The in vitro activity of sulopenem was assessed against a collection from 2014 to 2016 of 539 urinary isolates of Escherichia coli from Canadian patients by using CLSI-defined broth microdilution methodology. A concentration of sulopenem 0.03 µg/ml inhibited both 50% (MIC50) and 90% (MIC90) of isolates tested; sulopenem MICs ranged from 0.015 to 0.25 µg/ml.
KEYWORDS: Escherichia coli, penem, sulopenem, urinary
ABSTRACT
The in vitro activity of sulopenem was assessed against a collection from 2014 to 2016 of 539 urinary isolates of Escherichia coli from Canadian patients by using CLSI-defined broth microdilution methodology. A concentration of sulopenem 0.03 µg/ml inhibited both 50% (MIC50) and 90% (MIC90) of isolates tested; sulopenem MICs ranged from 0.015 to 0.25 µg/ml. The in vitro activity of sulopenem was unaffected by nonsusceptibility to trimethoprim-sulfamethoxazole and/or ciprofloxacin, multidrug-resistant phenotypes, extended-spectrum β-lactamases, or AmpC β-lactamases.
INTRODUCTION
Infections of the urinary tract are among the most common infections of humans (1–3). Escherichia coli is the etiological agent of 75% to 95% of uncomplicated urinary tract infections and ∼50% of complicated, recurrent, and hospital-acquired urinary tract infections (1–5). The Infectious Diseases Society of America recommends a 3-day course of double-strength trimethoprim-sulfamethoxazole (SXT) (160 mg trimethoprim/800 mg sulfamethoxazole twice daily) in settings where the prevalence of SXT resistance is <10% to 20%, a 5-day course of nitrofurantoin (100 mg twice daily), or a single dose of fosfomycin (3 g) as empirical treatment for acute uncomplicated bacterial cystitis in otherwise healthy adult nonpregnant women; fluoroquinolones and β-lactams (e.g., amoxicillin-clavulanate, cephalosporins) are recommended as second-line therapies (1). However, in North America and elsewhere, urinary isolates of E. coli commonly demonstrate rates of resistance to SXT that exceed 20% (5–8). SXT (e.g., enterococci) and nitrofurantoin (e.g., enterococci, Proteus spp.) do not possess activity against all bacterial species commonly identified as pathogens in urinary tract infections, and access to in vitro susceptibility testing results for fosfomycin is frequently limited, although most urinary isolates of E. coli and Enterococcus faecalis are susceptible in vitro to fosfomycin (9). Furthermore, 10% to 20% of urinary isolates of E. coli carry extended-spectrum β-lactamases (ESBLs) (5–8). The emergence and dissemination of E. coli sequence type 131 (ST131), which harbors an ESBL (CTX-M-14 or CTX-M-15) and fluoroquinolone resistance conferring mutations (in its gyrA/gyrB genes), has been responsible for most increases in resistance noted for these two antimicrobial classes in patients with community-onset and hospital-acquired disease (5–8, 10, 11).
The availability of an oral carbapenem may complement our current antimicrobial armamentarium and provide an efficacious oral treatment alternative for outpatients with infections caused by ESBL-producing pathogens, especially when isolates are not susceptible to first- or second-line agents, as well as offering potential avoidance of hospitalization or outpatient intravenous antimicrobial therapy. In the hospital setting, an oral carbapenem may provide flexibility and simplify selection of effective stepdown therapy in more serious infections (e.g., mixed aerobic/anaerobic infections), permitting hospital discharge of patients and potentially reducing the length of hospitalization.
