Abstract
Objectives
To investigate in vitro susceptibility patterns of bacterial pathogens recovered from the urine of outpatients (isolates from outpatient clinics or emergency departments) and hospital inpatients across Canada from 2009 to 2020 as part of the CANWARD study
Methods
Canadian hospital microbiology laboratories submitted bacterial pathogens cultured from urine to the CANWARD study coordinating laboratory on an annual basis (January 2009 to December 2020). Antimicrobial susceptibility testing was performed by CLSI broth microdilution, with MICs interpreted by current CLSI breakpoints.
Results
In total, 4644 urinary pathogens were included in this study. Escherichia coli was recovered most frequently (53.3% of all isolates), followed by Enterococcus faecalis, Klebsiella pneumoniae, Proteus mirabilis, Pseudomonas aeruginosa and Staphylococcus aureus. Together, these six species accounted for 84.2% of study isolates. Nitrofurantoin demonstrated excellent in vitro activity versus E. coli, with 97.6% of outpatient and 96.1% of inpatient isolates remaining susceptible. In contrast, E. coli susceptibility rates were lower for ciprofloxacin (outpatient 79.5%, inpatient 65.9%) and trimethoprim/sulfamethoxazole (outpatient 75.2%, inpatient 73.5%). The percentage of E. coli isolates that were phenotypically positive for ESBL production significantly increased from 4.2% (2009–11) to 11.3% (2018–20). A similar although less pronounced temporal trend was observed with ESBL-producing K. pneumoniae.
Conclusions
E. coli was the pathogen most frequently recovered from the urine of Canadian patients, and the proportion of isolates that were ESBL producers increased over time. Susceptibility data presented here suggest that ciprofloxacin and trimethoprim/sulfamethoxazole may be suboptimal for the empirical treatment of complicated urinary infections.
Introduction
Urinary tract infections (UTIs) are common. In the USA, UTIs were responsible for an estimated 8.6 million ambulatory care visits in 2007.1 Further, in 2011, approximately 400 000 patients in the USA were hospitalized for a UTI, resulting in a total healthcare cost estimated at $2.8 billion.2 UTIs that occur in young, otherwise healthy, non-pregnant, pre-menopausal, ambulatory women with no history suggestive of a functional or anatomical urinary tract abnormality are termed uncomplicated.3 In contrast, UTIs in individuals with medical conditions or abnormalities of the urinary tract (anatomical or functional) that may increase the risk of treatment failure are considered complicated.3 This latter group includes infections in pregnant women, children, males, immunocompromised patients, and patients with a urinary catheter.3Escherichia coli is the pathogen most frequently identified among patients presenting with uncomplicated cystitis and pyelonephritis.3,4 For patients with complicated UTIs, including hospitalized patients, E. coli remains the most common organism but the spectrum of pathogens encountered is more diverse.5–7 Of concern, ESBL producers are being detected with increasing frequency among urinary E. coli isolates, both in Canada and elsewhere in the world.8–11 ESBL-producing E. coli often demonstrate phenotypic resistance to multiple antimicrobials used in the empirical management of UTIs, complicating the selection of appropriate initial antimicrobial therapy.8
In the ambulatory care setting, women presenting with uncomplicated cystitis are often treated empirically with an oral agent and urine culture is not performed.12–14 For patients with pyelonephritis or a complicated urinary tract infection, urine culture is recommended.3,5 Initial therapy in this setting should be based on multiple factors including severity of illness, prior treatment history, previous microbiology results, and local or national antibiogram data. There has not been a large surveillance study describing the susceptibility patterns of common bacteria causing UTIs among Canadian patients published in recent years. The purpose of the current study was to investigate the in vitro susceptibility of pathogens frequently isolated from the urine of outpatients (persons attending outpatient clinics or seeking urgent care/emergency department services) and inpatients across Canada from 2009 to 2020, as well as to document changes in susceptibility to common antimicrobials over this time period.
Materials and methods
Bacterial isolates
The bacterial isolates tested here were obtained as part of the CANWARD surveillance study.15 CANWARD is an ongoing, national Canadian Antimicrobial Resistance Alliance (CARA)/Health Canada partnered study assessing antimicrobial resistance patterns of pathogens causing infections among patients receiving care at hospitals across Canada. Isolates cultured from urine specimens submitted to sentinel hospital microbiology laboratories in nine of the ten Canadian provinces (geographically distributed in a population-based fashion) were forwarded on to the CANWARD coordinating laboratory (Health Sciences Centre, Winnipeg, Canada) on an annual basis. Only clinically significant isolates were included, with significance determined based on local microbiology laboratory protocols. Isolates were shipped on Amies semi-solid transport medium, subcultured onto appropriate media, and stocked in skimmed milk at −80°C until MIC testing was performed. Species identities were confirmed biochemically or by MALDI-TOF MS (Bruker Daltonics, Billerica, MA, USA) at the coordinating laboratory as required (i.e. when the isolate morphology or susceptibility profile did not match the identification reported by the referring laboratory). For the purpose of this study, isolates were classified as outpatient if they were obtained from patients attending primary care and specialty medical clinics, and hospital emergency or urgent care departments. Isolates were considered inpatient if they were obtained from patients receiving care on medical, surgical or ICU wards.
Antimicrobial susceptibility testing
Following two subcultures from frozen stock, MICs for clinically relevant antimicrobials were determined using the CLSI reference broth microdilution method, with 96-well custom-designed microtitre plates containing doubling dilutions of agents in volumes of 100 µL/well.16 MICs were interpreted according to current CLSI breakpoints.17 Quality control testing was performed each day that clinical isolates were tested, as specified by CLSI. Colony counts were performed periodically to confirm starting inocula. Susceptibility data in this report are only provided for the six pathogens most frequently recovered from the urine of Canadian patients. Cefazolin was tested as a surrogate for cefalexin, as permitted by the CLSI M100 standard.17 Phenotypic screening and confirmation of ESBL-producing E. coli and Klebsiella pneumoniae was performed as described by CLSI.17
Statistical analysis
For the purpose of statistical analysis, isolates were defined as either susceptible or not susceptible (intermediate or resistant) to a tested antimicrobial agent using current CLSI breakpoints. The susceptible-dose-dependent category (cefepime and piperacillin/tazobactam tested against Enterobacterales) was included in the not-susceptible group. To estimate the change in antimicrobial susceptibility over time (from 2009 to 2020) in Canada, we performed a Cochrane–Armitage test of trend for four 3 year time periods (2009 to 2011, 2012 to 2014, 2015 to 2017, and 2018 to 2020) for the six most common pathogens isolated: E. coli, K. pneumoniae, Enterococcus faecalis, Proteus mirabilis, Pseudomonas aeruginosa and Staphylococcus aureus. P values ≤0.05 were considered statistically significant.
