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Objectives: To describe the in vitro activity of imipenem/relebactam (IMR) against non-Morganellaceae Enterobacterales (NME) and Pseudomonas aeruginosa, including piperacillin/tazobactam-nonsusceptible and meropenem-nonsusceptible isolates, infecting hospitalized patients in the Asia-Pacific region., Methods: From 2017 to 2020, 49 clinical laboratories in nine countries in the Asia-Pacific region participated in the SMART global surveillance program and contributed 26 783 NME and 6383 P. aeruginosa. Minimum inhibitory concentrations (MICs) were determined using CLSI broth microdilution and interpreted using CLSI M100 (2021) breakpoints. β-Lactamase genes were identified in selected isolate subsets (2017-2020) and oprD was sequenced in molecularly characterized P. aeruginosa collected in 2020., Results: Amikacin (97.9% susceptible), IMR (95.8%), meropenem (95.4%), and imipenem (92.6%) were the most active agents against NME. Among piperacillin/tazobactam-nonsusceptible NME (n=4070), 76.1% were IMR-susceptible (range by country, 97.5% [New Zealand] to 50.6% [Vietnam]); 22.4% of meropenem-nonsusceptible NME (n=1225) were IMR-susceptible (range by country, 68.8% [South Korea] to 7.6% [Thailand]). A total of 2.7% of NME carried a metallo-β-lactamase (MBL), 0.9% an OXA-48-like carbapenemase (MBL-negative), and 0.7% a KPC (MBL-negative). Amikacin (94.0% susceptible) and IMR (90.3%) were the most active agents against P. aeruginosa; 71.2% of isolates were imipenem-susceptible. Relebactam increased susceptibility to imipenem by 25.6% (from 40.5% to 66.1%) in piperacillin/tazobactam-nonsusceptible and by 44.8% (from 7.1% to 51.9%) in meropenem-nonsusceptible P. aeruginosa. Only 4.3% of P. aeruginosa were MBL-positive. A total of 70.3% (90/128) of IMR-nonsusceptible P. aeruginosa were oprD-deficient., Conclusion: In 2017-2020, 96% of NME and 90% of P. aeruginosa from the Asia-Pacific region were IMR-susceptible. IMR percent susceptible rates were higher in countries with lower MBL carriage., (Copyright © 2023 Merck Sharp & Dohme LLC., a subsidiary of Merck & Co., Inc., Rahway, NJ, USA, The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Multidrug-resistant (MDR) Pseudomonas aeruginosa infections compromise both empirical and definitive antimicrobial therapies. The Study for Monitoring Antimicrobial Resistance Trends (SMART) surveillance program identified 943 MDR P. aeruginosa (from a total of 4086 P. aeruginosa isolates [23.1%]) collected at 32 clinical laboratories in six countries in Western Europe from 2017 to 2020. Minimum inhibitory concentrations (MICs) for ceftolozane/tazobactam and 10 comparator agents were determined by broth microdilution and interpreted using 2021 EUCAST breakpoints. β-lactamase genes were identified in selected isolate subsets. Most isolates of P. aeruginosa in Western Europe (93.3%) were ceftolozane/tazobactam-susceptible. A total of 23.1% of P. aeruginosa isolates were MDR. Of these, 72.0% were ceftolozane/tazobactam-susceptible, which is similar to that for ceftazidime/avibactam (73.6%) but >40% higher than for carbapenems, piperacillin/tazobactam, third- and fourth-generation cephalosporins, and levofloxacin. Metallo-β-lactamases (MBLs) were carried by 8.8% of molecularly characterized MDR P. aeruginosa, and 7.6% of molecularly characterized MDR isolates carried Guiana Extended Spectrum (GES) carbapenemases. MBLs were identified in isolates from all six countries, ranging from 3.2% of all P. aeruginosa isolates from Italy to 0.4% of all isolates from the United Kingdom. Acquired β-lactamases were not identified in 80.0% of molecularly characterized MDR P. aeruginosa isolates. Percentages of MDR isolates without detected β-lactamases were higher in the United Kingdom (97.7%), Spain (88.2%), France (88.1%), and Germany (84.7%) than in Portugal (63.0%) and Italy (61.3%), where carbapenemases were more prevalent. Ceftolozane/tazobactam is an important treatment option for patients infected with MDR P. aeruginosa that are not susceptible to first-line antipseudomonal agents., Competing Interests: Competing Interests: SHL, SPH, and DFS work for IHMA, which receives funding from Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA for the SMART surveillance program. JAK is a consultant to IHMA. BA, CAD, FS, KY, and MRM are employees of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA, and own stock in Merck & Co., Inc., Rahway, NJ, USA. The IHMA authors and JAK do not have personal financial interests in the sponsor of this manuscript (Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA). All authors provided analysis input and have read and approved the final manuscript., (Copyright © 2023 Elsevier Ltd and International Society of Antimicrobial Chemotherapy. All rights reserved.)