Sulopenem, formerly CP-70,429, is an investigational thiopenem currently under development for the treatment of uncomplicated and complicated urinary tract infections and intra-abdominal infections (12), including multidrug-resistant (MDR) infections and infections attributable to quinolone-nonsusceptible and/or ESBL-producing Gram-negative bacilli (10). Sulopenem is in development in both parenteral and oral prodrug (sulopenem-etzadroxil) formulations, may be combined with probenecid, and has a safety and efficacy profile similar to those of other penems and β-lactams (10). Sulopenem is stable to renal dehydropeptidase I, unlike imipenem (13), and has been reported to be stable against hydrolytic attack by many β-lactamases, including ESBLs and AmpC enzymes, which confer resistance to third-generation cephalosporins (10). The activity of sulopenem addresses several of the most urgent, serious, and concerning drug-resistant antimicrobial threats defined by the CDC, including ESBL-producing Enterobacteriaceae (14).
(This work was presented in part as an abstract at ASM Microbe 2018, 7 to 11 June 2018, Atlanta, GA [15].)
The purpose of the current study was to assess the in vitro activity of sulopenem against recent (2014 to 2016) urinary tract infection isolates of E. coli. The isolates tested were collected as part of the CANWARD surveillance study, an annual (since 2007) national study designed to assess antimicrobial resistance and pathogen prevalence in patients receiving care at hospitals in major population centers across Canada (16) (www.can-r.ca). All isolates collected by the CANWARD surveillance study are shipped to the coordinating laboratory (Health Sciences Centre, Winnipeg, Manitoba, Canada), where they are subcultured; their identities are confirmed by colonial appearance, spot testing (17), and/or MALDI-TOF (matrix-assisted laser desorption ionization-time of flight) mass spectrometry (Bruker Daltonics, Billerica, MA, USA); and antimicrobial susceptibility testing is performed according to CLSI-defined broth microdilution methodology (18, 19). Cation-adjusted Mueller-Hinton II broth (BD BBL; Becton, Dickinson and Company, Sparks, MD) was used in 96-well broth microdilution panel production. The antimicrobial agents tested were acquired as laboratory-grade powders from their respective manufacturers or from a commercial source. All antimicrobial agents were tested against the same inoculum of each isolate of E. coli.
In total, 539 urinary isolates of E. coli were tested. Sulopenem MIC interpretative criteria have not been established to date. MICs of comparator antimicrobial agents were interpreted by using current CLSI M100 breakpoints (19). ESBL-producing isolates of E. coli were screened for and confirmed phenotypically following the CLSI method (19). Isolates of E. coli demonstrating an MIC of ≥1 μg/ml for ceftriaxone and/or ceftazidime (data not shown) and/or aztreonam (data not shown), having an MIC of ≥32 μg/ml for cefoxitin (data not shown), and testing phenotypically negative for ESBL production were considered putative AmpC producers (20). Putative AmpC-producing E. coli were then screened for blaENT, blaDHA, blaFOX, blaCIT, and blaCMY as previously described (21). All four isolates of E. coli putatively identified as producing AmpC were positive for a CMY-type β-lactamase by PCR. MDR isolates of E. coli were defined by using a published guideline (22). In this study, MDR was defined as nonsusceptible to ≥3 agents from different antimicrobial classes (ceftriaxone, amoxicillin-clavulanate, SXT, nitrofurantoin, ciprofloxacin, and gentamicin).
Sulopenem demonstrated a narrow (four doubling dilution) MIC range of 0.015 to 0.12 μg/ml, an MIC50 of 0.03 μg/ml, and an MIC90 of 0.03 μg/ml against all 539 urinary isolates of E. coli tested (Table 1). The in vitro activity of sulopenem (minimum MIC, maximum MIC, MIC50, and MIC90) was unaffected (≤1 doubling-dilution difference from comparator-susceptible subsets) by nonsusceptibility to trimethoprim-sulfamethoxazole, ciprofloxacin, or both, as well as isolates with MDR, ESBL-positive, and AmpC-positive phenotypes. The maximum MICs observed for sulopenem and meropenem against E. coli were both 0.12 μg/ml.
TABLE 1.
