Cumulative clinical experience from over a decade of use of levofloxacin in community-acquired pneumonia: critical appraisal and role in therapy

Levofloxacin is the synthetic L-isomer of the racemic fluoroquinolone, ofloxacin. It interferes with critical processes in the bacterial cell such as DNA replication, transcription, repair, and recombination by inhibiting bacterial topoisomerases. Levofloxacin has broad spectrum activity against several causative bacterial pathogens of community-acquired pneumonia (CAP). Oral levofloxacin is rapidly absorbed and is bioequivalent to the intravenous formulation such that patients can be conveniently transitioned between these formulations when moving from the inpatient to the outpatient setting. Furthermore, levofloxacin demonstrates excellent safety, and has good tissue penetration maintaining adequate concentrations at the site of infection. The efficacy and tolerability of levofloxacin 500 mg once daily for 10 days in patients with CAP are well established. Furthermore, a high-dose (750 mg) and short-course (5 days) of once-daily levofloxacin has been approved for use in the US in the treatment of CAP, acute bacterial sinusitis, acute pyelonephritis, and complicated urinary tract infections. The high-dose, short-course levofloxacin regimen maximizes its concentration-dependent antibacterial activity, decreases the potential for drug resistance, and has better patient compliance

Comparative Pharmacodynamics of Ceftobiprole, Daptomycin, Linezolid, Telavancin, Tigecycline, and Vancomycin in the Treatment of Methicillin Resistant \u3cem\u3eStaphylococcus aureus\u3c/em\u3e: A Monte Carlo Simulation Analysis

Background/Objectives: Appropriate initial treatment choices for methicillin resistant Staphylococcus aureus (MRSA) infections are very critical. The aim of this study was to compare the ability of Ceftobiprole, Daptomycin, Linezolid, Telavancin, Tigecycline, and Vancomycin to achieve their requisite pharmacokinetic/pharmacodynamic (PK/PD) target against clinical MRSA isolates. Methods: Monte Carlo Simulations were performed to simulate the PK/PD indices of the investigated antimicrobials. Population Pharmacokinetic data and Pharmacodynamic indices were integrated into Monte Carlo Simulation routine with 10,000 iterations. Probability of target attainment (PTA) was estimated at MIC values ranging from 0.03-32 μg/ml to define the PK/PD susceptibility breakpoints. Cumulative fraction of response (CFR) was computed using MIC data from the Canadian National Ward (CAN-Ward) study collected in 2007, 2008 and 2009. Results: Analysis of the simulation results suggested the breakpoints of 8μg/ml for Ceftobiprole, 0.12 μg/ml for Daptomycin and Tigecycline, 0.5 μg/ml for Telavancin and 1 μg/ml for Linezolid and Vancomycin. The estimated CFR were 100, 66.5, 84, 89.1, 98.2, 60, 97.5 % for Ceft obiprole, Daptomycin (4mg/kg/day), Daptomycin (6mg/kg/day), Linezolid, Telavancin, Tigecycline, Vancomycin (2gm/day) and Vancomycin (3gm/day), respectively. Conclusions: Ceftobiprole and Telavancin have the highest probability of achieving favorable outcome against MRSA infections. The susceptibility results suggested a further reduction of the vancomycin breakpoint to 1 μg/ml

Pharmacodynamic Activity of Ceftobiprole Compared with Vancomycin versus Methicillin-Resistant \u3cem\u3eStaphylococcus aureus\u3c/em\u3e (MRSA), Vancomycin-Intermediate \u3cem\u3eStaphylococcus aureus\u3c/em\u3e (VISA) and Vancomycin-Resistant \u3cem\u3eStaphylococcus aureus\u3c/em\u3e (VRSA) Using an In Vitro Model