This study aimed to determine the prevalence of extended-spectrum β-lactamase (ESBL) non-carbapenem-resistant Enterobacterales (non-CRE) phenotype among clinical Escherichia coli and Klebsiella pneumoniae isolates collected in 2018-2019 for the SMART global surveillance programme and review trends in prevalence over 5 years (2015-2019). MICs were determined by CLSI reference broth microdilution. ESBL non-CRE phenotypes were defined as non-susceptible to ceftriaxone (MIC ≥ 2 μg/mL) and susceptible to ertapenem (MIC ≤ 0.5 μg/mL). In 2018-2019, ESBL non-CRE phenotypes among E. coli were more common in respiratory tract infection isolates than other infection sources across all global regions; for K. pneumoniae there was wide variation by geographic region in the specimen source most frequently associated with this phenotype. In most regions, ESBL non-CRE phenotype isolates were found more frequently in samples from ICU patients than non-ICU patients and from patients with hospital length of stay at time of specimen collection ≥48 h versus <48 h. ESBL non-CRE phenotypes exceeded 50% of isolates for E. coli from India, Thailand, Vietnam, China, Russia, Mexico, Kenya and Kuwait and for K. pneumoniae from Lithuania and Kuwait. ESBL non-CRE phenotype E. coli increased significantly (P < 0.05) in Asia (excluding China), Australia/New Zealand and Latin America from 2015-2019, while ESBL non-CRE phenotype K. pneumoniae increased significantly in Latin America, USA and Canada. There was marked variability in ESBL rates across countries, over time, and by sample source and ward type. Trending data from 2015-2019 showed ESBL rates are increasing in many regions worldwide., Competing Interests: Declaration of Competing Interest JAK is a consultant to IHMA and an employee of the University of Manitoba and Shared Health Manitoba; SHL and DFS work for IHMA, which receives funding from Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA, for the SMART global surveillance programme; CAD, FS, KY and MRM are employees of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA, and own stock and options in Merck & Co., Inc., Kenilworth, NJ, USA. The IHMA authors and JAK do not have personal financial interests in the sponsor of this paper (Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA)., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

β-lactam- and multi-drug-resistant (MDR) Gram-negative bacilli frequently cause lower respiratory tract infections (LRTIs) in patients housed in intensive care units (ICUs). Relebactam, a novel diazabicyclooctane inhibitor of Ambler class A and C β-lactamases, in combination with imipenem-cilastatin was approved by the US Food and Drug Administration in July 2019 for the treatment of adults with complicated intra-abdominal infections and complicated urinary tract infections. A phase III study of imipenem/relebactam for the treatment of patients with respiratory tract infections, including antimicrobial-resistant Gram-negative infections, has also been completed. The Clinical and Laboratory Standards Institute's broth microdilution methodology was used to determine minimum inhibitory concentrations against non-Proteeae Enterobacteriaceae (NPE) and Pseudomonas aeruginosa collected from ICU patients with LRTIs at 26 US hospitals in 2015-2017. Percent susceptibilities to imipenem/relebactam were 97.0%, 66.4% and 98.1%, respectively, for all NPE (n=1298), imipenem-non-susceptible NPE (n=113, of which 71% were Serratia marcescens) and MDR NPE (n=206), and 92.2%, 77.2% and 79.6%, respectively, for all P. aeruginosa (n=638), imipenem-non-susceptible P. aeruginosa (n=219) and MDR P. aeruginosa (n=225). Percent susceptibilities to imipenem/relebactam were 98.0-98.6% for cefepime-, ceftazidime- and piperacillin-tazobactam-non-susceptible NPE and 77.8-82.5% for cefepime-, ceftazidime- and piperacillin-tazobactam-non-susceptible P. aeruginosa. Generally, only slight variations in susceptibility were observed across US census regions. Imipenem/relebactam may provide a valuable therapeutic option for the treatment of ICU patients with LRTI caused by Gram-negative bacilli resistant to commonly used β-lactams, as it demonstrated potent in-vitro activity against the majority of tested β-lactam-non-susceptible and MDR Gram-negative bacilli from ICU patients with LRTIs in US hospitals., (Copyright © 2019 Elsevier B.V. and International Society of Chemotherapy. All rights reserved.)