In vitro activity of sulopenem and comparator antimicrobial agents against E. coli isolated from urine specimens of Canadian patients from 2014 to 2016
| E. coli phenotype (no. of isolates tested) and antimicrobial agent | MIC data (µg/ml) |
MIC interpretation (%) |
||||
|---|---|---|---|---|---|---|
| MIC50 | MIC90 | Range | Susceptible | Intermediate | Resistant | |
| All isolates (539) | ||||||
| Sulopenem | 0.03 | 0.03 | 0.015 to 0.12 | NAa | NA | NA |
| Meropenem | ≤0.03 | ≤0.03 | ≤0.03 to 0.12 | 100 | 0 | 0 |
| Ceftriaxone | ≤0.25 | 1 | ≤0.25 to >64 | 90.4 | 0.1 | 9.5 |
| Amoxicillin-clavulanate | 4 | 16 | 0.5 to >32 | 81.3 | 14.6 | 4.1 |
| SXTb | ≤0.12 | >8 | ≤0.12 to >8 | 75.5 | NA | 24.5 |
| Nitrofurantoin | 16 | 16 | ≤1 to 256 | 97.8 | 1.5 | 0.7 |
| Ciprofloxacin | ≤0.06 | >16 | ≤0.06 to >16 | 76.3 | 0.1 | 23.6 |
| Gentamicin | ≤0.5 | 1 | ≤0.5 to >32 | 91.3 | 0.4 | 8.3 |
| Pansusceptiblec isolates (309) | ||||||
| Sulopenem | 0.03 | 0.03 | 0.015 to 0.06 | NA | NA | NA |
| Meropenem | ≤0.03 | ≤0.03 | ≤0.03 to 0.12 | 100 | 0 | 0 |
| Ceftriaxone | ≤0.25 | ≤0.25 | ≤0.25 to 1 | 100 | 0 | 0 |
| Amoxicillin-clavulanate | 4 | 8 | 0.5 to 8 | 100 | 0 | 0 |
| SXT | ≤0.12 | 0.25 | ≤0.12 to 2 | 100 | NA | 0 |
| Nitrofurantoin | 16 | 16 | 2 to 32 | 100 | 0 | 0 |
| Ciprofloxacin | ≤0.06 | ≤0.06 | ≤0.06 to 0.5 | 100 | 0 | 0 |
| Gentamicin | ≤0.5 | ≤0.5 | ≤0.5 to 2 | 100 | 0 | 0 |
| SXT-susceptible isolates (407) | ||||||
| Sulopenem | 0.03 | 0.03 | 0.015 to 0.12 | NA | NA | NA |
| Meropenem | ≤0.03 | ≤0.03 | ≤0.03 to 0.12 | 100 | 0 | 0 |
| Ceftriaxone | ≤0.25 | ≤0.25 | ≤0.25 to >64 | 94.3 | 0 | 5.7 |
| Amoxicillin-clavulanate | 4 | 16 | 0.5 to >32 | 88.0 | 9.1 | 2.9 |
| SXT | ≤0.12 | 0.25 | ≤0.12 to 2 | 100 | NA | 0 |
| Nitrofurantoin | 16 | 16 | ≤1 to 128 | 98.3 | 1.2 | 0.5 |
| Ciprofloxacin | ≤0.06 | >16 | ≤0.06 to >16 | 85.3 | 0 | 14.7 |
| Gentamicin | ≤0.5 | 1 | ≤0.5 to >32 | 95.1 | 0.5 | 4.4 |
| SXT-nonsusceptible isolates (132) | ||||||
| Sulopenem | 0.03 | 0.06 | 0.015 to 0.12 | NA | NA | NA |
| Meropenem | ≤0.03 | ≤0.03 | ≤0.03 to 0.06 | 100 | 0 | 0 |
| Ceftriaxone | ≤0.25 | >64 | ≤0.25 to >64 | 78.0 | 0.8 | 21.2 |
| Amoxicillin-clavulanate | 8 | 16 | 2 to >32 | 60.6 | 31.8 | 7.6 |
| SXT | >8 | >8 | 4 to >8 | 0 | NA | 100 |
