Abstract
We tested 868 urinary isolates of Escherichia coli collected from 2010 to 2013 as part of the Canadian national surveillance study CANWARD against fosfomycin by using the Clinical and Laboratory Standards Institute (CLSI) agar dilution method with MIC interpretation in accordance with the CLSI M100-S23 (2013) criteria. The concentrations of fosfomycin inhibiting 50 and 90% of the isolates were ≤1 and 4 μg/ml; 99.4% of the isolates were susceptible to fosfomycin.
TEXT
Escherichia coli is estimated to account for 75 to 90% of uncomplicated urinary tract infections and approximately 50 to 60% of the isolates from patients with recurrent or complicated infections (1). The currently recommended empirical antimicrobial regimen for treating acute uncomplicated bacterial cystitis in otherwise healthy adult nonpregnant females is a 5-day course of nitrofurantoin, a 3-day course of double-strength trimethoprim-sulfamethoxazole (SXT) in settings where the prevalence of SXT resistance is <10 to 20%, or a 3-g single dose of fosfomycin tromethamine; fluoroquinolones and β-lactams, such as amoxicillin-clavulanate, are second-line therapies (2).
The most recently published national surveillance data describing antimicrobial resistance among urinary pathogens in the United States and Canada reported SXT, ciprofloxacin, amoxicillin-clavulanate, and nitrofurantoin resistance rates of 22 to 24%, 17 to 19%, 1 to 10%, and <2%, respectively (3, 4). Fosfomycin, an agent known for >40 years, has received renewed interest recently because of increasing resistance to traditionally used agents. However, there is a paucity of published Clinical and Laboratory Standards Institute (CLSI) reference method in vitro antimicrobial susceptibility testing data available for fosfomycin because of the complexities associated with the agar dilution method (5).
Midstream and catheter urinary isolates of E. coli (n = 868) collected from January 2010 to May 2013 as part of the ongoing annual Canadian national surveillance study CANWARD (6) were tested; 74.8% (n = 649) of these isolates originated from outpatients attending hospital clinics and emergency rooms, and 25.2% (n = 219) were from inpatients in medical and surgical wards and intensive care units. The 15 participant laboratories were located in 12 cities in 8 of the 10 Canadian provinces. All isolates were deemed clinically significant by algorithms in place in the participating laboratories. To better delineate the activity of fosfomycin against β-lactam-resistant isolates of E. coli, an additional 254 extended-spectrum-β-lactamase (ESBL)-producing E. coli isolates, 119 AmpC-producing E. coli isolates, and two carbapenem-resistant E. coli isolates collected by the CANWARD surveillance study from January 2007 to May 2013 were tested. These additional isolates were from blood, respiratory, and wound specimens collected from 2007 to 2013 and from urine specimens collected from 2007 to 2009 (urine specimens collected from 2010 to 2013 were excluded from this data set, so they were tested only once); 34.9% (n = 131) of these isolates originated from outpatients attending hospital clinics and emergency rooms, and 65.1% (n = 244) were from inpatients in medical and surgical wards and intensive care units.
Fosfomycin antimicrobial susceptibility testing was performed by the CLSI agar dilution method (MHA supplemented with 25 μg/ml of glucose-6-phosphate); all other antibacterial agents were tested with in-house-prepared 96-well broth microdilution panels in accordance with CLSI guidelines (5, 7). Fosfomycin was supplied by Triton Pharma Inc. (Concord, Ontario, Canada) and manufactured by ZaCh System SpA (Almisano di Lonigo, Italy). Quality control was performed in accordance with CLSI recommendations, and MICs were interpreted by using CLSI M100-S23 (2013) breakpoints (5). Every isolate identified as fosfomycin intermediate or resistant was retested to confirm its phenotype.
CLSI criteria were used to screen for potential ESBL-producing isolates of E. coli (5). ESBL confirmatory testing was done by the CLSI disk diffusion method with disks containing ceftazidime (30 μg), ceftazidime-clavulanic acid (30 μg/10 μg), cefotaxime (30 μg), and cefotaxime-clavulanic acid (30 μg/10 μg) (5) supplied by Mast Diagnostics (United Kingdom). Any putative ESBL-producing E. coli isolate that was negative by the ESBL confirmatory test and resistant to cefoxitin (MICs, ≥32 μg/ml) was identified as a putative AmpC producer. Carbapenem-resistant isolates were identified by using the current CLSI breakpoints (M100-S23) (5). Multidrug-resistant (MDR) isolates were those resistant to three or more agents in different antimicrobial classes (i.e., SXT, nitrofurantoin, ciprofloxacin, and amoxicillin-clavulanate).