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 β-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., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Cefiderocol (S-649266) is a parenteral siderophore cephalosporin in phase III of clinical development. In this study, we determined the in vitro susceptibility to cefiderocol and comparators of a 2015-2016 collection of 8954 clinical isolates of Gram-negative bacilli (GNB), provided by 100 clinical laboratories in North America and Europe, using the Clinical and Laboratory Standards Institute broth microdilution method. Iron-depleted cation-adjusted Mueller-Hinton broth was used to test cefiderocol. The concentration of cefiderocol inhibiting 90% of isolates (MIC 90 ) was 0.5 mg/L (North America; n=2470) and 1 mg/L (Europe; n=3,543) for Enterobacteriaceae, 0.5 mg/L (North America; n=619) and 0.5 mg/L (Europe; n=921) for Pseudomonas aeruginosa, 1 mg/L (North America; n=308) and 2 mg/L (Europe; n=664) for Acinetobacter spp., 0.5 mg/L (North America; n=165) and 0.25 mg/L (Europe; n=175) for Stenotrophomonas maltophilia, and 0.12 mg/L (North America; n=40) and 0.5 mg/L (Europe; n=49) for Burkholderia cepacia complex spp. Cefiderocol MICs were ≤4 mg/L for 99.9% (6005/6013) of Enterobacteriaceae, 99.9% (1539/1540) of P. aeruginosa, 96.4% (937/972) of Acinetobacter spp., 99.4% (338/340) of S. maltophilia, and 94.4% (84/89) of Burkholderia cepacia complex spp. isolates tested. Against meropenem-non-susceptible isolates, MICs to cefiderocol were ≤4 mg/L for 99.6% (245/246) of Enterobacteriaceae, 99.7% (394/395) of P. aeruginosa, 96.1% (540/562) of Acinetobacter spp., and 87.1% (27/31) of B. cepacia complex spp. We conclude that cefiderocol demonstrated potent in vitro activity (MIC ≤4 mg/L) against the majority (99.4%, 8903/8954) of clinical isolates of GNB in a recent (2015-2016), multi-continent collection, including carbapenem-non-susceptible isolates., (Copyright © 2019 The Authors. Published by Elsevier B.V. All rights reserved.)

Pseudomonas aeruginosa is a nosocomial and community-acquired pathogen associated with considerable patient morbidity and mortality. Multidrug resistance in P. aeruginosa is a concern owing to the limited therapeutic options available to treat infections due to this organism. In this study, rates of antimicrobial resistance of P. aeruginosa isolates collected by The Surveillance Network Database-USA (Eurofins Medinet, Chantilly, VA) from 1997 to 2009 were examined. The patient population and specimens were stratified according to patient setting and age as well as specimen source. Multidrug resistance was defined as resistance to three or more of the following antimicrobial agents: aztreonam; cefepime; ciprofloxacin; imipenem; gentamicin; and piperacillin/tazobactam (TZP). A total of 924740 P. aeruginosa isolates were examined in this study. Changes in resistance rates to individual antimicrobial agents were <5% for all agents except ciprofloxacin. There was a statistically significant decreasing rate of multidrug-resistant P. aeruginosa to four, five and six antimicrobial agents. For isolates resistant to imipenem, aztreonam and gentamicin, ciprofloxacin had the highest cross-resistance rates. The greatest coverage against P. aeruginosa was by the combination of TZP plus amikacin (94%) followed by aztreonam plus amikacin (90%). Pseudomonas aeruginosa resistance rates remained steady or minimally declined to all antimicrobials from 1997 to 2009. Amongst the β-lactams, TZP has the greatest activity against P. aeruginosa., (Copyright © 2011 Elsevier B.V. and the International Society of Chemotherapy. All rights reserved.)