Results
This study included 4644 pathogens recovered from urine specimens obtained from Canadian patients between 2009 and 2020. Isolate demographics, stratified by bacterial species, are presented in Table S1. In total, 70.3% (3264/4644) of isolates were from female patients, while 29.7% (1380/4644) were from male patients. The distribution of isolates by patient age was as follows: 12.6% (587/4644) from patients ≤17 years of age, 37.6% (1747/4644) from patients 18 to 64 years of age, and 49.7% (2310/4644) from patients ≥65 years of age. The majority of isolates (3032; 65.3%) were classified as outpatient, with an almost even split between isolates obtained from clinic patients and isolates obtained from emergency room patients. The remaining 1612 isolates were classified as inpatient. The majority of these (1222; 75.8%) were from patients on medical wards. Isolates were obtained from across Canada, with roughly one-third from the eastern provinces, one-third from the western provinces, and one-third from Ontario (Canada’s most populated province, located near the geographical centre of the country).
The six most frequently recovered urinary pathogens were E. coli, E. faecalis, K. pneumoniae, P. mirabilis, P. aeruginosa and S. aureus (Table S1). Together, these species accounted for 84.2% of all isolates in the study. E. coli was the most common urinary pathogen irrespective of inpatient or outpatient location, patient gender, patient age or region of Canada. However, the relative frequency of E. coli isolation was lower for inpatients (42.7% of all inpatient isolates) in comparison with outpatients (58.9% of all outpatient isolates). Pathogens other than E. coli made up a greater proportion of inpatient isolates. E. faecalis accounted for 14.1% of inpatient isolates but only 8.8% of outpatient isolates. Similarly, P. aeruginosa and Enterobacter cloacae accounted from 6.2% and 3.4% of inpatient isolates but only 2.1% and 1.6% of outpatient isolates, respectively. The relative proportions of isolates other than E. coli also tended to be higher among male patients and those ≥65 years of age.
Antimicrobial susceptibility data for the six most common pathogens isolated in this study are presented in Table 1. The most active oral antimicrobials versus outpatient E. coli urinary isolates were nitrofurantoin (97.6% susceptible), cefalexin (92% susceptible, extrapolated from cefazolin) and amoxicillin/clavulanate (85.1% susceptible). In vitro susceptibility to ciprofloxacin and trimethoprim/sulfamethoxazole, two other common antimicrobials for the treatment of urinary tract infections, was only 79.5% and 75.2%, respectively. Inpatient E. coli isolates were less susceptible to oral antimicrobials than outpatient isolates, with susceptibility rates of 96.1% for nitrofurantoin, 84.6% for cefalexin, 76.8% for amoxicillin/clavulanate, 73.5% for trimethoprim/sulfamethoxazole and 65.9% for ciprofloxacin. Considering IV antimicrobials, meropenem was active in vitro versus 100% of E. coli isolates, while 97.5% and 94.9% outpatient and inpatient isolates, respectively, remained fully susceptible to piperacillin/tazobactam. Inpatient E. coli urinary isolates demonstrated reduced susceptibility to ceftriaxone (86.8% susceptible) relative to outpatient isolates (93.7% susceptible).
Table 1.
In vitro activities of antimicrobial agents against the six most common pathogens isolated from urine in the CANWARD 2009–20 study (split into outpatients and inpatients) (>100 isolates total)
| MIC (mg/L) | MIC interpretation (%) | |||||||
|---|---|---|---|---|---|---|---|---|
| Organism | Patient location (n) | Antimicrobial agent | MIC50 | MIC90 | MIC range | Susceptible | Intermediatea | Resistant |