Background This study compared the pharmacodynamics of ceftobiprole and vancomycin against methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-intermediate S. aureus (VISA) and vancomycin-resistant S. aureus (VRSA) using an in vitro model. Methods Two methicillin-susceptible S. aureus (MSSA), two community-associated (CA)-MRSA, one healthcare-associated (HA)-MRSA, three VISA and two VRSA were studied. The pharmacodynamic model was inoculated with a concentration of 1 × 106 cfu/mL and ceftobiprole dosed every 8 h (at 0, 8 and 16 h) to simulate the fCmax and t1/2 obtained after 500 mg intravenous (iv) every 8 h dosing (fCmax, 30 mg/L; t1/2, 3.5 h). Vancomycin was dosed every 12 h (at 0 and 12 h) to simulate fCmax and t1/2 obtained after 1 g iv every 12 h dosing (fCmax, 20 mg/L; t1/2, 8 h). Samples were collected over 24 h to assess viable growth. Results Ceftobiprole T \u3e MIC of ≥100% (ceftobiprole MICs, ≤2 mg/L) was bactericidal (≥3 log10 killing) against MSSA, CA-MRSA, HA-MRSA, VISA and VRSA at 16 and 24 h. Vancomycin fAUC24/MIC of 340 (vancomycin MIC, 1 mg/L for MSSA and MRSA) resulted in a 1.8–2.6 log10 reduction in colony count at 24 h. Vancomycin fAUC24/MIC of 85–170 (vancomycin MIC, 2–4 mg/L for VISA) resulted in a 0.4–0.7 log10 reduction at 24 h. Vancomycin fAUC24/MIC of 5.3 (vancomycin MIC, 64 mg/L for VRSA) resulted in a limited effect. Conclusions Ceftobiprole T \u3e MIC of ≥100% (ceftobiprole MICs, ≤2 mg/L) was bactericidal (≥3 log10 killing) against MSSA, CA-MRSA, HA-MRSA, VISA and VRSA at 16 and 24 h. Vancomycin was bacteriostatic against MSSA, MRSA and VISA, while demonstrating no activity against VRSA

Assessment of the Activity of Ceftaroline Against Clinical Isolates of Penicillin-Intermediate and Penicillin-Resistant \u3cem\u3eStreptococcus pneumoniae\u3c/em\u3e with elevated MICs of Ceftaroline Using an In Vitro Pharmacodynamic Model

Objectives This study assessed the pharmacodynamics of ceftaroline against penicillin-intermediate and penicillin-resistant Streptococcus pneumoniae with elevated MICs of ceftaroline using an in vitro pharmacodynamic model. Methods Nine isolates of S. pneumoniae, including one penicillin-susceptible isolate, one penicillin-intermediate isolate and seven penicillin-resistant isolates, were tested. The pharmacodynamic model was inoculated with a concentration of 1 × 106 cfu/mL and ceftaroline was dosed twice daily (at 0 and 12 h) to simulate the fCmax (maximum free concentration in serum) and t1/2 (half-life in serum) obtained after 600 mg intravenous doses every 12 h (fCmax, 16 mg/L; t1/2, 2.6 h). Ceftaroline was compared with ceftriaxone dosed once daily to simulate the fCmax and t1/2 obtained after a 1 g dose (fCmax, 18 mg/L; t1/2, 8.0 h). Samples were collected over 24 h to assess viable growth and possible changes in ceftaroline MICs over time. Results Ceftaroline fT\u3eMIC (time of free serum concentration over the MIC) of 100% (ceftaroline MICs, ≤0.5 mg/L) was bactericidal (≥3 log10 killing) against all isolates at 6 h and completely eradicated all organisms at 12 and 24 h. No bacterial regrowth occurred over the study period and no changes in ceftaroline MICs were observed. Upon ceftriaxone exposure, S. pneumoniae isolates with ceftriaxone MICs of 0.12 and 0.25 mg/L were eradicated, but isolates with ceftriaxone MICs of 1–8 mg/L resulted in initial bacterial reduction at 6 h with organism regrowth at 12 h and no reduction in organism concentration, relative to the starting inoculum, at 24 h. Conclusions Ceftaroline fT\u3eMIC of 100% (ceftaroline MICs, ≤0.5 mg/L) was bactericidal (≥3 log10 killing) and eradicated all S. pneumoniae at 12 and 24 h with no regrowth

