Activity of Plazomicin Tested against Enterobacterales Isolates Collected from U.S. Hospitals in 2016-2017: Effect of Different Breakpoint Criteria on Susceptibility Rates among Aminoglycosides.

Plazomicin was active against 97.0% of 8,783 Enterobacterales isolates collected in the United States (2016 and 2017), and only 6 isolates carried 16S rRNA methyltransferases conferring resistance to virtually all aminoglycosides. Plazomicin (89.2% to 95.9% susceptible) displayed greater activity than amikacin (72.5% to 78.6%), gentamicin (30.4% to 45.9%), and tobramycin (7.8% to 22.4%) against carbapenem-resistant and extensively drug-resistant isolates. The discrepancies among the susceptibility rates for these agents was greater when applying breakpoints generated using the same stringent contemporary methods applied to determine plazomicin breakpoints.

Polymyxin Susceptibility Testing and Interpretive Breakpoints: Recommendations from the United States Committee on Antimicrobial Susceptibility Testing (USCAST).

The polymyxins are important agents for carbapenem-resistant Gram-negative bacilli. The United States Committee on Antimicrobial Susceptibility Testing breakpoint recommendations for colistin and polymyxin B are that isolates of Pseudomonas aeruginosa, Acinetobacter baumannii, and Enterobacteriaceae are considered susceptible at MIC values of ≤2 mg/liter. These recommendations are contingent upon dosing and testing strategies that are described in this commentary. Importantly, these recommendations are not applicable to lower respiratory tract infections, for which we recommend no breakpoints. Furthermore, there is no breakpoint recommendation for polymyxin B for lower urinary tract infections.

The Infectious Diseases Society of America's 10 × '20 Initiative (10 New Systemic Antibacterial Agents US Food and Drug Administration Approved by 2020): Is 20 × '20 a Possibility?

BACKGROUND: Infections caused by antibiotic-resistant bacteria, including carbapenem-resistant Enterobacteriaceae, have increased in frequency, resulting in significant patient morbidity and mortality. The Infectious Diseases Society of America continues to propose legislative, regulatory, and funding solutions to address this escalating crisis. This report updates the status of development and approval of systemic antibiotics in the United States as of late 2018. METHODS: We performed a review of the published literature and on-line clinical trials registry at www.clinicaltrials.gov to identify new systemically acting orally and/or intravenously administered antibiotic drug candidates in the development pipeline, as well as agents approved by the US Food and Drug Administration since 2012. RESULTS: Since our 2013 pipeline status report, the number of new antibiotics annually approved for marketing in the United States has reversed its previous decline, likely influenced by new financial incentives and increased regulatory flexibility. Although our survey demonstrates progress in development of new antibacterial drugs that target infections caused by resistant bacterial pathogens, the majority of recently approved agents have been modifications of existing chemical classes of antibiotics, rather than new chemical classes. Furthermore, larger pharmaceutical companies continue to abandon the field, and smaller companies face financial difficulties as a consequence. CONCLUSIONS: Unfortunately, if 20 × '20 is achieved due to efforts embarked upon in decades past, it could mark the apex of antibiotic drug development for years to come. Without increased regulatory, governmental, industry, and scientific support and collaboration, durable solutions to the clinical, regulatory, and economic problems posed by bacterial multidrug resistance will not be found.

The Microbiology of Bloodstream Infection: 20-Year Trends from the SENTRY Antimicrobial Surveillance Program.