| E. coli | Outpatient (1786) | Amoxicillin/clavulanate | 4 | 16 | ≤ 0.06 to > 32 | 85.1 | 11.3 | 3.6 |
| Cefalexin (urine)b | 2 | 16 | ≤ 0.5 to > 128 | 92.0 | NAc | 8.0 | ||
| Cefepime | ≤ 0.25 | ≤ 0.25 | ≤ 0.25 to > 64 | 95.6 | 1.8 | 2.5 | ||
| Cefoxitin | 4 | 8 | ≤ 0.06 to > 32 | 92.9 | 4.5 | 2.6 | ||
| Ceftazidime | ≤ 0.25 | 1 | ≤ 0.25 to > 32 | 95.6 | 0.5 | 3.9 | ||
| Ceftriaxone | ≤ 0.25 | ≤ 0.25 | ≤ 0.25 to > 64 | 93.7 | 0.3 | 6.0 | ||
| Ciprofloxacin | ≤ 0.06 | > 16 | ≤ 0.06 to > 16 | 79.5 | 1.1 | 19.4 | ||
| Colistin | 0.25 | 0.5 | ≤ 0.06–8 | NA | 99.8 | 0.2 | ||
| Doxycycline | 2 | 32 | 0.25 to > 32 | 77.3 | 5.0 | 17.7 | ||
| Gentamicin | ≤ 0.5 | 1 | ≤ 0.5 to > 32 | 92.9 | 0.2 | 6.8 | ||
| Meropenem | ≤ 0.03 | ≤ 0.03 | ≤ 0.03–1 | 100 | 0 | 0 | ||
| Nitrofurantoin | 16 | 32 | ≤ 0.5 to > 512 | 97.6 | 1.3 | 1.1 | ||
| Piperacillin/tazobactam | 2 | 4 | ≤ 1 to > 512 | 97.5 | 1.0 | 1.6 | ||
| Trimethoprim/sulfamethoxazole | ≤ 0.12 | > 8 | ≤ 0.12 to > 8 | 75.2 | NA | 24.8 | ||
| Inpatient (689) | Amoxicillin/clavulanate | 8 | 16 | 0.5 to > 32 | 76.8 | 16.5 | 6.7 | |
| Cefalexin (urine)b | 2 | > 128 | ≤ 0.5 to > 128 | 84.6 | NA | 15.4 | ||
| Cefepime | ≤ 0.25 | 4 | ≤ 0.25 to > 64 | 89.3 | 2.9 | 7.8 | ||
| Cefoxitin | 4 | 16 | 0.5 to > 32 | 87.8 | 7.5 | 4.6 | ||
| Ceftazidime | ≤ 0.25 | 8 | ≤ 0.25 to > 32 | 89.4 | 1.5 | 9.1 | ||
| Ceftriaxone | ≤ 0.25 | 64 | ≤ 0.25 to > 64 | 86.8 | 0.1 | 13.1 | ||
| Ciprofloxacin | ≤ 0.06 | > 16 | ≤ 0.06 to > 16 | 65.9 | 0.7 | 33.4 | ||
| Colistin | 0.25 | 0.5 | ≤ 0.06–4 | NA | 99.8 | 0.2 | ||
| Doxycycline | 2 | 32 | 0.25 to > 32 | 71.1 | 5.8 | 23.1 | ||
| Gentamicin | ≤ 0.5 | 32 | ≤ 0.5 to > 32 | 88.1 | 0.7 | 11.2 | ||
| Meropenem | ≤ 0.03 | ≤ 0.03 | ≤ 0.03–0.12 | 100 | 0 | 0 | ||
| Nitrofurantoin | 16 | 32 | ≤ 1–256 | 96.1 | 2.1 | 1.8 | ||
| Piperacillin/tazobactam | 2 | 4 | ≤ 1–512 | 94.9 | 2.3 | 2.8 | ||
| Trimethoprim/sulfamethoxazole | ≤ 0.12 | > 8 | ≤ 0.12 to > 8 | 73.5 | NA | 26.5 | ||
| K. pneumoniae | Outpatient (295) | Amoxicillin/clavulanate | 2 | 8 | 1 to > 32 | 92.1 | 4.7 | 3.2 |
| Cefalexin (urine)b | 1 | 8 | ≤ 0.5 to > 128 | 92.5 | NA | 7.5 | ||
| Cefepime | ≤ 0.25 | ≤ 0.25 | ≤ 0.25 to > 64 | 95.0 | 1.2 | 3.9 | ||
| Cefoxitin | 4 | 8 | 0.5 to > 32 | 93.9 | 2.7 | 3.4 | ||
| Ceftazidime | ≤ 0.25 | 0.5 | ≤ 0.25 to > 32 | 95.9 | 0.3 | 3.7 | ||
| Ceftriaxone | ≤ 0.25 | ≤ 0.25 | ≤ 0.25 to > 64 | 94.6 | 0 | 5.4 | ||
| Ciprofloxacin | ≤ 0.06 | 0.5 | ≤ 0.06 to > 16 | 89.2 | 3.1 | 7.8 | ||
| Colistin | 0.5 | 1 | 0.12 to > 16 | NA | 96.9 | 3.1 | ||
| Doxycycline | 2 | 16 | 0.5 to > 32 | 84.5 | 5.0 | 10.5 | ||
| Gentamicin | ≤ 0.5 | ≤ 0.5 | ≤ 0.5 to > 32 | 97.6 | 0 | 2.4 | ||
| Meropenem | ≤ 0.03 | 0.06 | ≤ 0.03–0.5 | 100 | 0 | 0 | ||
| Nitrofurantoin | 64 | 128 | 2–512 | 39.6 | 39.2 | 21.2 | ||
| Piperacillin/tazobactam | 2 | 4 | ≤ 1–256 | 96.6 | 2.0 | 1.4 | ||
| Trimethoprim/sulfamethoxazole | ≤ 0.12 | 4 | ≤ 0.12 to > 8 | 89.5 | NA | 10.5 | ||
| Inpatient (172) | Amoxicillin/clavulanate | 2 | 16 | 0.5 to > 32 | 88.8 | 6.5 | 4.7 | |
| Cefalexin (urine)b | 1 | > 128 | 1 to > 128 | 86.6 | NA | 13.4 | ||
| Cefepime | ≤ 0.25 | 1 | ≤ 0.25 to > 64 | 90.7 | 2.1 | 7.1 | ||
| Cefoxitin | 2 | 8 | 0.5 to > 32 | 92.4 | 4.1 | 3.5 | ||
| Ceftazidime | ≤ 0.25 | 8 | ≤ 0.25 to > 32 | 89.0 | 1.7 | 9.3 | ||
| Ceftriaxone | ≤ 0.25 | 8 | ≤ 0.25 to > 64 | 89.0 | 0 | 11.0 | ||
| Ciprofloxacin | ≤ 0.06 | 4 | ≤ 0.06 to > 16 | 83.1 | 5.2 | 11.6 | ||
| Colistin | 0.5 | 1 | 0.12 to > 16 | NA | 98.3 | 1.7 | ||
| Doxycycline | 2 | 32 | 0.25 to > 32 | 73.9 | 5.2 | 20.9 | ||
| Gentamicin | ≤ 0.5 | ≤ 0.5 | ≤ 0.5 to > 32 | 94.8 | 0 | 5.2 | ||
| Meropenem | ≤ 0.03 | 0.06 | ≤ 0.03–0.25 | 100 | 0 | 0 | ||
| Nitrofurantoin | 64 | 128 | 4 to > 512 | 38.8 | 34.1 | 27.1 | ||
