Antimicrobial-resistant Pseudomonas aeruginosa and Acinetobacter baumannii From Patients With Hospital-acquired or Ventilator-associated Pneumonia in Vietnam.

PURPOSE: Multidrug-resistant bacterial pathogens are becoming a significant problem worldwide. Acinetobacter baumannii and Pseudomonas aeruginosa are problematic multidrug-resistant pathogens. This multicenter study in Vietnam determined the level of resistance to antimicrobial agents used to treat A baumannii and P aeruginosa infections in this country. METHODS: Five medical centers in Vietnam provided 529 P aeruginosa and 971 Acinetobacter species (904 A baumannii) isolates from patients with hospital-acquired or ventilator-associated pneumonia from 2012 to 2014. A central laboratory verified identification of the isolates and performed susceptibility testing using Clinical and Laboratory Standards Institute methods. FINDINGS: Resistance to cephalosporins, ß-lactam/ß-lactamase inhibitors, carbapenems, and fluoroquinolones was >90% against A baumannii. Aminoglycosides had only slightly better activity, with amikacin resistance >80%. Only colistin (MIC90, ≤0.25 mg/L) and tigecycline (MIC90, 4 mg/L) had appreciable activity against A baumannii. Similar activity was observed among the ß-lactams tested against P aeruginosa. Cefepime demonstrated the highest activity (60.1% susceptible), which was similar to doripenem (58.6% susceptible), the most active carbapenem tested. Amikacin was the most active aminoglycoside tested against P aeruginosa, with susceptibility of 81.7% compared with tobramycin (58.0%) and gentamicin (56.5%). Fluoroquinolones had limited activity against P aeruginosa with susceptibility to ciprofloxacin (55.0%). All P aeruginosa isolates had colistin MIC values ≤2 mg/L. IMPLICATIONS: The data from this 3-year longitudinal study in Vietnam demonstrate that 2 of the most common nonfermentative gram-negative pathogens associated with hospital-acquired and ventilator-associated pneumonia are significantly resistant to most of the available treatment options and require combination therapies unless new antimicrobial agents become available.

Discrepancy between genotypic and phenotypic extended-spectrum ß-lactamase rates in Escherichia coli from intra-abdominal infections in the USA.

Varying rates of false-positive results of phenotypic extended-spectrum ß-lactamase (ESBL) tests have been reported for different methods in different settings, species and geographic locations. This report describes discrepancies in Escherichia coli genotypic and phenotypic ESBL rates observed in a surveillance study of 29 US hospitals that participated in the Study for Monitoring Antimicrobial Resistance Trends (SMART). The ESBL phenotype was determined with the Clinical and Laboratory Standards Institute confirmatory broth microdilution test using cefotaxime and ceftazidime with and without clavulanate. Genes encoding ESBLs, carbapenemases and plasmidic AmpC ß-lactamases were detected using a combination of microarray and multiplex PCR assays. Among 168 molecularly characterized phenotypically ESBL-positive E. coli isolates from intra-abdominal infections, 4.8 % were genotypically negative from 2009 to 2012 and 29.5 % in 2013. Because of the high rate of false-positive phenotypic ESBL results in 2013, the 5-year phenotypic ESBL trend was skewed and showed a statistically significant increase (P<0.05) in ESBL-positive E. coli in the USA, which was not seen using the genotypic ESBL rates. The majority of false-positive phenotypic profiles had ceftazidime MICs of 2 µg ml-1 and a ≥3 doubling dilution decrease in MIC for only one of the two antimicrobial agents. False-positive ESBL results can adversely impact epidemiological surveillance and patient care (including inappropriate treatment, unnecessary patient isolation and higher costs). Careful evaluation and comparison of phenotypic and genotypic test results can yield the greatest insight, but the most accurate (and faster) detection of ESBL producers is usually based on molecular data.

In vitro activity of Ceftaroline against bacterial pathogens isolated from patients with skin and soft tissue and respiratory tract infections in African and Middle Eastern countries: AWARE global surveillance program 2012-2014.