Bloodstream infection (BSI) organisms were consecutively collected from >200 medical centers in 45 nations between 1997 and 2016. Species identification and susceptibility testing followed Clinical and Laboratory Standards Institute broth microdilution methods at a central laboratory. Clinical data and isolates from 264,901 BSI episodes were collected. The most common pathogen overall was Staphylococcus aureus (20.7%), followed by Escherichia coli (20.5%), Klebsiella pneumoniae (7.7%), Pseudomonas aeruginosa (5.3%), and Enterococcus faecalis (5.2%). S. aureus was the most frequently isolated pathogen overall in the 1997-to-2004 period, but E. coli was the most common after 2005. Pathogen frequency varied by geographic region, hospital-onset or community-onset status, and patient age. The prevalence of S. aureus isolates resistant to oxacillin (ORSA) increased until 2005 to 2008 and then declined among hospital-onset and community-acquired BSI in all regions. The prevalence of vancomycin-resistant enterococci (VRE) was stable after 2012 (16.4% overall). Daptomycin resistance among S. aureus and enterococci (DRE) remained rare (<0.1%). In contrast, the prevalence of multidrug-resistant (MDR) Enterobacteriaceae increased from 6.2% in 1997 to 2000 to 15.8% in 2013 to 2016. MDR rates were highest among nonfermentative Gram-negative bacilli (GNB), and colistin was the only agent with predictable activity against Acinetobacter baumannii-Acinetobacter calcoaceticus complex (97% susceptible). In conclusion, S. aureus and E. coli were the predominant causes of BSI worldwide during this 20-year surveillance period. Important resistant phenotypes among Gram-positive pathogens (MRSA, VRE, or DRE) were stable or declining, whereas the prevalence of MDR-GNB increased continuously during the monitored period. MDR-GNB represent the greatest therapeutic challenge among common bacterial BSI pathogens.

Dilution Factor of Quantitative Bacterial Cultures Obtained by Bronchoalveolar Lavage in Patients with Ventilator-Associated Bacterial Pneumonia.

Ventilator-associated bacterial pneumonia (VABP) is a difficult therapeutic problem. Considerable controversy exists regarding the optimal chemotherapy for this entity. The recent guidelines of the Infectious Diseases Society of America and the American Thoracic Society recommend a 7-day therapeutic course for VABP based on the balance of no negative impact on all-cause mortality, less resistance emergence, and fewer antibiotic treatment days, counterbalanced with a higher relapse rate for patients whose pathogen is a nonfermenter. The bacterial burden causing an infection has a substantial impact on treatment outcome and resistance selection. We describe the baseline bronchoalveolar lavage (BAL) fluid burden of organisms in suspected VABP patients screened for inclusion in a clinical trial. We measured the urea concentrations in plasma and BAL fluid to provide an index of the dilution of the bacterial and drug concentrations in the lung epithelial lining fluid introduced by the BAL procedure. We were then able to calculate the true bacterial burden as the diluted colony count times the dilution factor. The median dilution factor was 28.7, with the interquartile range (IQR) being 11.9 to 53.2. Median dilution factor-corrected colony counts were 6.18 log10(CFU/ml) [IQR, 5.43 to 6.46 log10(CFU/ml)]. In a subset of patients, repeat BAL on day 5 showed a good stability of the dilution factor. We previously showed that large bacterial burdens reduce or stop bacterial killing by granulocytes. (This study has been registered at ClinicalTrials.gov under registration no. NCT01570192.).

Assessment of 30/20-Microgram Disk Content versus MIC Results for Ceftazidime-Avibactam Tested against Enterobacteriaceae and Pseudomonas aeruginosa.

We evaluated the correlation between MIC and disk diffusion inhibition zones when testing ceftazidime-avibactam, using the 30/20-µg disk and the disk diffusion and MIC breakpoints established by the U.S. FDA and the Clinical and Laboratory Standards Institute (CLSI). Organisms used included 2 groups of Enterobacteriaceae isolates and 2 groups of Pseudomonas aeruginosa isolates; 1 group of each consisted of randomly selected isolates and the second group consisted of a challenge group from thousands of surveillance isolates with an increased proportion of organisms displaying ceftazidime-avibactam MIC values close to the breakpoints. Broth microdilution, disk diffusion tests, and data analysis were performed according to reference standardized methods. Ceftazidime-avibactam breakpoints of ≤8/4 (susceptible) and ≥16/4 µg/ml (resistant) for MIC and ≥21/≤20 mm for disk diffusion, as established by the U.S. FDA and the CLSI, were applied for Enterobacteriaceae and P. aeruginosa Ceftazidime-avibactam MIC and disk zone (30/20-µg disk) correlation were acceptable when testing Enterobacteriaceae (overall, very major [VM] and major [Ma] error rates of 0.4% and 0.0%, respectively) and nearly so when testing P. aeruginosa (2.3% VM and 2.9% Ma errors). In summary, disk diffusion and broth microdilution testing results demonstrated good categorical agreement for ceftazidime-avibactam against Enterobacteriaceae and P. aeruginosa, using 30/20-µg disks.