Pharmacodynamic Activity of Azithromycin Against Macrolide-Susceptible and Macrolide-Resistant \u3cem\u3eStreptococcus pneumoniae\u3c/em\u3e Simulating Clinically Achievable Free Serum, Epithelial Lining Fluid and Middle Ear Fluid Concentrations

Background: The association between macrolide resistance mechanisms and bacteriological eradication of Streptococcus pneumoniae remains poorly studied. The present study, using an in vitro pharmacodynamic model, assessed azithromycin activity against macrolide-susceptible and -resistant S. pneumoniae simulating clinically achievable free serum (S), epithelial lining fluid (ELF) and middle ear fluid (MEF) concentrations. Materials and methods: Two macrolide-susceptible [PCR-negative for both mef(A) and erm(B)] and six macrolide-resistant [five mef(A)-positive/erm(B)-negative displaying various degrees of macrolide resistance and one mef(A)-negative/erm(B)-positive] S. pneumoniae were tested. Azithromycin was modelled simulating a dosage of 500 mg/250 mg by mouth, once a day [free S: maximum concentration (Cmax) 0.2 mg/L, t1/2 68 h; free ELF Cmax 1.0 mg/L, t1/2 68 h] and 10 mg/kg by mouth, once a day (free MEF: Cmax 1.0 mg/L, t1/2 68 h) using a one compartment model. Starting inocula were 1 × 106 cfu/mL in Mueller–Hinton broth with 2% lysed horse blood. Sampling at 0, 2, 4, 6, 12, 24 and 48 h assessed the extent of bacterial killing (decrease in log10 cfu/mL versus initial inoculum). Results: Free azithromycin concentrations in serum, ELF and MEF simulating time above the MIC (T \u3e MIC) of 100% [area under the curve to MIC (AUC0–24/MIC] ≥ 36.7] were bactericidal (≥3 log10 killing) at 24 and 48 h versus macrolide-susceptible S. pneumoniae. Against macrolide-resistant S. pneumoniae, free serum concentrations providing T \u3e MIC of 0% or AUC0–24/MIC ≤ 1.1 demonstrated no bacterial inhibition followed by regrowth at 24 and 48 h, whereas free ELF and MEF providing T \u3e MIC of 0% or AUC0–24/MIC of 4.6 produced a bacteriostatic (0.2–0.5 log10 killing at 24 h) effect with a mef(A) strain with an azithromycin MIC of 2 mg/L. Against mef(A)-positive S. pneumoniae strains with azithromycin MICs ≥ 4 mg/L, no bacterial killing occurred at any time point and rapid regrowth was observed simulating ELF or MEF T \u3e MIC of 0% or AUC0–24/MIC ≤ 2.3. Conclusion: Azithromycin serum, ELF and MEF concentrations rapidly eradicated macrolide-susceptible S. pneumoniae but did not eradicate macrolide-resistant S. pneumoniae regardless of resistance phenotype

Dynamics of extended-spectrum cephalosporin resistance genes in Escherichia coli from Europe and North America

Extended-spectrum cephalosporins (ESCs) are critically important antimicrobial agents for human and veterinary medicine. ESC resistance (ESC-R) genes have spread worldwide through plasmids and clonal expansion, yet the distribution and dynamics of ESC-R genes in different ecological compartments are poorly understood. Here we use whole genome sequence data of Enterobacterales isolates of human and animal origin from Europe and North America and identify contrasting temporal dynamics. AmpC β-lactamases were initially more dominant in North America in humans and farm animals, only later emerging in Europe. In contrast, specific extended-spectrum β-lactamases (ESBLs) were initially common in animals from Europe and later emerged in North America. This study identifies differences in the relative importance of plasmids and clonal expansion across different compartments for the spread of different ESC-R genes. Understanding the mechanisms of transmission will be critical in the design of interventions to reduce the spread of antimicrobial resistance

Bearberry in the treatment of acute uncomplicated cystitis (BRUMI) : protocol of a multicentre, randomised double-blind clinical trial