The objective of this report was to document antimicrobial susceptibility testing surveillance data for ceftaroline and comparative agents from the AWARE (Assessing Worldwide Antimicrobial Resistance Evaluation) global surveillance program for bacterial pathogens causing skin and soft tissue and respiratory tract infections in African and Middle Eastern countries from 2012 through 2014. Pathogen identities were confirmed by MALDI-TOF and antimicrobial susceptibility testing performed by CLSI broth microdilution methodology in a central laboratory. All methicillin-susceptible Staphylococcus aureus (MSSA) (n= 923; MIC90, 0.25 µg/mL) and 91.8% of methicillin-resistant S. aureus (MRSA) (n= 1161; MIC90, 1 µg/mL) tested were susceptible to ceftaroline. The maximum ceftaroline MIC observed for isolates of MRSA was 2 µg/mL. All Streptococcus pyogenes (n= 174; MIC90, 0.008 µg/mL), Streptococcus agalactiae (n= 44; MIC90, 0.015 µg/mL), Streptococcus pneumoniae (n= 351; MIC90, 0.25 µg/mL), and Haemophilus influenzae (n= 84; MIC90, ≤0.015 µg/mL) were susceptible to ceftaroline. Rates of susceptibility to ceftaroline among ESBL-negative Escherichia coli (n= 338), Klebsiella pneumoniae (n= 241), and Klebsiella oxytoca (n= 97) were 89.1% (MIC90, 1 µg/mL), 94.2% (MIC90, 0.5 µg/mL), and 99.0% (MIC90, 0.5 µg/mL), respectively.

In Vitro Activity of Oral Antimicrobial Agents against Pathogens Associated with Community-Acquired Upper Respiratory Tract and Urinary Tract Infections: A Five Country Surveillance Study.

INTRODUCTION: Bacterial infections that cause community-acquired urinary tract infections (CA-UTI) and upper respiratory tract infections (CA-URTI) are most frequently treated empirically. However, an increase in antimicrobial resistance has become a problem when treating outpatients. METHODS: This study determined the in vitro activities of oral antibiotics among 1501 pathogens from outpatients with CA-UTI and CA-URTI in medical centers during 2012 and 2013 from Argentina, Mexico, Venezuela, Russia, and the Philippines. Minimal inhibitory concentrations (MICs) were determined using broth microdilution and susceptibility defined by Clinical Laboratory Standards Institute (CLSI) and European Committee for Antimicrobial Susceptibility Testing (EUCAST) criteria. RESULTS: Ceftibuten (MIC50, ≤0.25 mg/L) was more potent in vitro compared to other ß-lactams against Enterobacteriaceae from CA-UTI. Susceptibility to fluoroquinolones using CLSI criteria varied: Argentina and Mexico (50%), the Philippines (60%), Venezuela (70%), and Russia (80%). Fosfomycin susceptibility was >90% against Enterobacteriaceae in each country. Susceptibility among Enterobacteriaceae to trimethoprim-sulfamethoxazole was 30.6-75.6% and nitrofurantoin susceptibility also varied among the countries and was higher when EUCAST breakpoints were applied (65->90%) compared to CLSI (52-84%). All Haemophilus influenzae isolates from CA-URTI were susceptible to ceftibuten, cefixime, cefpodoxime, and cefuroxime using CLSI breakpoint criteria. EUCAST criteria produced intermediate and resistant MIC values for these oral cephalosporins. Country-specific susceptibility variation for fluoroquinolones, macrolides, and trimethoprim-sulfamethoxazole was observed among Streptococcus pneumoniae and Streptococcus pyogenes from CA-URTI. CONCLUSION: This study demonstrated that antimicrobial susceptibility patterns varied in the five countries investigated among pathogens from CA-UTI and CA-URTI. FUNDING: Merck & Co. Inc., Kenilworth, New Jersey, USA.

Global Dissemination of blaKPC into Bacterial Species beyond Klebsiella pneumoniae and In Vitro Susceptibility to Ceftazidime-Avibactam and Aztreonam-Avibactam.