Table 1 depicts the in vitro activities of fosfomycin and comparative orally administered antimicrobial agents against 868 urinary isolates of E. coli obtained by clinical laboratories across Canada from 2010 to 2013. Fosfomycin inhibited >99% of the isolates tested and inhibited 100% of the ESBL-producing, AmpC-producing, and MDR isolates of E. coli from urine (Table 1); fosfomycin was slightly less active against ciprofloxacin-resistant (97.9% of the isolates susceptible), amoxicillin-clavulanate-resistant (98.0% of the isolates susceptible), and SXT- and ciprofloxacin-resistant (98.1% of the isolates susceptible) isolates. Only five isolates of E. coli that were nonsusceptible to fosfomycin were identified from 2010 to 2013. Each of these isolates was from a different medical center in four different provinces; four isolates were collected in 2010, and one was collected in 2011. Fosfomycin MIC distribution data for all of the isolates and the isolates with defined antimicrobial susceptibility and resistance phenotypes are shown in Table 2.
TABLE 1.
In vitro activities of orally available antimicrobial agents against 868 urinary isolates of E. coli isolated by clinical laboratories across Canada from 2010 to 2013
| E. coli isolate phenotype(s) (no. of isolates) and antimicrobial agent | MIC50e | MIC90 | MIC range | % Susceptible | % Intermediate | % Resistant |
|---|---|---|---|---|---|---|
| All (868) | ||||||
| Fosfomycin | ≤1 | 4 | ≤1–512 | 99.4 | 0.5 | 0.1 |
| SXT | ≤0.12 | >8 | ≤0.12–>8 | 74.7 | 25.3 | |
| Nitrofurantoin | 16 | 32 | ≤1–512 | 96.1 | 2.4 | 1.5 |
| Ciprofloxacin | ≤0.06 | >16 | ≤0.06–>16 | 77.4 | 0.1 | 22.5 |
| Amoxicillin-clavulanate | 4 | 16 | 0.5–>32 | 81.3 | 13.0 | 5.7 |
| Pansusceptible (481)a | ||||||
| Fosfomycin | ≤1 | 2 | ≤1–64 | 100 | 0 | 0 |
| SXT | ≤0.12 | 0.25 | ≤0.12–2 | 100 | 0 | |
| Nitrofurantoin | 16 | 32 | ≤1–32 | 100 | 0 | 0 |
| Ciprofloxacin | ≤0.06 | ≤0.06 | ≤0.06–1 | 100 | 0 | 0 |
| Amoxicillin-clavulanate | 4 | 8 | 0.5–8 | 100 | 0 | 0 |
| SXT susceptible (647) | ||||||
| Fosfomycin | ≤1 | 4 | ≤1–512 | 99.5 | 0.3 | 0.2 |
| SXT | ≤0.12 | 0.25 | ≤0.12–2 | 100 | 0 | |
| Nitrofurantoin | 16 | 32 | ≤1–512 | 97.5 | 1.5 | 0.9 |
| Ciprofloxacin | ≤0.06 | >16 | ≤0.06–>16 | 86.2 | 0 | 13.8 |
| Amoxicillin-clavulanate | 4 | 16 | 0.5–>32 | 86.1 | 8.5 | 5.4 |
| SXT resistant (219) | ||||||
| Fosfomycin | 2 | 4 | ≤1–128 | 99.1 | 0.9 | 0 |
| SXT | >8 | >8 | 4–>8 | 0 | 100 | |
| Nitrofurantoin | 16 | 32 | ≤1–256 | 91.8 | 5.0 | 3.2 |
| Ciprofloxacin | 1 | >16 | ≤0.06–>16 | 51.6 | 0.5 | 47.9 |
| Amoxicillin-clavulanate | 8 | 16 | 1–>32 | 67.1 | 26.5 | 6.4 |
