Treatment of MDR urinary tract infections with oral fosfomycin: a retrospective analysis

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1 J Antimicrob Chemother 2016; 71: doi: /jac/dkw178 Advance Access publication 30 May 2016 Treatment of MDR urinary tract infections with oral fosfomycin: a retrospective analysis Justin T. Seroy 1, Shellee A. Grim 1,2, Gail E. Reid 1,3, Trevor Wellington 3 and Nina M. Clark 1,3 * 1 Department of Internal Medicine, Division of Infectious Diseases, Loyola University Medical Center, Maywood, IL, USA; 2 Department of Pharmacy Practice, University of Illinois at Chicago, Chicago, IL, USA; 3 Stritch School of Medicine, Loyola University Chicago, Chicago, IL, USA Introduction *Corresponding author. Tel: ; Fax: ; nmclark@lumc.edu Received 7 December 2015; returned 8 February 2016; revised 13 April 2016; accepted 18 April 2016 Objectives: Limited options for treating MDR organisms have led clinicians to turn to older antimicrobial agents that may display activity against such infections. One such agent is fosfomycin, an oral drug with activity against a variety of Gram-positive and -negative bacteria, but only approved for use in the USA for urinary tract infection (UTI) due to Escherichia coli and Enterococcus faecalis. The purpose of this study was to assess the efficacy of fosfomycin treatment of MDR UTI and identify predictors of outcome. Patients and methods: A retrospective review was performed of patients treated for MDR UTI at a large quaternary medical centre between 1 January 2010 and 30 September Sixty patients received 69 courses of fosfomycin in the inpatient or outpatient setting for UTIs due to Enterobacteriaceae, Pseudomonas aeruginosa or VRE. Results: In the 58 patients for whom follow-up data were available, the treatment success rate (no persistent or recurrent infection) was 55%. Chronic kidney disease was associated with persistent infection (OR¼3.56, 95% CI¼ , P¼0.04). No other factors, including comorbidities, infecting organism, fosfomycin MIC or number of doses of fosfomycin received, were associated with recurrent infection or treatment failure. Conclusions: This study supports the use of fosfomycin as an oral option for treating MDR UTIs. Additional studies are required to assess the optimal dosing and utility of combination therapy to decrease the incidence of treatment failure. Urinary tract infection (UTI) is one of the most common disorders treated by medical practitioners and UTIs account for a significant percentage of healthcare costs. 1 Many antibiotics once used to treat UTI are now ineffective due to the development of antimicrobial resistance. 2,3 The primary UTI pathogen is Escherichia coli, but other members of the Enterobacteriaceae family of organisms also commonly cause infection, including Klebsiella pneumoniae, Enterobacter and Citrobacter spp. 4 Emergence of MDR bacteria, including AmpC b-lactamase-, ESBL- and carbapenemase-producing strains of Enterobacteriaceae, has complicated treating patients with these infections. 3,5 The antibiotic fosfomycin tromethamine is approved in an oral powdered form in the USA for treatment of uncomplicated cystitis in women due to E. coli and Enterococcus faecalis. 6 Fosfomycin was discovered in 1969, but was not approved by the FDA until Its unique mechanism of action, inhibition of UDP-N-acetylglucosamine enolpyruvyl transferase, blocks the first step in bacterial cell wall synthesis. 3,7 Inhibition of this step occurs earlier than the action of b-lactam or glycopeptide antibiotics. 8 Fosfomycin resistance can be mediated by several mechanisms, 9 including enzymatic modification via transferable plasmid-mediated genes found in Gram-positive and -negative bacteria and chromosomal mutations that confer fosfomycin resistance via altered transport of the drug into bacteria. 13 However, fosfomycin s mechanism of action appears to limit cross-resistance and allows it to remain effective against MDR organisms. 