Bearberry (Arctostaphylos uva-ursi) leaf is available as a treatment of uncomplicated cystitis in several European countries. The antimicrobial activity of its extracts and some of its individual constituents has been observed in vitro; however, the efficacy of bearberry compared with standard antimicrobial therapy has not been assessed yet.The objective of the study is to assess the safety and non-inferiority of bearberry as an alternative therapy in the treatment of acute uncomplicated cystitis in comparison with standard antibiotic therapy (fosfomycin).This is a randomised controlled double-blinded multicentre trial. Eligible patients will be premenopausal women with a sum score of ≥6 for the typical acute uncomplicated cystitis symptoms (frequency, urgency, painful urination, incomplete emptying, suprapubic pain and visible haematuria) reported on the Acute Cystitis Symptom Score (ACSS) typical domain and pyuria. Patients will be randomly assigned to receive 3 g single dose of fosfomycin powder and two placebo tablets three times a day for 7 days or B a single dose of placebo powder and two tablets containing a dry extract of Uvae ursi folium. At least 504 patients (allocated as 1:1) will need to be enrolled to access non-inferiority with a non-inferiority limit of 14% for the primary endpoint.Improvement of symptoms of uncomplicated cystitis (based on the ACSS score) at day 7 is defined as the primary endpoint, whereas several secondary endpoints such as the number and ratio of patients with bacteriuria at day 7, frequency and severity of side effects; recurrence of urinary tract infection, concurrent use of other over the counter (OTC) medications and food supplements will be determined to elucidate more detailed differences between the groups. The number of recurrences and medications taken for treatment will be monitored for a follow-up period of 90 days (80-100 days).This study has been approved by the Scientific and Research Ethics Committee of the Hungarian Medical Research Council (IV/4225-1/2021/EKU). The results will be disseminated by publication of peer-reviewed manuscripts.NCT05055544

Real-life experience with ceftolozane/tazobactam in Canada: results from the CLEAR (Canadian LEadership on Antimicrobial Real-life usage) registry.

Objectives Ceftolozane/tazobactam is a cephalosporin/β-lactamase inhibitor combination with activity against Gram-negative bacilli. We report the use of ceftolozane/tazobactam in Canada using a national registry. Methods The CLEAR registry uses REDCapTM (Research Electronic Data Capture) (online survey, https://is.gd/CLEAR_ceftolozanetazobactam) to capture details associated with clinical use of ceftolozane/tazobactam. Results Data from 51 patients treated in 2020 with ceftolozane/tazobactam are available. Infections treated included hospital-acquired bacterial pneumonia (37.3% of patients), ventilator-associated bacterial pneumonia (15.7%), bone/joint infection (11.8%), complicated intra-abdominal infection (7.8%) and complicated skin and skin structure infection (7.8%). 17.6% of patients had bacteremia and 47.1% were in intensive care. Ceftolozane/tazobactam was primarily used as directed therapy for Pseudomonas aeruginosa infections (92.2% of patients). Ceftolozane/tazobactam was used because of resistance to (86.3%), failure of (11.7%), or adverse effects from (2.0%) previously prescribed antimicrobials. Ceftolozane/tazobactam susceptibility testing was performed on isolates from 88.2% of patients. Ceftolozane/tazobactam was used in combination with another antimicrobial active versus Gram-negative bacilli in 39.2% of patients (aminoglycosides [15.7%], fluoroquinolones [7.8%] and colistin/polymyxin B [7.8%]). The dosage regimen was customized in all patients based on their creatinine clearance. Treatment duration was primarily >10 days (60.8% of patients) with microbiological success in 60.5% and clinical success in 64.4% of patients. 7.8% of patients had adverse effects not requiring drug discontinuation. Conclusions In Canada, ceftolozane/tazobactam is used as directed therapy to treat a variety of severe infections caused MDR P. aeruginosa. It is commonly used in combination with other antimicrobials with relatively high microbiological/clinical cure rates, and an excellent safety profile

Global transmission of extended-spectrum cephalosporin resistance in Escherichia coli driven by epidemic plasmids

