Daniel F. Sahm

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

ABSTRACT The activity of ceftazidime-avibactam was assessed against 961 isolates of meropenem-nonsusceptible Enterobacteriaceae. Most meropenem-nonsusceptible metallo-β-lactamase (MBL)-negative isolates (97.7%) were susceptible to ceftazidime-avibactam. Isolates that carried KPC or OXA-48-like β-lactamases, both alone and in combination with extended-spectrum β-lactamases (ESBLs) and/or AmpC β-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-β-lactamases.

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

ABSTRACT Metallo-β-lactamases (MBLs) hydrolyze all classes of β-lactams except monobactams and are not inhibited by classic serine β-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.

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

ABSTRACT 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 β-lactamases (ESBLs), AmpC β-lactamases, or non-ESBL β-lactamases.

Enteric carriage of vancomycin-resistant Enterococcus faecium in patients tested for Clostridium difficile.

OBJECTIVE To identify independent risk factors for enteric carriage of vancomycin-resistant Enterococcus faecium (VREF) in hospitalized patients tested for Clostridium difficile toxin. DESIGN Retrospective case-cohort study. SETTING Tertiary-care teaching hospital. PATIENTS Convenience sample of 215 adult inpatients who had stool tested for C difficile between January 29 and February 25, 1996. RESULTS 41 (19%) of 215 patients had enteric carriage of VREE Five independent risk factors for enteric VREF were identified: history of prior C difficile (odds ratio [OR], 15.21; 95% confidence interval [CI95], 3.30-70.10; P < .001), parenteral treatment with vancomycin for > or = 5 days (OR, 4.06; CI95, 1.54-10.73; P = .005), treatment with antimicrobials effective against gram-negative organisms (OR, 3.44; CI95, 1.20-9.87; P = .021), admission from another institution (OR, 2.95; CI95, 1.21-7.18; P =.017), and age > 60 years (OR 2.57; CI95, 1.13-5.82; P = .024). These risk factors for enteric VREF were independent of the patients current C difficile status. CONCLUSIONS Antimicrobial exposures are the most important modifiable independent risk factors for enteric carriage of VREF in hospitalized patients tested for C difficile.

In Vitro Activity of Aztreonam-Avibactam against a Global Collection of Gram-Negative Pathogens from 2012 and 2013

ABSTRACT The combination of aztreonam plus avibactam is being developed for use in infections caused by metallo-β-lactamase-producing Enterobacteriaceae strains that also produce serine β-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 β-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-β-lactamases. In contrast, >99% of Enterobacteriaceae isolates producing all observed Ambler classes of β-lactamase enzymes were inhibited by ≤4 μg/ml aztreonam in combination with avibactam, including isolates that produced IMP-, VIM-, and NDM-type metallo-β-lactamases in combination with multiple serine β-lactamases.

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

ABSTRACT 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 β-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 β-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 β-lactamases.

In Vitro Susceptibility of Global Surveillance Isolates of Pseudomonas aeruginosa to Ceftazidime-Avibactam (INFORM 2012 to 2014)