9,14 Recent meta-analysis data indicate that fosfomycin has in vitro activity against the majority of E. coli isolates, as well as many other Enterobacteriaceae. 15 Fosfomycin therapy also appears safe, even in pregnant women. 14 The use of fosfomycin could prevent admission for treatment of MDR UTIs or decrease length of hospital stay by allowing substitution of oral for intravenous therapy. However, the optimal use of this agent remains unknown in terms of target organisms, patient population, dose and duration of therapy. Furthermore, MIC correlates of successful treatment of urinary pathogens for which fosfomycin is often used have not # The Author Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please journals.permissions@oup.com 2563

2 Seroy et al. been established. This retrospective study evaluates the use and efficacy of fosfomycin as an oral antibiotic option for MDR UTIs among patients seen at a large quaternary healthcare facility. Methods The study was conducted at Loyola University Medical Center (LUMC), a 560 bed facility in Maywood, IL, USA. A list of both hospitalized patients and outpatients aged 18 years for whom fosfomycin was prescribed between 1 January 2010 and 30 September 2014 was obtained from LUMC Pharmacy records. The medical records of patients who received fosfomycin for treatment of MDR lower tract UTI were further reviewed and data extracted as outlined below. Ethics Institutional Review Board approval was obtained for the study (LUMC protocol no ) and waiver of study subject consent was granted. Inclusion criteria Patients were included in the study if they received fosfomycin for UTI treatment due to an MDR organism as an inpatient or outpatient from 1 January 2010 through to 30 September UTI was defined by a positive urine culture and: (i) a urinalysis with more than five leucocytes per high-powered field or positive leucocyte esterase; plus (ii) documentation of clinical symptoms, including dysuria, increased frequency, urgency, suprapubic tenderness, haematuria or fever. Multidrug resistance was defined as resistance to at least one agent in three or more antimicrobial classes. 16 Patients included in the analysis were further evaluated for comorbid conditions, including diabetes mellitus, chronic kidney disease stage III or greater, renal replacement therapy, organ transplantation, HIV/AIDS, malignancy and genitourinary abnormalities, including urinary stents, chronic bladder catheterization, genitourinary strictures and neurogenic bladder. A Charlson comorbidity index score was calculated for each patient. 17 Microbiological data, including susceptibility testing for fosfomycin (determined via Etest; biomérieux) where performed, were collected. A fosfomycin MIC of 64 mg/l was defined as susceptible for Gram-negative organisms, extrapolating from the accepted CLSI breakpoint for E. coli. 6,18 Information on fosfomycin dosing was also recorded. Each dose consisted of 3 g of fosfomycin tromethamine. Exclusion criteria Patients who were prescribed but did not receive fosfomycin or did not have urinary bacterial isolates meeting the MDR definition were excluded. Patients who received fosfomycin for pyelonephritis or indications other than lower tract UTI were excluded. Patients with asymptomatic bacteriuria were also excluded. Patients with no follow-up after fosfomycin treatment (N¼2) were excluded from the outcome portion of the analysis. Outcomes Study patients were assessed for the presence of persistent and/or recurrent infection after fosfomycin treatment as well as death during treatment. Persistent infection was defined as isolation of the same organism from a urine culture obtained up to 7 days after fosfomycin treatment was completed. Recurrent infection was defined as evidence of the same organism from a urine culture obtained within 3 months after fosfomycin treatment was completed. Statistical analysis Data analysis was performed with PASW Statistics v (SPSS, Chicago, IL, USA) or SAS/STAT software, v. 9.4 (SAS