediated cephalo- CMY, FOX, ACT minimal parenchymal penetration.16 There sporinases (AmpC) are efficacy data for extended spectrum peni- Class D 2df Penicillinases and carbapen- OXA cillin derivatives, such as pivmecillinam or emases temocillin in uncomplicated UTIs in children, but these agents are not widely avail- to endemic areas.4,6,9 Neonates seem to be a ANTIMICROBIAL AGENTS FOR able.3,4 Carbapenemase-producing pathogens particularly high risk population and these ESBL E. COLI AND K. PNEUMONIAE have drawn attention to colistin.9 Colistin strains often cause outbreaks in neonatal UTIS is well tolerated in children and remains a wards, resulting in high rates of morbidity The usual first-line therapeutic second line option, but is associated with and mortality, and in colonization and UTIs choices, that is, penicillins and cephalospor- nephrotoxicity and is prone to emergence of by unusual pathogens months later.13 Rates of resistance, making the addition of another ins are in vitro ineffective against ESBL- 9 ESBL/AmpC-carriers healthy toddlers have producing E. coli and K. pneumoniae strains, antibiotic necessary. been reported to range from 4% to 6.5% in and coresistance to other agents narrows 4,6 Carbapenems Europe to 23% in Asia. Apart from health- further the therapeutic armamentarium. Car- care-associated factors, an important role of bapenems are the most reliable, and in severe Carbapenems with their excellent in vitro activity are reserved for children with widespread broad spectrum antibiotics in cases, the only, treatment option; however, 4,6 severe clinical presentation or nosocomial farming practices has been suggested. their judicious use is needed to avoid devel- infection. Most of the experience in pedi- opment of carbapenemase-producing patho- atrics is with imipenem or meropenem,9,16 gens. Given the limited development of novel LABORATORY IDENTIFICATION OF but recent reports have highlighted the use agents for resistant Gram-negative patho- ESBL E. COLI AND K. PNEUMONIAE of ertapenem particularly in UTIs.4 Car- gens, alternatives have been sought among Every Enterobacteriaceae uropathogen bapenemase production does not necessar- commonly used and overlooked antibiotics with resistance or reduced susceptibility to third ily translate to treatment failure and in such with potential activity.4,16 generation cephalosporins should be tested for cases combination therapy is recommended, ESBL production. ESBL producers hydrolyze Commonly Used Antibiotics based on meropenem minimal inhibitory third generation cephalosporins but not in the concentration (MIC) in susceptibility test- 14 Piperacillin-tazobactam, cefepime, presence of inhibitors such as clavulanic acid. ing.4,9,16 Carbapenem-containing combination aminoglycosides, trimethoprim-sulfameth- Guidance is similar for E. coli and K. pneumo- regimens are associated with more favorable oxazole and quinolones might be effective niae species and is provided by Clinical and outcomes in cases with relatively low MIC and can be considered as empirical therapy.4 Laboratory Standards Institute, European Com- (<8 mg/L) and meropenem given as a pro- Coresistance to aminoglycosides is common, mittee on Antimicrobial Susceptibility Testing longed infusion.9,16 and Food and Drug Administration.3,4 Accord- but amikacin may remain active.2,17 Pipera- ing to recent suggestions, isolated ESBL patho- cillin-tazobactam and cefepime may retain Novel and Emerging Agents gens are only considered resistant to third gen- their activity, especially against community Tigecycline, a semisynthetic tetra- eration cephalosporins and not by definition to ESBL E. coli but not against K. pneumo- 15,17 cycline, is among the newest agents against other β-lactams, such as cefepime or piperacil- niae strains. Both agents often show false Gram-negative pathogens; however, its role lin-tazobactam, which may retain their in vitro activity against strains with multiple resist- in UTIs is doubtful due to limited renal activity and hence their clinical value.15 Resist- ance mechanisms or might render ineffec- 3,16 excretion and its use is discouraged for ance to third generation cephalosporins and tive in cases with high bacterial inoculum, children younger than 8 years of age due to cefoxitin without inhibition by clavulanic acid such as children with bacteremic UTIs or permanent teeth discoloration.9 Agents in 4,13 raises the possibility of AmpC production. those who bear medical devices. For these development include combinations of cepha- Additional resistance mechanisms often coex- reasons, despite the new recommendations, losporins with newer β-lactamase inhibitors, ist in AmpC producers but might be missed in some laboratories still report ESBL patho- novel carbapenems and aminoglycosides, primary screening.14,16 Phenotypic confirmation gens as resistant to piperacillin-tazobactam 16 and ceftazidime-avibactam and ceftolozane- tests are available and should be considered in and cefepime even if susceptible in vitro. tazobactam are being investigated in children 14 every pathogen with cefoxitin resistance. Trimethoprim-sulfamethoxazole and qui- with complicated UTIs caused by multire- Carbapenemase production is sus- nolones, if active, are excellent options for sistant organisms.9,16,18 pected when a strain exhibits reduced sus- children who can be treated orally. Amino- ceptibility to a carbapenem, usually mero- glycosides and quinolones remain first-line penem.4,16 Phenotypic confirmation with an choices in combination regimens for carbap- CONSIDERATIONS FOR indicator carbapenem and several inhibitors enemase-producing strains.16 TREATMENT CHOICES is available and able to differentiate between The choice of the optimal regimen different carbapenemases,14 although molec- Re-emerging Agents for ESBL E. coli and K. pneumoniae UTIs ular techniques are required for definite con- Some unique class older antibiot- is often challenging and should be based on firmation and characterization. ics such as fosfomycin and nitrofurantoin disease severity and susceptibility testing.4

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FIGURE 1. Management of ESBL-, AmpC-, and carbapenemase-producing Escherichia coli and Klebsiella pneumoniae UTIs with level of evidence (Infectious Diseases Society of America - US Public Health Service Grading System for ranking recommendations in clinical guidelines as given in reference 23).