WCK 5222 (Cefepime-Zidebactam) Antimicrobial Activity against Clinical Isolates of Gram-Negative Bacteria Collected Worldwide in 2015.

WCK 5222 consists of cefepime combined with zidebactam, a bicyclo-acyl hydrazide ß-lactam enhancer antibiotic with a dual action involving binding to Gram-negative bacterial PBP2 and ß-lactamase inhibition. We evaluated the in vitro activity of cefepime-zidebactam against 7,876 contemporary (2015) clinical isolates of Enterobacteriaceae (n = 5,946), Pseudomonas aeruginosa (n = 1,291), and Acinetobacter spp. (n = 639) from the United States (n = 2,919), Europe (n = 3,004), the Asia-Pacific (n = 1,370), and Latin America (n = 583). The isolates were tested by a reference broth microdilution method for susceptibility against cefepime-zidebactam (1:1 and 2:1 ratios) and comparator agents. Cefepime-zidebactam was the most active compound tested against Enterobacteriaceae (MIC50/90, ≤0.03/0.12 µg/ml [1:1] and 0.06/0.25 µg/ml [2:1]; 99.9% of isolates were inhibited at ≤4 [1:1] and ≤8 µg/ml [2:1]). Cefepime-zidebactam was active against individual Enterobacteriaceae species (MIC50/90, ≤0.03 to 0.06/≤0.03 to 0.5 µg/ml [1:1]) and retained potent activity against carbapenem-resistant isolates (MIC50/90, 1/4 µg/ml; 99.3% of isolates were inhibited at ≤8 µg/ml [1:1]). Cefepime-zidebactam activity was consistent among geographic regions, and only one isolate showed MIC values of >8 µg/ml (1:1). Cefepime-zidebactam was also very active against P. aeruginosa with MIC50/90 values of 1/4 µg/ml, and 99.5% of isolates were inhibited at ≤8 µg/ml (1:1). The MIC values for cefepime-zidebactam at the 1:1 ratio were generally 2-fold lower than those for cefepime-zidebactam at the 2:1 ratio (MIC50/90, 2/8 µg/ml) and zidebactam alone (MIC50/90, 4/8 µg/ml). Against Acinetobacter spp., cefepime-zidebactam at 1:1 and 2:1 ratios (MIC50/90, 16/32 µg/ml for both) was 4-fold more active than cefepime or ceftazidime. Zidebactam exhibited potent in vitro antimicrobial activity against some organisms. These results support the clinical development of WCK 5222 for the treatment of Gram-negative bacterial infections, including those caused by multidrug-resistant isolates.

Antimicrobial Activity of High-Proportion Cefepime-Tazobactam (WCK 4282) against a Large Number of Gram-Negative Isolates Collected Worldwide in 2014.