Institute, Cary, NC, USA). Continuous variables were compared using independent t-tests and categorical variables were compared using either a x 2 test or Fisher s exact test, as appropriate. Spearman correlation was used to assess the association between fosfomycin MIC and the number of fosfomycin doses received. Binary logistic regression models (with penalized likelihood) were performed to examine predictors of outcome. Results One hundred and twenty-five courses of fosfomycin were prescribed during the study period for 115 patients. Fifty-five patients were excluded for the following reasons: 9 did not take the medication (per review of medical records); 27 were treated for non-mdr organisms; 10 patients were treated for infections other than UTI (UTI suppression and wound infection); 8 patients had asymptomatic bacteriuria; and 1 patient lacked a urinalysis or adequate physician documentation of UTI. Therefore, 69 courses of treatment for 60 patients were included in the analysis (7 patients were treated with fosfomycin on two different occasions and 1 patient on three different occasions). Study patients were predominately female and white with an average age of 62 years and an average Charlson comorbidity index of 3.3 (Table 1). Of the patients, 38% were diabetic, 33% had stage III or greater chronic kidney disease and 30% had genitourinary abnormalities, including strictures or stents. The majority of infections were due to E. coli (33/69; 48%) and Table 1. Demographics (N¼60 a ) Age (years), average (range) 62.2 (19 91) Sex, n (%) female 44 (73) male 16 (27) Ethnicity, n (%) white 45 (75) black 12 (20) Asian 2 (3) other 1 (2) Charlson comorbidity index, average (range) 3.3 (0 10) Specific conditions, n (%) diabetes mellitus 23 (38) chronic kidney disease stage III or greater 20 (33) haemodialysis 1 (2) transplant recipient 7 (12) AIDS 0 (0) malignancy 11 (18) genitourinary abnormality b 18 (30) a Seven patients included in the analysis were treated with fosfomycin twice during the study period and one patient was treated three times. b Genitourinary abnormality includes any patient with known stricture, indwelling urinary stent, neurogenic bladder or chronic bladder catheterization. 2564

3 Fosfomycin treatment of MDR UTIs JAC Table 2. Urinary infection characteristics (N¼69 episodes) Fosfomycin treatment Response, N¼67 a Organism (number of infections) Percentage of infection episodes, N¼69 first-line, n (%) MIC range (mg/l) percentage susceptible mean number of doses (range) persistence, n (%) recurrence, n (%) E. coli (N¼13) b 19 9 (69) , N¼2 100, N¼2 1.5 (1 3) 2 (17), N¼12 1 (8), N¼12 E. coli EBSL (N¼20) (60) , N¼15 100, N¼ (1 6) 5 (25) 3 (15) K. pneumoniae (N¼2) 3 1 (50) NA NA 2.0 (1 3) 0 1 (50) K. pneumoniae ESBL (N¼8) 12 5 (63) 16 24, N¼3 100, N¼3 4.6 (1 14) 3 (38) 1 (13) K. pneumoniae CRE (N¼13) 19 9 (69) , N¼6 83, N¼6 3.0 (1 10) 5 (39) 3 (23) E. cloacae (N¼1) 1 1 (100) 48, N¼1 100, N¼ (100) Proteus vulgaris (N¼1) 1 1 (100) NA NA P. mirabilis (N¼2) b 3 2 (100) , N¼2 100, N¼2 1.0 (1) 0, N¼1 0, N¼1 P. mirabilis ESBL (N¼6) 9 3 (50) 2 12, N¼4 100, N¼4 2.0 (1 3) 0 3 (50) VRE (N¼2) 3 2 (100) NA NA 1.5 (1 2) 0 0 P. aeruginosa (N¼3) 4 2 (67) 3 192, N¼3 67, N¼3 3.7 (1 7) 1 (50), N¼2 0, N¼2 Total 103 c 46 (67) , N¼36 94, N¼ (1 14) 16 (24), N¼67 14 (21), N¼67 NA, not available. a Two patients were lost to follow-up, one with mixed E. coli and P. mirabilis infection and one with P. aeruginosa infection. b Two patients had mixed infection (one with E. coli and non-vre Enterococcus and one with E. coli and P. mirabilis). c Total is.100% due to two mixed infections. K. pneumoniae (23/69; 33%) (Table 2). Other MDR isolates included Enterobacter cloacae, Proteus spp., Pseudomonas aeruginosa and VRE. ESBL-producing organisms and carbapenem-resistant Enterobacteriaceae (CRE) comprised 47/69 infections (68%) and all CRE isolates were K. pneumoniae. Fosfomycin was used as first-line therapy in 46/69 (67%) episodes of infection (Table 2). MICs of