Occurrence of multidrug resistance to oral antibiotics among Escherichia coli urine isolates from outpatient departments in Germany: Extended-spectrum β-lactamases and the role of fosfomycin

doi:10.1016/j.ijantimicag.2014.05.020

International Journal of Antimicrobial Agents

Volume 44, Issue 4, October 2014, Pages 295-300

https://doi.org/10.1016/j.ijantimicag.2014.05.020 Get rights and content

Highlights

•
We report on the spread of resistance to oral antibiotics in 499 E. coli urine isolates from outpatients in Germany.
•
5.8% of isolates showed combined resistance to amoxicillin, cefuroxime, ciprofloxacin and cotrimoxazole.
•
8% of isolates produced an extended-spectrum β-lactamase.
•
69.2% of the ESBL-producing isolates harboured CTX-M-15.
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Only 1.2% of the isolates, including one ESBL-positive strain, were resistant to fosfomycin.

Abstract

The in vitro activities of fosfomycin and seven other antibiotics commonly used for oral treatment of urinary tract infections (UTIs) were evaluated for 499 Escherichia coli isolated from urine samples during a nationwide laboratory-based surveillance study in 2010. Overall, the highest resistance rates were found for amoxicillin (42.9%), followed by amoxicillin/clavulanic acid (32.7%), trimethoprim/sulfamethoxazole (SXT) (30.9%), ciprofloxacin (19.8%), cefuroxime (10.0%), cefpodoxime (8.6%) and cefixime (8.2%). One-half of the isolates (n = 252; 50.5%) were fully susceptible to the eight drugs, whilst only 6 strains (1.2%) were resistant to fosfomycin. Combined resistance to amoxicillin, cefuroxime, ciprofloxacin and SXT was detected in 29 isolates (5.8%). Moreover, 40 isolates (8.0%) produced an extended-spectrum β-lactamase (ESBL), including CTX-M-type ESBLs detected in 39/40 isolates (97.5%) and a TEM-52 ESBL in 1 strain (2.5%). The predominant CTX-M-type ESBL was CTX-M-15 (27/39; 69.2%). Of the 27 CTX-M-15 producers, 19 (70.4%) belonged to the clonal lineage E. coli O25b-ST131. All but one ESBL-producing strains were fosfomycin-susceptible. In view of the emergence of multidrug resistance to standard oral antibiotics, these data support that oral fosfomycin (trometamol salt) may represent a valuable option in the treatment of uncomplicated UTIs.

Introduction

Yearly, more than 150 million urinary tract infections (UTIs) occur throughout the world [1], with Escherichia coli being involved in 70–80% of uncomplicated UTIs [2]. Increased acquired resistance to a variety of orally administered antibiotics in E. coli has complicated the management of UTIs in the outpatient setting [3]. The spread of extended-spectrum β-lactamase (ESBL)-producing E. coli strains, which are usually cross-resistant to many other classes of antibiotics, has been recognised worldwide as a significant cause of community-acquired infections [4]. In particular, the CTX-M-15 ESBL has been shown to be linked to the widespread clonal group of E. coli serotype O25b-sequence type 131 (O25b-ST131) isolates causing different community-onset infections [5].

Use of fosfomycin in the form of a single oral dose of its trometamol salt has attracted increasing attention as first-line therapy of uncomplicated UTIs. Fosfomycin exhibits bactericidal activity against a broad spectrum of aerobic bacteria, including E. coli, and does not exhibit cross-resistance to other classes of antibiotics, including those associated with high or increasing rates of resistance [6], [7]. Studies from many countries detected low rates of fosfomycin resistance (usually <2%) among E. coli pathogens [2], [3], [7], [8]. However, higher and increasing rates of fosfomycin resistance (up to 14.4%) have been detected in ESBL-producing strains from South Korea and Spain [9], [10], [11]. The objectives of the present study were (i) to evaluate the occurrence of multidrug-resistant (MDR) strains among uropathogenic E. coli from outpatients, (ii) to identify the ESBLs in these isolates, (iii) to investigate the presence of CTX-M-15-producing O25b-ST131 strains and (iv) to evaluate the susceptibility of these isolates to fosfomycin.

Section snippets

Bacterial strains

In a laboratory-based surveillance study carried out between October and December 2010 by the Working Party ‘Antimicrobial Resistance’ of the Paul-Ehrlich-Society for Chemotherapy, 25 microbiological laboratories throughout Germany were requested each to collect 20 consecutive, non-duplicate E. coli urine isolates from outpatients. Additional available information collected with each isolate was isolation date as well as age and sex of the patients. At the end of the collection period, all

Results

Twenty-four laboratories each provided 20 isolates (as requested) and one laboratory provided 19 isolates. Hence, a total of 499 isolates were collected, including 71 isolates (14.2%) from men and 428 (85.8%) from women. Among the group of women, 87 isolates (17.4%) were from young females (<18 years), 166 (33.3%) were from females aged 18–65 years and 175 (35.1%) were from elderly females (>65 years). Patient age ranged from <1 year to 98 years (median 59 years).