| Nitrofurantoin | 16 | 32 | ≤1 to 256 | 96.2 | 2.3 | 1.5 |
| Ciprofloxacin | 16 | >16 | ≤0.06 to >16 | 48.5 | 0.7 | 50.8 |
| Gentamicin | ≤0.5 | 32 | ≤0.5 to >32 | 79.5 | 0 | 20.5 |
| Ciprofloxacin-susceptible isolates (411) | ||||||
| Sulopenem | 0.03 | 0.03 | 0.015 to 0.12 | NA | NA | NA |
| Meropenem | ≤0.03 | ≤0.03 | ≤0.03 to 0.12 | 100 | 0 | 0 |
| Ceftriaxone | ≤0.25 | ≤0.25 | ≤0.25 to >64 | 96.6 | 0.2 | 3.2 |
| Amoxicillin-clavulanate | 4 | 16 | 0.5 to >32 | 86.9 | 10.2 | 2.9 |
| SXT | ≤0.12 | >8 | ≤0.12 to >8 | 84.4 | NA | 15.6 |
| Nitrofurantoin | 16 | 16 | ≤1 to 128 | 99.8 | 0 | 0.2 |
| Ciprofloxacin | ≤0.06 | 0.12 | ≤0.06 to 1 | 100 | 0 | 0 |
| Gentamicin | ≤0.5 | 1 | ≤0.5 to >32 | 95.9 | 0.2 | 3.9 |
| Ciprofloxacin-nonsusceptible isolates (128) | ||||||
| Sulopenem | 0.03 | 0.06 | 0.015 to 0.12 | NA | NA | NA |
| Meropenem | ≤0.03 | ≤0.03 | ≤0.03 to 0.06 | 100 | 0 | 0 |
| Ceftriaxone | ≤0.25 | >64 | ≤0.25 to >64 | 70.3 | 0 | 29.7 |
| Amoxicillin-clavulanate | 8 | 16 | 1 to >32 | 63.3 | 28.9 | 7.8 |
| SXT | >8 | >8 | ≤0.12 to >8 | 46.9 | NA | 53.1 |
| Nitrofurantoin | 16 | 32 | ≤1 to 256 | 91.4 | 6.3 | 2.3 |
| Ciprofloxacin | >16 | >16 | 2 to >16 | 0 | 0.8 | 99.2 |
| Gentamicin | ≤0.5 | >32 | ≤0.5 to >32 | 76.6 | 0.7 | 22.7 |
| SXT- and ciprofloxacin-susceptible isolates (347)d | ||||||
| Sulopenem | 0.03 | 0.03 | 0.015 to 0.12 | NA | NA | NA |
| Meropenem | ≤0.03 | ≤0.03 | ≤0.03 to 0.12 | 100 | 0 | 0 |
| Ceftriaxone | ≤0.25 | ≤0.25 | ≤0.25 to >64 | 97.7 | 0 | 2.3 |
| Amoxicillin-clavulanate | 4 | 8 | 0.5 to >32 | 90.8 | 6.6 | 2.6 |
| SXT | ≤0.12 | ≤0.12 | ≤0.12 to 2 | 100 | NA | 0 |
| Nitrofurantoin | 16 | 16 | ≤1 to 32 | 100 | 0 | 0 |
| Ciprofloxacin | ≤0.06 | ≤0.06 | ≤0.06 to 0.5 | 100 | 0 | 0 |
| Gentamicin | ≤0.5 | 1 | ≤0.5 to >32 | 98.3 | 0.3 | 1.4 |
| SXT- and ciprofloxacin-nonsusceptible isolates (68)d | ||||||
| Sulopenem | 0.03 | 0.06 | 0.015 to 0.12 | NA | NA | NA |
| Meropenem | ≤0.03 | ≤0.03 | ≤0.03 to 0.06 | 100 | 0 | 0 |
| Ceftriaxone | ≤0.25 | >64 | ≤0.25 to >64 | 66.2 | 0 | 33.8 |
| Amoxicillin-clavulanate | 8 | 32 | 2 to >32 | 55.9 | 33.8 | 10.3 |
| SXT | >8 | >8 | 4 to >8 | 0 | NA | 100 |
| Nitrofurantoin | 16 | 32 | ≤1 to 256 | 94.1 | 4.4 | 1.5 |
| Ciprofloxacin | >16 | >16 | 2 to >16 | 0 | 1.5 | 98.5 |
| Gentamicin | ≤0.5 | >32 | ≤0.5 to >32 | 76.5 | 0 | 23.5 |