The Klebsiella pneumoniae carbapenemase (KPC), first described in the United States in 1996, is now a widespread global problem in several Gram-negative species. A worldwide surveillance study collected Gram-negative pathogens from 202 global sites in 40 countries during 2012 to 2014 and determined susceptibility to ß-lactams and other class agents by broth microdilution testing. Molecular mechanisms of ß-lactam resistance among carbapenem-nonsusceptible Enterobacteriaceae and Pseudomonas aeruginosa were determined using PCR and sequencing. Genes encoding KPC enzymes were found in 586 isolates from 22 countries (76 medical centers), including countries in the Asia-Pacific region (32 isolates), Europe (264 isolates), Latin America (210 isolates), and the Middle East (19 isolates, Israel only) and the United States (61 isolates). The majority of isolates were K. pneumoniae (83.4%); however, KPC was detected in 13 additional species. KPC-2 (69.6%) was more common than KPC-3 (29.5%), with regional variation observed. A novel KPC variant, KPC-18 (KPC-3[V8I]), was identified during the study. Few antimicrobial agents tested remained effective in vitro against KPC-producing isolates, with ceftazidime-avibactam (MIC90, 4 µg/ml), aztreonam-avibactam (MIC90, 0.5 µg/ml), and tigecycline (MIC90, 2 µg/ml) retaining the greatest activity against Enterobacteriaceae cocarrying KPC and other ß-lactamases, whereas colistin (MIC90, 2 µg/ml) demonstrated the greatest in vitro activity against KPC-positive P. aeruginosa This analysis of surveillance data demonstrated that KPC is widely disseminated. KPC was found in multiple species of Enterobacteriaceae and P. aeruginosa and has now become a global problem.

Assessment of the In Vitro Activity of Ceftazidime-Avibactam against Multidrug-Resistant Klebsiella spp. Collected in the INFORM Global Surveillance Study, 2012 to 2014.

Increasing resistance in Gram-negative bacilli, including Klebsiella spp., has reduced the utility of broad-spectrum cephalosporins. Avibactam, a novel non-ß-lactam ß-lactamase inhibitor, protects ß-lactams from hydrolysis by Gram-negative bacteria that produce extended-spectrum ß-lactamases (ESBLs) and serine carbapenemases, including Ambler class A and/or class C and some class D enzymes. In this analysis, we report the in vitro activity of ceftazidime-avibactam and comparators against multidrug-resistant (MDR) Klebsiella spp. from the 2012-2014 INFORM surveillance study. Isolates collected from 176 sites were sent to a central laboratory for confirmatory identification and tested for susceptibility to ceftazidime-avibactam and comparator agents, including ceftazidime alone. A total of 2,821 of 10,998 (25.7%) Klebsiella species isolates were classified as MDR, based on resistance to three or more classes of antimicrobials. Among the MDR isolates, 99.4% had an ESBL screen-positive phenotype, and 27.4% were not susceptible to meropenem as an example of a carbapenem. Ceftazidime-avibactam was highly active against MDR isolates, including ESBL-positive and serine carbapenemase-producing isolates, with MIC50/90 values of 0.5/2 µg/ml and 96.6% of all MDR isolates and ESBL-positive MDR isolates inhibited at the FDA breakpoint (MIC value of ≤8 µg/ml). Ceftazidime-avibactam did not inhibit isolates producing class B enzymes (metallo-ß-lactamases) either alone or in combination with other enzymes. These in vitro results support the continued investigation of ceftazidime-avibactam for the treatment of MDR Klebsiella species infections.

Pathogen Prevalence and Antimicrobial Susceptibility Among Enterobacteriaceae Causing Hospital-associated Intra-abdominal Infections in Adults in the United States (2012-2013).

PURPOSE: Selection and prompt initiation of the appropriate empiric antimicrobial therapy are critical to decrease morbidity and mortality and shorten the length of hospitalization among patients with hospital-associated intra-abdominal infections (HA-IAIs). Therapeutic choices for the treatment of patients with HA-IAI require careful consideration. This study was conducted to evaluate the antimicrobial susceptibility of common pathogens collected from adult patients with HA-IAI in the United States. METHODS: Gram-negative bacilli (N = 1285) were collected during 2012-2013 from SMART (Study for Monitoring Antimicrobial Resistance Trends). Isolates were tested at a central laboratory by using Clinical and Laboratory Standards Institute methods and interpretation of susceptibility to 12 antimicrobial agents. FINDINGS: Most of the isolates (80.8%) were Enterobacteriaceae, and Escherichia coli was the most common species. Susceptibility to frequently used antimicrobial agents for treating IAI showed that ertapenem, imipenem, and amikacin were more active than other agents against Enterobacteriaceae, including multidrug-resistant isolates. More than 92% of E coli, including extended-spectrum ß-lactamase (ESBL) producers, and Klebsiella pneumoniae isolates were susceptible to ertapenem, imipenem, and amikacin. Cefepime was the most active (>90% susceptibility) cephalosporin against all species except K pneumoniae (86.6%) but with much reduced activity against isolates with ESBLs. Piperacillin/tazobactam had reduced activity against Enterobacter species (70.4%-76.4% susceptible) and ESBL-producing K pneumoniae (22.5% susceptible). Fluoroquinolones exhibited poor activity against E coli (overall susceptibility <70%). IMPLICATIONS: Proper empiric antimicrobial treatment, including combining appropriate agents, of HA-IAI requires detailed understanding of the epidemiology of common pathogens and antimicrobial resistance patterns. In light of rising rates of antimicrobial resistance, ongoing surveillance is critical for clinical decision-making.