| Ciprofloxacin susceptible (672) | ||||||
| Fosfomycin | ≤1 | 2 | ≤1–512 | 99.9 | 0 | 0.1 |
| SXT | ≤0.12 | >8 | ≤0.12–>8 | 83.2 | 16.8 | |
| Nitrofurantoin | 16 | 32 | ≤1–512 | 97.5 | 1.8 | 0.7 |
| Ciprofloxacin | ≤0.06 | ≤0.06 | ≤0.06–1 | 100 | 0 | 0 |
| Amoxicillin-clavulanate | 4 | 16 | 0.5–>32 | 85.7 | 8.9 | 5.4 |
| Ciprofloxacin resistant (195) | ||||||
| Fosfomycin | 2 | 4 | ≤1–128 | 97.9 | 2.1 | 0 |
| SXT | >8 | >8 | ≤0.12–>8 | 45.9 | 54.1 | |
| Nitrofurantoin | 16 | 32 | ≤1–256 | 91.3 | 4.6 | 4.1 |
| Ciprofloxacin | >16 | >16 | 4–>16 | 0 | 0 | 100 |
| Amoxicillin-clavulanate | 8 | 16 | 1–>32 | 66.0 | 27.3 | 6.7 |
| Amoxicillin-clavulanate susceptible (704) | ||||||
| Fosfomycin | ≤1 | 2 | ≤1–128 | 99.6 | 0.4 | 0 |
| SXT | ≤0.12 | >8 | ≤0.12–>8 | 79.1 | 20.9 | |
| Nitrofurantoin | 16 | 32 | ≤1–256 | 96.7 | 2.3 | 1.0 |
| Ciprofloxacin | ≤0.06 | >16 | ≤0.06–>16 | 81.7 | 0.1 | 18.2 |
| Amoxicillin-clavulanate | 4 | 8 | 0.5–8 | 100 | 0 | 0 |
| Amoxicillin-clavulanate resistant (49) | ||||||
| Fosfomycin | 2 | 32 | ≤1–512 | 98.0 | 0 | 2.0 |
| SXT | ≤0.12 | >8 | ≤0.12–>8 | 71.4 | 28.6 | |
| Nitrofurantoin | 16 | 32 | 8–512 | 91.9 | 2.0 | 6.1 |
| Ciprofloxacin | ≤0.06 | >16 | ≤0.06–>16 | 73.5 | 0 | 26.5 |
| Amoxicillin-clavulanate | 32 | >32 | 32–>32 | 0 | 0 | 100 |
| SXT and ciprofloxacin resistant (105) | ||||||
| Fosfomycin | 2 | 4 | ≤1–128 | 98.1 | 1.9 | 0 |
| SXT | >8 | >8 | 4–>8 | 0 | 100 | |
| Nitrofurantoin | 16 | 64 | 4–256 | 88.6 | 6.7 | 4.8 |
| Ciprofloxacin | >16 | >16 | 4–>16 | 0 | 0 | 100 |
| Amoxicillin-clavulanate | 8 | 16 | 2–>32 | 56.2 | 35.2 | 8.6 |
| ESBL producing (42)b | ||||||
| Fosfomycin | 2 | 4 | ≤1–4 | 100 | 0 | 0 |
| SXT | >8 | >8 | ≤0.12–>8 | 35.7 | 64.3 | |
| Nitrofurantoin | 16 | 64 | ≤1–256 | 83.3 | 11.9 | 4.8 |
| Ciprofloxacin | >16 | >16 | ≤0.06–>16 | 9.5 | 0 | 90.5 |
| Amoxicillin-clavulanate | 16 | 32 | 1–32 | 33.3 | 54.8 | 11.9 |
| AmpC producing (16)c | ||||||
| Fosfomycin | 2 | 4 | ≤1–4 | 100 | 0 | 0 |
| SXT | ≤0.12 | >8 | ≤0.12–>8 | 75.0 | 25.0 | |
| Nitrofurantoin | 16 | 32 | 8–32 | 100 | 0 | 0 |
| Ciprofloxacin | ≤0.06 | >16 | ≤0.06–>16 | 75.0 | 0 | 25.0 |
| Amoxicillin-clavulanate | 32 | >32 | 8–>32 | 6.3 | 6.3 | 87.4 |
| MDR (15)d | ||||||
| Fosfomycin | 2 | 4 | ≤1–4 | 100 | 0 | 0 |
| SXT | >8 | >8 | ≤0.12–>8 | 6.7 | 93.3 | |
| Nitrofurantoin | 16 | 128 | 16–256 | 60.0 | 0 | 40.0 |
| Ciprofloxacin | >16 | >16 | 8–>16 | 0 | 0 | 100 |
| Amoxicillin-clavulanate | 32 | >32 | 8–>32 | 13.3 | 20.0 | 66.7 |
Pansusceptible is defined as susceptible to SXT, nitrofurantoin, ciprofloxacin, and amoxicillin-clavulanate.