Background: Extended-spectrum cephalosporins (ESCs) are third and fourth generation cephalosporin antimicrobials used in humans and animals to treat infections due to multidrug-resistant (MDR) bacteria. Resistance to ESCs (ESC-R) in Enterobacterales is predominantly due to the production of extended-spectrum β-lactamases (ESBLs) and plasmid-mediated AmpC β-lactamases (AmpCs). The dynamics of ESBLs and AmpCs are changing across countries and host species, the result of global transmission of ESC-R genes. Plasmids are known to play a key role in this dissemination, but the relative importance of different types of plasmids is not fully understood. Methods: In this study, Escherichia coli with the major ESC-R genes bla CTX-M-1, bla CTX-M-15, bla CTX-M-14 (ESBLs) and bla CMY-2 (AmpC), were selected from diverse host species and other sources across Canada, France and Germany, collected between 2003 and 2017. To examine in detail the vehicles of transmission of the ESC-R genes, long- and short-read sequences were generated to obtain complete contiguous chromosome and plasmid sequences (n = 192 ESC-R E. coli). The types, gene composition and genetic relatedness of these plasmids were investigated, along with association with isolate year, source and geographical origin, and put in context with publicly available plasmid sequences. Findings: We identified five epidemic resistance plasmid subtypes with distinct genetic properties that are associated with the global dissemination of ESC-R genes across multiple E. coli lineages and host species. The IncI1 pST3 bla CTX-M-1 plasmid subtype was found in more diverse sources than the other main plasmid subtypes, whereas IncI1 pST12 bla CMY-2 was more frequent in Canadian and German human and chicken isolates. Clonal expansion also contributed to the dissemination of the IncI1 pST12 bla CMY-2 plasmid in ST131 and ST117 E. coli harbouring this plasmid. The IncI1 pST2 bla CMY-2 subtype was predominant in isolates from humans in France, while the IncF F31:A4:B1 bla CTX-M-15 and F2:A-:B- bla CTX-M-14 plasmid subtypes were frequent in human and cattle isolates across multiple countries. Beyond their epidemic nature with respect to ESC-R genes, in our collection almost all IncI1 pST3 bla CTX-M-1 and IncF F31:A4:B1 bla CTX-M-15 epidemic plasmids also carried multiple antimicrobial resistance (AMR) genes conferring resistance to other antimicrobial classes. Finally, we found genetic signatures in the regions surrounding specific ESC-R genes, identifying the predominant mechanisms of ESC-R gene movement, and using publicly available databases, we identified these epidemic plasmids from widespread bacterial species, host species, countries and continents. Interpretation: We provide evidence that epidemic resistance plasmid subtypes contribute to the global dissemination of ESC-R genes, and in addition, some of these epidemic plasmids confer resistance to multiple other antimicrobial classes. The success of these plasmids suggests that they may have a fitness advantage over other plasmid types and subtypes. Identification and understanding of the vehicles of AMR transmission are crucial to develop and target strategies and interventions to reduce the spread of AMR. Funding: This project was supported by the (Theme 1, Epidemiology and Evolution of Pathogens in the Food Chain)

Analysis of 1560 inpatient and outpatient Escherichia coli isolates from across Canada - Results from the CANWARD 2007 study CANWARD 2007

