JAC Advance Access originally published online on March 24, 2006
Journal of Antimicrobial Chemotherapy 2006 57(6):1262-1263; doi:10.1093/jac/dkl102
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Correspondence |
Treatment of lower urinary tract infection caused by multidrug-resistant extended-spectrum-ß-lactamase-producing Escherichia coli with amoxicillin/clavulanate: case report and characterization of the isolate
1 Department of Medical Microbiology and Infectious Diseases, Faculty of Medicine, University of Manitoba 5th Floor, Basic Medical Sciences Building, 730 William Avenue, Winnipeg, Manitoba, R3E 0W3, Canada 2 Clinical Microbiology, Health Sciences Centre MS673-820 Sherbrook Street, Winnipeg, Manitoba, R3A 1R9, Canada 3 Department of Internal Medicine, Health Sciences Centre and University of Manitoba 820 Sherbrook Street, Winnipeg, Manitoba, R3A 1R9, Canada 4 Nosocomial Infections, National Microbiology Laboratory, Public Health Agency of Canada 1015 Arlington Street, Winnipeg, Manitoba, R3E 3P6, Canada
*Correspondence address. Clinical Microbiology, Health Sciences Centre, MS673-820 Sherbrook Street, Winnipeg, Manitoba, R3A 1R9, Canada. Tel: +1-204-787-2071; Fax: +1-204-789-3926; E-mail: plagacewiens{at}hotmail.com
Keywords: cystitis , CTX-M-15 , ESBLs , UTIs
Sir,
Extended-spectrum ß-lactamase (ESBL)-producing Escherichia coli are increasingly common.1 They are assumed to be resistant to all ß-lactams and many are also resistant to other antimicrobials.1,2 Multidrug-resistant organisms present therapeutic dilemmas, and treatment with intravenous agents is often recommended because of in vitro resistance to oral antimicrobials.1 However, in vitro inactivation of ESBLs by oral ß-lactamase inhibitors makes their use in minor infections a theoretically attractive option that has not been well studied.1 We report a case of clinically and microbiologically cured cystitis caused by a multidrug-resistant ESBL-producing E. coli using amoxicillin/clavulanate, including microbiological and genetic analysis of the isolate.
A 78-year-old man with a history of prostatic hypertrophy presented to casualty with symptoms of cystitis of 10 days duration. The symptoms included fever, urgency, frequency and dysuria, without haematuria, flank pain and tenesmus. He had recently returned from a trip to India, but did not report any medical problems while travelling. He was completing a 7 day course of oral ciprofloxacin, 250 mg twice daily. His symptoms had not improved. On examination, the patient looked well and was afebrile. Abdominal examination showed mild suprapubic tenderness. Rectal examination revealed a moderately tender prostate. Urinalysis showed pyuria and occult haematuria, and was positive for nitrites. An ultrasound revealed only simple renal cysts and prostatic hypertrophy. The urine culture obtained the week prior had grown >108 cfu/L E. coli with an ESBL phenotype, confirmed using the CLSI method,3 with co-resistance to fluoroquinolones and sulphonamides. A presumptive diagnosis of cystitis and possible prostatitis was made. Based on his mild symptoms and knowledge of the molecular basis of resistance to ß-lactams, the urine was re-cultured and a 6 week trial of oral amoxicillin/clavulanate 500/125 mg thrice daily was prescribed. Although ß-lactams are not optimal therapy for acute prostatitis, we hoped to successfully treat it with a long course of therapy. The re-cultured urine also grew >108 cfu/L E. coli. His symptoms of cystitis resolved within 10 days of treatment. Post-treatment urine culture revealed no growth. He remains asymptomatic and without recurrence.
Antimicrobial susceptibilities of the isolate were determined using microbroth dilution and again with the VitekTM GN-09 card (Table 1). The ESBL phenotype was reconfirmed using the CLSI method. Pulsed-field gel electrophoresis was performed and the analysis of restriction fragment patterns revealed that the organism had a unique fingerprint compared with 28 locally circulating ESBL-producing E. coli strains, possibly acquired during his trip to India. PCR and sequencing of blaCTX-M, blaSHV and blaTEM demonstrated that the only ß-lactamase gene present was CTX-M-15.
