scholarly journals Antimicrobial Activity of Ceftazidime-Avibactam Tested against Multidrug-Resistant Enterobacteriaceae and Pseudomonas aeruginosa Isolates from U.S. Medical Centers, 2013 to 2016

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.

2017 ◽  
Vol 4 (suppl_1) ◽  
pp. S376-S376
Author(s):  
Helio S Sader ◽  
Mariana Castanheira ◽  
Dee Shortridge ◽  
Rodrigo E Mendes ◽  
Robert K Flamm

Abstract Background The in vitro activity of ceftazidime-avibactam (CAZ-AVI) and many comparator agents were tested against various resistant subsets of organisms selected among 36,380 Enterobacteriaceae and 7,868 P. aeruginosa isolates. Methods Isolates were consecutively collected from 94 US hospitals in 2013–2016 and tested for susceptibility by reference broth microdilution methods in a central monitoring laboratory (JMI Laboratories) as part of the International Network for Optimal Resistance Monitoring (INFORM) program. Enterobacteriaceae strains with elevated CAZ-AVI MIC values (≥16 μg/mL) were evaluated for the presence of genes encoding extended-spectrum β-lactamases, KPC, NDM, and transferable AmpC enzymes. Results CAZ-AVI inhibited >99.9% of all Enterobacteriaceae at the susceptible (S) breakpoint of ≤8 μg/mL and was active against multidrug-resistant (MDR; n = 2,953; MIC50/90, 0.25/1 μg/mL; 99.2%S, extensively drug-resistant (XDR; n = 448; MIC50/90, 0.5/2 μg/mL; 97.8%S), and carbapenem-resistant isolates (CRE; n = 513; MIC50/90, 0.5/2 μg/mL; 97.5%S). Only 82.2% of MDR Enterobacteriaceae and 64.2% of ceftriaxone-nonsusceptible (NS) Klebsiella pneumoniae (n = 1,063) were meropenem-S. Among Enterobacter cloacae (n = 3,740; 22.2% ceftazidime-NS), 99.8% of isolates, including 99.3% of ceftazidime-NS isolates, were CAZ-AVI-S. Only 22 of 36,380 Enterobacteriaceae (0.06%) isolates were CAZ-AVI-NS, including 8 MBL-producers (0.02%) and 2 KPC-producing strains with porin alteration; the remaining 12 strains showed negative results for all β-lactamases tested. CAZ-AVI showed potent activity against P. aeruginosa (n = 7,868; MIC50/90, 2/4 μg/mL; 97.1% S), including meropenem-NS (n = 1,471; MIC50/90, 4/16 μg/mL; 87.2%S) and MDR (n = 1,562; MIC50/90, 4/16 μg/mL; 86.5%S) isolates, and inhibited 71.8% of isolates NS to meropenem, piperacillin-tazobactam, and ceftazidime (n = 628). Conclusion CAZ-AVI demonstrated potent activity against a large US collection (n = 44,248) of contemporary gram-negative bacilli, including organisms resistant to most currently available agents, such as CRE and meropenem-NS P. aeruginosa. Disclosures H. S. Sader, Allergan: Research Contractor, Research grant; M. Castanheira, Allergan: Research Contractor, Research grant; D. Shortridge, Allergan: Research Contractor, Research grant; R. E. Mendes, Allergan: Research Contractor, Research grant; R. K. Flamm, Allergan: Research Contractor, Research grant


2020 ◽  
Vol 64 (3) ◽  
Author(s):  
Temilolu Idowu ◽  
George G. Zhanel ◽  
Frank Schweizer

ABSTRACT Ceftolozane-tazobactam is a potent β-lactam/β-lactamase inhibitor combination approved for the treatment of complicated intraabdominal and complicated urinary tract infections and, more recently, the treatment of hospital-acquired and ventilator-associated bacterial pneumonia. Although the activities of ceftolozane are not enhanced by tazobactam against Pseudomonas aeruginosa, it remains the most potent antipseudomonal agent approved to date. Emerging data worldwide has included reports of microbiological failure in patients with serious bacterial infections caused by multidrug-resistant (MDR) P. aeruginosa as a result of ceftolozane resistance developed within therapy. The objective of this study is to compare the efficacy of a tobramycin homodimer plus ceftolozane versus ceftolozane-tazobactam alone against MDR and extensively drug-resistant (XDR) P. aeruginosa. Tobramycin homodimer, a synthetic dimer of two monomeric units of tobramycin, was developed to abrogate the ribosomal properties of tobramycin with a view to mitigating aminoglycoside-related toxicity and resistance. Herein, we report that tobramycin homodimer, a nonribosomal aminoglycoside derivative, potentiates the activities of ceftolozane versus MDR/XDR P. aeruginosa in vitro and delays the emergence of resistance to ceftolozane-tazobactam in the wild-type PAO1 strain. This combination is also more potent than a standard ceftazidime-avibactam combination against these isolates. Conversely, a tobramycin monomer with intrinsic ribosomal properties does not potentiate ceftolozane under similar conditions. Susceptibility and checkerboard studies were assessed using serial 2-fold dilution assays, following the Clinical and Laboratory Standards Institute (CLSI) guidelines. This strategy provides an avenue to further preserve the clinical utility of ceftolozane and enhances its spectrum of activity against one of the most difficult-to-treat pathogens in hospitals.


2015 ◽  
Vol 59 (6) ◽  
pp. 3656-3659 ◽  
Author(s):  
Helio S. Sader ◽  
Mariana Castanheira ◽  
Rodrigo E. Mendes ◽  
Robert K. Flamm ◽  
David J. Farrell ◽  
...  

ABSTRACTPseudomonas aeruginosaisolates (n= 3,902) from 75 U.S. medical centers were tested against ceftazidime-avibactam and comparator agents by the reference broth microdilution method. Overall, 96.9% of the strains were susceptible (MIC, ≤8 μg/ml) to ceftazidime-avibactam, while the rates of susceptibility for ceftazidime, meropenem, and piperacillin-tazobactam were 83.8, 81.9, and 78.5%, respectively. Multidrug-resistant and extensively drug-resistant phenotypes were observed in 14.9 and 8.7% of the strains, respectively, and 81.0 and 73.7% of the strains were susceptible to ceftazidime-avibactam, respectively.


2017 ◽  
Vol 62 (2) ◽  
Author(s):  
Michael A. Pfaller ◽  
Rodrigo E. Mendes ◽  
Leonard R. Duncan ◽  
Robert K. Flamm ◽  
Helio S. Sader

ABSTRACT We evaluated trends in Streptococcus pneumoniae antimicrobial susceptibility in United States hospitals in the 2010 to 2016 period. A total of 8,768 clinical isolates from 47 medical centers were tested for susceptibility by broth microdilution methods. Multidrug-resistant (MDR) and extensively drug-resistant (XDR) rates decreased from 25.7% and 12.4%, respectively, in 2010 to 17.7% and 3.6%, respectively, in 2016. The susceptibilities to most comparator antimicrobial agents increased, whereas the susceptibilities to ceftaroline, levofloxacin, linezolid, and tigecycline remained stable. Ceftaroline retained potent activity against S. pneumoniae (>99.9%) with no marked variations.


2015 ◽  
Vol 59 (12) ◽  
pp. 7915-7918 ◽  
Author(s):  
João Pires ◽  
Thissa N. Siriwardena ◽  
Michaela Stach ◽  
Regula Tinguely ◽  
Sara Kasraian ◽  
...  

ABSTRACTThein vitroactivity of the novel antimicrobial peptide dendrimer G3KL was evaluated against 32Acinetobacter baumannii(including 10 OXA-23, 7 OXA-24, and 11 OXA-58 carbapenemase producers) and 35Pseudomonas aeruginosa(including 18 VIM and 3 IMP carbapenemase producers) strains and compared to the activities of standard antibiotics. Overall, both species collections showed MIC50/90values of 8/8 μg/ml and minimum bactericidal concentrations at which 50% or 90% of strains tested are killed (MBC50/90) of 8/8 μg/ml. G3KL is a promising molecule with antibacterial activity against multidrug-resistant and extensively drug-resistantA. baumanniiandP. aeruginosaisolates.


2018 ◽  
Vol 62 (8) ◽  
Author(s):  
Zhaojing Zong ◽  
Wei Jing ◽  
Jin Shi ◽  
Shu'an Wen ◽  
Tingting Zhang ◽  
...  

ABSTRACT Oxazolidinones are efficacious in treating mycobacterial infections, including tuberculosis (TB) caused by drug-resistant Mycobacterium tuberculosis. In this study, we compared the in vitro activities and MIC distributions of delpazolid, a novel oxazolidinone, and linezolid against multidrug-resistant TB (MDR-TB) and extensively drug-resistant TB (XDR-TB) in China. Additionally, genetic mutations in 23S rRNA, rplC, and rplD genes were analyzed to reveal potential mechanisms underlying the observed oxazolidinone resistance. A total of 240 M. tuberculosis isolates were included in this study, including 120 MDR-TB isolates and 120 XDR-TB isolates. Overall, linezolid and delpazolid MIC90 values for M. tuberculosis isolates were 0.25 mg/liter and 0.5 mg/liter, respectively. Based on visual inspection, we tentatively set epidemiological cutoff (ECOFF) values for MIC determinations for linezolid and delpazolid at 1.0 mg/liter and 2.0 mg/liter, respectively. Although no significant difference in resistance rates was observed between linezolid and delpazolid among XDR-TB isolates (P > 0.05), statistical analysis revealed a significantly greater proportion of linezolid-resistant isolates than delpazolid-resistant isolates within the MDR-TB group (P = 0.036). Seven (53.85%) of 13 linezolid-resistant isolates were found to harbor mutations within the three target genes. Additionally, 1 isolate exhibited an amino acid substitution (Arg126His) within the protein encoded by rplD that contributed to high-level resistance to linezolid (MIC of >16 mg/liter), compared to a delpazolid MIC of 0.25. In conclusion, in vitro susceptibility testing revealed that delpazolid antibacterial activity was comparable to that of linezolid. A novel mutation within rplD that endowed M. tuberculosis with linezolid, but not delpazolid, resistance was identified.


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 62 (1) ◽  
Author(s):  
Manoon Leechawengwongs ◽  
Therdsak Prammananan ◽  
Sarinya Jaitrong ◽  
Pamaree Billamas ◽  
Nampueng Makhao ◽  
...  

ABSTRACT New fluoroquinolones (FQs) have been shown to be more active against drug-resistant Mycobacterium tuberculosis strains than early FQs, such as ofloxacin. Sitafloxacin (STFX) is a new fluoroquinolone with in vitro activity against a broad range of bacteria, including M. tuberculosis. This study aimed to determine the in vitro activity of STFX against all groups of drug-resistant strains, including multidrug-resistant M. tuberculosis (MDR M. tuberculosis), MDR M. tuberculosis with quinolone resistance (pre-XDR), and extensively drug-resistant (XDR) strains. A total of 374 drug-resistant M. tuberculosis strains were tested for drug susceptibility by the conventional proportion method, and 95 strains were randomly submitted for MIC determination using the microplate alamarBlue assay (MABA). The results revealed that all the drug-resistant strains were susceptible to STFX at a critical concentration of 2 μg/ml. Determination of the MIC90s of the strains showed different MIC levels; MDR M. tuberculosis strains had a MIC90 of 0.0625 μg/ml, whereas pre-XDR and XDR M. tuberculosis strains had identical MIC90s of 0.5 μg/ml. Common mutations within the quinolone resistance-determining region (QRDR) of gyrA and/or gyrB did not confer resistance to STFX, except that double mutations of GyrA at Ala90Val and Asp94Ala were found in strains with a MIC of 1.0 μg/ml. The results indicated that STFX had potent in vitro activity against all the groups of drug-resistant M. tuberculosis strains and should be considered a new repurposed drug for treatment of multidrug-resistant and extensively drug-resistant TB.


2017 ◽  
Vol 62 (1) ◽  
Author(s):  
Helio S. Sader ◽  
Rodrigo E. Mendes ◽  
Michael A. Pfaller ◽  
Dee Shortridge ◽  
Robert K. Flamm ◽  
...  

ABSTRACT A total of 10,451 contemporary (2016) Enterobacteriaceae isolates from 84 U.S. medical centers and 116 metallo-β-lactamase- and/or OXA-48-like-producing Enterobacteriaceae isolates from other countries were tested against aztreonam-avibactam and comparators. All U.S. isolates were inhibited at aztreonam-avibactam MICs of ≤8 μg/ml (MIC50, ≤0.03 μg/ml; MIC90, 0.12 μg/ml), including Klebsiella pneumoniae carbapenemase-producing isolates (n = 102; MIC50, 0.25 μg/ml; MIC90, 0.5 μg/ml), multidrug-resistant isolates (n = 876; MIC50, 0.06 μg/ml; MIC90, 0.25 μg/ml), and extensively drug-resistant isolates (n = 111; MIC50, 0.12 μg/ml; MIC90, 0.5 μg/ml). The highest aztreonam-avibactam MIC value among ex-U.S. isolates was 4 μg/ml.


2019 ◽  
Vol 85 (9) ◽  
Author(s):  
Jongsoo Jeon ◽  
Dongeun Yong

ABSTRACT Extensively drug-resistant Pseudomonas aeruginosa (XDR-PA) is a life-threatening pathogen that causes serious global problems. Here, we investigated two novel P. aeruginosa bacteriophages (phages), Bϕ-R656 and Bϕ-R1836, in vitro, in silico, and in vivo to evaluate the potential of phage therapy to control XDR-PA clinical strains. Bϕ-R656 and Bϕ-R1836 belong to the Siphoviridae family and exhibited broad host ranges which could lyse 18 (64%) and 14 (50%) of the 28 XDR-PA strains. In addition, the two phages showed strong bacteriolytic activity against XDR-PA host strains from pneumonia patients. The whole genomes of Bϕ-R656 and Bϕ-R1836 have linear double-stranded DNA of 60,919 and 37,714 bp, respectively. The complete sequence of Bϕ-R656 had very low similarity to the previously discovered P. aeruginosa phages in GenBank, but phage Bϕ-R1836 exhibited 98% and 91% nucleotide similarity to Pseudomonas phages YMC12/01/R24 and PA1/KOR/2010, respectively. In the two in vivo infection models, treatment with Bϕ-R656 and Bϕ-R1836 enhanced the survival of Galleria mellonella larvae (50% and 60%, respectively) at 72 h postinfection and pneumonia-model mice (66% and 83%, respectively) at 12 days postinfection compared with untreated controls. Treatment with Bϕ-R656 or Bϕ-R1836 also significantly decreased the bacterial load in the lungs of the mouse pneumonia model (>6 log10 CFU and >4 log10 CFU, respectively) on day 5. IMPORTANCE In this study, two novel P. aeruginosa phages, Bϕ-R656 and Bϕ-R1836, were evaluated in vitro, in silico, and in vivo for therapeutic efficacy and safety as an alternative antibacterial agent to control XDR-PA strains collected from pneumonia patients. Both phages exhibited potent bacteriolytic activity and greatly improved survival in G. mellonella larva infection and a mouse acute pneumonia model. Based on these results, we strongly predict that these two new phages could be used as fast-acting and safe alternative biological weapons against XDR-PA infections.


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