fosfomycin were determined for 36 of the 71 urinary isolates (51%; two patients had more than one MDR for a UTI episode), with the lowest MICs for E. coli (i.e.,1 mg/l) and the highest for CRE (i.e mg/l). Of the 36 isolates tested for fosfomycin susceptibility, 34 (94%) were susceptible, with only 1 CRE isolate and 1 P. aeruginosa isolate displaying MICs.64 mg/l. Follow-up on two patients was missing: one patient with mixed E. coli and Proteus mirabilis infection and one patient with P. aeruginosa infection. Thirty out of 67 patients had persistent or recurrent infection, so the overall cure rate with fosfomycin was 55% (37/67). For CRE isolates, the cure rate was 38% (5/13; P¼not significant); there was one persistent infection and one recurrent infection due to fosfomycin-susceptible CRE (MIC¼12 mg/l). Twenty-four percent of episodes (16/67) resulted in persistent infection despite fosfomycin therapy and 13/16 (81%) of these occurred in episodes due to ESBL-producing organisms and CRE. The range of fosfomycin MICs for organisms that persisted (where performed, N¼7) was mg/l. Fosfomycin MICs for the 27 tested organisms from patients who did not have persistent infection were all 48 mg/l. Recurrent infection within 3 months after fosfomycin treatment occurred in 21% (14/67) of episodes. The range of fosfomycin MICs for the initial isolates that were followed by recurrent infection was mg/l (N¼6) and only one had an MIC.32 mg/l. Only one patient had persistent and recurrent infection (E. coli) and no fosfomycin MIC was available for that isolate. There were 32 UTI episodes with fosfomycin MICs and follow-up. For these, if the fosfomycin MIC was 64 mg/l, the cure rate (no persistent or recurrent infection) was 63% (19/30) compared with 0% (0/2) if the fosfomycin MIC was.64 mg/l (P¼not significant). Both episodes with MIC.64 mg/l resulted in persistent infection. Following fosfomycin treatment, repeat fosfomycin MICs were performed in six episodes: two episodes of persistent infection and four of recurrent infection. The MICs were the same before and after fosfomycin treatment in one of the persistent episodes and increased from 12 to 16 mg/l in the other persistent episode, but, in three of the four recurrent episodes, fosfomycin MICs increased significantly, in one case changing from 48 to 64 mg/l, in another from 24 to.1024 mg/l and in a third from 12 to 384 mg/l. An attempt was made to identify additional predictors of persistent infection (Table 3). Only the first episodes of UTI were included in this analysis and two patients were excluded due to lack of follow-up (N¼58). Chronic kidney disease was the only variable associated with persistent infection (OR¼3.56, 95% CI , P¼0.04). No other factors, including demographics (age, gender and race/ethnicity), comorbidities, infecting organism or number of fosfomycin doses, were associated with persistent infection. Multiple doses of fosfomycin were generally used for treatment (range 2 14), with the most common regimen being 3 doses of 3 g each (30/69; 43%). Thirty-two percent of episodes (22/69) were treated with a single 3 g dose. None of the variables analysed was associated with recurrent infection (data not shown) or with treatment failure (either recurrent or persistent infection) (Table 4). Two of 69 patients died after receiving fosfomycin for UTI and bothhadreceivedfosfomycinasinitialtherapy.oneofthe patients was a liver transplant recipient and the other was a patient with cirrhosis awaiting liver transplant. Both patients had UTI due to a carbapenem-resistant K. pneumoniae. The 2565