ABSTRACT Broth microdilution antimicrobial susceptibility testing was performed for ceftazidime-avibactam and comparator agents against 7,062 clinical isolates of Pseudomonas aeruginosa collected from 2012 to 2014 in four geographic regions (Europe, Asia/South Pacific, Latin America, Middle East/Africa) as part of the International Network for Optimal Resistance Monitoring (INFORM) global surveillance program. The majority of isolates were susceptible to ceftazidime-avibactam, with the proportions susceptible differing marginally across the four regions (MIC90, 8 to 16 μg/ml; 88.7 to 93.2% susceptible), in contrast to lower susceptibilities to the following comparator β-lactam agents: ceftazidime (MIC90, 32 to 64 μg/ml; 71.5 to 80.8% susceptible), meropenem (MIC90, >8 μg/ml; 64.9 to 77.4% susceptible), and piperacillin-tazobactam (MIC90, >128 μg/ml; 62.3 to 71.3% susceptible). Compared to the overall population, susceptibility to ceftazidime-avibactam of isolates that were nonsusceptible to ceftazidime (n = 1,627) was reduced to between 56.8% (Middle East/Africa; MIC90, 64 μg/ml) and 68.9% (Asia/South Pacific; MIC90, 128 μg/ml), but these percentages were higher than susceptibilities to other β-lactam agents (0 to 44% susceptible, depending on region and agent; meropenem MIC90, >8 μg/ml; 26.5 to 43.9% susceptible). For this subset of isolates, susceptibilities to amikacin (MIC90, >32 μg/ml; 53.2 to 80.0% susceptible) and colistin (MIC90, 1 μg/ml; 98.5 to 99.5% susceptible) were comparable to or higher than that of ceftazidime-avibactam. A similar observation was made with isolates that were nonsusceptible to meropenem (n = 1,926), with susceptibility to ceftazidime-avibactam between 67.8% (Middle East/Africa; MIC90, 64 μg/ml) and 74.2% (Europe; MIC90, 32 μg/ml) but again with reduced susceptibility to comparators except for amikacin (MIC90, >32 μg/ml; 56.8 to 78.7% susceptible) and colistin (MIC90, 1 μg/ml; 98.9 to 99.3% susceptible). Of the 8% of isolates not susceptible to ceftazidime-avibactam, the nonsusceptibility of half could be explained by their possession of genes encoding metallo-β-lactamases. The data reported here are consistent with results from other country-specific and regional surveillance studies and show that ceftazidime-avibactam demonstrates in vitro activity against globally collected clinical isolates of P. aeruginosa, including isolates that are resistant to ceftazidime and meropenem.

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

ABSTRACT 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-β-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 β-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 Gepotidacin, a Novel Triazaacenaphthylene Bacterial Topoisomerase Inhibitor, Against a Broad Spectrum of Bacterial Pathogens

ABSTRACT Gepotidacin inhibits bacterial DNA replication through a mode different from that of fluoroquinolones. Gepotidacin and comparators were tested by broth and agar dilution against clinical isolates. The in vitro activities of gepotidacin were comparable against methicillin-susceptible and -resistant Staphylococcus aureus (MSSA and MRSA, respectively) isolates (MIC90, 0.5 μg/ml). The gepotidacin MIC90s were as follows (in micrograms per milliliter) for the indicated bacteria: Streptococcus pyogenes, 0.25; Escherichia coli, 2; Moraxella catarrhalis, ≤0.06; Streptococcus pneumoniae (0.25), Haemophilus influenzae, 1; Clostridium perfringens, 0.5; and Shigella spp., 1, including levofloxacin-resistant subsets. Gepotidacin warrants further investigation for clinical development.

Regional differences and trends in antimicrobial susceptibility of Acinetobacter baumannii

Acinetobacter baumannii, although representing a small percentage of Gram-negative bacilli isolates in intra-abdominal infections (IAIs) and urinary tract infections (UTIs), is frequently multidrug-resistant (MDR) and can pose difficult therapeutic challenges. From 2011 to 2014, 2337 A. baumannii were collected from IAIs and UTIs at 453 hospital sites in 48 countries as part of the SMART ongoing surveillance initiative. Current susceptibility and multidrug resistance, defined as resistance to at least three of the tested drug classes, were determined in a subset of 1011 isolates from 2013 to 2014. A. baumannii comprised 0.7-4.6% of all aerobic and facultative Gram-negative bacilli isolated in six global regions. MDR rates were lowest in North America (47%) and highest in Europe and the Middle East (>93%), with higher rates in ICUs than in non-ICU wards in almost all regions. Antimicrobial susceptibility profiles varied by region but resistance was high everywhere, with no drug inhibiting >70% of A. baumannii isolates in any region. Susceptibility to imipenem was highest in North America (64%) and lowest in Europe and the Middle East (≤11%). Amikacin overall was the most active of the studied agents, including against MDR isolates (of which 11-38% were susceptible). Trend analysis of only those countries that contributed isolates in each study year (2011-2014) demonstrated an increasing trend in MDR rates in the Middle East as well as decreasing susceptibility to several single antimicrobial agents in Africa, Europe and the Middle East. These patterns and trends can help direct antimicrobial therapy and infection control efforts.