Activity of Ceftazidime-Avibactam against Extended-Spectrum- and AmpC ß-Lactamase-Producing Enterobacteriaceae Collected in the INFORM Global Surveillance Study from 2012 to 2014.

The in vitro activity of ceftazidime-avibactam was evaluated against 34,062 isolates of Enterobacteriaceae from patients with intra-abdominal, urinary tract, skin and soft-tissue, lower respiratory tract, and blood infections collected in the INFORM (International Network For Optimal Resistance Monitoring) global surveillance study (176 medical center laboratories in 39 countries) in 2012 to 2014. Overall, 99.5% of Enterobacteriaceae isolates were susceptible to ceftazidime-avibactam using FDA approved breakpoints (susceptible MIC of ≤8 µg/ml; resistant MIC of ≥16 µg/ml). For individual species of the Enterobacteriaceae, the ceftazidime-avibactam MIC inhibiting ≥90% of isolates (MIC90) ranged from 0.06 µg/ml for Proteus species to 1 µg/ml for Enterobacter spp. and Klebsiella pneumoniae Carbapenem-susceptible isolates of Escherichia coli, K. pneumoniae, Klebsiella oxytoca, and Proteus mirabilis with a confirmed extended-spectrum ß-lactamase (ESBL) phenotype, or a ceftazidime MIC of ≥16 µg/ml if the ESBL phenotype was not confirmed by clavulanic acid inhibition, were characterized further to identify the presence of specific ESBL- and plasmid-mediated AmpC ß-lactamase genes using a microarray-based assay and additional PCR assays. Ceftazidime-avibactam demonstrated potent activity against molecularly confirmed ESBL-producing (n = 5,354; MIC90, 0.5 µg/ml; 99.9% susceptible), plasmid-mediated AmpC-producing (n = 246; MIC90, 0.5 µg/ml; 100% susceptible), and ESBL- and AmpC-producing (n = 152; MIC90, 1 µg/ml; 100% susceptible) isolates of E. coli, K. pneumoniae, K. oxytoca, and P. mirabilis We conclude that ceftazidime-avibactam demonstrates potent in vitro activity against globally collected clinical isolates of Enterobacteriaceae, including isolates producing ESBLs and AmpC ß-lactamases.

In Vitro Susceptibility to Ceftazidime-Avibactam of Carbapenem-Nonsusceptible Enterobacteriaceae Isolates Collected during the INFORM Global Surveillance Study (2012 to 2014).

The activity of ceftazidime-avibactam was assessed against 961 isolates of meropenem-nonsusceptible Enterobacteriaceae Most meropenem-nonsusceptible metallo-ß-lactamase (MBL)-negative isolates (97.7%) were susceptible to ceftazidime-avibactam. Isolates that carried KPC or OXA-48-like ß-lactamases, both alone and in combination with extended-spectrum ß-lactamases (ESBLs) and/or AmpC ß-lactamases, were 98.7% and 98.5% susceptible to ceftazidime-avibactam, respectively. Meropenem-nonsusceptible, carbapenemase-negative isolates demonstrated 94.7% susceptibility to ceftazidime-avibactam. Ceftazidime-avibactam activity was compromised only in isolates for which carbapenem resistance was mediated through metallo-ß-lactamases.

In Vitro Activity of Ceftaroline against Staphylococcus aureus Isolated in 2012 from Asia-Pacific Countries as Part of the AWARE Surveillance Program.