| MDRe isolates (71) | ||||||
| Sulopenem | 0.03 | 0.06 | 0.015 to 0.12 | NA | NA | NA |
| Meropenem | ≤0.03 | ≤0.03 | ≤0.03 to 0.06 | 100 | 0 | 0 |
| Ceftriaxone | 16 | >64 | ≤0.25 to >64 | 46.5 | 0 | 53.5 |
| Amoxicillin-clavulanate | 16 | 32 | 4 to >32 | 32.4 | 50.7 | 16.9 |
| SXT | >8 | >8 | ≤0.12 to >8 | 23.9 | NA | 76.1 |
| Nitrofurantoin | 16 | 64 | 2 to 256 | 87.3 | 8.5 | 4.2 |
| Ciprofloxacin | >16 | >16 | ≤0.06 to >16 | 11.3 | 0 | 88.7 |
| Gentamicin | 1 | >32 | ≤0.5 to >32 | 56.3 | 1.4 | 42.3 |
| ESBL-negative isolates (490) | ||||||
| Sulopenem | 0.03 | 0.03 | 0.03 to 0.12 | NA | NA | NA |
| Meropenem | ≤0.03 | ≤0.03 | ≤0.03 to 0.12 | 100 | 0 | 0 |
| Ceftriaxone | ≤0.25 | ≤0.25 | ≤0.25 to >64 | 99.2 | 0 | 0.8 |
| Amoxicillin-clavulanate | 4 | 16 | 0.5 to >32 | 83.9 | 12.8 | 3.3 |
| SXT | ≤0.12 | >8 | ≤0.12 to >8 | 78.8 | NA | 21.2 |
| Nitrofurantoin | 16 | 16 | ≤1 to 256 | 98.2 | 1.4 | 0.4 |
| Ciprofloxacin | ≤0.06 | >16 | ≤0.06 to >16 | 81.4 | 0.2 | 18.4 |
| Gentamicin | ≤0.5 | 1 | ≤0.5 to >32 | 93.7 | 0 | 6.3 |
| ESBL-positive isolates (49) | ||||||
| Sulopenem | 0.03 | 0.06 | 0.03 to 0.12 | NA | NA | NA |
| Meropenem | ≤0.03 | ≤0.03 | ≤0.03 to 0.06 | 100 | 0 | 0 |
| Ceftriaxone | >64 | >64 | 1 to >64 | 2.0 | 2.1 | 95.9 |
| Amoxicillin-clavulanate | 8 | 32 | 4 to >32 | 55.1 | 32.7 | 12.2 |
| SXT | >8 | >8 | ≤0.12 to >8 | 42.9 | NA | 57.1 |
| Nitrofurantoin | 16 | 16 | 2 to 256 | 93.9 | 2.0 | 4.1 |
| Ciprofloxacin | >16 | >16 | ≤0.06 to >16 | 24.5 | 0 | 75.5 |
| Gentamicin | ≤0.5 | >32 | ≤0.5 to >32 | 67.3 | 4.1 | 28.6 |
| AmpC-positive isolates (4) | ||||||
| Sulopenem | NA | NA | 0.03 to 0.12 | NA | NA | NA |
| Meropenem | NA | NA | ≤0.03 to 0.06 | 100 | 0 | 0 |
| Ceftriaxone | NA | NA | ≤0.25 to >64 | 25.0 | 0 | 75.0 |
| Amoxicillin-clavulanate | NA | NA | 32 to >32 | 0 | 0 | 100 |
| SXT | NA | NA | 0.25 to >8 | 50.0 | NA | 50.0 |
| Nitrofurantoin | NA | NA | 8 to 32 | 100 | 0 | 0 |
| Ciprofloxacin | NA | NA | ≤0.06 to >16 | 50.0 | 0 | 50.0 |
| Gentamicin | NA | NA | ≤0.5 to 1 | 100 | 0 | 0 |
NA, there are no MIC breakpoints defined for this antimicrobial agent or no intermediate MIC breakpoint for this antimicrobial agent, or there were <30 isolates tested and an MIC50 and MIC90 could not be generated.