Cefepime-tazobactam (WCK 4282) is currently under clinical development for use at a dosage of 2 g/2 g every 8 h. A total of 7,981 isolates were collected from 146 medical centers (39 countries) in 2014 as a part of the SENTRY Antimicrobial Surveillance Program, and their susceptibilities to cefepime-tazobactam (with tazobactam at fixed concentrations of 4 and 8 µg/ml) were tested by a reference broth microdilution method. Isolates were mainly from patients with pneumonia (29.5%) and bloodstream infections (26.9%). Cefepime-tazobactam (with tazobactam at a fixed concentration of 8 µg/ml) and cefepime inhibited 96.9 and 87.9% of Enterobacteriaceae strains at ≤8 µg/ml. The activity of cefepime-tazobactam against Enterobacteriaceae strains was comparable to that of meropenem (96.7% of isolates were susceptible) and greater than that of piperacillin-tazobactam (87.7% susceptible). All Enterobacteriaceae species from the United States except Klebsiella pneumoniae had >99.0% of isolates inhibited by cefepime-tazobactam at ≤8/8 µg/ml. The prevalence of the extended-spectrum ß-lactamase (ESBL)-screening-positive phenotype was the highest among Escherichia coli isolates in China (66.3%) and among K. pneumoniae isolates (58.0%) in Latin America. Cefepime-tazobactam at ≤8/8 µg/ml inhibited 98.7 and 71.3% of ESBL-screening-positive phenotype E. coli strains and K. pneumoniae strains, respectively. Meropenem showed limited activity against ESBL-screening-positive phenotype K. pneumoniae strains (69.6% susceptible). Cefepime-tazobactam was active against Enterobacter spp. (MIC50 and MIC90, 0.06 and 0.5 µg/ml, respectively), including ceftazidime-nonsusceptible isolates (96.1% of isolates were inhibited by cefepime-tazobactam at ≤8/8 µg/ml). The activity of cefepime-tazobactam against Pseudomonas aeruginosa (82.4 and 91.6% of isolates were inhibited by cefepime-tazobactam at ≤8/8 and ≤16/8 µg/ml, respectively) was comparable to that of meropenem and piperacillin-tazobactam (79.2% susceptible). In summary, cefepime-tazobactam was highly active against P. aeruginosa and Enterobacteriaceae strains, including ESBL-screening-positive phenotype E. coli strains and ceftazidime-nonsusceptible Enterobacter spp. These results support the further clinical development of the cefepime-tazobactam combination.

Determination of Disk Diffusion and MIC Quality Control Guidelines for High-Dose Cefepime-Tazobactam (WCK 4282), a Novel Antibacterial Combination Consisting of a ß-Lactamase Inhibitor and a Fourth-Generation Cephalosporin.

High-dose cefepime-tazobactam (1:1; WCK 4282), a novel antibacterial combination consisting of the ß-lactamase inhibitor tazobactam and a fourth-generation cephalosporin, is under clinical development for the treatment of serious Gram-negative infections. A quality control (QC) study was performed to establish disk diffusion and MIC ranges for cefepime-tazobactam for multiple QC reference strains. The cefepime-tazobactam QC ranges for a fixed tazobactam MIC of 8 µg/ml and disk diffusion (30/20-µg disk) test methods were approved by the CLSI Subcommittee on Antimicrobial Susceptibility Testing in January 2015 and January 2016. These QC ranges will be important for accurate in vitro activity evaluations of cefepime-tazobactam when tested against clinical Gram-negative bacteria during clinical studies and routine patient care.

WCK 5222 (cefepime/zidebactam) antimicrobial activity tested against Gram-negative organisms producing clinically relevant ß-lactamases.

