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

2015 ◽  
Vol 60 (2) ◽  
pp. 1067-1078 ◽  
Author(s):  
Krystyna M. Kazmierczak ◽  
Sharon Rabine ◽  
Meredith Hackel ◽  
Robert E. McLaughlin ◽  
Douglas J. Biedenbach ◽  
...  

ABSTRACTMetallo-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-nonsusceptibleEnterobacteriaceaeandPseudomonas aeruginosawere characterized forblagenes 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),Klebsiellaspp. (85),Enterobacterspp. (39),Proteeae(16),Citrobacter freundii(12),Escherichia coli(6), andSerratia 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]). Thein vitroactivities of all tested antibiotics against MBL-positiveEnterobacteriaceaewere 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-positiveP. aeruginosaisolates (>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.

2017 ◽  
Vol 61 (11) ◽  
Author(s):  
Helio S. Sader ◽  
Mariana Castanheira ◽  
Dee Shortridge ◽  
Rodrigo E. Mendes ◽  
Robert K. Flamm

ABSTRACT The in vitro activity of ceftazidime-avibactam and many comparator agents was determined against various resistant subsets of organisms selected among 36,380 Enterobacteriaceae and 7,868 Pseudomonas aeruginosa isolates. The isolates were consecutively collected from 94 U.S. hospitals, and all isolates were tested for susceptibility by reference broth microdilution methods in a central monitoring laboratory (JMI Laboratories). Enterobacteriaceae isolates resistant to carbapenems (CRE) and/or ceftazidime-avibactam (MIC ≥ 16 μg/ml) were evaluated for the presence of genes encoding extended-spectrum β-lactamases and carbapenemases. Ceftazidime-avibactam inhibited >99.9% of all Enterobacteriaceae at the susceptible breakpoint of ≤8 μg/ml and was active against multidrug-resistant (MDR; n = 2,953; MIC50/90, 0.25/1 μg/ml; 99.2% susceptible), extensively drug-resistant (XDR; n = 448; MIC50/90, 0.5/2 μg/ml; 97.8% susceptible), and CRE (n = 513; MIC50/90, 0.5/2 μg/ml; 97.5% susceptible) isolates. Only 82.2% of MDR Enterobacteriaceae (n = 2,953) and 64.2% of ceftriaxone-nonsusceptible Klebsiella pneumoniae (n = 1,063) isolates were meropenem susceptible. Among Enterobacter cloacae (22.2% ceftazidime nonsusceptible), 99.8% of the isolates, including 99.3% of the ceftazidime-nonsusceptible isolates, were ceftazidime-avibactam susceptible. Only 23 of 36,380 Enterobacteriaceae (0.06%) isolates were ceftazidime-avibactam nonsusceptible, including 9 metallo-β-lactamase producers and 2 KPC-producing strains with porin alteration; the remaining 12 strains showed negative results for all β-lactamases tested. Ceftazidime-avibactam showed potent activity against P. aeruginosa (MIC50/90, 2/4 μg/ml; 97.1% susceptible), including MDR (MIC50/90, 4/16 μg/ml; 86.5% susceptible) isolates, and inhibited 71.8% of isolates nonsusceptible to meropenem, piperacillin-tazobactam, and ceftazidime (n = 628). In summary, ceftazidime-avibactam demonstrated potent activity against a large collection (n = 44,248) of contemporary Gram-negative bacilli isolated from U.S. patients, including organisms resistant to most currently available agents, such as CRE and meropenem-nonsusceptible P. aeruginosa.


2015 ◽  
Vol 59 (7) ◽  
pp. 4239-4248 ◽  
Author(s):  
Douglas J. Biedenbach ◽  
Krystyna Kazmierczak ◽  
Samuel K. Bouchillon ◽  
Daniel F. Sahm ◽  
Patricia A. Bradford

ABSTRACTThe combination of aztreonam plus avibactam is being developed for use in infections caused by metallo-β-lactamase-producingEnterobacteriaceaestrains that also produce serine β-lactamases. Thein vitroactivities of aztreonam-avibactam and comparator antimicrobials were determined against year 2012 and 2013 clinical isolates ofEnterobacteriaceae,Pseudomonas aeruginosa, andAcinetobacter baumanniiusing 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. MIC90values of aztreonam and aztreonam-avibactam against all collected isolates ofEnterobacteriaceae(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 MIC90was 32 μg/ml for both aztreonam and aztreonam-avibactam againstP. aeruginosa(n= 3,766). Aztreonam alone or in combination with avibactam had noin vitroactivity against isolates ofA. baumannii. PCR and sequencing were used to characterize 5,076 isolates for β-lactamase genes. Aztreonam was not active against mostEnterobacteriaceaeisolates producing class A or class C enzymes alone or in combination with class B metallo-β-lactamases. In contrast, >99% ofEnterobacteriaceaeisolates 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.


2015 ◽  
Vol 59 (4) ◽  
pp. 2280-2285 ◽  
Author(s):  
Robert K. Flamm ◽  
Paul R. Rhomberg ◽  
Ronald N. Jones ◽  
David J. Farrell

ABSTRACTRX-P873 is a novel antibiotic from the pyrrolocytosine series which exhibits high binding affinity for the bacterial ribosome and broad-spectrum antibiotic properties. The pyrrolocytosines have shownin vitroactivity against multidrug-resistant Gram-negative and Gram-positive strains of bacteria known to cause complicated urinary tract, skin, and lung infections, as well as sepsis.Enterobacteriaceae(657),Pseudomonas aeruginosa(200), andAcinetobacter baumannii(202) isolates from North America and Europe collected in 2012 as part of a worldwide surveillance program were testedin vitroby broth microdilution using Clinical and Laboratory Standards Institute (CLSI) methodology. RX-P873 (MIC90, 0.5 μg/ml) was >32-fold more active than ceftazidime and inhibited 97.1% and 99.5% ofEnterobacteriaceaeisolates at MIC values of ≤1 and ≤4 μg/ml, respectively. There were only three isolates with an MIC value of >4 μg/ml (all were indole-positiveProtea). RX-P873 (MIC50/90, 2/4 μg/ml) was highly active againstPseudomonas aeruginosaisolates, including isolates which were nonsusceptible to ceftazidime or meropenem. RX-P873 was 2-fold less active againstP. aeruginosathan tobramycin (MIC90, 2 μg/ml; 91.0% susceptible) and colistin (MIC90, 2 μg/ml; 99.5% susceptible) and 2-fold more potent than amikacin (MIC90, 8 μg/ml; 93.5% susceptible) and meropenem (MIC90, 8 μg/ml; 76.0% susceptible). RX-P873, the most active agent againstAcinetobacter baumannii(MIC90, 1 μg/ml), was 2-fold more active than colistin (MIC90, 2 μg/ml; 97.0% susceptible) and 4-fold more active than tigecycline (MIC90, 4 μg/ml). This novel agent merits further exploration of its potential against multidrug-resistant Gram-negative bacteria.


2011 ◽  
Vol 77 (13) ◽  
pp. 4383-4389 ◽  
Author(s):  
Liam F. Fitzsimmons ◽  
Stevenson Flemer ◽  
A. Sandy Wurthmann ◽  
P. Bruce Deker ◽  
Indra Neil Sarkar ◽  
...  

ABSTRACTCholine is abundant in association with eukaryotes and plays roles in osmoprotection, thermoprotection, and membrane biosynthesis in many bacteria. Aerobic catabolism of choline is widespread among soil proteobacteria, particularly those associated with eukaryotes. Catabolism of choline as a carbon, nitrogen, and/or energy source may play important roles in association with eukaryotes, including pathogenesis, symbioses, and nutrient cycling. We sought to generate choline analogues to study bacterial choline catabolismin vitroandin situ. Here we report the characterization of a choline analogue, propargylcholine, which inhibits choline catabolism at the level of Dgc enzyme-catalyzed dimethylglycine demethylation inPseudomonas aeruginosa. We used genetic analyses and13C nuclear magnetic resonance to demonstrate that propargylcholine is catabolized to its inhibitory form, propargylmethylglycine. Chemically synthesized propargylmethylglycine was also an inhibitor of growth on choline. Bioinformatic analysis suggests that there are genes encoding DgcA homologues in a variety of proteobacteria. We examined the broader utility of propargylcholine and propargylmethylglycine by assessing growth of other members of the proteobacteria that are known to grow on choline and possess putative DgcA homologues. Propargylcholine showed utility as a growth inhibitor inP. aeruginosabut did not inhibit growth in other proteobacteria tested. In contrast, propargylmethylglycine was able to inhibit choline-dependent growth in all tested proteobacteria, includingPseudomonas mendocina,Pseudomonas fluorescens,Pseudomonas putida,Burkholderia cepacia,Burkholderia ambifaria, andSinorhizobium meliloti. We predict that chemical inhibitors of choline catabolism will be useful for studying this pathway in clinical and environmental isolates and could be a useful tool to study proteobacterial choline catabolismin situ.


2020 ◽  
Vol 64 (7) ◽  
Author(s):  
José Manuel Ortiz de la Rosa ◽  
Patrice Nordmann ◽  
Laurent Poirel

ABSTRACT Many transferable quinolone resistance mechanisms have been identified in Gram-negative bacteria. The plasmid-encoded 65-amino-acid-long ciprofloxacin-modifying enzyme CrpP was recently identified in Pseudomonas aeruginosa isolates. We analyzed a collection of 100 clonally unrelated and multidrug-resistant P. aeruginosa clinical isolates, among which 46 were positive for crpP-like genes, encoding five CrpP variants conferring variable levels of reduced susceptibility to fluoroquinolones. These crpP-like genes were chromosomally located as part of pathogenicity genomic islands.


2018 ◽  
Vol 62 (7) ◽  
pp. e02584-17 ◽  
Author(s):  
Gregory G. Stone ◽  
Paul Newell ◽  
Patricia A. Bradford

ABSTRACT The increasing prevalence of multidrug-resistant Gram-negative pathogens has generated a requirement for new treatment options. Avibactam, a novel non-β-lactam–β-lactamase inhibitor, restores the activity of ceftazidime against Ambler class A, C, and some class D β-lactamase-producing strains of Enterobacteriaceae and Pseudomonas aeruginosa. The in vitro activities of ceftazidime-avibactam versus comparators were evaluated against 1,440 clinical isolates obtained in a phase 3 clinical trial in patients with complicated intra-abdominal infections (cIAI; ClinicalTrials.gov identifier NCT01499290). Overall, in vitro activities were determined for 803 Enterobacteriaceae, 70 P. aeruginosa, 304 Gram-positive aerobic, and 255 anaerobic isolates obtained from 1,066 randomized patients at baseline. Susceptibility was determined by broth microdilution. The most commonly isolated Gram-negative, Gram-positive, and anaerobic pathogens were Escherichia coli (n = 549), Streptococcus anginosus (n = 130), and Bacteroides fragilis (n = 96), respectively. Ceftazidime-avibactam was highly active against isolates of Enterobacteriaceae, with an overall MIC90 of 0.25 mg/liter. In contrast, the MIC90 for ceftazidime alone was 32 mg/liter. The MIC90 value for ceftazidime-avibactam (4 mg/liter) was one dilution lower than that of ceftazidime alone (8 mg/liter) against isolates of Pseudomonas aeruginosa. The ceftazidime-avibactam MIC90 for 109 ceftazidime-nonsusceptible Enterobacteriaceae isolates was 2 mg/liter, and the MIC range for 6 ceftazidime-nonsusceptible P. aeruginosa isolates was 8 to 32 mg/liter. The MIC90 values were within the range of susceptibility for the study drugs permitted per the protocol in the phase 3 study to provide coverage for aerobic Gram-positive and anaerobic pathogens. These findings demonstrate the in vitro activity of ceftazidime-avibactam against bacterial pathogens commonly observed in cIAI patients, including ceftazidime-nonsusceptible Enterobacteriaceae. (This study has been registered at ClinicalTrials.gov under identifier NCT01499290.)


2018 ◽  
Vol 63 (1) ◽  
Author(s):  
Andrew Walkty ◽  
James A. Karlowsky ◽  
Melanie R. Baxter ◽  
Heather J. Adam ◽  
George G. Zhanel

ABSTRACTThe Clinical and Laboratory Standards Institute (CLSI) broth microdilution method was used to evaluate thein vitroactivities of plazomicin and comparator antimicrobial agents against 7,712 Gram-negative and 4,481 Gram-positive bacterial pathogens obtained from 2013 to 2017 from patients in Canadian hospitals as part of the CANWARD Surveillance Study. Plazomicin demonstrated potentin vitroactivity againstEnterobacteriaceae(MIC90≤ 1 µg/ml for all species tested exceptProteus mirabilisandMorganella morganii), including aminoglycoside-nonsusceptible, extended-spectrum β-lactamase (ESBL)-positive, and multidrug-resistant (MDR) isolates. Plazomicin was equally active against methicillin-susceptible and methicillin-resistant isolates ofStaphylococcus aureus.


2016 ◽  
Vol 60 (7) ◽  
pp. 4387-4390 ◽  
Author(s):  
Benjamin Miller ◽  
Myra W. Popejoy ◽  
Ellie Hershberger ◽  
Judith N. Steenbergen ◽  
John Alverdy

ABSTRACTCeftolozane-tazobactam is active against Gram-negative pathogens, including multidrug-resistantPseudomonas aeruginosa. In a subgroup analysis of patients with complicated intra-abdominal infections (cIAIs) involvingP. aeruginosafrom a phase 3 program, ceftolozane-tazobactam demonstrated potentin vitroactivity againstP. aeruginosa. Clinical cure in the microbiologically evaluable population was 100% (26/26) for ceftolozane-tazobactam plus metronidazole and 93.1% (27/29) for meropenem. These findings support the use of ceftolozane-tazobactam in the management of cIAI whenP. aeruginosais suspected or confirmed. (This study has been registered at ClinicalTrials.gov under registration no. NCT01445665 and NCT01445678.)


2015 ◽  
Vol 59 (6) ◽  
pp. 3623-3626 ◽  
Author(s):  
Andrew J. Denisuik ◽  
James A. Karlowsky ◽  
Tyler Denisuik ◽  
Wright W. Nichols ◽  
Thomas A. Keating ◽  
...  

ABSTRACTThe mechanism of aminoglycoside resistance among 338 gentamicin-nonsusceptible Gram-negative bacteria (207Enterobacteriaceaeand 131Pseudomonas aeruginosa) was assessed, and thein vitroactivity of ceftazidime-avibactam against these isolates was determined. Aminoglycoside-modifying enzymes were detected in 91.8% ofEnterobacteriaceaeand 13.7% ofP. aeruginosaisolates. A single strain ofKlebsiella pneumoniaeharbored a 16S rRNA methylase (ArmA). The ceftazidime-avibactam MIC90values were 0.5 μg/ml (MIC, ≤8 μg/ml for 100% of isolates) and 16 μg/ml (MIC, ≤8 μg/ml for 87.8% of isolates) against gentamicin-nonsusceptibleEnterobacteriaceaeandP. aeruginosaisolates, respectively.


2018 ◽  
Vol 62 (7) ◽  
Author(s):  
James A. Karlowsky ◽  
Krystyna M. Kazmierczak ◽  
Samuel K. Bouchillon ◽  
Boudewijn L. M. de Jonge ◽  
Gregory G. Stone ◽  
...  

ABSTRACT The in vitro activities of ceftazidime-avibactam and comparators against 9,149 isolates of Enterobacteriaceae and 2,038 isolates of Pseudomonas aeruginosa collected by 42 medical centers in nine countries in the Asia-Pacific region from 2012 to 2015 were determined as part of the International Network for Optimal Resistance Monitoring (INFORM) global surveillance program. Antimicrobial susceptibility testing was conducted by Clinical and Laboratory Standards Institute (CLSI) broth microdilution, and isolate subset analysis was performed on the basis of the resistant phenotypes and β-lactamase content. Ceftazidime-avibactam demonstrated potent in vitro activity (MIC, ≤8 μg/ml) against all Enterobacteriaceae tested (99.0% susceptible) and was the most active against isolates that were metallo-β-lactamase (MBL) negative (99.8% susceptible). Against P. aeruginosa , 92.6% of all isolates and 96.1% of MBL-negative isolates were susceptible to ceftazidime-avibactam (MIC, ≤8 μg/ml). The rates of susceptibility to ceftazidime-avibactam ranged from 97.0% (Philippines) to 100% (Hong Kong, South Korea) for Enterobacteriaceae and from 83.1% (Thailand) to 100% (Hong Kong) among P. aeruginosa isolates, with lower susceptibilities being observed in countries where MBLs were more frequently encountered (Philippines, Thailand). Ceftazidime-avibactam inhibited 97.2 to 100% of Enterobacteriaceae isolates, per country, that carried serine β-lactamases, including extended-spectrum β-lactamases, AmpC cephalosporinases, and carbapenemases (KPC, GES, OXA-48-like). It also inhibited 91.3% of P. aeruginosa isolates that were carbapenem nonsusceptible in which no acquired β-lactamase was detected. Among MBL-negative Enterobacteriaceae isolates that were ceftazidime nonsusceptible, meropenem nonsusceptible, colistin resistant, and multidrug resistant, ceftazidime-avibactam inhibited 96.1, 87.7, 100, and 98.8% of isolates, respectively, and among MBL-negative P. aeruginosa isolates that were ceftazidime nonsusceptible, meropenem nonsusceptible, colistin resistant, and multidrug resistant, ceftazidime-avibactam inhibited 79.6, 83.6, 83.3, and 68.2% of isolates, respectively. Overall, clinical isolates of Enterobacteriaceae and P. aeruginosa collected in nine Asia-Pacific countries from 2012 to 2015 were highly susceptible to ceftazidime-avibactam.


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