4 Seroy et al. Table 3. Predictors of persistent infection (N¼58 first episodes with follow-up available) Variable Persistent infection (N¼14) No persistent infection (N¼44) OR 95% CI P Comorbidity, n (%) diabetes mellitus 5 (36) 18 (41) chronic kidney disease stage III 8 (57) 12 (27) malignancy 4 (29) 7 (16) transplant 2 (14) 5 (11) haemodialysis 0 (0) 1 (2) genitourinary abnormality 3 (21) 14 (32) Charlson comorbidity index Fosfomycin first-line therapy, n (%) 11 (79) 32 (73) mean number of doses MIC range , N¼ , N¼ percentage susceptible (MIC 64 mg/l) 67, N¼6 100, N¼ MIC.32 mg/l 33, N¼6 10, N¼ Organism, n (%) E. coli 2 (14) 9 (21) E. coli ESBL 4 (29) 12 (27) K. pneumoniae 0 (0) 1 (2) K. pneumoniae ESBL 2 (14) 5 (11) K. pneumoniae CRE 5 (36) 7 (16) P. vulgaris 0 (0) 1 (2) P. mirabilis 0 (0) 1 (2) P. mirabilis ESBL 0 (0) 5 (11) P. aeruginosa 1 (7) 1 (2) E. cloacae 0 (0) 1 (2) VRE 0 (0) 2 (5) mixed infection 0 (0) 1 (2) ESBL-producing organism 6 (43) 22 (50) transplant recipient had poor graft function immediately after transplant and prolonged mechanical ventilator dependence. He was clinically stable when he developed UTI 3 weeks after liver transplant and received three doses of fosfomycin. He also had respiratory colonization by carbapenem-resistant K. pneumoniae. Due to worsening respiratory status and presumed pneumonia 2 days after completing fosfomycin, he was started on colistin, tigecycline and meropenem. Twenty-four days after starting colistin, tigecycline and meropenem, blood cultures revealed carbapenem-resistant K. pneumoniae. Care was eventually withdrawn and he died 3 weeks after the bacteraemia onset. The other patient was clinically well other than lower urinary tract symptoms when he received four doses of fosfomycin as an outpatient, but was unable to tolerate additional doses due to nausea. Fourteen days after completion of fosfomycin, he developed bacteraemia with carbapenem-resistant K. pneumoniae, deteriorated and died. Discussion This is the largest reported series of patients treated with fosfomycin for MDR UTI. The majority of first episodes of treatment where there was follow-up, 55%, had successful outcome with neither persistence nor recurrence of infection by the same organism. This outcome is similar to that demonstrated in another retrospective review of fosfomycin treatment of MDR urinary pathogens where there was microbiological cure in 59% of patients (24/41). 19 Pullukcu et al. 20 reported higher success rates in 52 patients with ESBL-producing E. coli UTI treated with fosfomycin. In that study, there were clinical and microbiological success rates of 94.3% and 78.5%, respectively. These outcomes are better than the 31% clearance rate reported in a retrospective review of renal transplant recipients with UTIs, although the latter was a smaller study of 14 episodes in nine patients. 21 There was no association in this study of fosfomycin MIC and outcome, but the number of resistant isolates was probably too small to assess correlation. Furthermore, fosfomycin MICs were not performed for almost half of the urinary isolates. In addition, the effects of total dose and dosing interval on fosfomycin efficacy are unknown. Many patients in the present study were given fosfomycin every 72 h or given only one dose. Dosing regimen may be another important factor in determining treatment outcome, even for isolates with fosfomycin MICs 64 mg/l. 2566

5 Fosfomycin treatment of MDR UTIs JAC Table 4. Predictors of persistent or recurrent infection (N¼58 first episodes with follow-up available) Variable Persistent or recurrent infection, N¼26 (%) No persistent or recurrent infection, N¼32 (%) OR 95% CI P Comorbidity, n (%) diabetes mellitus 12 (46) 11 (34) chronic kidney disease stage III 12 (46) 8 (25) malignancy 5 (19) 6 (19) transplant 5 (19) 2 (6) haemodialysis 0 1 (3) genitourinary abnormality 7 (27) 10 (31) Charlson comorbidity index Fosfomycin first-line therapy, n (%) 20 (77) 23 (72) mean number of doses MIC range , N¼ , N¼ percentage susceptible (MIC 64 mg/l) 83, N¼12 100, N¼ MIC.32 mg/l 25, N¼12 7, N¼ Organism, n (%) E. coli 4 (15) 7 (22) E. coli ESBL 7 (27) 9 (28) K. pneumoniae 1 (4) 0 K. pneumoniae ESBL 3 (12) 4 (13) K. pneumoniae CRE 8 (31) 4 (13) P. vulgaris 0 1 (3) P. mirabilis 0 1 (3) P. mirabilis ESBL 2 (8) 3 (9) P. aeruginosa 1 (4) 1 (3) E. cloacae 1 (4) 0 VRE 0 2 (6) mixed infection 1 (4) 0 ESBL-producing organism 12 (46) 16 (50) Finally, we cannot rule out the presence of occult pyelonephritis, microabscesses or nephrolithiasis leading to failure, as genitourinary imaging was not performed in all cases. Although 94% of all isolates tested from initial UTI episodes were susceptible to fosfomycin, the rate of fosfomycin susceptibility for CRE was only 83% for six isolates (seven isolates not tested). Others have reported fosfomycin susceptibility rates for CRE varying between 60% 22 and 93%. 