| Piperacillin/tazobactam | 2 | 8 | ≤ 1 to > 512 | 92.4 | 2.3 | 5.2 | ||
| Trimethoprim/sulfamethoxazole | ≤ 0.12 | > 8 | ≤ 0.12 to > 8 | 82.0 | NA | 18.0 | ||
| E. faecalis | Outpatient (268) | Ampicillin | 0.5 | 1 | 0.12–2 | 100 | NA | 0 |
| Ciprofloxacin | 1 | > 16 | 0.12 to > 16 | 69.2 | 12.4 | 18.4 | ||
| Daptomycin | 0.5 | 2 | ≤ 0.03–4 | 97.0 | 3.0 | 0 | ||
| Doxycycline | 8 | 16 | ≤ 0.12–32 | 26.4 | 41.0 | 32.6 | ||
| Linezolid | 2 | 2 | 0.5–4 | 93.5 | 6.5 | 0 | ||
| Nitrofurantoin | 8 | 16 | 2–128 | 99.0 | 0.5 | 0.5 | ||
| Vancomycin | 1 | 2 | 0.5–4 | 100 | 0 | 0 | ||
| Inpatient (228) | Ampicillin | 0.5 | 1 | 0.12–8 | 100 | NA | 0 | |
| Ciprofloxacin | 1 | > 16 | 0.25 to > 16 | 60.2 | 7.1 | 32.7 | ||
| Daptomycin | 0.5 | 2 | ≤ 0.03–4 | 98.7 | 1.3 | 0.0 | ||
| Doxycycline | 8 | 16 | ≤ 0.12–16 | 29.3 | 42.8 | 27.9 | ||
| Linezolid | 2 | 2 | 0.5–4 | 90.3 | 9.7 | 0 | ||
| Nitrofurantoin | 8 | 16 | 2–16 | 100 | 0 | 0 | ||
| Vancomycin | 1 | 2 | 0.5–2 | 100 | 0 | 0 | ||
| P. mirabilis | Outpatient (121) | Amoxicillin/clavulanate | 1 | 4 | 0.5 to > 32 | 94.7 | 3.5 | 1.8 |
| Cefalexin (urine)b | 4 | 8 | 2 to > 128 | 95.0 | NA | 5.0 | ||
| Cefepime | ≤ 0.25 | ≤ 0.25 | ≤ 0.25–1 | 100 | 0 | 0 | ||
| Cefoxitin | 4 | 4 | 2–32 | 97.5 | 1.7 | 0.8 | ||
| Ceftazidime | ≤ 0.25 | ≤ 0.25 | ≤ 0.25–4 | 100 | 0 | 0 | ||
| Ceftriaxone | ≤ 0.25 | ≤ 0.25 | ≤ 0.25–1 | 100 | 0 | 0 | ||
| Ciprofloxacin | ≤ 0.06 | 2 | ≤ 0.06 to > 16 | 86.0 | 0 | 14.0 | ||
| Gentamicin | 1 | 2 | ≤ 0.5 to > 32 | 96.7 | 0.8 | 2.5 | ||
| Meropenem | 0.06 | 0.12 | ≤ 0.03–0.25 | 100 | 0 | 0 | ||
| Nitrofurantoin | 128 | 128 | 64–512 | 0 | 20.4 | 79.6 | ||
| Piperacillin/tazobactam | ≤ 1 | ≤ 1 | ≤ 1–8 | 100 | 0 | 0 | ||
| Trimethoprim/sulfamethoxazole | ≤ 0.12 | > 8 | ≤ 0.12 to > 8 | 80.2 | NA | 19.8 | ||
| Inpatient (76) | Amoxicillin/clavulanate | 1 | 4 | 0.5 to > 32 | 93.3 | 1.3 | 5.3 | |
| Cefalexin (urine)b | 4 | 16 | 1 to > 128 | 93.4 | NA | 6.6 | ||
| Cefepime | ≤ 0.25 | ≤ 0.25 | ≤ 0.25–16 | 96.8 | 1.6 | 1.6 | ||
| Cefoxitin | 4 | 8 | 1 to > 32 | 96.1 | 1.3 | 2.6 | ||
| Ceftazidime | ≤ 0.25 | ≤ 0.25 | ≤ 0.25–8 | 98.7 | 1.3 | 0 | ||
| Ceftriaxone | ≤ 0.25 | ≤ 0.25 | ≤ 0.25 to > 64 | 94.7 | 2.6 | 2.6 | ||
| Ciprofloxacin | ≤ 0.06 | 2 | ≤ 0.06 to > 16 | 80.3 | 1.3 | 18.4 | ||
| Gentamicin | ≤ 0.5 | 8 | ≤ 0.5 to > 32 | 89.5 | 2.6 | 7.9 | ||
| Meropenem | 0.06 | 0.12 | ≤ 0.03–0.25 | 100 | 0 | 0 | ||
| Nitrofurantoin | 128 | 128 | 64–256 | 0 | 17.6 | 82.4 | ||
| Piperacillin/tazobactam | ≤ 1 | ≤ 1 | ≤ 1–32 | 97.4 | 1.3 | 1.3 | ||
| Trimethoprim/sulfamethoxazole | ≤ 0.12 | > 8 | ≤ 0.12 to > 8 | 77.6 | NA | 22.4 | ||
| P. aeruginosa | Outpatient (63) | Cefepime | 4 | 16 | 0.5 to > 64 | 89.5 | 5.3 | 5.3 |
| Ceftazidime | 4 | 16 | 1 to > 32 | 85.7 | 6.3 | 7.9 | ||
| Ceftolozane/tazobactam | 1 | 2 | 0.25–8 | 98.4 | 1.6 | 0 | ||
| Ciprofloxacin | 0.25 | 8 | ≤ 0.06 to > 16 | 76.2 | 6.3 | 17.5 | ||
| Colistin | 1 | 2 | 0.5–4 | NA | 98.4 | 1.6 | ||
| Gentamicin | 2 | 4 | ≤ 0.5 to > 32 | 92.1 | 4.8 | 3.2 | ||
| Meropenem | 1 | 4 | 0.06 to > 32 | 84.1 | 6.3 | 9.5 | ||
| Piperacillin/tazobactam | 8 | 32 | 2–512 | 88.9 | 6.3 | 4.8 | ||
| Inpatient (100) | Cefepime | 2 | 16 | 0.5 to > 64 | 86.0 | 8.1 | 5.8 | |
| Ceftazidime | 4 | 32 | 0.5 to > 32 | 83.0 | 4.0 | 13.0 | ||
| Ceftolozane/tazobactam | 0.5 | 2 | ≤ 0.12 to > 64 | 97.0 | 1.0 | 2.0 | ||
| Ciprofloxacin | 0.25 | 16 | ≤ 0.06 to > 16 | 75.0 | 5.0 | 20.0 | ||
| Colistin | 1 | 2 | 0.25–8 | NA | 96.0 | 4.0 | ||
| Gentamicin | 2 | 8 | ≤ 0.5 to > 32 | 89.0 | 6.0 | 5.0 | ||
| Meropenem | 1 | 4 | ≤ 0.03 to > 32 | 87.0 | 5.0 | 8.0 | ||
| Piperacillin/tazobactam | 4 | 32 | 2–512 | 86.0 | 9.0 | 5.0 | ||
| S. aureus | Outpatient (63) | Cefoxitin | 4 | > 32 | 0.5 to > 32 | 74.6 | NA | 25.4 |
| Ciprofloxacin | 0.5 | > 16 | 0.12 to > 16 | 54.0 | 1.6 | 44.4 | ||