Ceftaroline, the active metabolite of the prodrug ceftaroline-fosamil, is an advanced-generation cephalosporin with activity against methicillin-resistant Staphylococcus aureus (MRSA). This investigation provides in vitro susceptibility data for ceftaroline against 1,971 S. aureus isolates collected in 2012 from seven countries (26 centers) in the Asia-Pacific region as part of the Assessing Worldwide Antimicrobial Resistance and Evaluation (AWARE) program. Broth microdilution as recommended by the CLSI was used to determine susceptibility. In all, 62% of the isolates studied were MRSA, and the ceftaroline MIC90 for all S. aureus isolates was 2 µg/ml (interpretive criteria: susceptible, ≤1 µg/ml). The overall ceftaroline susceptibility rate for S. aureus was 86.9%, with 100% of methicillin-sensitive S. aureus isolates and 78.8% of MRSA isolates susceptible to this agent. The highest percentages of ceftaroline-nonsusceptible MRSA isolates came from China (47.6%), all of which showed intermediate susceptibility, and Thailand (37.1%), where over half (52.8%) of isolates were resistant to ceftaroline (MIC, 4 µg/ml). Thirty-eight ceftaroline-nonsusceptible isolates (MIC values of 2 to 4 µg/ml) were selected for molecular characterization. Among the isolates analyzed, sequence type 5 (ST-5) was the most common sequence type encountered; however, all isolates analyzed from Thailand were ST-228. Penicillin-binding protein 2a (PBP2a) substitution patterns varied by country, but all isolates from Thailand had the Glu239Lys substitution, and 12 of these also carried an additional Glu447Lys substitution. Ceftaroline-fosamil is a useful addition to the antimicrobial agents that can be used to treat S. aureus infections. However, with the capability of this species to develop resistance to new agents, it is important to recognize and monitor regional differences in trends as they emerge.

In vitro activity of ceftaroline against bacterial pathogens isolated from skin and soft tissue infections in Europe, Russia and Turkey in 2012: results from the Assessing Worldwide Antimicrobial Resistance Evaluation (AWARE) surveillance programme.

OBJECTIVES: The objective of this study was to analyse antimicrobial susceptibility testing data generated by the Assessing Worldwide Antimicrobial Resistance Evaluation (AWARE) global surveillance programme for pathogens causing skin and soft tissue infections (SSTIs) in European countries in 2012. METHODS: Confirmation of pathogen identity by MALDI-TOF and antimicrobial susceptibility testing following the CLSI broth microdilution method were performed by a central laboratory. RESULTS: Using CLSI breakpoint criteria, ceftaroline was active against MSSA (n = 1116; MIC90, 0.25 mg/L; 99.8% susceptible), MRSA (n = 1467; MIC90, 1 mg/L; 92.2% susceptible) and Streptococcus pyogenes (n = 312; MIC90, 0.008 mg/L; 100% susceptible). By CLSI interpretative criteria, two S. aureus isolates (2/2583, 0.08%) were ceftaroline resistant (MIC, ≥4 mg/L) and 114 isolates (114/2583, 4.4%) were ceftaroline intermediate (2 mg/L). By EUCAST interpretative criteria (MIC, >1 mg/L), 4.5% (116/2583) of S. aureus isolates were ceftaroline resistant. Most ceftaroline-non-susceptible isolates (81.0%, 94/116) were from Russia, Turkey, Italy and Hungary. Ceftaroline susceptibility was equal to or exceeded 99% for S. aureus isolates submitted by 7 of 17 countries. Against Escherichia coli (n = 349), Klebsiella pneumoniae (n = 215), Klebsiella oxytoca (n = 74) and Proteus mirabilis (n = 121), ceftaroline activity was dependent upon ESBL production. For ESBL-negative E. coli, K. pneumoniae, K. oxytoca and P. mirabilis, 87.5% (MIC90, 1 mg/L), 92.3% (MIC90, 0.5 mg/L), 93.2% (MIC90, 0.5 mg/L) and 85.1% (MIC90, 2 mg/L) of isolates were susceptible to ceftaroline, respectively. CONCLUSIONS: Ceftaroline demonstrated potent in vitro activity against a contemporary collection of bacterial pathogens from patients with SSTIs in European countries, Russia and Turkey. Surveillance programmes such as AWARE are essential to global efforts to improve antimicrobial stewardship.

Multiyear, Multinational Survey of the Incidence and Global Distribution of Metallo-ß-Lactamase-Producing Enterobacteriaceae and Pseudomonas aeruginosa.