23 Several studies have reported high fosfomycin susceptibility rates of ESBL-producing E. coli (95% 97%) and Enterobacter spp. (91% 100%). 15,24 26 Neuner et al. 19 reported an overall susceptibility rate of MDR pathogens of 75%, with 92% susceptibility for carbapenemase-producing K. pneumoniae, and found improved outcomes if urinary isolates displayed lower fosfomycin MICs ( 128 mg/l). Data from that study affirm the importance of determining fosfomycin susceptibility testing when its use is being considered for treatment of MDR UTI. It is also notable that in three of the four recurrent episodes where repeat fosfomycin MICs were performed, there were significant increases to 64 mg/l. While a small sample, these data are concerning for induction of resistance following exposure. The CLSI has established that for E. coli and Enterococcus, susceptibility to fosfomycin is defined as an MIC 64 mg/l, 6,18 but MIC breakpoints are lacking for other Gram-negative organisms. Approximately 40% of an oral dose of fosfomycin is excreted unchanged in urine 27 and following oral administration of a single dose, the mean urine fosfomycin concentration is 706 (+466) mg/l and declines to 10 mg/l in samples collected h after the dose. 6 EUCAST defines a fosfomycin MIC 32 mg/l as susceptible for urinary Enterobacteriaceae and Pseudomonas isolates. 28 Fosfomycin displays synergy in vitro when used with other antibiotics against MDR organisms, 3 but more data are needed prior to recommending such combination therapy. Limitations of our study include its retrospective nature, lack of fosfomycin MIC data for all patients, lack of urinary tract imaging on all patients to rule out upper urinary tract disease and variable dosing regimens used. Additionally, while fosfomycin was most often used as first-line therapy, for some episodes it was used subsequent to other agents, thus raising the possibility of effects of prior antimicrobial agents. Still, our data demonstrate that 2567

6 Seroy et al. fosfomycin may be a valid option for oral treatment of MDR lower tract UTIs in the appropriate clinical setting. In some patients, particularly those with lower fosfomycin MICs, its use may prevent hospitalization for administration of intravenous antibiotics or may reduce length of hospital stay. Given its poor penetration of the kidneys and low serum levels, however, it should not be used to treat pyelonephritis or used to treat critically ill patients. 29 Further data are required to determine optimal dosing of fosfomycin and benefits of combination therapy, particularly for CRE. Funding This study was supported by internal funding. Transparency declarations None to declare. References 1 Dielubanza EJ, Schaeffer AJ. Urinary tract infections in women. Med Clin North Am 2011; 95: Nakamura T, Komatsu M, Yamasaki K et al. Susceptibility of various oral antibacterial agents against extended spectrum b-lactamase producing Escherichia coli and Klebsiella pneumoniae. J Infect Chemother 2014; 20: Reffert JL, Smith WJ. Fosfomycin for the treatment of resistant gramnegative bacterial infections. Insights from the Society of Infectious Diseases Pharmacists. Pharmacotherapy 2014; 34: Foxman B. The epidemiology of urinary tract infection. Nat Rev Urol 2010; 7: Hickmann AK, Langner S, Kirsch M et al. The value of perfusion computed tomography in predicting clinically relevant vasospasm in patients with aneurysmal subarachnoid hemorrhage. Neurosurg Rev 2013; 36: ; discussion Monurol Prescribing