Background: Zidebactam is a ß-lactam enhancer antibiotic with a dual mechanism of action involving binding to Gram-negative PBP2 and ß-lactamase inhibition. Cefepime combined with zidebactam (WCK 5222) is under clinical development for treatment of Gram-negative infections. Objectives: To evaluate the in vitro activities of cefepime and zidebactam separately and combined at 1:1 and 2:1 ratios when tested against Gram-negative organisms producing the most clinically relevant ß-lactamase types. Methods: ß-Lactamase-producing (193) and WT (71) isolates were tested for susceptibility by broth microdilution method against cefepime/zidebactam, cefepime and zidebactam. Results: Cefepime/zidebactam (1:1) was very active against Enterobacteriaceae producing CTX-M-15 (21; MIC 50/90 0.25/1 mg/L), SHV (20; MIC 50/90 0.12/0.25 mg/L), other ESBLs (20, including GES-18, OXA-1/30 and OXY-, PER-, TEM- and VEB-like; MIC 50/90 0.25/1 mg/L), plasmidic AmpC (10; MIC 50/90 ≤0.06/≤0.06 mg/L), derepressed AmpC (23; MIC 50/90 0.12/0.5 mg/L), KPC (35; MIC 50/90 0.25/1 mg/L) and metallo-ß-lactamases (MBLs; 20 including VIM, IMP and NDM; MIC 50/90 0.5/8 mg/L). Cefepime/zidebactam (1:1) was also active against Pseudomonas aeruginosa with overexpression of AmpC (21; MIC 50/90 4/8 mg/L) and MBLs [12 (VIM and IMP); MIC 50/90 4/8 mg/L]. Zidebactam alone exhibited potent in vitro activity against some Enterobacteriaceae and P. aeruginosa , including ß-lactamase-producing strains. Cefepime/zidebactam MIC values were lower than those of each agent tested alone for many ß-lactamase-producing strains, indicating synergy. Cefepime/zidebactam showed moderate activity against OXA-23/24/58-producing Acinetobacter baumannii [MIC 50/90 32 mg/L (1:1)]. Conclusions: Cefepime/zidebactam showed potent activities against Enterobacteriaceae and P. aeruginosa producing various clinically relevant ß-lactamases, including ESBLs, KPCs, AmpC and MBLs for which limited treatment options are currently available.

High Rates of Nonsusceptibility to Ceftazidime-avibactam and Identification of New Delhi Metallo-ß-lactamase Production in Enterobacteriaceae Bloodstream Infections at a Major Cancer Center.

Resistance to the novel ß-lactam/ß-lactamase inhibitor combination ceftazidime-avibactam (CAZ-AVI) among carbapenem-resistant Enterobacteriaceae (CRE) has infrequently been reported in the United States. We report unexpectedly high rates of resistance to CAZ-AVI in CRE bloodstream isolates at our institution associated with the nonoutbreak spread of New Delhi metallo-ß-lactamase in diverse Enterobacteriaceae species.

Dalbavancin Activity When Tested against Streptococcus pneumoniae Isolated in Medical Centers on Six Continents (2011 to 2014).

Dalbavancin, a novel lipoglycopeptide, was approved for use in 2014 by regulatory agencies in the United States and Europe for the treatment of skin and skin structure infections. The activity of dalbavancin was also widely assessed by determination of its activity against Streptococcus pneumoniae clinical isolates collected from patients on six continents monitored during two time intervals (2011 to 2013 and 2014). A total of 18,186 pneumococcal isolates were obtained from 49 nations and submitted to a monitoring laboratory as part of the SENTRY Antimicrobial Surveillance Program for reference susceptibility testing. The potency of dalbavancin against S. pneumoniae was consistent across the years that it was monitored, with the MIC50 and MIC90 being 0.015 and 0.03 µg/ml, respectively, and all isolates were inhibited by ≤0.12 µg/ml. The activity of dalbavancin was not adversely influenced by nonsusceptibility to ß-lactams (ceftriaxone or penicillin), macrolides, clindamycin, fluoroquinolones, or tetracyclines or multidrug resistance (MDR). Regional variations in dalbavancin activity were not detected, but S. pneumoniae strains isolated in the Asia-Pacific region were more likely to be nonsusceptible to penicillin and ceftriaxone as well as to be MDR than strains isolated in North or South America and Europe. Direct comparisons of potency illustrated that dalbavancin (MIC50 and MIC90, 0.015 and 0.03 µg/ml, respectively) was 16-fold or more active than vancomycin (MIC50, 0.25 µg/ml), linezolid (MIC50, 1 µg/ml), levofloxacin (MIC50, 1 µg/ml), ceftriaxone (MIC90, 1 µg/ml), and penicillin (MIC90, 2 µg/ml). In conclusion, dalbavancin had potent and consistent activity against this contemporary (2011 to 2014) collection of S. pneumoniae isolates.