SXT, trimethoprim-sulfamethoxazole.
Pansusceptible isolates were susceptible to meropenem, ceftriaxone, amoxicillin-clavulanate, SXT, nitrofurantoin, ciprofloxacin, and gentamicin and excluded MDR isolates and isolates resistant to one (n = 89) and two (n = 70) of the aforementioned list of antimicrobial agents.
There were 124 isolates of E. coli that were SXT susceptible and ciprofloxacin nonsusceptible or SXT nonsusceptible and ciprofloxacin susceptible that were excluded from this analysis.
MDR was defined as nonsusceptible to ≥3 agents from different antimicrobial classes (ceftriaxone, amoxicillin-clavulanate, SXT, nitrofurantoin, ciprofloxacin, and gentamicin). The most common MDR phenotypes were isolates nonsusceptible to amoxicillin-clavulanate, ciprofloxacin, and SXT (n = 13; 18.3% of MDR isolates); isolates nonsusceptible to ceftriaxone, ciprofloxacin, and SXT (n = 9; 12.7% of MDR isolates); isolates nonsusceptible to amoxicillin-clavulanate, ceftriaxone, ciprofloxacin, and SXT (n = 7; 9.9% of MDR isolates); isolates nonsusceptible to ciprofloxacin, SXT, and gentamicin (n = 6; 8.5% of MDR isolates); isolates nonsusceptible to amoxicillin-clavulanate, ceftriaxone, and ciprofloxacin (n = 4; 5.6% of MDR isolates); and isolates nonsusceptible to amoxicillin-clavulanate, ciprofloxacin, SXT, and gentamicin (n = 4; 5.6% of MDR isolates).
To date, publication of data describing the in vitro activity of sulopenem has been limited. Sulopenem has been reported to inhibit the growth of most isolates of aerobic and anaerobic Gram-positive and Gram-negative bacteria, including methicillin-susceptible Staphylococcus aureus, Streptococcus pneumoniae (penicillin-susceptible and -resistant isolates), group A and B β-hemolytic streptococci, Listeria monocytogenes, Enterobacteriaceae, Haemophilus influenzae, and Moraxella catarrhalis but excluding P. aeruginosa and Stenotrophomonas maltophilia, at a concentration of ≤1 μg/ml (10, 13, 23–27).