OBJeCtIveS: Escherichia coli was the most common pathogen isolated in the Canadian Ward Surveillance Study (CANWARD 2007) and remains one of the most common pathogens isolated in all health care settings. An in-depth analysis of all E coli isolates was performed to determine the distribution and demographics associated with resistance to antimicrobials, presence of extended-spectrum beta-lactamases (ESBLs) and multidrug resistance (MDR; concurrent resistance to agents from three or more different antimicrobial classes). MethODS: The CANWARD 2007 study characterized pathogens isolated from inpatient (surgical and medical wards, and intensive care units) and outpatient (emergency departments and clinics) areas of 12 Canadian hospitals between January and December 2007. E coli susceptibility to 12 antimicrobials was determined, ESBL production was determined, and a multivariate nominal logistic regression model was designed to determine if sex, isolation from a sterile site, inpatient versus outpatient status, and age were significantly associated with susceptibility to the tested antimicrobials, MDR or ESBL production. ReSuLtS: In total, 1702 E coli isolates, representing 21.6% of all isolates collected in the CANWARD 2007 study, were investigated. Of these, 1560 isolates fell within the primary objective of the study and were included in the present analysis. Susceptibilities were greater than 90% for meropenem (100%), ertapenem (100%), tigecycline (99.9%), piperacillin-tazobactam (97.9%), cefepime (97.9%), ceftriaxone (95.4%), nitrofurantoin (95.2%), cefoxitin (94.8%), amoxicillinclavulanate (92.9%) and gentamicin (91.4%). Cefazolin (89.4%), the fluoroquinolones (ciprofloxacin, 79.4%; levofloxacin, 79.9%) and trimethoprim-sulfamethoxazole (75.7%) were less active agents. In the multivariate model, invasive isolates were significantly associated with lower susceptibility rates for trimethoprim-sulfamethoxazole. Increasing age was associated with lower susceptibility to fluoroquinolones, ceftriaxone, cefepime, gentamicin and nitrofurantoin, as well as ESBL production. Sex was not associated with resistance to any antimicrobial or to ESBL production. Inpatient status was associated with higher resistance rates to amoxicillin-clavulanate, cefazolin, fluoroquinolones and trimethoprim-sulfamethoxazole. Isolation of an ESBL producer was only found to be independently associated with age, being more common in older patients. MDR was not found to be associated with any variable measured when ESBL producers were excluded from analysis. CONCLuSIONS: E coli antimicrobial susceptibility varies according to patient factors. Age and inpatient status were the most important determinants in the present analysis and should be considered when prescribing empirical antimicrobial therapy. Fluoroquinolones and sulfonamides should be used cautiously and in consideration of local resistance patterns for infections caused by E coli, due to lower susceptibility rates. Independent factors associated with antimicrobial resistance were age, inpatient status and isolation from a sterile site. These factors should be considered when empirically treating infections likely caused by E coli. Local antimicrobial prescribing practices, in particular the liberal use of fluoroquinolones, and inadequate infection control practices may be reducing susceptibility rates. OBJeCtIFS : L'Escherichia coli était le pathogène le plus isolé dans l'étude CANWARD 2007 sur la surveillance des services aux hospitalisés canadiens et demeure l'un des pathogènes les plus isolés en milieu de santé. On a effectué une analyse approfondie de tous les isolats d'E coli pour déterminer la répartition et la démographie associées à la résistance aux antimicrobiens ainsi qu'à la présence de bêta-lactamases à large spectre (ESBL) et de multirésistance (résistance conjointe à au moins trois classes d'antimicrobiens). MÉthODOLOGIe : L'étude CANWARD 2007 caractérisait les pathogènes isolés de patients hospitalisés (service de chirurgie, service médical et unité de soins intensifs) et ambulatoires (urgence et cliniques) de 12 hôpitaux canadiens entre janvier et décembre 2007. On a déterminé la susceptibilité de l'E coli à 12 antimicrobiens ainsi que la production d'ESBL et conçu un modèle de régression logistique nominale multivariée pour déterminer si le sexe, l'isolement d'un foyer stérile, le statut de patient hospitalisé ou ambulatoire et l'âge s'associaient de manière significative à la susceptibilité aux antimicrobiens vérifiés, à la multirésistance ou à la production d'ESBL. RÉSuLtAtS : Au total, on a évalué 1 072 isolats d'E coli, représentant 21,6 % de tous les isolats prélevés dans le cadre de l'étude CANWARD 2007. De ce nombre, 1 560 isolats respectaient l'objectif primaire de l'étude et ont été inclus dans la présente analyse. Les susceptibilités étaient supérieures à 90 % pour le méropénem (100 %), l'ertapénem (100 %), la tigécycline (99,9 %), la