Effect of the ß-Lactamase Inhibitor Vaborbactam Combined with Meropenem against Serine Carbapenemase-Producing Enterobacteriaceae.

Klebsiella pneumoniae carbapenemase (KPC)-producing isolates have become increasingly prevalent worldwide, and these organisms are often multidrug resistant, limiting the therapeutic options available for treating infections. We evaluated the activity of meropenem combined with the serine ß-lactamase inhibitor vaborbactam (formerly RPX7009) against 315 serine carbapenemase-producing Enterobacteriaceae (CPE) isolates by use of checkerboard-designed panels to assess the optimal inhibitor concentration (range tested, 0.5 to 32 µg/ml). Overall, meropenem alone (MIC50 and MIC90, 16 and >64 µg/ml, respectively) inhibited only 2.2% of the isolates at ≤1 µg/ml (the CLSI susceptibility breakpoint) and 7.3% of the isolates at ≤2 µg/ml (the EUCAST breakpoint). Vaborbactam restored meropenem activity for 72.7 to 98.1% of CPE isolates at ≤2 µg/ml, and maximum potentiation was achieved with fixed concentrations of ≥8 µg/ml of the inhibitor (≥96.5% of isolates were inhibited at ≤2 µg/ml of meropenem-vaborbactam). Meropenem-vaborbactam with a fixed concentration of 8 µg/ml of the inhibitor (MIC50, ≤0.06 µg/ml for all organisms) inhibited 93.7% of the CPE isolates displaying elevated meropenem MICs at ≤1 µg/ml. Meropenem-vaborbactam MICs were elevated for isolates producing metallo-ß-lactamases (MIC, 16 to >64 µg/ml) or displaying decreased expression of OmpK37 and/or elevated expression of the AcrAB-TolC efflux system (MIC, 16 µg/ml). Vaborbactam showed no antibacterial activity alone (all MICs, >64 µg/ml). Meropenem-vaborbactam appears to be a good candidate for further development and it could increase the options for treatment of serious infections caused by carbapenemase-producing pathogens.

Activity of Fusidic Acid Tested against Staphylococci Isolated from Patients in U.S. Medical Centers in 2014.

Fusidic acid (FA) activity was evaluated against 2,002 clinical staphylococcal isolates collected in U.S. hospitals during 2014. FA (MIC50/90, 0.12/0.12 µg/ml) inhibited 99.8% of Staphylococcus aureus isolates at ≤1 µg/ml. Only four S. aureus isolates displayed FA values of >2 µg/ml (three strains with fusC and one with an L461K substitution in fusA), and they were isolated from patients in four states. In conclusion, FA demonstrated sustained, potent activity against this recent collection of U.S. staphylococci.

Results from the Solithromycin International Surveillance Program (2014).

Solithromycin, a fourth-generation macrolide (a fluoroketolide with enhanced activity against macrolide-resistant bacteria due to interaction with three ribosomal sites) and the first fluoroketolide, was tested against a 2014 collection of 6,115 isolates, including Streptococcus pneumoniae (1,713 isolates), Haemophilus influenzae (1,308), Moraxella catarrhalis (577), Staphylococcus aureus (1,024), and beta-hemolytic streptococci (1,493), by reference broth microdilution methods. The geographic samples included 2,748 isolates from the United States, 2,536 from Europe, 386 from Latin America, and 445 from the Asia-Pacific region. Solithromycin was observed to be very active against S. pneumoniae (MIC50/90, 0.008/0.12 µg/ml), demonstrating 2-fold greater activity than telithromycin (MIC50/90, 0.015/0.25 µg/ml) and 16- to >256-fold greater activity than azithromycin (MIC50/90, 0.12/>32 µg/ml), with all strains being inhibited at a solithromycin MIC of ≤1 µg/ml. Against H. influenzae, solithromycin showed potency identical to that of telithromycin (MIC50/90, 1/2 µg/ml), and both of these compounds were 2-fold less active than azithromycin (MIC50/90, 0.5/1 µg/ml). All but one of the M. catarrhalis isolates were inhibited by solithromycin at ≤0.25 µg/ml. Solithromycin inhibited 85.3% of S. aureus isolates at ≤1 µg/ml, and its activity was lower against methicillin-resistant (MIC50/90, 0.06/>32 µg/ml) than against methicillin-susceptible (MIC50/90, 0.06/0.06 µg/ml) isolates. Little variation in solithromycin activity was observed by geographic region for the species tested. Solithromycin was very active against beta-hemolytic streptococci (MIC50/90, 0.015/0.03 µg/ml), and all isolates were inhibited at MIC values of ≤0.5 µg/ml. In conclusion, solithromycin demonstrated potent activity against global and contemporary (2014) pathogens that represent the major causes of community-acquired bacterial pneumonia. These data support the continued clinical development of solithromycin for the treatment of this important indication.