The ESBL positivity rate of E. coli was 4.8% (42/868).
The AmpC positivity rate of E. coli was 1.8% (16/868).
MDR isolates were defined as those that were resistant to three or more agents in different antimicrobial classes (SXT, nitrofurantoin, ciprofloxacin, and amoxicillin-clavulanate).
MIC50, concentration inhibiting 50% of the isolates; MIC90, concentration inhibiting 90% of the isolates. MICs are reported in μg/ml.
TABLE 2.
Distributions of fosfomycin MIC for 868 urinary isolates of E. coli isolated by clinical laboratories across Canada from 2010 to 2013 stratified by susceptibility or resistance phenotype
In the follow-up, larger set of ESBL-producing and AmpC-producing isolates of E. coli, fosfomycin inhibited 94.9% of the ESBL-producing and 96.6% of the AmpC-producing isolates (Table 3); 17 fosfomycin-nonsusceptible E. coli isolates were identified in this set of isolates (13/17 isolates were ESBL producers, and 4 were AmpC producers). The 13 ESBL-producing, fosfomycin-nonsusceptible E. coli isolates were identified by 11 different laboratories in seven provinces; 3 isolates each were collected in 2007 and 2009, 2 isolates each were collected in 2008 and 2012, and 1 isolate each was collected in 2010, 2011, and 2013. The four AmpC-producing, fosfomycin-nonsusceptible E. coli isolates were identified in four different laboratories in four provinces. The four isolates were collected, one per year, in 2007 to 2010. Two carbapenem-resistant E. coli isolates were also identified. The MICs for these isolates were as follows: fosfomycin, 2 and 2 μg/ml; SXT, >8 and >8 μg/ml; nitrofurantoin, 8 and 16 μg/ml; ciprofloxacin, >16 and >16 μg/ml; amoxicillin-clavulanate, >32 and >32 μg/ml.
TABLE 3.
In vitro activity of fosfomycin against ESBL- and AmpC-producing E. coli isolates obtained by clinical laboratories across Canada from 2007 to 2013, excluding urinary isolates obtained from 2010 to 2013
| Organism (no. of isolates tested) | MIC50c | MIC90 | MIC range | % Susceptible | % Intermediate | % Resistant |
|---|---|---|---|---|---|---|
| ESBL-producing E. coli (254)a | ||||||
| Fosfomycin | 2 | 4 | ≤1–>512 | 94.9 | 3.9 | 1.2 |
| SXT | >8 | >8 | ≤0.12–>8 | 30.7 | 69.3 | |
| Nitrofurantoin | 16 | 32 | 4–256 | 90.6 | 6.3 | 3.1 |
| Ciprofloxacin | >16 | >16 | ≤0.06–>16 | 11.4 | 0.8 | 87.8 |
| Amoxicillin-clavulanate | 8 | 16 | 2–>32 | 59.4 | 33.5 | 7.1 |
| AmpC-producing E. coli (119)b | ||||||
| Fosfomycin | 2 | 16 | ≤1–>512 | 96.6 | 1.7 | 1.7 |
| SXT | 0.25 | >8 | ≤0.12–>8 | 64.7 | 35.3 | |
| Nitrofurantoin | 16 | 64 | ≤1–256 | 89.1 | 6.7 | 4.2 |
| Ciprofloxacin | 0.12 | >16 | ≤0.06–>16 | 62.2 | 0.8 | 37.0 |
| Amoxicillin-clavulanate | 32 | >32 | 1–>32 | 26.9 | 21.0 | 52.1 |
The 254 ESBL-producing E. coli isolates included 151 isolates from blood (2007 to 2013), 52 isolates from urine (2007 to 2009), 40 isolates from respiratory sources (2007 to 2013), and 11 isolates from wound specimens (2007 to 2013).
The 119 AmpC-producing E. coli isolates included 63 isolates from blood (2007 to 2013), 27 isolates from urine (2007 to 2009), 20 isolates from respiratory sources (2007 to 2013), and 9 isolates from wound specimens (2007 to 2013).
MIC50, concentration inhibiting 50% of the isolates; MIC90, concentration inhibiting 90% of the isolates. MICs are reported in μg/ml. MICs are reported in μg/ml.