Over the last 20 years, Canadian pneumococcal surveillance studies have documented a steady rise in macrolide resistance. In the current study, we probed the nature of associations between the emergence of macrolide-resistant Streptococcus pneumoniae in Canada and changes in macrolide (azithromycin, clarithromycin and erythromycin) prescription rates. Macrolide susceptibility testing data for respiratory tract isolates of S. pneumoniae (n=15109) were acquired from two published national Canadian surveillance databases, and dispensed outpatient macrolide prescription data were acquired from the proprietary Intercontinental Medical Statistics (IMS) Health Canada CompuScript database. Nationally, macrolide resistance increased from 3.7% in 1995 to 19.0% in 2005 (P=0.003) as the annual macrolide prescription rate increased from 106.7 to 123.2 prescriptions/1000 persons per year (P=0.003). From 1995 to 2005, azithromycin and clarithromycin prescriptions increased from 4.8 to 52.5 prescriptions/1000 persons per year (P<0.0001) and from 24.7 to 58.4 prescriptions/1000 persons per year (P=0.005), respectively, whilst erythromycin prescriptions decreased from 77.2 to 12.3 prescriptions/1000 persons per year (P<0.0001). By univariate regression analysis, increasing rates of azithromycin (R(2)=0.931; P<0.0001) and clarithromycin (R(2)=0.725; P=0.0009) prescriptions and a decreasing rate of erythromycin prescriptions (R(2)=-0.963; P<0.0001) were all associated with increasing macrolide resistance from 1995 to 2005. Multivariate regression analysis showed that a model including all three macrolide prescription rates provided the best fit to the trend of increasing macrolide resistance. When the data were analysed by provincial origin, no statistically significant associations were found between prescription rates of any macrolide and macrolide resistance rates by univariate and multivariate regression analyses. We conclude that increasing macrolide resistance among respiratory isolates of pneumococci in Canada from 1995 to 2005 was associated both with decreasing prescriptions for erythromycin and concurrent increases in prescriptions for azithromycin and clarithromycin (azithromycin>clarithromycin by univariate regression analysis). Resistance development is complex and factors other than macrolide use may also be associated with observed increases in macrolide resistance in Canada from 1995 to 2005.

The North American Urinary Tract Infection Collaborative Alliance (NAUTICA) study determined the antibiotic susceptibility to commonly used agents for urinary tract infections of outpatient Escherichia coli urinary isolates obtained from various geographic regions in the USA and Canada. NAUTICA involved 40 medical centres (30 from the USA and 10 from Canada). From April 2003 to June 2004 inclusive, each centre submitted up to 50 consecutive outpatient midstream urine isolates. All isolates were identified to species level by each laboratory's existing protocol. Susceptibility testing was determined using the Clinical and Laboratory Standards Institute (CLSI) microdilution method. Ampicillin (resistant>or=32 microg/mL), sulphamethoxazole/trimethoprim (SMX/TMP) (resistant>or=4 microg/mL), nitrofurantoin (resistant>or=128 microg/mL), ciprofloxacin (resistant>or=4 microg/mL) and levofloxacin (resistant>or=8 microg/mL) resistance breakpoints used were those published by the CLSI. Of the 1142 E. coli collected, 75.5% (862) were collected from the USA and 280 (24.5%) were from Canada. Patient demographics revealed a mean age of 48.1 years (range, 2 months to 99 years), with female patients representing 79.4% of patients and males representing 20.6%. Overall, resistance to ampicillin was 37.7%, followed by SMX/TMP (21.3%), nitrofurantoin (1.1%), ciprofloxacin (5.5%) and levofloxacin (5.1%). Resistance rates for all antimicrobials were higher in US medical centres compared with Canadian centres (P<0.05). Fluoroquinolone resistance was highest in patients>or=65 years of age (P<0.05). Resistance rates demonstrated considerable geographic variability both in the USA and Canada. This study reports higher rates of antibiotic resistance in US versus Canadian outpatient urinary isolates of E. coli and demonstrates the continuing evolution of resistance to antimicrobial agents.