Antimicrobial Activities of Ceftazidime-Avibactam and Comparator Agents against Gram-Negative Organisms Isolated from Patients with Urinary Tract Infections in U.S. Medical Centers, 2012 to 2014.

A total of 7,272 unique patient clinical isolates were collected from 71 U.S. medical centers from patients with urinary tract infections in 2012 to 2014 and tested for susceptibility to ceftazidime-avibactam and comparators by broth microdilution methods. Ceftazidime-avibactam inhibited >99.9% of all Enterobacteriaceae at the susceptible breakpoint of ≤8 µg/ml (there were only three nonsusceptible strains). Ceftazidime-avibactam was also active against Pseudomonas aeruginosa isolates (MIC50, 2 µg/ml; MIC90, 4 µg/ml; 97.7% susceptible), including many isolates not susceptible to meropenem, ceftazidime, and/or piperacillin-tazobactam.

Changes in the Frequencies of ß-Lactamase Genes among Enterobacteriaceae Isolates in U.S. Hospitals, 2012 to 2014: Activity of Ceftazidime-Avibactam Tested against ß-Lactamase-Producing Isolates.

Among 15,588 Enterobacteriaceae isolates collected in 63 U.S. hospitals from 2012 to 2014, 2,129 (13.7%) displayed an extended-spectrum ß-lactamase (ESBL) phenotype. These rates were similar over time (13.2 to 13.9%); however, differences among Escherichia coli (12.7 and 15.1% in 2012 and 2014; P = 0.007) and Klebsiella pneumoniae (18.9 and 15.5% in 2012 and 2014; P = 0.006) were noted when comparing 2014 and 2012. Carbapenem-resistant Enterobacteriaceae (CRE) (2.3 and 1.8%) and carbapenem-resistant K. pneumoniae (6.8 and 5.1%; P = 0.003) rates were lower in 2014 than in 2012. Isolates carrying blaCTX-M-15-like genes were stable (42.1 to 42.4%), but a decrease among E. coli isolates (59.1 and 49.7%; P = 0.008) and an increase among K. pneumoniae isolates (32.7 and 41.2%; P = 0.022) in 2014 were observed. Isolates carrying blaKPC (304) decreased over the years (16.5 and 10.9%; P = 0.008), mainly due to the decrease in K. pneumoniae isolates harboring blaKPC (n = 285; 35.6 and 28.4%; P = 0.041) in hospitals in the Mid-Atlantic and South Atlantic regions, where these isolates were highly prevalent during 2012 and 2013. Isolates carrying blaCMY-2-like and blaCTX-M-14-like genes increased (8.2 and 11.9% and 9.1 and 12.9%, respectively; P = 0.04 for both), and those producing blaSHV ESBL decreased (24.9 and 12.7%; P < 0.001) over the studied years, due to a decreased occurrence of the enzymes among K. pneumoniae isolates. Other enzymes were detected in smaller numbers of isolates, including four K. pneumoniae isolates carrying blaNDM-1 metallo-ß-lactamase (two in 2012 and two in 2014). Ceftazidime-avibactam, a recently approved ß-lactamase inhibitor combination, was very active against the ESBL phenotype isolates (MIC50/90, 0.12 and 1 µg/ml; 99.7% susceptible) and CRE strains (MIC50/90, 0.5 and 2 µg/ml; 98.5% susceptible) that displayed elevated MIC values for many comparator agents. In conclusion, significant changes were noted in the frequencies of isolates harboring various ß-lactamases among U.S. hospitals between 2012 and 2014 that will require continued monitoring.