Metallo-ß-lactamases (MBLs) hydrolyze all classes of ß-lactams except monobactams and are not inhibited by classic serine ß-lactamase inhibitors. Gram-negative pathogens isolated from patient infections were collected from 202 medical centers in 40 countries as part of a global surveillance study from 2012 to 2014. Carbapenem-nonsusceptible Enterobacteriaceae and Pseudomonas aeruginosa were characterized for bla genes encoding VIM, IMP, NDM, SPM, and GIM variants using PCR and sequencing. A total of 471 MBL-positive isolates included the following species (numbers of isolates are in parentheses): P. aeruginosa (308), Klebsiella spp. (85), Enterobacter spp. (39), Proteeae (16), Citrobacter freundii (12), Escherichia coli (6), and Serratia marcescens (5) and were submitted by sites from 34 countries. Of these, 69.6% were collected in 9 countries (numbers of isolates are in parentheses): Russia (72), Greece (61), Philippines (54), Venezuela (29), and Kuwait, Nigeria, Romania, South Africa, and Thailand (20 to 25 isolates each). Thirty-two different MBL variants were detected (14 VIM, 14 IMP, and 4 NDM enzymes). Seven novel MBL variants were encountered in the study, each differing from a previously reported variant by one amino acid substitution: VIM-42 (VIM-1 [V223I]), VIM-43 (VIM-4 [A24V]), VIM-44 (VIM-2 [K257N]), VIM-45 (VIM-2 [T35I]), IMP-48 (IMP-14 [I69T]), IMP-49 (IMP-18 [V49F]), and NDM-16 (NDM-1 [R264H]). The in vitro activities of all tested antibiotics against MBL-positive Enterobacteriaceae were significantly reduced with the exception of that of aztreonam-avibactam (MIC90, 0.5 to 1 µg/ml), whereas colistin was the most effective agent against MBL-positive P. aeruginosa isolates (>97% susceptible). Although the global percentage of isolates encoding MBLs remains relatively low, their detection in 12 species, 34 countries, and all regions participating in this surveillance study is concerning.

Correlation of ß-Lactamase Production and Colistin Resistance among Enterobacteriaceae Isolates from a Global Surveillance Program.

The increasing use of carbapenems for treating multidrug-resistant (MDR) Gram-negative bacterial infections has contributed to the global dissemination of carbapenem-resistant Enterobacteriaceae (CRE). Serine and metallo-ß-lactamases (MBLs) that hydrolyze carbapenems have become prevalent and endemic in some countries, necessitating the use of older classes of agents, such as colistin. A total of 19,719 isolates of Enterobacteriaceae (excluding Proteeae and Serratia spp., which have innate resistance to colistin) were collected from infected patients during 2012 and 2013 in a global surveillance program and tested for antimicrobial susceptibility using CLSI methods. Isolates of CRE were characterized for carbapenemases and extended-spectrum ß-lactamases (ESBLs) by PCR and sequencing. Using EUCAST breakpoints, the rate of colistin susceptibility was 98.4% overall, but it was reduced to 88.0% among 482 carbapenemase-positive isolates. Colistin susceptibility was higher among MBL-positive isolates (92.6%) than those positive for a KPC (87.9%) or OXA-48 (84.2%). Of the agents tested, only tigecycline (MIC90, 2 to 4 µg/ml) and aztreonam-avibactam (MIC90, 0.5 to 1 µg/ml) consistently tested with low MIC values against colistin-resistant, ESBL-positive, and carbapenemase-positive isolates. Among the 309 (1.6%) colistin-resistant isolates from 10 species collected in 38 countries, 58 carried a carbapenemase that included KPCs (38 isolates), MBLs (6 isolates), and OXA-48 (12 isolates). These isolates were distributed globally (16 countries), and 95% were Klebsiella pneumoniae. Thirty-nine (67.2%) isolates carried additional ESBL variants of CTX-M, SHV, and VEB. This sample of Enterobacteriaceae demonstrated a low prevalence of colistin resistance overall. However, the wide geographic dispersion of colistin resistance within diverse genus and species groups and the higher incidence observed among carbapenemase-producing MDR pathogens are concerning.

In vitro activity of oritavancin and comparator agents against staphylococci, streptococci and enterococci from clinical infections in Europe and North America, 2011-2014.