Anidulafungin, an echinocandin, is in late stage development for the treatment of fungal infections. We investigated the activity of anidulafungin in combination with other antifungal agents (fluconazole, itraconazole, ketoconazole, amphotericin B and 5-fluorocytosine) against four isolates each of Candida albicans, Candida glabrata, Candida parapsilosis and Candida tropicalis, and two isolates of Candida krusei using a macrobroth chequerboard method with interactions evaluated by fractional inhibitory concentration indices (FICIs). Additive activity (FICI > 0.5 to 1) or indifference (FICI > 1 to < 4) was observed in 85 of 90 interactions of anidulafungin with another antifungal agent. Synergy with itraconazole (FICIor=4), a drug rarely used systemically, was noted for four strains of C. tropicalis. The combination of anidulafungin and amphotericin B demonstrated additive activity for each of the 18 isolates of Candida tested. These results suggest additional studies are warranted, for example in animal models, to evaluate further the potential of combination antifungal therapy with anidulafungin for Candida infections.

Prokaryotic efflux mechanisms can effectively increase the intrinsic resistance of bacteria by actively transporting antibiotics out of cells, thus reducing the effective concentration of these agents. The fluoroquinolones, similar to most other antimicrobial classes, are susceptible to efflux mechanisms, particularly in Gram-negative organisms, such as Pseudomonas aeruginosa. Resistant P. aeruginosa clones isolated after fluoroquinolone therapy frequently over express at least one of the multiple efflux pump mechanisms found in this organism. Gram-positive bacteria, such as Streptococcus pneumoniae, also possess efflux mechanisms, though their effect on fluoroquinolone resistance seems to be more limited and selective. In the future, efflux pump inhibitors may offer effective adjunctive therapy to antibiotics for the treatment of difficult infections by efflux mutants. In the meantime, appropriate antibiotic selection and optimal dosing strategies should aim to eradicate the causative pathogen before a resistant efflux mutant can emerge.

Bone infections, which can be acute or chronic, often require aggressive antibiotic therapy, whether treated at home or in the community. Surveillance programmes are essential tools in the monitoring of antimicrobial resistance and can act as a resource to maintain effective prescribing. The Surveillance Network (TSN), which collects organism and patient-specific data from a network of laboratories across the United States, was used to analyse susceptibility of common bacterial species isolated from bone infections during 2000-2002. Narrow-spectrum antimicrobials such as vancomycin, quinupristin-dalfopristin and linezolid demonstrated good activity against Staphylococcus aureus and streptococci, and were active against 100% of isolates. However, Gram-negative species were also commonly isolated from these sites of infection. Later-generation cephalosporins, represented by ceftriaxone, cefotaxime and cefepime, exhibited a broad spectrum of activity including Enterobacteriaceae, streptococci and methicillin-susceptible S. aureus, but they were not active against methicillin-resistant S. aureus (MRSA) and showed variable activity against Pseudomonas aeruginosa. Using ceftazidime as a marker for extended spectrum beta-lactamase (ESBL) expression, less than 3% of Escherichia coli or Klebsiella pneumoniae expressed this phenotype. Based on current in vitro activity, the third-generation cephalosporins provide broad-spectrum coverage useful for the empirical therapy of suspected bone infections, especially for patients treated in the community or hospitalised with community-acquired infections.