pipéracilline-tazobactam (97,9 %), la céfépime (97.9 %), la ceftriaxone (95,4 %), la nitrofurantoïne (95,2 %), la céfoxitine (94,8 %), l'amoxicilline-clavulanate (92,9 %) et la gentamicine (91,4 %). La céfazoline (89,4 %), les fluoroquinolones (ciprofloxacine, 79,4 %, lévofloxacine, 79,9 %) et le triméthoprim-sulfaméthoxazole (75,7 %) étaient moins actifs. Dans le modèle multivarié, les isolats envahissants étaient associés de manière marquée à des taux de susceptibilité plus faibles pour le triméthoprim-sulfaméthoxazole. Le vieillissement s'associait à une susceptibilité plus faible aux fluoroquinolones, à la ceftriaxone, à la suite page suivante Lagacé-Wiens et al Can J Infect Dis Med Microbiol Vol 20 Suppl A Spring 2009 50A E scherichia coli is the most commonly isolated clinically relevant Gram-negative organism in most health care settings (1-3). Although most commonly associated with urinary tract infections, all body sites can be involved. Furthermore, resistance to multiple antimicrobials is increasing and multidrug resistant (MDR; concurrent resistance to agents from three or more different antimicrobial classes) isolates are common (1,4,5). Appropriate empirical antimicrobial choice must take into account local resistance patterns and other demographic variables such as patient age, site and severity of infection, sex, inpatient status as well as previous antimicrobial use, stay in hospitals or personal care homes, and colonization with antimicrobial resistant organisms (1,6). The purpose of the present study was to provide an in-depth analysis of patient factors associated with drug resistance in the most commonly isolated organism overall in Canadian hospitals. MethODS E coli isolates were obtained as part of the Canadian Ward Surveillance Study (CANWARD 2007), which collected isolates submitted to 12 clinical microbiology laboratories from tertiary care hospitals in seven provinces across Canada. Submitting sites and collection strategy are described elsewhere in the present supplement (2). Isolates had to be deemed clinically significant by the referring laboratory's current specimen work-up protocol. Demographic information collected with each isolate included patient age, sex, site of infection and the location of patient contact (surgical or medical ward, emergency room, intensive care unit [ICU] or hospital clinic). A minimum number of isolates from each hospital location and anatomical site was requested to provide more power to the study. The implication of this collection strategy is that the anatomical distribution of pathogen isolation and inpatient versus outpatient distribution does not reflect the true distribution in the population studied. Isolates were collected within both primary and secondary study objectives and only isolates collected within the primary objective were considered in this analysis. For statistical analysis, age was divided into four categories: 20 years and younger, 21 to 60 years, 61 to 80 years, and 81 years and older, and location of patient contact was divided into either inpatient (wards and ICUs) or outpatient (emergency room and clinics). Information on previous antimicrobial exposure, hospitalization duration and underlying medical conditions was not available. Antimicrobial susceptibility to amoxicillin-clavulanate, cefazolin, cefepime, ceftriaxone, ciprofloxacin, gentamicin, nitrofurantoin, levofloxacin, meropenem, ertapenem, piperacillin-tazobactam, tigecycline and trimethoprim-sulfamethoxazole was determined using broth dilution as described elsewhere in the present supplement (2). Screening for ESBL production was achieved using a 1 µg/mL or greater ceftriaxone breakpoint and confirmation was with the Clinical and Laboratory Standards Institute-recommended disk diffusion method (7). Univariate analysis using the c 2 (or Fisher's exact test where required) was undertaken to identify relationships between susceptibility to each of the antimicrobials and ESBL production; and the following variables: sex, age group, inpatient/outpatient status and isolation from a sterile site (blood, cerebrospinal fluid, synovial fluid). Relationships where the P<0.20 in the univariate analysis were included in a multivariate nominal logistic regression model to determine independent explanatory variables. Initially, a full factorial multiple logistic regression analysis was performed using the potential explanatory variables identified in the univariate analysis for each antimicrobial, and then a backward selection so that all factors remaining in the model were statistically significant at a 5% level (P<0.05). Statistical analysis was undertaken using JMP software version 7.0 (SAS Institute Inc, USA). ReSuLtS Of 7881 total organisms, 1702 E coli (21.6%) were collected from the CANWARD 2007 study, making it the most common organism isolated from patients in Canadian hospitals overall. Of these, 1560 fell within the primary objective and the remaining 142 were submitted