Oritavancin is a lipoglycopeptide that has been approved for the treatment of acute bacterial skin and skin-structure infections (ABSSSIs) caused by susceptible organisms. Oritavancin causes cell death by inhibiting cell wall synthesis as well as depolarising and permeabilising the cellular membrane of Gram-positive pathogens. The activities of oritavancin in comparison with vancomycin, daptomycin and linezolid were determined against a collection of over 11000 recent clinical Gram-positive isolates from patient infections (2011-2014), including skin and skin-structure infections. A total of 7253 Staphylococcus aureus, 839 coagulase-negative staphylococci (CoNS), 1464 enterococci and 1637 ß-haemolytic streptococci (ßHS) were collected from the USA and Europe. Minimum inhibitory concentrations (MICs) were determined using Clinical and Laboratory Standards Institute (CLSI) broth microdilution methods, and susceptibility was determined using CLSI and US Food and Drug Administration (FDA) (for oritavancin) breakpoint criteria. Equivalent in vitro activity (MIC50/90, 0.015-0.03/0.06 µg/mL) was observed for oritavancin against meticillin-resistant S. aureus (MRSA), meticillin-susceptible S. aureus (MSSA) and Enterococcus faecalis in both regions. Slightly higher oritavancin MICs were obtained against CoNS, Streptococcus agalactiae, Enterococcus faecium (MIC90, 0.12 µg/mL) and against other ßHS (MIC90, 0.25 µg/mL). Oritavancin demonstrated comparatively lower MICs than daptomycin and vancomycin when tested against multidrug-resistant S. aureus, vancomycin-resistant enterococci and erythromycin-resistant ßHS. Oritavancin exhibited potent in vitro activity against the most common pathogens associated with ABSSSIs in the USA and Europe.

In Vitro Activity of Ceftaroline against Staphylococcus aureus Isolates Collected in 2012 from Latin American Countries as Part of the AWARE Surveillance Program.

The in vitro activities of ceftaroline and comparators, using broth microdilution, were determined against 1,066 Staphylococcus aureus isolates from hospitalized patients. Seventeen medical centers from Latin American countries contributed isolates. Methicillin-resistant S. aureus (MRSA) percentages ranged from 46% (Brazil) to 62% (Argentina). All methicillin-susceptible S. aureus (MSSA) isolates were susceptible to ceftaroline. Ceftaroline activity against MRSA varied with MIC90s of 0.5 (Venezuela) to 2 (Brazil, Chile, and Colombia) µg/ml, which was the highest MIC value. ST-5 was the most common sequence type.

In Vitro Activity of AZD0914, a Novel Bacterial DNA Gyrase/Topoisomerase IV Inhibitor, against Clinically Relevant Gram-Positive and Fastidious Gram-Negative Pathogens.

AZD0914, a new spiropyrimidinetrione bacterial DNA gyrase inhibitor with a novel mode of inhibition, has activity against bacterial species commonly cultured from patient infection specimens, including fluoroquinolone-resistant isolates. This study assessed the in vitro activity of AZD0914 against key Gram-positive and fastidious Gram-negative clinical isolates collected globally in 2013. AZD0914 demonstrated potent activity, with MIC90s for AZD0914 of 0.25 mg/liter against Staphylococcus aureus (n = 11,680), coagulase-negative staphylococci (n = 1,923), streptococci (n = 4,380), and Moraxella catarrhalis (n = 145), 0.5 mg/liter against Staphylococcus lugdunensis (n = 120) and Haemophilus influenzae (n = 352), 1 mg/liter against Enterococcus faecalis (n = 1,241), and 2 mg/liter against Haemophilus parainfluenzae (n = 70). The activity against Enterococcus faecium was more limited (MIC90, 8 mg/liter). The spectrum and potency of AZD0914 included fluoroquinolone-resistant isolates in each species group, including methicillin-resistant staphylococci, penicillin-resistant streptococci, vancomycin-resistant enterococci, ß-lactamase-producing Haemophilus spp., and M. catarrhalis. Based on these in vitro findings, AZD0914 warrants further investigation for its utility against a variety of Gram-positive and fastidious Gram-negative bacterial species.

In vitro activity of aztreonam-avibactam against a global collection of Gram-negative pathogens from 2012 and 2013.