According to our interpretation of available that antibiotics can be used as treatment will contribute to the formulation of appro- data (Fig. 1), risk factors for ESBL infection regardless of susceptibility results. priate therapeutic guidelines for these infec- should be taken into account for the choice UTIs by resistant E. coli and K. pneu- tions. of initial agents, but this does not necessar- moniae do not pose a greater risk for recur- ily involve the use of carbapenems for every rences or permanent renal lesions, as shown REFERENCES child. Noncarbapenem agents, such as ami- in comparative studies17,19,21; hence pro- 1. Stultz JS, Doern CD, Godbout E. Antibiotic kacin and piperacillin-tazobactam, could be longed intravenous or overall treatment is not resistance in pediatric urinary tract infections. used for initial empirical treatment of uncom- required. However, longer hospitalization may Curr Infect Dis Rep. 2016;18:40. plicated, community-acquired infections, be required due to limited options for oral 2. Han SB, Lee SC, Lee SY, et al. Aminoglycoside as adequate disease control without adverse treatment.4 Oral agents, such as trimethoprim- therapy for childhood urinary tract infection due long-term outcomes has well been reported sulfamethoxazole, fosfomycin or nitrofuran- to extended-spectrum β-lactamase-producing toin, might be of use for this purpose, as well Escherichia coli or Klebsiella pneumoniae. BMC for children with pyelonephritis from ESBL- Infect Dis. 2015;15:414. producing organisms.2,17,19–22 Despite in vitro as for afebrile cases of cystitis.4,16 Carbapenems should be reserved for 3. Khoshnood S, Heidary M, Mirnejad R, et al. Drug- resistance, empirical treatment with ceftri- resistant gram-negative uropathogens: a review. axone was successful against ESBL E. coli severe clinical presentation, suspicion of bac- Biomed Pharmacother. 2017;94:982–994. 4,16 pyelonephritis and was maintained as defini- teremia and complicated urologic history. 4. Moxon CA, Paulus S. Beta-lactamases in tive treatment in one study.22 For carbapenemase-producing strains, car- Enterobacteriaceae infections in children. J An important issue that has not been bapenem-containing combination treatment Infect. 2016;72(suppl):S41–S49. adequately addressed is whether treatment is recommended with a second effective 5. Flokas ME, Detsis M, Alevizakos M, et al. 16 modification according to susceptibility test- agent (Fig. 1). In exceptional cases with Prevalence of ESBL-producing Enterobacteriaceae high MIC carbapenem resistance, colistin- in paediatric urinary tract infections: a system- ing is required in patients who have already atic review and meta-analysis. J Infect. 2016;73: responded clinically and microbiologically based combination therapy might be required 547–557. as a last-resort option.16 to initial treatment. A few studies that have 6. Lukac PJ, Bonomo RA, Logan LK. addressed this issue in children with ESBL Extended-spectrum β-lactamase-producing E. coli and K. pneumoniae UTIs suggested Enterobacteriaceae in children: old foe, emerg- CONCLUSIONS ing threat. Clin Infect Dis. 2015;60:1389–1397. that clinical and microbiologic response are The rates of ESBL E. coli and K. 7. Livermore DM, Canton R, Gniadkowski M, et al. achieved despite inappropriate treatment pneumoniae as UTI pathogens are increas- 2,17,19–22 CTX-M: changing the face of ESBLs in Europe. according to susceptibility tests. These ing even in community-acquired infections. J Antimicrob Chemother. 2007;59:165–174. results are potentially explained by the higher Risk factors in children, especially recent or 8. Ding H, Yang Y, Lu Q, et al. The prevalence concentrations of the drugs in the urine than current exposure to antibiotics, have been of plasmid-mediated AmpC beta-lactamases those achieved systemically.1,4,16 However, adequately identified and should be taken among clinical isolates of Escherichia coli and these findings should be interpreted with cau- into account in treatment decisions. Although Klebsiella pneumoniae from five children’s hos- pitals in China. Eur J Clin Microbiol Infect Dis. tion due to very small sample sizes and study carbapenems remain the cornerstone of treat- 2008;27:915–921. limitations. While it appears that susceptibil- ment in more severe cases, alternative agents 9. Chiotos K, Han JH, Tamma PD. Carbapenem- ity testing cannot always predict outcomes, are worth of consideration in uncomplicated resistant Enterobacteriaceae infections in chil- there is still not enough evidence suggesting UTIs. Well-designed clinical outcome studies dren. Curr Infect Dis Rep. 2016;18:2. e334 | www.pidj.com © 2019 Wolters Kluwer Health, Inc. All rights reserved.

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