Susceptibility data for all organisms associated with a range of skin and soft tissue infections (SSTI) in hospitalised patients were studied. Data were reported by clinical laboratories in the USA, France, Germany, Italy and Spain during 2001 which participate in The Surveillance Network (TSN). Staphylococcus aureus, Enterococcus spp. and coagulase-negative staphylococci (CNS), Escherichia coli and Pseudomonas aeruginosa were the most prevalent pathogens in all countries. MRSA was detected in 44.4, 34.7, 12.4, 41.8 and 32. 4% of S. aureus in each country, respectively. The majority of MRSA were cross resistant to other compound classes tested except for vancomycin (100% susceptible) trimethoprim-sulphamethoxazole with range 1.7% (France) to 15.9% (Italy) resistant, and gentamicin with range 12.2% (France) to 87.0% (Italy) resistant. More than 99.0% of MSSA tested susceptible to ceftriaxone and >94.9% to trimethoprim-sulphamethoxazole. 87.2% (France) to 94.6% of MSSA (Germany) were ciprofloxacin susceptible; 73.2% (USA) to 86.6% (Spain) were erythromycin susceptible; 85.4% (Italy) to 99.2% (France) were gentamicin susceptible. MSSA were more frequently found and generally more antibiotic susceptible from out patients. Overall, 100% of Streptococcus agalactiae and Streptococcus pyogenes were susceptible to penicillin, ceftriaxone and cefotaxime. Macrolide resistance was common among S. agalactiae (20.7%, Germany to 10%, Italy and Spain), S. pyogenes (19.2%, France to 11.1%, USA) and viridans streptococci (25.7%, France to 14.1%, Germany). Vancomycin-resistant Enterococcus spp. were uncommon outside the USA (17.5%) and Italy (7.4%). For all countries susceptibility of E. coli was 100% to imipenem, >98.7% to amikacin, >96.0% to ceftriaxone and cefotaxime. Susceptibility of E. coli isolates to ciprofloxacin was 77.6% in Spain to 94.3% in Germany. Klebsiella spp., Proteus spp., Citrobacter spp. and Enterobacter spp. displayed varying susceptibilities between countries to drugs tested. Putative extended spectrum beta-lactamase expression in E. coli remained rare comprising 4-5% of isolates in USA, Italy and Spain and in France and Germany <2%. For P. aeruginosa piperacillin-tazobactam, amikacin, imipenem and ceftazidime were the most active compounds tested irrespective of region. Surveillance data should be considered when selecting empirical therapy for treating SSTI.

During 1999-2000, 5015 isolates were collected from 13 countries and tested against levofloxacin. Overall, levofloxacin resistance minimum inhibitory concentration (MIC>or =8 mg/l) was found in 40 isolates (0.8%). The highest resistance rates were in Hong Kong (8.0%), China (3.3%) and Spain (1.6%). Levofloxacin retained an MIC(90) of 1 mg/l in all countries. Pulsed-field gel electrophoresis analysis of resistant isolates demonstrated the presence of clones in countries where levofloxacin resistance exceeded 1%, suggesting that the elevated resistance rates could result from resistant clones within participating hospitals. DNA-sequence analysis of the quinolone-resistance-determining regions of gyrA, gyrB, parC and parE genes showed that the most common mutations were in GyrA (Ser81Phe), ParC (Ser79Phe, Lys137Asn) and ParE (Ile460Val), accounting for 40% of the isolates tested. Levofloxacin-resistant isolates were generally non-susceptible to other fluoroquinolones tested. Future studies to characterise resistant isolates by other molecular methods may ensure that the appropriate counter-measures can be taken to control the spread of resistant isolates.

Antimicrobial susceptibilities of clinical isolates of Streptococcus pneumoniae, Haemophilus influenzae, and Moraxella catarrhalis were determined in two consecutive respiratory seasons in the US and suggested that national susceptibilities to commonly tested antimicrobials changed only slightly from the 1999-2000 to the 2000-2001 respiratory season. However, a significant regional variation in S. pneumoniae susceptibilities was observed, as was a decrease in beta-lactamase rates among H. influenzae from the 1999-2000 to 2000-2001 respiratory seasons.