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No published reports of clinical and microbiological cure of cystitis caused by multidrug-resistant ESBL-producing E. coli exist. In vitro susceptibilities of isolates expressing ESBLs have been reported and vary substantially based on genotype, inoculum size and the ß-lactamase inhibitor studied.1 Retrospective studies suggest that ß-lactamase inhibitors should not be used for life-threatening infections, but no published data exist for the management of less serious infections.1 Despite this controversy, some experts recommend amoxicillin/clavulanate as second-line treatment for cystitis caused by ESBL producers.1 Despite the lack of prospective or retrospective trials, some in vitro data supporting this approach exist. In vitro, the CTX-M-15 ß-lactamase is readily inactivated by tazobactam and clavulanate and less so by sulbactam.4 Thus, isolates expressing CTX-M-15 may be susceptible to amoxicillin/clavulanate at achievable urine concentrations provided additional ß-lactam resistance mechanisms are not present. SHV and TEM ESBLs are also inactivated by clavulanate in vitro.1 Furthermore, urine bactericidal activity from volunteers given a single 500/125 mg dose of amoxicillin/clavulanate has been tested against multiple SHV ESBL producers, some with amoxicillin/clavulanate MICs of 64 mg/L.5For all strains tested, bactericidal activity was maintained up to 8 h post-dosing. Physiological concentrating may explain this observation. A pharmacodynamic study showed peak amoxicillin urine concentration between 647 and 1547 mg/L and peak clavulanate concentration between 150 and 439 mg/L at 2–4 h following an oral dose of 250/125 mg.6 The urinary half-life of amoxicillin was 65 min and that of clavulanate was 50 min. Based on this study, the urinary concentration of amoxicillin/clavulanate would exceed the MIC for our isolate for >75% of the dosing interval, which may explain why our patient experienced long-term clinical cure and microbiological eradication of the organism despite in vitro resistance to amoxicillin/clavulanate (Table 1). Furthermore, the higher dose we prescribed would have resulted in an even higher urinary concentration. Physiological concentrating of amoxicillin/clavulanate does not occur in prostate tissue, and cure in the face of in vitro resistance suggests that prostatitis may not have been present.
Prospective studies are urgently needed to address the management of cystitis caused by ESBL producers. Given the theoretical inactivation of ESBLs by clavulanate, the physiological concentration of the agent in urine and this evidence of cure, it may be reasonable to consider amoxicillin/clavulanate for the treatment of outpatients with uncomplicated cystitis caused by ESBL-producing E. coli when first-line oral agents cannot be used.
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References
1
Paterson DL and Bonomo RA. (2005) Extended-spectrum ß-lactamases: a clinical update. Clin Microbiol Rev 18:657–86.
2
Boyd DA, Tyler S, Christianson S, et al. (2004) Complete nucleotide sequence of a 92-kilobase plasmid harboring the CTX-M-15 extended-spectrum ß-lactamase involved in an outbreak in long-term-care facilities in Toronto, Canada. Antimicrob Agents Chemother 48:3758–64.
3 Performance Standards for Antimicrobial Susceptibility Testing: Fifteenth Informational Supplement M100-S15 Clinical and Laboratory Standards Institute. (2005) (CLSI, Wayne, PA, USA).
4 Walther-Rasmussen J and Hoiby N. (2004) Cefotaximases (CTX-M-ases), an expanding family of extended-spectrum ß-lactamases. Can J Microbiol 50:137–65.[CrossRef][Web of Science][Medline]
5 Bedenic B, Vranes J, Suto S, et al. (2005) Bactericidal activity of oral ß-lactam antibiotics in plasma and urine versus isogenic Escherichia coli strains producing broad- and extended-spectrum ß-lactamases. Int J Antimicrob Agents 25:479–87.[CrossRef][Web of Science][Medline]
6 Weber DJ, Tolkoff-Rubin NE, Rubin RH. (1984) Amoxicillin and potassium clavulanate: an antibiotic combination. Mechanism of action, pharmacokinetics, antimicrobial spectrum, clinical efficacy and adverse effects. Pharmacotherapy 4:122–36.[Medline]
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