Discussion

The present surveillance study involving 25 clinical microbiological laboratories across Germany has investigated the occurrence of resistance to eight oral antibiotics among 499 E. coli isolated from urine samples of outpatients. As expected, the vast majority of isolates (>85%) were obtained from women. The finding that ca. 40% of the isolates were resistant to amoxicillin, 30% to SXT and 20% to ciprofloxacin is consistent with that of E. coli isolates from uncomplicated cystitis in women

Acknowledgment

The technical assistance of G. Anlauf, A. Frank, J. Fritz, E. Luhmer, N. Scheliga and N. Schmandt is gratefully acknowledged.

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Las infecciones del tracto urinario (ITU) son una consulta ambulatoria frecuente, afectan mayormente a mujeres y han ido en aumento en todas las edades, especialmente en adultos mayores. A su vez, la resistencia antimicrobiana está aumento progresivamente en el tiempo y esquemas antibióticos tradicionales han perdido su utilidad clínica. En particular, el aumento de resistencia de E. coli, como principal uropatógeno, es una realidad presente en diversos países y un mayor desafío lo constituyen las ITU causadas por cepas de E. coli productoras de betalactamasas de espectro expandido. El presente artículo revisa los factores de riesgo asociados al aislamiento de cepas resistentes, los cuadros clínicos más frecuentes, y también el diagnóstico y manejo en la situación actual a nivel ambulatorio.
Urinary tract infections (UTI) are a frequent outpatient consultation, it affects mostly women, and is becoming more common in all ages, especially in the elderly. Concurrently, antimicrobial resistance is progressively increasing over time and traditional antibiotic regimens have lost their clinical efficacy. In particular, in many countries the increase in resistance of E. coli (the main uropathogen) is a reality, making UTIs caused by E. coli strains that produce expanded spectrum beta-lactamases the greater challenge. This article reviews the risk factors associated with the isolation of resistant strains, common clinical presentations, and also current diagnosis and management of outpatients.
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Antimicrobial resistance patterns among different Escherichia coli isolates in the Kingdom of Saudi Arabia. This study aimed to investigate the patterns of antimicrobial resistance in E. coli isolated from different samples, and to identify potential pathogenic isolates in Riyadh, Kingdom of Saudi Arabia (KSA). In total, 51 bacterial isolates were recovered from 113 samples of human urine, food (raw meat, raw chicken, raw egg surface, and fresh vegetables), water, and air. Twenty-four E. coli isolates were tested for susceptibility to 26 antibiotics. The air sample isolates were most resistant to amoxicillin, ampicillin, amoxicillin/clavulanic acid, amoxicillin/sulbactam, piperacillin/tazobactam, cefalotin, cefuroxime, cefoxitin, cefixime, nitrofurantoin, and trimethoprim/sulfamethoxazol. The isolates from vegetable samples were resistant to amoxicillin, ampicillin, amoxicillin/clavulanic acid, amoxicillin/sulbactam, cefalotin, cefuroxime, cefoxitin, and cefixime. By contrast, the isolates from the water samples were resistant only to amoxicillin and ampicillin. The isolates from the human urine samples were most frequently resistant to norfloxacin (80%) followed by amoxicillin and ampicillin (70%), trimethoprim/sulfamethoxazole (55%), ciprofloxacin and ofloxacin (50%), cefalotin (30%), cefuroxime, cefixime and cefotaxime (25%), ceftazidime, ceftriaxone, cefepime and aztreonam (20%), amoxicillin/clavulanic acid, piperacillin/tazobactam and gentamicin (10%), and amoxicillin/sulbactam and cefoxitin (5%). Almost all (23/25, 95.8%) (n = 23) of the isolates were multi-drug resistant (MDR) (i.e., resistant to 3 or more classes of antibiotics), and 16.7% (n = 4) of those were positive for extended spectrum β-lactamase (ESBL). Of the 4 ESBL-producers, 3 were positive for blaCTX_-M-15 and blaCTX_-M1_group, 2 were positive for blaCMY_-2, and 1 each was positive for blaCTX_{-M-2 group,} blaSHV, and blaOXA_-47. The quinolone resistance gene qnrS was detected in 25% (n = 6) of the E. coli strains isolated from urine (N = 5) and air (N = 1) samples. The considerable number of antimicrobial resistance genes detected among E. coli isolates tested here is alarming and should raise public health concern.
A rapid, antibiotic susceptibility test for multidrug-resistant, Gram-negative bacterial uropathogens using the biochemical assay, DETECT
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In particular, the dissemination of pathogens that demonstrate phenotypic resistance to extended-spectrum cephalosporins, such as extended-spectrum β-lactamase (ESBL)-producing and plasmid-mediated AmpC (pAmpC)-producing Enterobacterales, are becoming increasingly common. Treatment options for ESBL- and pAmpC-producing Enterobacterales can be limited, as they are frequently multidrug-resistant (MDR), possessing resistance to a number of first-line agents used for empiric treatment of UTI, including the fluoroquinolones, nitrofurantoin, and trimethoprim/sulfamethoxazole (Kresken et al. 2014; Lee et al. 2015; Tulara 2018; Tacconelli et al. 2019). This has been highlighted in a recent study, where the prevalence of MDR among UTI isolates expressing CTX-M-type β-lactamases (the most common class of ESBL) was reported to reach 91% (Tarlton et al. 2020).
The increasing prevalence of extended spectrum β-lactamases (ESBLs) and plasmid-mediated AmpC (pAmpC) β-lactamases among Enterobacterales threatens our ability to treat urinary tract infections (UTIs). These organisms are resistant to most β-lactam antibiotics and are frequently multidrug-resistant (MDR). Consequently, they are often resistant to antibiotics used to empirically treat UTIs. The lack of rapid diagnostic and antibiotic susceptibility tests (AST) makes clinical management of UTIs caused by such organisms difficult, as standard culture and susceptibility assays require several days. We have adapted a biochemical detection assay, termed dual-enzyme trigger-enabled cascade technology (DETECT) for rapid detection of resistance (time-to-result of 3 h) to other antibiotics commonly used in treatment of UTIs. DETECT is activated by the presence of CTX-M and pAmpC β-lactamases. In this proof-of-concept study, the adapted DETECT assay (AST-DETECT) has been performed on pure-cultures of Klebsiella pneumoniae and Escherichia coli (48 isolates) expressing ESBL or pAmpC β-lactamases to perform AST for ciprofloxacin (sensitivity 96.9%, specificity 100%, accuracy 97.9%) nitrofurantoin (sensitivity 95.7%, specificity 91.7%, accuracy 94%) and trimethoprim/sulfamethoxazole (sensitivity 83.3%, specificity 100%, accuracy 89.4%). These results suggest that AST-DETECT may be adapted as a potential diagnostic platform to rapidly detect multidrug-resistant E. coli and K. pneumoniae that cause UTI.
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Oral fosfomycin may constitute an alternative for the treatment of lower urinary tract infections (UTIs) in kidney transplant recipients (KTRs), particularly in view of recent safety concerns with fluroquinolones. Specific data on the efficacy and safety of fosfomycin in KTR are scarce. We performed a retrospective study in 14 Spanish hospitals including KTRs treated with oral fosfomycin (calcium and trometamol salts) for posttransplant cystitis between January 2005 and December 2017. A total of 133 KTRs developed 143 episodes of cystitis. Most episodes (131 [91.6%]) were produced by gram-negative bacilli (GNB), and 78 (54.5%) were categorized as multidrug resistant (including extended-spectrum β-lactamase-producing Enterobacteriaceae [14%] or carbapenem-resistant GNB [3.5%]). A median daily dose of 1.5 g of fosfomycin (interquartile range [IQR]: 1.5-2) was administered for a median of 7 days (IQR: 3-10). Clinical cure (remission of UTI-attributable symptoms at the end of therapy) was achieved in 83.9% (120/143) episodes. Among those episodes with follow-up urine culture, microbiological cure at month 1 was achieved in 70.2% (59/84) episodes. Percutaneous nephrostomy was associated with a lower probability of clinical cure (adjusted odds ratio: 10.50; 95% confidence interval: 0.98-112.29; P = 0.052). In conclusion, fosfomycin is an effective orally available alternative for treating cystitis among KTRs.
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View all citing articles on Scopus