Data generated by the current study (Table 1) confirm previously published data describing the in vitro activity of sulopenem against E. coli, including ESBL- and AmpC-positive isolates (10, 13, 23, 24, 28, 29). Puttagunta et al. (10) reported sulopenem MIC90s of 0.03 and 0.06 μg/ml, respectively, for ESBL-negative (n = 169) and ESBL-positive (n = 20) E. coli (all MICs were ≤0.12 μg/ml). In the same study, the sulopenem MIC90s were 0.06 and 0.25 μg/ml, respectively, for ESBL-negative (n = 108) and ESBL-positive (n = 16) Klebsiella spp. (all MICs were ≤0.25 μg/ml), and 97.9% of all isolates of Enterobacteriaceae tested (n = 682) had sulopenem MICs of ≤1 µg/ml. Aronin et al. (24) reported MIC50 and MIC90 of 0.03 and 0.06 μg/ml, respectively, for 32 ESBL-positive E. coli urinary isolates from the United States and Europe, whereas Duignan et al. (28) reported that sulopenem had an MIC90 of 0.03 μg/ml and an MIC range of 0.015 to 0.25 μg/ml for 17 isolates of ESBL-positive E. coli. Minamimura et al. (13) reported a sulopenem MIC90 of 0.05 μg/ml when tested against 100 isolates of E. coli. The repeated observation of one-doubling-dilution higher MIC90s for ESBL-positive isolates of Enterobacteriaceae compared with those of ESBL-negative isolates may be explained by weak sulopenem hydrolytic activity of β-lactamases, including ESBLs, in these isolates. The common cooccurrence of ESBLs in isolates nonsusceptible to ciprofloxacin and in MDR isolates likely explains the correlation between these phenotypes and their one-doubling-dilution higher MIC90s for sulopenem compared with susceptible isolate groups. Although a one-doubling-dilution higher MIC90 is likely not significant in vitro, additional resistance determinants, such as membrane impermeability and hyperproduction of ESBLs or other noncarbapenemase β-lactamases, may potentially lead to clinically relevant increases in MIC.
β-Lactams are widely used in clinical medicine to treat various Gram-positive and Gram-negative bacterial infections because of their proven efficacy and safety. However, resistance to β-lactams does occur and may limit the utility of some or all β-lactams currently marketed for infections caused by specific pathogens. Sulopenem, like other penems, is not expected to have activity against carbapenemase-producing isolates of E. coli or other species of Enterobacteriaceae carrying class A (e.g., Klebsiella pneumoniae carbapenemase [KPC]), class B (metallo-β-lactamases), or class D (e.g., OXA) β-lactamases. However, when indicated, oral sulopenem has the potential to provide reliable therapy similar to that of existing carbapenems; a phase I clinical trial in healthy volunteers who received a single 500-mg dose of oral sulopenem-etzadroxil (with or without 500 mg of probenecid) achieved urine concentrations of sulopenem that remained above the MIC range of E. coli tested in the current study (0.015 to 0.12 µg/ml) for ≥12 h after dose administration (12, 29).
In conclusion, sulopenem, given its in vitro potency and its oral and parenteral formulations, may represent a valuable new option to treat patients with urinary tract infections caused by pathogens resistant to first- and second-line antimicrobial agents. In the current study, sulopenem demonstrated potent in vitro activity (MIC range, 0.015 to 0.12 µg/ml) against current urinary isolates of E. coli. Our data support further development of sulopenem for the treatment of urinary tract infections.
ACKNOWLEDGMENTS
We thank staff in the following hospital laboratories that participated in the CANWARD surveillance study from 2014 to 2016: Vancouver Hospital, Vancouver, British Columbia; University of Alberta Hospital, Edmonton, Alberta; Royal University Hospital, Saskatoon, Saskatchewan; Health Sciences Centre, Winnipeg, Manitoba; London Health Sciences Centre, London, Ontario; University Health Network, Mount Sinai Hospital, and St. Michael’s Hospital, Toronto, Ontario; Children’s Hospital of Eastern Ontario and The Ottawa Hospital, Ottawa, Ontario; Cite de la Sante de Laval, Laval, Québec; Hopital Maisonneuve-Rosemont, Montreal, Québec; CHRTR Pavilion Ste. Marie, Trois-Rivieres, Québec; Centre Hospitalier Universitaire de Sherbrooke, Sherbrooke, Québec; L’Hotel-Dieu de Québec, Québec City, Québec; South East Regional Health Authority, Moncton, New Brunswick; and Queen Elizabeth II Health Sciences Centre, Halifax, Nova Scotia.
The CANWARD surveillance study was supported in part by the Health Sciences Centre (Winnipeg, Manitoba, Canada), the University of Manitoba (Winnipeg, Manitoba, Canada), the Public Health Agency of Canada–National Microbiology Laboratory (Winnipeg, Manitoba, Canada), and Iterum Therapeutics (Old Saybrook, CT, USA).
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