as putative ESBL producers for separate analysis and excluded from the present analysis. The mean age of patients infected with E coli was 56.9 years; 12.3% of E coli isolates were from patients younger than 21 years, 34.7% were 21 to 60 years of age, 33.9% were 61 to 80 years of age and 19.1% were older than 80 years of age. There were more samples from women (59.3%); with both sexes combined, 50.5% were invasive isolates (all bloodstream), and 40.7% were from urine, 6.4% from respiratory sources and 2.4% from wounds. Note that the sampling strategy was biased to include a surplus of bloodstream isolates to have greater numbers of these for analysis and this does not represent the true source distribution of E coli infections. The distribution among provinces was British Columbia, 9.7%; Alberta, 7.6%; Saskatchewan, 9.1%; Manitoba, 9.2%; Ontario, 28.3%; Quebec, 29.2% and Nova Scotia, 6.9%. Isolates were not obtained from Newfoundland, Nunavut, the Northwest Territories, Yukon, New Brunswick or Prince Edward Island. Minimum inhibitory concentrations (MICs) required to inhibit 50% and 90% of organisms (MIC 50 , MIC 90 ) and percentage of isolates susceptible to the antimicrobials are provided in Resistance in E coli from Canadian inpatients and outpatients Can J Infect Dis Med Microbiol DISCuSSION Low susceptibility of ICU E coli isolates to fluoroquinolones and trimethoprim-sulfamethoxazole was not unexpected given the wide use of these antimicrobials in both inpatients and outpatients. In particular, the dramatic increase in fluoroquinolone resistance has been observed in many settings (8-10). Our observations suggest that first-generation cephalosporins and amoxicillin-clavulanate are still useful agents for infections caused by E coli in that susceptibility rates remain near 90% overall. This is particularly true of outpatient isolates where susceptibility is greater than 90% for both these agents. On the contrary, low susceptibility to fluoroquinolones even in the outpatient setting (84%) begins to bring into question the use of these agents as first line for infections commonly caused by E coli, such as urinary tract infections. Trimethoprimsulfamethoxazole susceptibility rates are below 80% in both inpatient and outpatient settings and should only be used for infections empirically in the context of supportive data from local antibiograms or definitive susceptibility data. In our multivariate model, increasing age was independently associated with reduced susceptibility to fluoroquinolones, nitrofurantoin, ceftriaxone, cefepime, gentamicin and ESBL production. The association between age and fluoroquinolone susceptibility has been demonstrated previously and is likely due to increasing exposure to fluoroquinolones over time and avoidance of fluoroquinolone use in children Predictably, inpatient isolates had lower susceptibility to several antibiotics, including amoxicillin-clavulanate, fluoroquinolones, cefazolin and trimethoprim-sulfamethoxazole. Interestingly, susceptibility to antimicrobials commonly used in the inpatient setting (ceftriaxone, cefepime, gentamicin, carbapenems and piperacillin-tazobactam) did not appear to be significantly affected by inpatient status. This is reassuring in that these antimicrobials maintain good activity overall in the hospital setting. The reason that antimicrobials commonly used in the community are most affected by inpatient status is not known, but may be due to general practitioners using these antimicrobials to treat outpatients and selection bias occurring because poor response due to antimicrobial resistance requires admission for parenteral antimicrobials. Interestingly, sex was not a predictor of susceptibility to any of the antimicrobials tested after adjusting for other factors in the multivariate model. Although large differences were seen between susceptibility to fluoroquinolones, both inpatient status and age appeared to be confounding factors in the effect of sex on fluoroquinolone resistance. The absence of a sex effect contradicts the findings of others Meropenem, ertapenem, piperacillin-tazobactam, tigecycline and cefoxitin were not significantly associated with any demographic variable in the multivariate model. Low overall resistance rates accounts for these observations. Our study had some limitations. We could not collect patient information such as length of stay, previous antimicrobial exposure and underlying disease. Although of great interest for the prediction of antimicrobial resistance, the effect of these variables cannot be determined with our data. Also, our isolates reflect only information from the 12 centres studied and our data may not reflect the antimicrobial susceptibility patterns of all hospitals in Canada. However, this study does provide valuable information about the factors predicting antimicrobial susceptibility of E coli in one of the largest of inpatient and outpatient populations in Canada studied to date