The combination of aztreonam plus avibactam is being developed for use in infections caused by metallo-ß-lactamase-producing Enterobacteriaceae strains that also produce serine ß-lactamases. The in vitro activities of aztreonam-avibactam and comparator antimicrobials were determined against year 2012 and 2013 clinical isolates of Enterobacteriaceae, Pseudomonas aeruginosa, and Acinetobacter baumannii using the broth microdilution methodology recommended by the Clinical and Laboratory Standards Institute (CLSI). A total of 28,501 unique clinical isolates were obtained from patients in 190 medical centers within 39 countries. MIC90 values of aztreonam and aztreonam-avibactam against all collected isolates of Enterobacteriaceae (n = 23,516) were 64 and 0.12 µg/ml, respectively, with 76.2% of the isolates inhibited by ≤4 µg/ml of aztreonam (the CLSI breakpoint) and 99.9% of the isolates inhibited by ≤4 µg/ml of aztreonam-avibactam using a fixed concentration of 4 µg/ml of avibactam. The MIC90 was 32 µg/ml for both aztreonam and aztreonam-avibactam against P. aeruginosa (n = 3,766). Aztreonam alone or in combination with avibactam had no in vitro activity against isolates of A. baumannii. PCR and sequencing were used to characterize 5,076 isolates for ß-lactamase genes. Aztreonam was not active against most Enterobacteriaceae isolates producing class A or class C enzymes alone or in combination with class B metallo-ß-lactamases. In contrast, >99% of Enterobacteriaceae isolates producing all observed Ambler classes of ß-lactamase enzymes were inhibited by ≤4 µg/ml aztreonam in combination with avibactam, including isolates that produced IMP-, VIM-, and NDM-type metallo-ß-lactamases in combination with multiple serine ß-lactamases.

Resistance Rates of Intra-Abdominal Isolates from Intensive Care Units and Non-Intensive Care Units in the United States: The Study for Monitoring Antimicrobial Resistance Trends 2010-2012.

BACKGROUND: Enterobacteriaceae (3,235 isolates), Pseudomonas aeruginosa (476 isolates), and Acinetobacter baumannii (106 isolates) from inpatient intra-abdominal infections (IAIs) were collected for the 2010-2012 Study for Monitoring Antimicrobial Resistance Trends (SMART) program in the United States. This report evaluates the in vitro activity of several antimicrobial agents recommended for treatment of IAIs and compares profiles of isolates from intensive care units (ICUs) and non-intensive care units (non-ICUs). METHODS: Gram-negative bacilli from hospitalized patients with IAIs were obtained each year from 2010-2012 from hospitals in the United States and tested for susceptibility to 12 antibiotics according to 2012 Clinical and Laboratory Standards Institute (CLSI) guidelines. RESULTS: The most active agents against members of the Enterobacteriaceae family from both ICUs and non-ICUs were amikacin, ertapenem, and imipenem-cilastatin, whereas the least active agent was ampicillin-sulbactam. Amikacin was the only agent with good activity against P. aeruginosa, whereas none of the agents tested exhibited substantial activity against A. baumannii. Amikacin, ceftazidime, ceftriaxone, ciprofloxacin, levofloxacin, and imipenem-cilastatin were significantly less active against Enterobacteriaceae from ICU patients, whereas cefepime and ceftazidime were significantly less active against P. aeruginosa from ICU patients. Intensive care unit isolates were more likely to be multi-drug-resistant than non-ICU isolates, although there was no difference in extended-spectrum ß-lactamase (ESBL) production rates between the two patient groups. CONCLUSIONS: Despite increasing resistance trends, in this study amikacin, ertapenem, and imipenem-cilastatin were shown to have good in vitro activity against the most frequently isolated gram-negative bacilli from IAIs in ICU and non-ICU settings.

Trends in susceptibility of Escherichia coli from intra-abdominal infections to ertapenem and comparators in the United States according to data from the SMART program, 2009 to 2013.

Antimicrobial resistance in Enterobacteriaceae, including resistance to carbapenems, is increasing worldwide. However, using U.S. Study for Monitoring Antimicrobial Resistance Trends (SMART) data for 2009 to 2013, no statistically significant decreasing susceptibility trends were found overall for Escherichia coli isolates from patients with intra-abdominal infections. In the subset of isolates from community-associated infections, susceptibility to levofloxacin decreased significantly and the increasing rate of multidrug-resistant E. coli approached statistical significance. In 2013, ertapenem, imipenem, and amikacin showed the highest susceptibility rates (≥99%) and fluoroquinolones the lowest (<70%). The 10 non-ertapenem-susceptible isolates (0.3% of all E. coli isolates) encoded one or more carbapenemases, extended-spectrum ß-lactamases (ESBLs), AmpC ß-lactamases, or non-ESBL ß-lactamases.