Ceftriaxone was introduced into clinical practice in the USA in 1985 and was the first extended-spectrum (third-generation) cephalosporin approved for once-daily treatment of patients with Gram-positive or Gram-negative infections. Review of ceftriaxone activity is important given its continued use since the mid-1980s and reports of emerging resistance among all antimicrobial agent classes. We reviewed the activity of ceftriaxone and relevant comparative agents against five Gram-positive and 11 Gram-negative species for a 5-year period, 1996-2000, using data from The Surveillance Network (TSN) Database-USA. All MIC results were interpreted using NCCLS breakpoint criteria. Ceftriaxone resistance among isolates of Streptococcus pneumoniae (n=17219) remained essentially unchanged over the 5 years studied and in fact was lower from 1998 to 2000 (5.0-5.1%) than in 1996 (6.3%) and 1997 (6.6%). Ceftriaxone resistance (range, 5.1-6.9%) among viridans group streptococci (n=6621) varied by <2% from 1997 to 2000. Beta-lactam-resistant Streptococcus pyogenes (n=935) and group B beta-haemolytic streptococci (n=2267) were not identified in any year. Among methicillin-susceptible Staphylococcus aureus (n=39 284) ceftriaxone resistance was 0.1-0.3% per year from 1996 to 2000. Ceftriaxone resistance among Escherichia coli (n=472407; range, 0.2-0.4%), Klebsiella oxytoca (n=16231; range, 3.5-4.8%), Klebsiella pneumoniae (n=117754; range, 1.9-2.6%), Proteus mirabilis (n=67692; range, 0.2-0.3%), Morganella morganii (n=11251; range, 0.3-2.1%) and Serratia marcescens (n=26519; range, 1.6-3.8%) was low and consistent from 1996 to 2000. Resistance to ceftriaxone among Enterobacter cloacae (n=48114; range, 21.7-23.9%) was relatively high, compared with other Enterobacteriaceae, but unchanged from 1996 to 2000. Rates of resistance to ceftriaxone among Acinetobacter spp. (n=20813) increased from 24.8% in 1996 to 45.1% in 2000. All Haemophilus influenzae (n=7911) and Neisseria gonorrhoeae (n=218) were susceptible to ceftriaxone, as were 99.7% of Moraxella catarrhalis (n=312) tested in 1996 and 1997. In summary, ceftriaxone has retained its potent activity against the most commonly encountered Gram-positive and Gram-negative human pathogens despite widespread and ongoing clinical use for more than 15 years.

Haemophilus influenzae (n=2791) and Moraxella catarrhalis (n=1249) isolated from patient specimens during 1999 were collected from 290 laboratories participating in a moxifloxacin surveillance study as part of the LIBRA Surveillance initiative. Isolates were tested for in vitro susceptibility to a panel of agents suitable for the treatment of respiratory tract infections. beta-Lactamase production was identified in 32.2% of H. influenzae and 94.2% of M. catarrhalis. These percentages differed by less than 1.5% from results of a study conducted in 1997-1998 and were similar to results from other recent US surveillance studies. Resistance among H. influenzae to trimethoprim-sulphamethoxazole increased considerably, from 2% in the 1997-1998 study (n=6588 H. influenzae) to 15.5% in the current study. One isolate of H. influenzae had an MIC of 8 mg/l to both levofloxacin and moxifloxacin; all other isolates had MICs of < or =0.5 mg/l and < or =0.25 mg/l, respectively. beta-Lactamase production was found to confer ampicillin resistance in nearly all isolates. For M. catarrhalis, beta-lactamase-negative isolates had MICs < or =0.12-0.25 mg/l for ampicillin and < or =0.03-0.12 mg/l for ceftriaxone. In contrast, beta-lactamase production resulted in MICs of < or = 0.12->16 mg/l for ampicillin and < or = 0.03-4 mg/l for ceftriaxone. All M. catarrhalis had MICs < or =0.12 mg/l for moxifloxacin and < or =1 mg/l for levofloxacin. In summary, antimicrobial susceptibilities and the prevalence of beta-lactamase production in H. influenzae and M. catarrhalis in the United States has remained essentially unchanged from 1997-1998 to 1999.