¹: See Appendix A for list of participants.

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Occurrence of multidrug resistance to oral antibiotics among Escherichia coli urine isolates from outpatient departments in Germany: Extended-spectrum β-lactamases and the role of fosfomycin

Highlights

Abstract

Introduction

Section snippets

Bacterial strains

Results

Discussion

Acknowledgment

Int J Antimicrob Agents

Enferm Infecc Microbiol Clin

Clin Microbiol Infect

Urinary tract infections: disease panorama and challenges

J Infect Dis

Surveillance study in Europe and Brazil on clinical aspects and Antimicrobial Resistance Epidemiology in Females with Cystitis (ARESC): implications for empiric therapy

Eur Urol

Community infections caused by extended-spectrum β-lactamase-producing Escherichia coli

Arch Intern Med

Intercontinental emergence of Escherichia coli clone O25:H4-ST131 producing CTX-M-15

J Antimicrob Chemother

Fosfomycin trometamol: activity in vitro against urinary tract pathogens

Infection

Antimicrobial susceptibility of clinical Escherichia coli isolates from uncomplicated cystitis in women over a 1-year period in Spain

Rev Esp Quimioter

Increasing prevalence of fosfomycin resistance in extended-spectrum-β-lactamase-producing Escherichia coli urinary isolates (2005–2009–2011)

Rev Esp Quimioter

Parallel increase in community use of fosfomycin and resistance to fosfomycin in extended-spectrum β-lactamase (ESBL)-producing Escherichia coli

J Antimicrob Chemother

Prevalence of acquired fosfomycin resistance among extended-spectrum β-lactamase-producing Escherichia coli and Klebsiella pneumoniae clinical isolates in Korea and IS26-composite transposon surrounding fosA3

J Antimicrob Chemother

Breakpoint tables for interpretation of MICs and zone diameters. Version 4.0

Performance standards for antimicrobial susceptibility testing: twenty-first informational supplement. Document M100-S21