Activities of Tedizolid and Linezolid Determined by the Reference Broth Microdilution Method against 3,032 Gram-Positive Bacterial Isolates Collected in Asia-Pacific, Eastern Europe, and Latin American Countries in 2014.

Tedizolid and linezolid in vitro activities against 3,032 Gram-positive pathogens collected in Asia-Pacific, Eastern European, and Latin American medical centers during 2014 were assessed. The isolates were tested for susceptibility by the current reference broth microdilution methods. Due to concern over the effect of MIC endpoint criteria on the results of testing the oxazolidinones tedizolid and linezolid, MIC endpoint values were read by two methods: (i) reading the MIC at the first well where the trailing began without regard for pinpoint trailing, according to CLSI M07-A10 and M100-S26 document instructions for reading linezolid (i.e., 80% inhibition of growth; these reads were designated tedizolid 80 and linezolid 80), and (ii) at 100% inhibition of growth (designated tedizolid 100 and linezolid 100). All Staphylococcus aureus, Streptococcus pyogenes, Streptococcus agalactiae, Streptococcus anginosus group, and Enterococcus faecalis isolates were inhibited at tedizolid 80 and 100 MIC values of 0.25 and 0.5, 0.25 and 0.25, 0.25 and 0.5, 0.12 and 0.25, and 0.5 and 1 µg/ml, respectively. Generally, MIC50 and MIC90 results for tedizolid 80 and linezolid 80 were one doubling dilution lower than those read at 100% inhibition. Tedizolid was 4- to 8-fold more potent than linezolid against all the isolates tested regardless of the MIC endpoint criterion used. Despite the differences in potency, >99.9% of isolates tested in this survey were susceptible to both linezolid and tedizolid using CLSI and EUCAST interpretive criteria. In conclusion, tedizolid demonstrated greater in vitro potency than linezolid against Gram-positive pathogens isolated from patients in medical centers across the Asia-Pacific region, Eastern Europe, and Latin America.

Oritavancin Activity Tested against Molecularly Characterized Staphylococci and Enterococci Displaying Elevated Linezolid MIC Results.

Oritavancin (MIC50/90, 0.03/0.06 to 0.12 µg/ml) had potent activity against linezolid-resistant staphylococci, as well as Enterococcus faecalis and Enterococcus faecium (oritavancin MIC50/90, 0.015/0.12 µg/ml against both species). All linezolid-resistant isolates were inhibited by oritavancin at ≤0.12 µg/ml. These results confirmed the absence of cross-resistance between linezolid and oritavancin in staphylococci and enterococci.

Antimicrobial Activities of Ceftaroline and Comparator Agents against Bacterial Organisms Causing Bacteremia in Patients with Skin and Skin Structure Infections in U.S. Medical Centers, 2008 to 2014.

We evaluated the antimicrobial susceptibility of 1,454 organisms consecutively collected from patients with bacteremia associated with skin and skin structure infections. The most common organisms obtained wereStaphylococcus aureus(670 organisms [46.1%]),Escherichia coli(200 organisms [13.8%]), ß-hemolytic streptococci (ßHS) (138 organisms [9.5%]), andKlebsiella pneumoniae(109 organisms [7.5%]). The susceptibility rates for ceftaroline were 97.9% forS. aureus(95.9% among methicillin-resistantS. aureus[MRSA]), 100.0% for ßHS, 86.5% forE. coli, and 89.0% forK. pneumoniae Ceftaroline and tigecycline provided the best overall coverage.