Fosfomycin is a phosphonic acid derivative that inactivates UDP-N-acetylglucosamine-3-enolpyruvyltransferase (MurA), the enzyme responsible for ligating phosphoenolpyruvate to the 3′-hydroxyl group of UDP-N-acetylglucosamine in the first step of peptidoglycan synthesis (8). Resistance to fosfomycin most commonly arises via mutations in the genes encoding the hexose phosphate transport (UhpT) and glycerol-3-phosphate transport (GlpT) pathways (9) but may also result from a myriad of other mechanisms, including modification, inactivation, or overexpression of the target site (MurA); fosfomycin kinases; or the presence of enzymes associated with fosfomycin inactivation (e.g., those encoded by fosA, fosB, and fosX) (8). Cross-resistance between fosfomycin and other antimicrobial agents is not widely anticipated, given fosfomycin's unique structure and distinct mechanism of action (8, 10).
Fosfomycin has been recommended by some investigators for the treatment of urinary tract infections caused by ESBL-producing E. coli (8, 10, 11). All of the ESBL-producing, AmpC-producing, and MDR isolates identified in our original study of 868 isolates of E. coli were susceptible to fosfomycin. However, in our supplementary data set, fosfomycin appeared slightly less active, with 94.9% of the ESBL-producing and 96.6% of the AmpC-producing isolates being susceptible to fosfomycin (Table 3). Studies by other investigators are limited but have generally reported that fosfomycin retains activity against ESBL-producing E. coli (12, 13). One contradictory study has been published by Spanish researchers who reported that an increase in the use of fosfomycin in the community correlated with an increase in resistance to fosfomycin in ESBL-producing E. coli and that rates of resistance to fosfomycin varied by the specific ESBL present in isolates (5.1, 5.6, and 15.3% of the SHV-12-positive, CTX-M-14-positive, and CTX-M-15-positive isolates were fosfomycin resistant, respectively) (14). This observation may also be important because the plasmid-mediated fosfomycin resistance gene fosA3 has emerged in isolates harboring CTX-M type ESBLs (9) and CTX-M type ESBLs (specifically, CTX-M-15 and CTX-M-14) are frequently identified in E. coli and Klebsiella pneumoniae in Canada and worldwide (15).
In conclusion, rates of resistance to SXT and fluoroquinolones among urinary isolates of E. coli in Canada exceed limits that support their empirical use as therapies for the treatment of these infections (Table 1) (2). In this study, 99.4% of 868 recently (2010 to 2013) obtained urinary isolates of E. coli were susceptible to fosfomycin; fosfomycin also demonstrated marked activity against β-lactamase-producing isolates of E. coli, as 94.9 to 100% of the ESBL-producing and 96.6 to 100% of the AmpC-producing isolates were susceptible to fosfomycin, suggesting that it may be a reliable empirical therapeutic option for urinary tract infections caused by these organisms.
ACKNOWLEDGMENTS
The CANWARD study is supported in part by the University of Manitoba, Winnipeg, Health Sciences Centre; the National Microbiology Laboratory; and Triton Pharma, Inc.
The medical centers (investigators) that participated in the CANWARD study in 2010 to 2013 were Vancouver Hospital, Vancouver, British Columbia (D. Roscoe); University of Alberta Hospital, Edmonton, Alberta (R. Rennie and J. Fuller); Royal University Hospital, Saskatoon, Saskatchewan (J. Blondeau); Health Sciences Centre, Winnipeg, Manitoba (D. Hoban); London Health Sciences Centre, London, Ontario (Z. Hussain); University Health Network and Mount Sinai Hospital, Toronto, Ontario (S. Poutanen); St. Michael's Hospital, Toronto, Ontario (L. Matukas); Children's Hospital of Eastern Ontario, Ottawa, Ontario (F. Chan); The Ottawa Hospital, Ottawa, Ontario (M. Desjardins); Royal Victoria Hospital, Montreal, Quebec (V. Loo); Montreal General Hospital, Montreal, Quebec (V. Loo); Hôpital Maisonneuve-Rosemont, Montreal, Quebec (M. Laverdière); Centre Hospitalier Régional de Trois Rivières, Pavillon Sainte Marie, Trois Rivières, Quebec (M. Goyette); Hôpital de la Cité-de-la-Santé, Laval, Quebec (M. Bergevin); L'Hôtel-Dieu de Quebec, Quebec City, Quebec (R. Pelletier); South-East Regional Health Authority, Moncton, New Brunswick (M. Kuhn); and Queen Elizabeth II Health Sciences Centre, Halifax, Nova Scotia (R. Davidson).
Footnotes
Published ahead of print 9 December 2013
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