From January to May 2000, as part of the Tracking Resistance in the United States Today (TRUST) surveillance initiative, clinical isolates of Enterobacteriaceae (n=2519) and non-fermentative Gram-negatives (n=580) were prospectively collected from 26 hospital laboratories across the United States. Isolates were tested for susceptibility to three fluoroquinolones (ciprofloxacin, levofloxacin, gatifloxacin) and seven other agents. In addition, data for the same period were collected from The Surveillance Network (TSN) Database-USA, an electronic surveillance network that receives data from more than 200 laboratories in the US. Both surveillance methods produced similar results. Against isolates of Enterobacteriaceae, imipenem was the most active agent, followed by the fluoroquinolones; > or = 86.7% of isolates of all species of Enterobacteriaceae except Providencia spp. were susceptible to fluoroquinolones by TRUST and TSN surveillance. TRUST identified differences in susceptibility to the three fluoroquinolones of > or = 2% for Citrobacter spp., Enterobacter cloacae, Proteus mirabilis and Serratia marcescens. Isolates of P. mirabilis were considerably more susceptible to levofloxacin (94.0%) than to ciprofloxacin (87.7%) and gatifloxacin (87.7%). Other results from TRUST included Pseudomonas aeruginosa being slightly more susceptible to ciprofloxacin (73.5%) and levofloxacin (73.0%) than gatifloxacin (71.0%). Imipenem was the only compound with significant activity (95.1% susceptible, TRUST; 87.4% susceptible, TSN) against Acinetobacter baumannii, but it was inactive against Stenotrophomonas maltophilia. S. maltophilia isolates were more susceptible to levofloxacin and gatifloxacin (77.7-79.8%) than ciprofloxacin (29.7-33.0%). Against 513 urinary isolates of Escherichia coli in TRUST, levofloxacin, gatifloxacin and ciprofloxacin were equipotent. Age and gender had no clear effect on the activity of levofloxacin, ciprofloxacin or gatifloxacin. Similar results for all three fluoroquinolones were seen in outpatients and inpatients. TRUST and TSN data indicated that resistance rates had not changed appreciably for any compound studied since a similar study conducted in 1999. TRUST centralized in vitro and electronic (TSN) surveillance methods provided an effective strategy for monitoring trends in resistance.

In the United States, trimethoprim-sulphamethoxazole (TMP-SMX) is the recommended first-line treatment for uncomplicated urinary tract infections (UTIs) in females, in regions with resistance rates of <10-20%. Unfortunately, current data on regional resistance is often not readily available to physicians and regional variability in resistance remains largely unknown. This report presents antimicrobial susceptibility data for TMP-SMX and three other commonly tested antimicrobials organized by state and region to demonstrate current regional variability in resistance in the US. In the last quarter of 1999, 5739 fresh clinical isolates of Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis and Staphylococcus saprophyticus were collected from 202 laboratories throughout the US. Susceptibility testing was performed against TMP-SMX, cephalothin, nitrofurantoin and ciprofloxacin using broth microdilution. Data were analyzed by patient age and specimen source, and by state and region. In the US as a whole, resistance to TMP-SMX was 16.8% for E. coli, 7.8% for K. pneumoniae, 12.1% for P. mirabilis and 3.0% for S. saprophyticus, but these rates showed considerable regional variation. By state, E. coli resistance ranged from 7.4% in Pennsylvania to 33.3% in Iowa (among states with > or =50 isolates tested). Regionally, resistance for all uropathogens taken together ranged from 8.5% in East South-Central to 22.8% in West South-Central. Ciprofloxacin demonstrated the broadest activity of the antimicrobials tested and was more active than TMP-SMX against all pathogens. Resistance to TMP-SMX among E. coli now approaches or exceeds 20% in some areas. As resistance among uropathogens reaches clinically significant levels in many areas, continued regional surveillance is essential to ensure the provision of effective empiric therapy for urinary tract infections.