| Clarithromycin | 0.5 | > 32 | ≤ 0.03 to > 32 | 52.4 | 0 | 47.6 | ||
| Clindamycin | ≤ 0.12 | > 8 | ≤ 0.12 to > 8 | 79.4 | 0 | 20.6 | ||
| Daptomycin | 0.25 | 0.5 | 0.12–0.5 | 100 | NA | NA | ||
| Doxycycline | ≤ 0.12 | 0.25 | ≤ 0.12–0.5 | 100 | 0 | 0 | ||
| Gentamicin | ≤ 0.5 | ≤ 0.5 | ≤ 0.5–2 | 100 | 0 | 0 | ||
| Linezolid | 2 | 4 | 1–4 | 100 | NA | 0 | ||
| Nitrofurantoin | 16 | 16 | 4–32 | 100 | 0 | 0 | ||
| Trimethoprim/sulfamethoxazole | ≤ 0.12 | ≤ 0.12 | ≤ 0.12–0.5 | 100 | NA | 0 | ||
| Vancomycin | 1 | 1 | 0.25–1 | 100 | 0 | 0 | ||
| Inpatient (49) | Cefoxitin | 4 | > 32 | 2 to > 32 | 75.0 | NA | 25.0 | |
| Ciprofloxacin | 0.5 | > 16 | 0.12 to > 16 | 60.4 | 0 | 39.6 | ||
| Clarithromycin | 0.25 | > 32 | 0.12 to > 32 | 62.5 | 0 | 37.5 | ||
| Clindamycin | ≤ 0.12 | > 8 | 0.12 to > 8 | 85.4 | 0 | 14.6 | ||
| Daptomycin | 0.25 | 0.25 | 0.12–1 | 100 | NA | NA | ||
| Doxycycline | ≤ 0.12 | 0.25 | ≤ 0.12–2 | 100 | 0 | 0 | ||
| Gentamicin | ≤ 0.5 | ≤ 0.5 | ≤ 0.5–1 | 100 | 0 | 0 | ||
| Linezolid | 2 | 4 | 1–4 | 100 | NA | 0 | ||
| Nitrofurantoin | 16 | 16 | 8–16 | 100 | 0 | 0 | ||
| Trimethoprim/sulfamethoxazole | ≤ 0.12 | ≤ 0.12 | ≤ 0.12–0.5 | 100 | NA | 0 | ||
| Vancomycin | 1 | 1 | 0.5–2 | 100 | 0 | 0 | ||
The % susceptible-dose dependent (SDD) value is given in the % intermediate box for cefepime and piperacillin/tazobactam tested against Enterobacterales; the CLSI does not published an intermediate MIC breakpoint for cefepime or piperacillin/tazobactam versus Enterobacterales.
For cefalexin, cefazolin urine MIC breakpoints (16/—/32) were used for E. coli, K. pneumoniae and P. mirabilis.
NA, not applicable.
The most active oral antimicrobials versus outpatient urinary K. pneumoniae isolates were cefalexin (92.5% susceptible) and amoxicillin/clavulanate (92.1% susceptible), followed by trimethoprim/sulfamethoxazole (89.5% susceptible) and ciprofloxacin (89.2% susceptible). Susceptibility rates to oral antimicrobials for inpatient urinary K. pneumoniae isolates were approximately 3% to 7% lower than for outpatient isolates, depending on the antimicrobial. All K. pneumoniae isolates were susceptible to meropenem, while susceptibility to piperacillin/tazobactam was 96.6% among outpatient isolates and 92.4% among inpatient isolates. Ceftriaxone susceptibility was lower for inpatient urinary K. pneumoniae isolates than outpatient isolates (89% versus 94.6%).
Outpatient P. mirabilis urinary isolates were generally susceptible to amoxicillin/clavulanate (94.7%), cefalexin (95%), ceftriaxone (100%), meropenem (100%) and piperacillin/tazobactam (100%). Susceptibility rates for ciprofloxacin (86%) and trimethoprim/sulfamethoxazole (80.2%) were lower. Inpatient P. mirabilis urinary isolates were marginally less susceptible to all antimicrobials tested, relative to outpatient isolates (Table 1). For P. aeruginosa urinary isolates, ceftolozane/tazobactam was the most active antimicrobial in vitro (97% of inpatient isolates and 98.4% of outpatient isolates testing susceptible). Susceptibility versus other common antipseudomonal antimicrobials ranged from 83% to 92% depending on the agent. The notable exception was ciprofloxacin, for which only 76.2% of outpatient and 75% of inpatient P. aeruginosa urinary isolates tested susceptible.
All E. faecalis isolates were susceptible to ampicillin and vancomycin, and over 99% were susceptible to nitrofurantoin. Antimicrobial susceptibility rates for outpatient and inpatient S. aureus urinary isolates were similar. Approximately 75% of S. aureus isolates were methicillin-susceptible (inferred from cefoxitin) and 100% remained susceptible to daptomycin, doxycycline, linezolid, nitrofurantoin, trimethoprim/sulfamethoxazole and vancomycin.