Information. St Louis, MO: Forest Laboratories, Kahan FM, Kahan JS, Cassidy PJ et al. The mechanism of action of fosfomycin (phosphonomycin). Ann N Y Acad Sci 1974; 235: PopovicM,SteinortD,PillaiSet al. Fosfomycin: an old, new friend? Eur J Clin Microbiol Infect Dis 2010; 29: Michalopoulos AS, Livaditis IG, Gougoutas V. The revival of fosfomycin. Int J Infect Dis 2011; 15: e Xu X, Chen C, Lin D et al. The fosfomycin resistance gene fosb3 is located on a transferable, extrachromosomal circular intermediate in clinical Enterococcus faecium isolates. PLoS One 2013; 8: e Etienne J, Gerbaud G, Courvalin P et al. Plasmid-mediated resistance to fosfomycin in Staphylococcus epidermidis. FEMS Microbiol Lett 1989; 52: Arca P, Rico M, Brana AF et al. Formation of an adduct between fosfomycin and glutathione: a new mechanism of antibiotic resistance in bacteria. Antimicrob Agents Chemother 1988; 32: Kadner RJ, Winkler HH. Isolation and characterization of mutations affecting the transport of hexose phosphates in Escherichia coli. J Bacteriol 1973; 113: Falagas ME, Vouloumanou EK, Togias AG et al. Fosfomycin versus other antibiotics for the treatment of cystitis: a meta-analysis of randomized controlled trials. J Antimicrob Chemother 2010; 65: Falagas ME, Kastoris AC, Kapaskelis AM et al. Fosfomycin for the treatment of multidrug-resistant, including extended-spectrum b-lactamase producing, Enterobacteriaceae infections: a systematic review. Lancet Infect Dis 2010; 10: Magiorakos AP, Srinivasan A, Carey RB et al. Multidrug-resistant, extensively drug-resistant and pandrug-resistant bacteria: an international expert proposal for interim standard definitions for acquired resistance. Clin Microbiol Infect 2012; 18: Charlson ME, Pompei P, Ales KL et al. A new method of classifying prognostic comorbidity in longitudinal studies: development and validation. J Chronic Dis 1987; 40: Clinical and Laboratory Standards Institute. Performance Standards for Antimicrobial Susceptibility Testing: Twenty-fourth Informational Supplement M100-S24. CLSI, Wayne, PA, USA, Neuner EA, Sekeres J, Hall GS et al. Experience with fosfomycin for treatment of urinary tract infections due to multidrug-resistant organisms. Antimicrob Agents Chemother 2012; 56: Pullukcu H, Tasbakan M, Sipahi OR et al. Fosfomycin in the treatment of extended spectrum b-lactamase-producing Escherichia coli-related lower urinary tract infections. Int J Antimicrob Agents 2007; 29: Reid GE, Grim SA, Layden JE et al. The use of fosfomycin to treat urinary tract infections in kidney transplant recipients. Transplantation 2013; 96: e Maraki S, Samonis G, Rafailidis PI et al. Susceptibility of urinary tract bacteria to fosfomycin. Antimicrob Agents Chemother 2009; 53: Endimiani A, Patel G, Hujer KM et al. In vitro activity of fosfomycin against bla KPC -containing Klebsiella pneumoniae isolates, including those nonsusceptible to tigecycline and/or colistin. Antimicrob Agents Chemother 2010; 54: Prakash V, Lewis JS II, Herrera ML et al. Oral and parenteral therapeutic options for outpatient urinary infections caused by Enterobacteriaceae producing CTX-M extended-spectrum b-lactamases. Antimicrob Agents Chemother 2009; 53: AuerS,WojnaA,HellM.Oraltreatmentoptionsforambulatory patients with urinary tract infections caused by extended-spectrumb-lactamase-producing Escherichia coli. Antimicrob Agents Chemother 2010; 54: Chislett RJ, White G, Hills T et al. Fosfomycin susceptibility among extended-spectrum-b-lactamase-producing Escherichia coli in Nottingham, UK. J Antimicrob Chemother 2010; 65: Bergan T, Thorsteinsson SB, Albini E. Pharmacokinetic profile of fosfomycin trometamol. Chemotherapy 1993; 39: Pasteran F, Lucero C, Rapoport M et al. Tigecycline and intravenous fosfomycin zone breakpoints equivalent to the EUCAST MIC criteria for Enterobacteriaceae. J Infect Dev Ctries 2012; 6: Ode B, Haidl S, Hoffstedt B et al. Fosfomycin versus ampicillin in the treatment of acute pyelonephritis. Chemioterapia 1988; 7: