In vitro activity of sulopenem against 1880 bacterial pathogens isolated from Canadian patients with urinary tract infections (CANWARD, 2014-21).

INTRODUCTION: There are limited oral antimicrobial options for the treatment of urinary infections caused by ESBL-producing and MDR Enterobacterales. Sulopenem is an investigational thiopenem antimicrobial that is being developed as both an oral and IV formulation. The purpose of this study was to evaluate the in vitro activity of sulopenem versus bacterial pathogens recovered from the urine of patients admitted to or assessed at hospitals across Canada (CANWARD). MATERIALS AND METHODS: The in vitro activity of sulopenem and clinically relevant comparators was determined for 1880 Gram-negative and Gram-positive urinary isolates obtained as part of the CANWARD study (2014 to 2021) using the CLSI broth microdilution method. RESULTS: Sulopenem demonstrated excellent in vitro activity versus members of the Enterobacterales, with MIC90 values ranging from 0.06 to 0.5 mg/L for all species tested. Over 90% of ESBL-producing, AmpC-producing and MDR (not susceptible to ≥1 antimicrobial from ≥3 classes) Escherichia coli were inhibited by ≤0.25 mg/L of sulopenem. Sulopenem had an identical MIC90 to meropenem for ESBL-producing and MDR E. coli. The MIC90 of sulopenem and meropenem versus MSSA was 0.25 mg/L. Sulopenem was not active in vitro versus Pseudomonas aeruginosa (similar to ertapenem), and it demonstrated poor activity versus Enterococcus faecalis (similar to meropenem). CONCLUSIONS: Sulopenem demonstrated excellent in vitro activity versus bacterial pathogens recovered from the urine of Canadian patients. These data suggest that sulopenem may have a role in the treatment of urinary infections caused by antimicrobial-resistant Enterobacterales, but additional clinical studies are required.

In vitro activity of fosfomycin against bacterial pathogens isolated from urine specimens in Canada from 2007 to 2020: CANWARD surveillance study.

BACKGROUND: Multiple susceptible breakpoints are published to interpret fosfomycin MICs: ≤64 mg/L for Escherichia coli and Enterococcus faecalis grown from urine (CLSI M100); ≤32 mg/L for Enterobacterales and staphylococci when parenteral fosfomycin is prescribed (EUCAST); and ≤8 mg/L for uncomplicated urinary tract infection with E. coli when oral fosfomycin is used (EUCAST). Clinical laboratories are frequently requested to test fosfomycin against antimicrobial-resistant urinary isolates not included in standard documents. METHODS: The in vitro activity of fosfomycin was determined using the CLSI agar dilution method for a 2007-20 collection of clinically significant Gram-negative (3656 Enterobacterales; 140 Pseudomonas aeruginosa) and Gram-positive (346 E. faecalis; 94 Staphylococcus aureus) urinary isolates from the CANWARD surveillance study. Comparator agents were tested using CLSI broth microdilution. RESULTS: Using the CLSI MIC breakpoint (≤64 mg/L), 99.2% of E. coli (n = 2871; MIC90, 4 mg/L), including 96.7% of ESBL-positive isolates, were fosfomycin susceptible. Similarly, 95.8% of E. coli, including 95.2% of ESBL-positive isolates, were fosfomycin susceptible at ≤8 mg/L (EUCAST oral susceptible MIC breakpoint). All other species of Enterobacterales (except Citrobacter freundii) and P. aeruginosa had higher fosfomycin MICs (MIC90s, 64 to >512 mg/L) than E. coli. Using published breakpoints, 88.4% of E. faecalis (MIC ≤64 mg/L) and 97.9% of S. aureus (MIC ≤32 mg/L) isolates were fosfomycin susceptible. CONCLUSIONS: Fosfomycin demonstrated in vitro activity against frequently encountered Gram-positive and Gram-negative urinary pathogens; however, the extrapolation of current CLSI and EUCAST MIC breakpoints to pathogens not specified by standard methods requires further study and is currently not recommended.

In Vitro Activity of Cefiderocol against Extensively Drug-Resistant Pseudomonas aeruginosa: CANWARD, 2007 to 2019.

Cefiderocol was evaluated by broth microdilution versus 1,050 highly antimicrobial-resistant Pseudomonas aeruginosa clinical isolates from the CANWARD study (2007 to 2019). Overall, 98.3% of isolates remained cefiderocol susceptible (MIC, ≤4 µg/mL), including 97.4% of extensively drug-resistant (XDR) (n = 235) and 97.9% of multidrug-resistant (MDR) (n = 771) isolates. Most isolates testing not susceptible to ceftolozane-tazobactam, ceftazidime-avibactam, and imipenem-relebactam remained susceptible to cefiderocol. In vitro data suggest that cefiderocol may be a treatment option for infections caused by MDR and XDR P. aeruginosa. IMPORTANCE After testing cefiderocol against a large collection of clinical isolates of highly antimicrobial-resistant Pseudomonas aeruginosa, we report that cefiderocol is active versus 97.4% of extensively drug-resistant (XDR) and 97.9% of multidrug-resistant (MDR) (n = 771) isolates. These data show that cefiderocol may be a treatment option for infections caused by MDR and XDR P. aeruginosa.

Omadacycline: A Novel Oral and Intravenous Aminomethylcycline Antibiotic Agent.

Omadacycline is a novel aminomethylcycline antibiotic developed as a once-daily, intravenous and oral treatment for acute bacterial skin and skin structure infection (ABSSSI) and community-acquired bacterial pneumonia (CABP). Omadacycline, a derivative of minocycline, has a chemical structure similar to tigecycline with an alkylaminomethyl group replacing the glycylamido group at the C-9 position of the D-ring of the tetracycline core. Similar to other tetracyclines, omadacycline inhibits bacterial protein synthesis by binding to the 30S ribosomal subunit. Omadacycline possesses broad-spectrum antibacterial activity against Gram-positive and Gram-negative aerobic, anaerobic, and atypical bacteria. Omadacycline remains active against bacterial isolates possessing common tetracycline resistance mechanisms such as efflux pumps (e.g., TetK) and ribosomal protection proteins (e.g., TetM) as well as in the presence of resistance mechanisms to other antibiotic classes. The pharmacokinetics of omadacycline are best described by a linear, three-compartment model following a zero-order intravenous infusion or first-order oral administration with transit compartments to account for delayed absorption. Omadacycline has a volume of distribution (Vd) ranging from 190 to 204 L, a terminal elimination half-life (t½) of 13.5-17.1 h, total clearance (CLT) of 8.8-10.6 L/h, and protein binding of 21.3% in healthy subjects. Oral bioavailability of omadacycline is estimated to be 34.5%. A single oral dose of 300 mg (bioequivalent to 100 mg IV) of omadacycline administered to fasted subjects achieved a maximum plasma concentration (Cmax) of 0.5-0.6 mg/L and an area under the plasma concentration-time curve from 0 to infinity (AUC0-∞) of 9.6-11.9 mg h/L. The free plasma area under concentration-time curve divided by the minimum inhibitory concentration (i.e., fAUC24h/MIC), has been established as the pharmacodynamic parameter predictive of omadacycline antibacterial efficacy. Several animal models including neutropenic murine lung infection, thigh infection, and intraperitoneal challenge model have documented the in vivo antibacterial efficacy of omadacycline. A phase II clinical trial on complicated skin and skin structure infection (cSSSI) and three phase III clinical trials on ABSSSI and CABP demonstrated the safety and efficacy of omadacycline. The phase III trials, OASIS-1 (ABSSSI), OASIS-2 (ABSSSI), and OPTIC (CABP), established non-inferiority of omadacycline to linezolid (OASIS-1, OASIS-2) and moxifloxacin (OPTIC), respectively. Omadacycline is currently approved by the FDA for use in treatment of ABSSSI and CABP. Phase II clinical trials involving patients with acute cystitis and acute pyelonephritis are in progress. Mild, transient gastrointestinal events are the predominant adverse effects associated with use of omadacycline. Based on clinical trial data to date, the adverse effect profile of omadacycline is similar to studied comparators, linezolid and moxifloxacin. Unlike tigecycline and eravacycline, omadacycline has an oral formulation that allows for step-down therapy from the intravenous formulation, potentially facilitating earlier hospital discharge, outpatient therapy, and cost savings. Omadacycline has a potential role as part of an antimicrobial stewardship program in the treatment of patients with infections caused by antibiotic-resistant and multidrug-resistant Gram-positive [including methicillin-resistant Staphylococcus aureus (MRSA)] and Gram-negative pathogens.

Characterization of carbapenem-resistant and XDR Pseudomonas aeruginosa in Canada: results of the CANWARD 2007-16 study.

OBJECTIVES: Carbapenem-resistant Pseudomonas aeruginosa are emerging worldwide with increasing reports of carbapenemase-producing isolates. Carbapenem-resistant isolates may also be XDR. This study characterized carbapenem-resistant and XDR P. aeruginosa isolated from patients receiving care at Canadian hospitals from 2007 to 2016. METHODS: Antimicrobial susceptibility testing was performed using CLSI broth microdilution methods. PCR was used to detect carbapenemases (GES, KPC, NDM, IMP, VIM, OXA-48) and other resistance markers; specific carbapenemase gene variants were identified by DNA sequencing. Genetic relatedness was assessed by MLST and PFGE. RESULTS: From 2007 to 2016, 3864 isolates of P. aeruginosa were collected; 466 (12.1%) isolates were carbapenem resistant. The prevalence of carbapenem-resistant P. aeruginosa reached a peak of 17.3% in 2014. Colistin (94% susceptible) and ceftolozane/tazobactam (92.5%) were the most active agents against carbapenem-resistant P. aeruginosa. XDR P. aeruginosa comprised 4.5% of isolates; they were found to be genetically diverse and remained susceptible to colistin and ceftolozane/tazobactam. Only 4.3% (n = 20) of carbapenem-resistant P. aeruginosa harboured a carbapenemase; most were blaGES-5 (35%, n = 7). Wide genetic diversity was observed among carbapenem-resistant P. aeruginosa with >200 different sequence types identified. CONCLUSIONS: Although the prevalence of carbapenem-resistant P. aeruginosa in Canada spiked in 2014 and 2015, carbapenemase-producing P. aeruginosa remain rare with only 20 (4.3%) isolates identified over a 10 year period. Broad genetic diversity was observed among both carbapenem-resistant and XDR phenotypes of P. aeruginosa. Pan-drug-resistant P. aeruginosa have not yet been identified in Canada.

In vitro susceptibility of urinary Escherichia coli isolates to first- and second-line empirically prescribed oral antimicrobials: CANWARD surveillance study results for Canadian outpatients, 2007-2016.

Escherichia coli isolates (n = 2035) from urine specimens of outpatients presenting to Canadian medical clinics and hospital emergency departments from 2007-2016 were collected as part of the CANWARD surveillance study. Isolate identification and antimicrobial susceptibility testing (AST) were performed at a central site (Health Sciences Centre, Winnipeg, Canada). AST of first- and second-line oral antimicrobial agents was performed using CLSI methods (M07, 11th ed, 2018); fosfomycin was tested by agar dilution and all other agents by broth microdilution. Minimum inhibitory concentrations (MICs) were interpreted using CLSI M100 (2018) criteria. Fosfomycin (99.2% of isolates susceptible), nitrofurantoin (97.5%) and cefalexin (93.6%) were the most active agents tested; amoxicillin/clavulanic acid (AMC) (85.6%), ciprofloxacin (83.0%) and trimethoprim/sulfamethoxazole (SXT) (77.0%) were less active. Annual percentages of isolates positive for extended-spectrum ß-lactamases (ESBLs) or demonstrating multidrug-resistant (MDR) phenotypes increased from 0.8% (2007) to 10.1% (2016), and from 9.7% (2007) to 16.5% (2016), respectively, whilst the annual frequency of AmpC-positive isolates decreased from a high of 3.2% in 2008 to 0.7% in 2016. The most common MDR phenotype of E. coli was non-susceptibility to AMC, ciprofloxacin, and SXT, accounting for 12.7% (26/205) of all MDR isolates. Rates of susceptibility were higher for fosfomycin than for the five other oral agents tested against ESBL-positive (96.1% susceptible) and MDR (95.1%) isolates and were equal to nitrofurantoin (96.4%) against AmpC-positive isolates. Prudent use of antimicrobials and close monitoring of antimicrobial susceptibilities of clinical uropathogenic E. coli isolates are imperative to help preserve the utility of oral antimicrobials.

Cefiderocol: A Siderophore Cephalosporin with Activity Against Carbapenem-Resistant and Multidrug-Resistant Gram-Negative Bacilli.

Cefiderocol is an injectable siderophore cephalosporin discovered and being developed by Shionogi & Co., Ltd., Japan. As with other ß-lactam antibiotics, the principal antibacterial/bactericidal activity of cefiderocol occurs by inhibition of Gram-negative bacterial cell wall synthesis by binding to penicillin binding proteins; however, it is unique in that it enters the bacterial periplasmic space as a result of its siderophore-like property and has enhanced stability to ß-lactamases. The chemical structure of cefiderocol is similar to both ceftazidime and cefepime, which are third- and fourth-generation cephalosporins, respectively, but with high stability to a variety of ß-lactamases, including AmpC and extended-spectrum ß-lactamases (ESBLs). Cefiderocol has a pyrrolidinium group in the side chain at position 3 like cefepime and a carboxypropanoxyimino group in the side chain at position 7 of the cephem nucleus like ceftazidime. The major difference in the chemical structures of cefiderocol, ceftazidime and cefepime is the presence of a catechol group on the side chain at position 3. Together with the high stability to ß-lactamases, including ESBLs, AmpC and carbapenemases, the microbiological activity of cefiderocol against aerobic Gram-negative bacilli is equal to or superior to that of ceftazidime-avibactam and meropenem, and it is active against a variety of Ambler class A, B, C and D ß-lactamases. Cefiderocol is also more potent than both ceftazidime-avibactam and meropenem versus Acinetobacter baumannii, including meropenem non-susceptible and multidrug-resistant (MDR) isolates. Cefiderocol's activity against meropenem-non-susceptible and Klebsiella pneumoniae carbapenemase (KPC)-producing Enterobacteriales is comparable or superior to ceftazidime-avibactam. Cefiderocol is also more potent than both ceftazidime-avibactam and meropenem against all resistance phenotypes of Pseudomonas aeruginosa and against Stenotrophomonas maltophilia. The current dosing regimen being used in phase III studies is 2 g administered intravenously every 8 h (q8 h) using a 3-h infusion. The pharmacokinetics of cefiderocol are best described by a three-compartment linear model. The mean plasma half-life (t½) was ~ 2.3 h, protein binding is 58%, and total drug clearance ranged from 4.6-6.0 L/h for both single- and multi-dose infusions and was primarily renally excreted unchanged (61-71%). Cefiderocol is primarily renally excreted unchanged and clearance correlates with creatinine clearance. Dosage adjustment is thus required for both augmented renal clearance and in patients with moderate to severe renal impairment. In vitro and in vivo pharmacodynamic studies have reported that as with other cephalosporins the pharmacodynamic index that best predicts clinical outcome is the percentage of time that free drug concentrations exceed the minimum inhibitory concentration (%fT > MIC). In vivo efficacy of cefiderocol has been studied in a variety of humanized drug exposure murine and rat models of infection utilizing a variety of MDR and extremely drug resistant strains. Cefiderocol has performed similarly to or has been superior to comparator agents, including ceftazidime and cefepime. A phase II prospective, multicenter, double-blind, randomized clinical trial assessed the safety and efficacy of cefiderocol 2000 mg q8 h versus imipenem/cilastatin 1000 mg q8 h, both administered intravenously for 7-14 days over 1 h, in the treatment of complicated urinary tract infection (cUTI, including pyelonephritis) or acute uncomplicated pyelonephritis in hospitalized adults. A total of 452 patients were initially enrolled in the study, with 303 in the cefiderocol arm and 149 in the imipenem/cilastatin arm. The primary outcome measure was a composite of clinical cure and microbiological eradication at the test-of-cure (TOC) visit, that is, 7 days after the end of treatment in the microbiological intent-to-treat (MITT) population. Secondary outcome measures included microbiological response per pathogen and per patient at early assessment (EA), end of treatment (EOT), TOC, and follow-up (FUP); clinical response per pathogen and per patient at EA, EOT, TOC, and FUP; plasma, urine and concentrations of cefiderocol; and the number of participants with adverse events. The composite of clinical and microbiological response rates was 72.6% (183/252) for cefiderocol and 54.6% (65/119) for imipenem/cilastatin in the MITT population. Clinical response rates per patient at the TOC visit were 89.7% (226/252) for cefiderocol and 87.4% (104/119) for imipenem/cilastatin in the MITT population. Microbiological eradication rates were 73.0% (184/252) for cefiderocol and 56.3% (67/119) for imipenem/cilastatin in the MITT population. Additionally, two phase III clinical trials are currently being conducted by Shionogi & Co., Ltd., Japan. The two trials are evaluating the efficacy of cefiderocol in the treatment of serious infections in adult patients caused by carbapenem-resistant Gram-negative pathogens and evaluating the efficacy of cefiderocol in the treatment of adults with hospital-acquired bacterial pneumonia, ventilator-associated pneumonia or healthcare-associated pneumonia caused by Gram-negative pathogens. Cefiderocol appears to be well tolerated (minor reported adverse effects were gastrointestinal and phlebitis related), with a side effect profile that is comparable to other cephalosporin antimicrobials. Cefiderocol appears to be well positioned to help address the increasing number of infections caused by carbapenem-resistant and MDR Gram-negative bacilli, including ESBL- and carbapenemase-producing strains (including metallo-ß-lactamase producers). A distinguishing feature of cefiderocol is its activity against resistant P. aeruginosa, A. baumannii, S. maltophilia and Burkholderia cepacia.

In Vitro Activity of Sulopenem, an Oral Penem, against Urinary Isolates of Escherichia coli.

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 ß-lactamases, or AmpC ß-lactamases.

Antimicrobial-resistant pathogens in Canadian ICUs: results of the CANWARD 2007 to 2016 study.

OBJECTIVES: To describe the microbiology and antimicrobial resistance patterns of cultured samples acquired from Canadian ICUs. METHODS: From 2007 to 2016, tertiary care centres from across Canada submitted 42938 bacterial/fungal isolates as part of the CANWARD surveillance study. Of these, 8130 (18.9%) were from patients on ICUs. Susceptibility testing guidelines and MIC interpretive criteria were defined by CLSI. RESULTS: Of the 8130 pathogens collected in this study, 58.2%, 36.3%, 3.1% and 2.4% were from respiratory, blood, wound and urine specimens, respectively. The top five organisms collected from Canadian ICUs accounted for 55.4% of all isolates and included Staphylococcus aureus (21.5%), Pseudomonas aeruginosa (10.6%), Escherichia coli (10.4%), Streptococcus pneumoniae (6.5%) and Klebsiella pneumoniae (6.4%). MRSA accounted for 20.7% of S. aureus collected, with community-associated (CA) MRSA genotypes increasing in prevalence over time (P < 0.001). The highest susceptibility rates among MRSA were 100% for vancomycin, 100% for ceftobiprole, 100% for linezolid, 99.7% for ceftaroline, 99.7% for daptomycin and 99.7% for tigecycline. The highest susceptibility rates among E. coli were 100% for tigecycline, 99.9% for meropenem, 99.7% for colistin and 94.2% for piperacillin/tazobactam. MDR was identified in 26.3% of E. coli isolates, with 10.1% producing an ESBL. The highest susceptibility rates among P. aeruginosa were 97.5% for ceftolozane/tazobactam, 96.1% for amikacin, 94.7% for colistin and 93.3% for tobramycin. CONCLUSIONS: The most active agents against Gram-negative bacilli were the carbapenems, tigecycline and piperacillin/tazobactam. Against Gram-positive cocci, the most active agents were vancomycin, daptomycin and linezolid. The prevalence of CA-MRSA genotypes and ESBL-producing E. coli collected from ICUs increased significantly over time.

Evaluation of three MALDI-TOF mass spectrometry libraries for the identification of filamentous fungi in three clinical microbiology laboratories in Manitoba, Canada.

Matrix-assisted laser desorption ionisation-time of flight mass spectrometry (MALDI-TOF MS) is commonly used by clinical microbiology laboratories to identify bacterial pathogens and yeasts, but not for the identification of moulds. Recent progress in extraction protocols and the composition of comparative libraries support potential application of MALDI-TOF MS for mould identification in clinical microbiology laboratories. We evaluated the performance of the Bruker Microflex™ MALDI-TOF MS instrument (Billerica, MA, USA) to identify clinical isolates and reference strains of moulds using 3 libraries, the Bruker mould library, the National Institutes of Health (NIH) library and the Mass Spectrometry Identification (MSI) online library, and compared those results to conventional (morphological) and molecular (18S/ITS; gold standard) identification methods. All 3 libraries demonstrated greater accuracy in genus identification (≥94.9%) than conventional methods (86.4%). MALDI-TOF MS identified 73.3% of isolates to species level compared to only 31.7% by conventional methods. The MSI library demonstrated the highest rate of species-level identification (72.0%) compared to NIH (19.5%) and Bruker (13.6%) libraries. Greater than 20% of moulds remained unidentified to species level by all 3 MALDI-TOF MS libraries primarily because of library limitations or imperfect spectra. The overall identification rate of each MALDI-TOF MS library depended on the number of species and the number of spectra representing each species in the library.

In vitro activity of Oritavancin against gram-positive pathogens isolated in Canadian hospital laboratories from 2011 to 2015.

Gram-positive bacterial pathogens isolated from patient specimens submitted to 15 Canadian hospital laboratories from 2011 to 2015 were tested in the coordinating laboratory for susceptibility to oritavancin and comparative antimicrobial agents using the Clinical and Laboratory Standards Institute M07-A10 (2015) broth microdilution method. Oritavancin's in vitro activity was equivalent to, or more potent than, vancomycin, daptomycin, linezolid, and tigecycline against methicillin-susceptible Staphylococcus aureus (n=2680; oritavancin MIC90, 0.12µg/mL; 99.9% oritavancin-susceptible), methicillin-resistant S. aureus (n=728; oritavancin MIC90, 0.12µg/mL; 99.7% oritavancin-susceptible), Streptococcus pyogenes (n=218; oritavancin MIC90, 0.25µg/mL; 100% oritavancin-susceptible), Streptococcus agalactiae (n=269; oritavancin MIC90, 0.12µg/mL; 100% oritavancin-susceptible), and vancomycin-susceptible Enterococcus faecalis (n=508; oritavancin MIC90, 0.06µg/mL; 100% oritavancin-susceptible). Oritavancin, dalbavancin, and telavancin demonstrated equivalent in vitro activities (MIC90, µg/mL) against 602 isolates of MSSA (0.06, 0.06, 0.06, respectively) and 144 isolates of MRSA (0.12, 0.06, 0.06, respectively) collected in 2015.

Solithromycin: A Novel Fluoroketolide for the Treatment of Community-Acquired Bacterial Pneumonia.

Solithromycin is a novel fluoroketolide developed in both oral and intravenous formulations to address increasing macrolide resistance in pathogens causing community-acquired bacterial pneumonia (CABP). When compared with its macrolide and ketolide predecessors, solithromycin has several structural modifications which increase its ribosomal binding and reduce its propensity to known macrolide resistance mechanisms. Solithromycin, like telithromycin, affects 50S ribosomal subunit formation and function, as well as causing frame-shift errors during translation. However, unlike telithromycin, which binds to two sites on the ribosome, solithromycin has three distinct ribosomal binding sites. Its desosamine sugar interacts at the A2058/A2059 cleft in domain V (as all macrolides do), an extended alkyl-aryl side chain interacts with base pair A752-U2609 in domain II (similar to telithromycin), and a fluorine at C-2 of solithromycin provides additional binding to the ribosome. Studies describing solithromycin activity against Streptococcus pneumoniae have reported that it does not induce erm-mediated resistance because it lacks a cladinose moiety, and that it is less susceptible than other macrolides to mef-mediated efflux due to its increased ribosomal binding and greater intrinsic activity. Solithromycin has demonstrated potent in vitro activity against the most common CABP pathogens, including macrolide-, penicillin-, and fluoroquinolone-resistant isolates of S. pneumoniae, as well as Haemophilus influenzae and atypical bacterial pathogens. Solithromycin displays multi-compartment pharmacokinetics, a large volume of distribution (>500 L), approximately 67% bioavailability when given orally, and serum protein binding of 81%. Its major metabolic pathway appears to follow cytochrome P450 (CYP) 3A4, with metabolites of solithromycin undergoing biliary excretion. Its serum half-life is approximately 6-9 h, which is sufficient for once-daily administration. Pharmacodynamic activity is best described as fAUC0-24/MIC (the ratio of the area under the free drug concentration-time curve from 0 to 24 h to the minimum inhibitory concentration of the isolate). Solithromycin has completed one phase II and two phase III clinical trials in patients with CABP. In the phase II trial, oral solithromycin was compared with oral levofloxacin and demonstrated similar clinical success rates in the intention-to-treat (ITT) population (84.6 vs 86.6%). Clinical success in the clinically evaluable patients group was 83.6% of patients receiving solithromycin compared with 93.1% for patients receiving levofloxacin. In SOLITAIRE-ORAL, a phase III trial which assessed patients receiving oral solithromycin or oral moxifloxacin for CABP, an equivalent (non-inferior) early clinical response in the ITT population was demonstrated for patients receiving either solithromycin (78.2%) or moxifloxacin (77.9%). In a separate phase III trial, SOLITAIRE-IV, patients receiving intravenous-to-oral solithromycin (79.3%) demonstrated non-inferiority as the primary outcome of early clinical response in the ITT population compared with patients receiving intravenous-to-oral moxifloxacin (79.7%). Overall, solithromycin has been well tolerated in clinical trials, with gastrointestinal adverse events being most common, occurring in approximately 10% of patients. Transaminase elevation occurred in 5-10% of patients and generally resolved following cessation of therapy. None of the rare serious adverse events that occurred with telithromycin (i.e., hepatotoxicity) have been noted with solithromycin, possibly due to the fact that solithromycin (unlike telithromycin) does not possess a pyridine moiety in its chemical structure, which has been implicated in inhibiting nicotinic acetylcholine receptors. Because solithromycin is a possible substrate and inhibitor of both CYP3A4 and P-glycoprotein (P-gp), it may display drug interactions similar to macrolides such as clarithromycin. Overall, the in vitro activity, clinical efficacy, tolerability, and safety profile of solithromycin demonstrated to date suggest that it continues to be a promising treatment for CABP.

Fosfomycin: A First-Line Oral Therapy for Acute Uncomplicated Cystitis.

Fosfomycin is a new agent to Canada approved for the treatment of acute uncomplicated cystitis (AUC) in adult women infected with susceptible isolates of E. coli and Enterococcus faecalis. We reviewed the literature regarding the use of oral fosfomycin for the treatment of AUC. All English-language references from 1975 to October 2015 were reviewed. In Canada, fosfomycin tromethamine is manufactured as Monurol® and is available as a 3-gram single dose sachet. Fosfomycin has a unique chemical structure, inhibiting peptidoglycan synthesis at an earlier site compared to ß-lactams with no cross-resistance with other agents. Fosfomycin displays broad-spectrum activity against ESBL-producing, AmpC-producing, carbapenem-non-susceptible, and multidrug-resistant (MDR) E. coli. Resistance to fosfomycin in E. coli is rare (<1%). Fosfomycin is excreted unchanged in the urine by glomerular filtration with peak urinary concentration ~4000 µg/mL and remains at concentrations >100 µg/mL for 48 hours after a single 3-gram oral dose. No dosage adjustments are required in elderly patients, in pregnant patients, or in either renal or hepatic impairment. Fosfomycin demonstrates a favorable safety profile, and clinical trials have demonstrated efficacy in AUC that is comparable to ciprofloxacin, nitrofurantoin, and trimethoprim-sulfamethoxazole. Fosfomycin's in vitro activity against common uropathogens, including MDR isolates, its favorable safety profile including pregnancy patients, drug interactions, and clinical trials data demonstrating efficacy in AUC, has resulted in Canadian, US, and European guidelines/authorities recommending fosfomycin as a first line agent for the treatment of AUC.

Fidaxomicin: A novel agent for the treatment of Clostridium difficile infection.

BACKGROUND: Due to the limitations of existing treatment options for Clostridium difficile infection (CDI), new therapies are needed. OBJECTIVE: To review the available data on fidaxomicin regarding chemistry, mechanisms of action and resistance, in vitro activity, pharmacokinetic and pharmacodynamic properties, efficacy and safety in clinical trials, and place in therapy. METHODS: A search of PubMed using the terms "fidaxomicin", "OPT-80", "PAR-101", "OP-1118", "difimicin", "tiacumicin" and "lipiarmycin" was performed. All English-language articles from January 1983 to November 2014 were reviewed, as well as bibliographies of all articles. RESULTS: Fidaxomicin is the first macrocyclic lactone antibiotic with activity versus C difficile. It inhibits RNA polymerase, therefore, preventing transcription. Fidaxomicin (and its active metabolite OP-1118) is bactericidal against C difficile and exhibits a prolonged postantibiotic effect (approximately 10 h). Other than for C difficile, fidaxomicin demonstrated only moderate inhibitory activity against Gram-positive bacteria and was a poor inhibitor of normal colonic flora, including anaerobes and enteric Gram-negative bacilli. After oral administration (200 mg two times per day for 10 days), fidaxomicin achieved low serum concentration levels but high fecal concentration levels (mean approximately 1400 µg/g stool). Phase 3 clinical trials involving adults with CDI demonstrated that 200 mg fidaxomicin twice daily for 10 days was noninferior to 125 mg oral vancomycin four times daily for 10 days in regard to clinical response at the end of therapy. Fidaxomicin was, however, reported to be superior to oral vancomycin in reducing recurrent CDI and achieving a sustained clinical response (assessed at day 28) for patients infected with non-BI/NAP1/027 strains. CONCLUSION: Fidaxomicin was noninferior to oral vancomycin with regard to clinical response at the end of CDI therapy. Fidaxomicin has been demonstated to be as safe as oral vancomycin, but superior to vancomycin in achieving a sustained clinical response for CDI in patients infected with non-BI/NAP1/027 strains. Caution should be exercised in using fidaxomicin monotherapy for treatment of severe complicated CDI because limited data are available. Whether fidaxomicin is cost effective (due to its significantly higher acquisition cost versus oral vancomycin) depends on the acceptable willingness to pay threshold per quality-adjusted life year as a measure of assessing cost effectiveness.

HISTORIQUE: Étant donné le peu de traitements de l'infection à Clostridium difficile (ICD), il faut en trouver de nouveaux. OBJECTIF: Examiner les données sur les caractéristiques chimiques, les mécanismes d'action, la résistance, l'activité in vitro, les propriétés pharmacocinétiques et pharmacodynamiques, l'efficacité et l'innocuité de la fidaxomicine dans les essais cliniques, ainsi que la place qu'elle occupe dans les traitements. MÉTHODOLOGIE: Les chercheurs ont fouillé dans PubMed à l'aide des termes fidaxomicin, OPT-80, PAR-101, OP-1118, difimicin, tiacumicin et lipiarmycin. Ils en ont extrait tous les articles en anglais entre janvier 1983 et novembre 2014, de même que les bibliographies de tous les articles. RÉSULTATS: La fidaxomicine est la première lactone macrocyclique à résister au C difficile. Elle inhibe la polymérase de l'ARN et, par conséquent, en empêche la transcription. La fidaxomicine (et son métabolite actif, l'OP-1118) est bactéricide contre le C difficile et possède un effet postantibiotique prolongé (environ dix heures). À par d'autres infections que le C difficile, la fidaxomicine a une activité inhibitrice modérée contre les bactéries Gram positif et est un mauvais inhibiteur de la flore colique normale, y compris les anaérobies et les bacilles entériques Gram négatif. Après son administration par voie orale (200 mg deux fois par jour pendant dix jours), la fidaxomicine était peu concentrée dans le sérum, mais très concentrée dans les selles (moyenne d'environ 1 400 µg/g par selle). Des essais cliniques de phase 3 auprès d'adultes atteints d'une ICD a démontré qu'à la fin du traitement, la réponse clinique à la prise de 200 mg de fidaxomicine pendant dix jours n'était pas inférieure à celle de la prise de 125 mg de vancomycine par voie orale quatre fois par jour pendant dix jours. La fidaxomicine était toutefois supérieure à la vancomycine par voie orale pour réduire les ICD récurrentes et parvenir à une réponse clinique soutenue (évaluée le jour 28) chez les patients infectés par d'autres souches que les BI/NAP1/027. CONCLUSION: La réponse clinique de la fidaxomicine n'était pas inférieure à celle de la vancomycine par voie orale à la fin du traitement de l'ICD. Il est démontré que la fidaxomicine est tout aussi sécuritaire que la vancomycine par voie orale, mais qu'elle est supérieure à cet antibiotique pour assurer une réponse clinique soutenue à l'ICD chez les patients infectés par d'autres souches que les BI/NAP1/027. Il faut faire preuve de prudence lorsqu'on utilise la monothérapie à la fidaxomicine pour traiter une IDC très complexe, car il existe peu de données sur le sujet. L'efficience de la fidaxomicine (en raison de son coût d'acquisition beaucoup plus élevé que celui de la vancomycine par voie orale) dépend de la volonté acceptable de payer un seuil par année de vie pondérée par la qualité.

In vitro activity of ceftaroline-avibactam against gram-negative and gram-positive pathogens isolated from patients in Canadian hospitals from 2010 to 2012: results from the CANWARD surveillance study.

The in vitro activities of ceftaroline-avibactam, ceftaroline, and comparative agents were determined for a collection of bacterial pathogens frequently isolated from patients seeking care at 15 Canadian hospitals from January 2010 to December 2012. In total, 9,758 isolates were tested by using the Clinical and Laboratory Standards Institute (CLSI) broth microdilution method (document M07-A9, 2012), with MICs interpreted by using CLSI breakpoints (document M100-S23, 2013). Ceftaroline-avibactam demonstrated potent activity (MIC90, ≤ 0.5 µg/ml) against Escherichia coli, Klebsiella pneumoniae, Klebsiella oxytoca, Proteus mirabilis, Enterobacter cloacae, Enterobacter aerogenes, Serratia marcescens, Morganella morganii, Citrobacter freundii, and Haemophilus influenzae; >99% of isolates of E. coli, K. pneumoniae, K. oxytoca, P. mirabilis, M. morganii, C. freundii, and H. influenzae were susceptible to ceftaroline-avibactam according to CLSI MIC interpretative criteria for ceftaroline. Ceftaroline was less active than ceftaroline-avibactam against all species of Enterobacteriaceae tested, with rates of susceptibility ranging from 93.9% (P. mirabilis) to 54.0% (S. marcescens). All isolates of methicillin-susceptible Staphylococcus aureus (MIC90, 0.25 µg/ml) and 99.6% of methicillin-resistant S. aureus isolates (MIC90, 1 µg/ml) were susceptible to ceftaroline; the addition of avibactam to ceftaroline did not alter its activity against staphylococci or streptococci. All isolates of Streptococcus pneumoniae (MIC90, 0.03 µg/ml), Streptococcus pyogenes (MIC90, ≤ 0.03 µg/ml), and Streptococcus agalactiae (MIC90, 0.015 µg/ml) tested were susceptible to ceftaroline. We conclude that combining avibactam with ceftaroline expanded its spectrum of activity to include most isolates of Enterobacteriaceae resistant to third-generation cephalosporins, including extended-spectrum ß-lactamase (ESBL)- and AmpC-producing E. coli and ESBL-producing K. pneumoniae, while maintaining potent activity against staphylococci and streptococci.

Prevalence of antimicrobial resistance among clinical isolates of Bacteroides fragilis group in Canada in 2010-2011: CANWARD surveillance study.

Clinical isolates of the Bacteroides fragilis group (n = 387) were collected from patients attending nine Canadian hospitals in 2010-2011 and tested for susceptibility to 10 antimicrobial agents using the Clinical and Laboratory Standards Institute (CLSI) broth microdilution method. B. fragilis (59.9%), Bacteroides ovatus (16.3%), and Bacteroides thetaiotaomicron (12.7%) accounted for ~90% of isolates collected. Overall rates of percent susceptibility were as follows: 99.7%, metronidazole; 99.5%, piperacillin-tazobactam; 99.2%, imipenem; 97.7%, ertapenem; 92.0%, doripenem; 87.3%, amoxicillin-clavulanate; 80.9%, tigecycline; 65.9%, cefoxitin; 55.6%, moxifloxacin; and 52.2%, clindamycin. Percent susceptibility to cefoxitin, clindamycin, and moxifloxacin was lowest for B. thetaiotaomicron (n = 49, 24.5%), Parabacteroides distasonis/P. merdae (n = 11, 9.1%), and B. ovatus (n = 63, 31.8%), respectively. One isolate (B. thetaiotaomicron) was resistant to metronidazole, and two isolates (both B. fragilis) were resistant to both piperacillin-tazobactam and imipenem. Since the last published surveillance study describing Canadian isolates of B. fragilis group almost 20 years ago (A.-M. Bourgault et al., Antimicrob. Agents Chemother. 36:343-347, 1992), rates of resistance have increased for amoxicillin-clavulanate, from 0.8% (1992) to 6.2% (2010-2011), and for clindamycin, from 9% (1992) to 34.1% (2010-2011).