Antimicrobial susceptibility trends over time for the six most frequently isolated urinary pathogens are presented in Table 2. For E. coli, the percentage of isolates that were phenotypically positive for ESBL production significantly increased from 4.2% (2009–11) to 11.3% (2018–20). Over the same time periods, a significant drop in the percentage of isolates testing susceptible to amoxicillin/clavulanate, cefazolin, cefepime, cefalexin, ceftazidime, ceftriaxone and piperacillin/tazobactam was observed, presumably secondary to the increased recovery of ESBL producers. A similar, although less pronounced, temporal trend was observed with K. pneumoniae isolates, with the proportion of ESBL producers increasing from 4.3% (2009–11) to 6.2% (2018–20). Again, this was associated with a reduction over time in susceptibility rates for several β-lactams including amoxicillin/clavulanate, cefalexin, cefepime, ceftazidime and ceftriaxone. Interestingly, there was no statistically significant change in susceptibility for ciprofloxacin, nitrofurantoin or trimethoprim/sulfamethoxazole versus E. coli and K. pneumoniae over the course of this study. Susceptibility rates for most antimicrobials remained relatively stable during the study for E. faecalis and P. mirabilis. For P. aeruginosa, susceptibility to cefepime, ceftazidime, ceftolozane/tazobactam and piperacillin/tazobactam declined over the course of the study. For S. aureus, methicillin susceptibility increased from 61.4% (2009–11) to 83.3% (2018–20), although this change did not reach statistical significance.
Table 2.
Annual rates of in vitro susceptibility of oral and parenteral antimicrobial agents for urine isolates in Canada, 2009–20 (minimum 20 isolates/3 year group)a
| % of isolates susceptible | ||||||
|---|---|---|---|---|---|---|
| Organism | Antimicrobial agent | 2009–11 | 2012–14 | 2015–17 | 2018–20 | P value |
| E. coli | Amoxicillin/clavulanate | 86.42 | 82.46 | 77.76 | 75.23 | <0.0001 |
| Cefazolin (systemic) | 72.66 | 73.51 | 73.27 | 64.06 | 0.0121 | |
| Cefalexin (urine) | 92.46 | 91.23 | 88.22 | 84.35 | <0.0001 | |
| Cefepime | 96.01 | 95.34 | 93.27 | 89.49 | <0.0001 | |
| Cefoxitin | 90.65 | 94.78 | 90.84 | 89.98 | 0.6313 | |
| Ceftazidime | 95.98 | 94.22 | 92.52 | 90.22 | <0.0001 | |
| Ceftriaxone | 94.17 | 92.54 | 90.47 | 86.80 | <0.0001 | |
| Ciprofloxacin | 75.58 | 77.61 | 74.77 | 74.57 | 0.5894 | |
| Colistin (I) | 100 | 99.81 | 99.63 | 99.51 | 0.0538 | |
| Doxycycline | 75.53 | 75.56 | 76.64 | 74.33 | 0.7792 | |
| Gentamicin | 90.95 | 91.42 | 93.64 | 90.71 | 0.5148 | |
| Meropenem | 100 | 100 | 100 | 100 | N/A | |
| Nitrofurantoin | 97.28 | 96.98 | 97.76 | 97.28 | 0.9309 | |
| Piperacillin/tazobactam | 97.59 | 97.57 | 95.14 | 95.84 | 0.0306 | |
| Trimethoprim/sulfamethoxazole | 73.74 | 76.87 | 75.14 | 73.84 | 0.8465 | |
| ESBL | 4.22 | 6.90 | 8.22 | 11.25 | <0.0001 | |
| K. pneumoniae | Amoxicillin/clavulanate | 93.21 | 93.81 | 90.74 | 82.93 | 0.0138 |
| Cefazolin (systemic) | 84.57 | 84.54 | 87.96 | 76.00 | 0.1983 | |
| Cefalexin (urine) | 92.59 | 91.75 | 93.52 | 82.00 | 0.0217 | |
| Cefepime | 97.87 | 95.88 | 93.52 | 87.00 | 0.0017 | |
| Cefoxitin | 94.44 | 92.78 | 93.52 | 92.00 | 0.4886 | |
| Ceftazidime | 96.91 | 95.88 | 93.52 | 85 | 0.0003 | |
| Ceftriaxone | 95.06 | 94.85 | 93.52 | 85.00 | 0.0061 | |
| Ciprofloxacin | 87.65 | 86.60 | 87.96 | 85.00 | 0.6407 | |
| Colistin (I) | 98.77 | 96.91 | 95.37 | 98.00 | 0.4113 | |
| Doxycycline | 86.67 | 77.32 | 85.19 | 78.00 | 0.6750 | |
| Gentamicin | 95.06 | 97.94 | 98.15 | 96.00 | 0.5089 | |
| Meropenem | 100 | 100 | 100 | 100 | N/A | |
| Nitrofurantoin | 29.27 | 43.40 | 42.59 | 38.00 | 0.5794 | |
| Piperacillin/tazobactam | 95.68 | 96.91 | 95.37 | 92.00 | 0.2079 | |
| Trimethoprim/sulfamethoxazole | 88.27 | 83.51 | 90.74 | 83.00 | 0.5077 | |
| ESBL | 4.32 | 4.12 | 5.56 | 6.21 | 0.0209 | |
| E. faecalis | Ampicillin | 100 | 100 | 100 | 100 | N/A |
| Ciprofloxacin | 62.33 | 70.91 | 64.52 | 64.86 | 0.6637 | |
| Daptomycin | 98.11 | 97.27 | 96.77 | 98.65 | 0.9237 | |
| Doxycycline | 17.07 | 34.55 | 27.96 | 22.97 | 0.7637 | |
| Linezolid | 91.04 | 97.27 | 82.80 | 98.65 | 0.6174 | |
| Nitrofurantoin | 98.15 | 100 | 100 | 98.65 | 0.8299 | |
| Vancomycin | 100 | 100 | 100 | 100 | N/A | |
| Proteus mirabilis | Amoxicillin/clavulanate | 95.31 | 95.56 | 89.74 | 95.12 | 0.6493 |
| Cefazolin (systemic) | 6.25 | 6.67 | 0 | 4.08 | 0.3328 | |
| Cefalexin (urine) | 95.31 | 91.11 | 89.74 | 100 | 0.4166 | |
| Cefepime | 100 | 100 | 94.87 | 100 | 0.5733 | |
| Cefoxitin | 98.44 | 95.56 | 94.87 | 97.96 | 0.7840 | |
| Ceftazidime | 100 | 100 | 97.44 | 100 | 0.5912 | |
| Ceftriaxone | 100 | 95.56 | 94.87 | 100 | 0.8238 | |
| Ciprofloxacin | 85.94 | 91.11 | 71.79 | 83.67 | 0.3126 | |
| Gentamicin | 98.44 | 95.56 | 87.18 | 91.84 | 0.0555 | |
| Meropenem | 100 | 100 | 100 | 100 | N/A | |
| Nitrofurantoin | 0 | 0 | 0 | 0 | N/A | |
| Piperacillin/tazobactam | 100 | 100 | 94.87 | 100 | 0.4467 | |
| Trimethoprim/sulfamethoxazole | 85.94 | 84.44 | 56.41 | 83.67 | 0.1883 | |
| P. aeruginosa | Cefepime | 94.29 | 93.10b | 89.19 | 76.19 | 0.0141 |
| Ceftolozane/tazobactam | 100 | 100b | 97.30 | 92.86 | 0.0228 | |
| Ceftazidime | 90.91 | 86.21b | 89.19 | 69.05 | 0.0097 | |
| Ciprofloxacin | 69.09 | 68.97b | 86.49 | 78.57 | 0.1208 | |
| Colistin (I) | 94.55 | 100b | 100 | 95.24 | 0.6973 | |
| Gentamicin | 87.27 | 93.10b | 91.89 | 90.48 | 0.5855 | |
| Meropenem | 89.09 | 86.21b | 86.49 | 80.95 | 0.2848 | |
| Piperacillin/tazobactam | 90.91 | 96.55b | 89.19 | 73.81 | 0.0146 | |
| S. aureus | Cefoxitin | 61.36 | 95.65b | 73.08b | 83.33b | 0.0954 |
| Ciprofloxacin | 47.73 | 60.87b | 61.54b | 66.67b | 0.1327 | |
| Clarithromycin | 38.64 | 65.22b | 73.08b | 66.67b | 0.0069 | |
| Clindamycin | 70.45 | 82.61b | 92.31b | 94.44b | 0.0069 | |
| Daptomycin | 100 | 100b | 100b | 100b | N/A | |
| Doxycycline | 100b | 100b | 100b | 100b | N/A | |
| Gentamicin | 100 | 100b | 100b | 100b | N/A | |
| Linezolid | 100 | 100b | 100b | 100b | N/A | |
| Nitrofurantoin | 100b | 100b | 100b | 100b | N/A | |
| Trimethoprim/sulfamethoxazole | 100 | 100b | 100b | 100b | N/A | |
| Vancomycin | 100 | 100b | 100b | 100b | N/A | |
Number of isolates/year group: 2009–11: 995 E. coli, 162 K. pneumoniae, 218 E. faecalis, 64 P. mirabilis, 55 P. aeruginosa and 44 S. aureus. 2012–14: 536 E. coli, 97 K. pneumoniae, 110 E. faecalis, 45 P. mirabilis, 29 P. aeruginosa and 23 S. aureus. 2015–17: 535 E. coli, 108 K. pneumoniae, 94 E. faecalis, 39 P. mirabilis, 37 P. aeruginosa and 26 S. aureus. 2018–20: 409 E. coli, 100 K. pneumoniae, 74 E. faecalis, 49 P. mirabilis, 42 P. aeruginosa and 19 S. aureus.
Fewer than 30 isolates in this block were tested against drug. S. aureus had <30 isolates for three out of four of the time periods. P. aeruginosa had 29 isolates in the 2012–14 time period.
Discussion
Several recent studies have been published describing the in vitro susceptibilities of common urinary pathogens.6,11,18 Aronin et al.11 assessed the susceptibility of 546 716 E. coli urine isolates from patients hospitalized in the USA over a 10 year period (2011–20). Overall, 35.1% of isolates were not susceptible to fluoroquinolones, 30.6% were not susceptible to trimethoprim/sulfamethoxazole and 13.1% demonstrated an ESBL phenotype. Kaye et al.18 investigated the in vitro susceptibilities of 1 513 882 E. coli urinary isolates from female outpatients in the USA obtained between 2011 and 2019. The percentage of isolates testing not susceptible to trimethoprim/sulfamethoxazole, fluoroquinolones and nitrofurantoin were 25.4%, 21.1% and 3.8%, respectively, and 6.4% were positive for ESBL production. Lodise et al.6 evaluated the in vitro activity of common antimicrobials versus bacterial isolates obtained from patients presenting to emergency departments in the USA from 2013 to 2018 with a diagnosis of complicated UTI, stratified by whether the patient was admitted to hospital or in the emergency room (ER) only. Among 106 038 E. coli isolates, resistance rates to fluoroquinolones were 16.4% for ER patients and 35.6% for admitted patients, resistance rates to trimethoprim/sulfamethoxazole were 27.8% for ER patients and 33.2% for admitted patients, and resistance rates to nitrofurantoin were 3.4% for ER patients and 5.6% for admitted patients. In addition, 5.0% of isolates from ER patients demonstrated third-generation cephalosporin resistance versus 12.5% of isolates from admitted patients. Of concern, data from these publications, as well as the current study, have generally found >20% of E. coli urinary isolates are no longer susceptible to fluoroquinolones and trimethoprim/sulfamethoxazole. A resistance prevalence of 20% has been suggested as a threshold at which an agent is no longer recommended for the treatment of acute cystitis.12 Nitrofurantoin typically remains active in vitro versus the majority of E. coli urinary isolates.6,11,18
Resistance rates were higher among inpatient isolates relative to outpatient isolates in the present study. It is speculated that this is related to more frequent antimicrobial exposure among inpatients, and potential acquisition of resistant pathogens in the hospital environment. Several studies have previously demonstrated that older patient age, male gender, recent hospitalization, prior use of antimicrobials and specific geographical locations are risk factors associated with increased antimicrobial resistance rates, including resistance to trimethoprim/sulfamethoxazole and fluoroquinolones.19,20
In our dataset, the proportion of E. coli and K. pneumoniae urinary isolates that were phenotypically positive for ESBL production increased from 2009–11 to 2018–20. Other investigators have similarly demonstrated an increase in the proportion of Enterobacterales urinary isolates that are ESBL producers over time.8–11 This has been observed to a greater extent with E. coli and likely reflects, at least in part, successful dissemination of E. coli ST131, which possesses plasmid-mediated ESBL (CTX-M-14 or CTX-M-15) genes.8 ESBL production likely accounts for the decline in β-lactam susceptibility among E. coli and K. pneumoniae isolates in our study from 2009–11 to 2018–20. Among the P. aeruginosa isolates included in our study, susceptibility to cefepime, ceftazidime, ceftolozane/tazobactam and piperacillin/tazobactam declined over time. These trends should be viewed with caution given the small number of P. aeruginosa isolates tested on an annual basis. Other North American publications have reported relatively stable susceptibility rates for P. aeruginosa over time versus common antipseudomonal antimicrobials.21,22
There are several important limitations to the data presented here that deserve attention. The CANWARD study does not obtain clinical details on the patients from whom the isolates are obtained. Clinical significance of the urinary isolates included here was based on local microbiology laboratory protocols. As such, it is likely that some of the included isolates were from patients with asymptomatic bacteriuria. Urine cultures are often not obtained for women presenting with acute, uncomplicated cystitis. Hence, the susceptibility data presented here do not necessarily apply to this patient population. It is likely that the urine specimens submitted to the microbiology laboratory in our study were from patients with complicated UTIs, patients who had failed prior therapy and/or patients with more severe illness (e.g. pyelonephritis). However, our data do represent real-world isolates that can be expected to be grown from outpatient and inpatient urine specimens submitted to clinical microbiology laboratories for culture and antimicrobial susceptibility testing. Antimicrobial susceptibility rates in countries other than Canada may differ from what is presented here, due to differences in the prevalence of various resistance mechanisms. Fosfomycin susceptibility was not assessed because this antimicrobial must by tested by disc diffusion or agar dilution rather than broth microdilution (the method used here). Hospital laboratories participating in the CANWARD study varied slightly from year to year. This may have influenced susceptibility trends observed over time. Finally, for several pathogens (P. aeruginosa, S. aureus), the number of isolates obtained on an annual basis was relatively small and changes in susceptibility over time for these species should be regarded with caution.
In conclusion, the most common bacterial pathogen isolated from urine specimens of Canadian outpatients and inpatients submitted to sentinel hospital laboratories between 2009 and 2020 was E. coli, followed in descending order by E. faecalis, K. pneumoniae, P. mirabilis, P. aeruginosa and S. aureus. In general, susceptibility rates for urinary pathogens were lower for inpatient isolates, relative to outpatient isolates. Over 20% of urinary E. coli isolates were not susceptible to ciprofloxacin and trimethoprim/sulfamethoxazole, while the majority remained susceptible to nitrofurantoin. These data suggest that ciprofloxacin and trimethoprim/sulfamethoxazole may not be optimal as empirical therapy for UTIs among Canadian patients with complicated UTIs and/or severe infection requiring hospitalization. However, use of local antibiogram data is highly encouraged when making treatment decisions. An increase in the proportion of E. coli and K. pneumoniae urinary isolates that were ESBL producers was observed over the course of this study. Consideration should be given to empirical coverage of ESBL producers among patients presenting with severe illness due to a UTI. Nitrofurantoin remains a reasonable option for cystitis caused by E. coli based on the data presented here.
Supplementary Material
Acknowledgements
We would like to thank staff in the following hospital laboratories that participated in the CANWARD Surveillance Study: 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; Hamilton Health Sciences Centre, Hamilton, Ontario; University Health Network/Mount Sinai Hospital, Toronto, Ontario; Children’s Hospital of Eastern Ontario, Ottawa, Ontario; Cité de la Santé de Laval, Laval, Québec; Jewish General Hospital, Montréal, Québec; CHRTR Pavillon Ste. Marie, Trois-Rivières, Québec; Centre Hospitalier Universitaire de Sherbrooke, Sherbrooke, Québec; L’Hôtel-Dieu de Québec, Québec City, Québec; South East Regional Health Authority, Moncton, New Brunswick; and Queen Elizabeth II Health Sciences Centre, Halifax, Nova Scotia.
Contributor Information
Andrew Walkty, Max Rady College of Medicine, University of Manitoba, 502 Basic Medical Sciences Building, 745 Bannatyne Avenue, Winnipeg R3E 0J9, Manitoba, Canada; Shared Health, Winnipeg, Manitoba, Canada.
James A Karlowsky, Max Rady College of Medicine, University of Manitoba, 502 Basic Medical Sciences Building, 745 Bannatyne Avenue, Winnipeg R3E 0J9, Manitoba, Canada; Shared Health, Winnipeg, Manitoba, Canada.
Philippe Lagace-Wiens, Max Rady College of Medicine, University of Manitoba, 502 Basic Medical Sciences Building, 745 Bannatyne Avenue, Winnipeg R3E 0J9, Manitoba, Canada; Shared Health, Winnipeg, Manitoba, Canada.
Melanie R Baxter, Max Rady College of Medicine, University of Manitoba, 502 Basic Medical Sciences Building, 745 Bannatyne Avenue, Winnipeg R3E 0J9, Manitoba, Canada.
Heather J Adam, Max Rady College of Medicine, University of Manitoba, 502 Basic Medical Sciences Building, 745 Bannatyne Avenue, Winnipeg R3E 0J9, Manitoba, Canada; Shared Health, Winnipeg, Manitoba, Canada.
George G Zhanel, Max Rady College of Medicine, University of Manitoba, 502 Basic Medical Sciences Building, 745 Bannatyne Avenue, Winnipeg R3E 0J9, Manitoba, Canada.
Funding
The CANWARD Surveillance Study was supported in part by the Health Sciences Centre (Winnipeg, Manitoba, Canada) and the University of Manitoba (Winnipeg, Manitoba, Canada), the Public Health Agency of Canada—National Microbiology Laboratory (Winnipeg, Manitoba, Canada), Avir, Iterum, Merck and Verity.
Transparency declarations
The authors have no conflicts of interest to disclose related to this work. G.G.Z. received research funding from Avir Pharma, Iterum Therapeutics, Merck Canada and Verity Pharma.
Supplementary data
Table S1 is available as Supplementary data at JAC-AMR Online.
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