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1. Activity of Aztreonam-avibactam and other β-lactamase inhibitor combinations against Gram-negative bacteria isolated from patients hospitalized with pneumonia in United States medical centers (2020–2022)

Author: Helio S. Sader, Rodrigo E. Mendes, S. J. Ryan Arends, Timothy B. Doyle, and Mariana Castanheira
Subjects: Nosocomial pneumonia, Enterobacterales, CRE, Pseudomonas aeruginosa, Stenotrophomonas maltophilia, Metallo-beta-lactamase, Diseases of the respiratory system, RC705-779
Abstract: Abstract Background Initial antimicrobial therapy for pneumonia is frequently empirical and resistance to antimicrobial agents represents a great challenge to the treatment of patients hospitalized with pneumonia. We evaluated the frequency and antimicrobial susceptibility of Gram-negative bacteria causing pneumonia in US hospitals. Methods Bacterial isolates were consecutively collected (1/patient) from patients hospitalized with pneumonia and the susceptibility of Gram-negative bacilli (3,911 Enterobacterales and 2,753 non-fermenters) was evaluated by broth microdilution in a monitoring laboratory. Isolates were collected in 69 medical centers in 2020–2022. Aztreonam-avibactam was tested with avibactam at fixed 4 mg/L and a pharmacokinetic/pharmacodynamic susceptible (S) breakpoint of ≤ 8 mg/L was applied for comparison. Carbapenem-resistant Enterobacterales (CRE; isolates with MIC values of > 2 mg/L for imipenem and/or meropenem) isolates were screened for carbapenemases by whole genome sequencing. Results Gram-negative bacilli represented 71.1% of organisms. The most common Gram-negative species were Pseudomonas aeruginosa (22.4% of organisms), Klebsiella pneumoniae (8.8%), Escherichia coli (6.6%), Serratia marcescens (6.2%), Stenotrophomonas maltophilia (4.9%), and Enterobacter cloacae complex (4.8%). Aztreonam-avibactam inhibited 100.0% of Enterobacterales at ≤ 8 mg/L and 99.9% at ≤ 4 mg/L and showed potent activity against CRE (MIC50/90, 0.25/1 mg/L). Ceftazidime-avibactam and meropenem-vaborbactam were active against 89.4% and 88.5% of CREs, respectively. Aztreonam-avibactam retained activity against Enterobacterales non-susceptible to ceftazidime-avibactam and/or meropenem-vaborbactam (n = 19; MIC50/90, 0.25/4 mg/L). The most common carbapenemases were KPC (69.2% of CREs), NDM (9.6%), and SME (4.8%). A carbapenemase gene was not identified in 16.3% of CREs. Ceftazidime-avibactam and meropenem-vaborbactam were highly active against KPC and SME producers but showed limited activity against MBL producers. The most active comparators against CRE were tigecycline (95.2%S), amikacin (73.1%S), and gentamicin (60.6%S). Among Pseudomonas aeruginosa, 79.1% were inhibited at ≤ 8 mg/L of aztreonam-avibactam, 77.2% were meropenem susceptible, and 77.2% were piperacillin-tazobactam susceptible. Aztreonam-avibactam was highly active against S. maltophilia, inhibiting 99.5% of isolates at ≤ 8 mg/L. Conclusions Aztreonam-avibactam displayed potent in vitro activity against a large collection of contemporary Gram-negative organisms isolated from patients hospitalized with pneumonia, including CRE isolates resistant to ceftazidime-avibactam and/or meropenem-vaborbactam. Results of surveillance programs are valuable for planning empiric antimicrobial therapy guidelines and infection control measures.
Published: 2025
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2. The plethora of resistance mechanisms in Pseudomonas aeruginosa: transcriptome analysis reveals a potential role of lipopolysaccharide pathway proteins to novel β-lactam/β-lactamase inhibitor combinations

Author: Mariana Castanheira, Timothy B. Doyle, Cory M. Hubler, Timothy D. Collingsworth, Sean DeVries, and Rodrigo E. Mendes
Subjects: Pseudomonas aeruginosa, Transcriptome, β-lactam resistance, Microbiology, QR1-502
Abstract: ABSTRACT: Objectives: Whole genome and transcriptome analysis of 213 Pseudomonas aeruginosa isolates resistant to antipseudomonal β-lactams collected in 30 countries was performed to evaluate resistance mechanisms against these agents. Methods: Isolates were susceptibility tested by reference broth microdilution. Whole genome and transcriptome sequencing were performed, and data were analysed using open-source tools. A statistical analysis of changes in the expression of >5500 genes was compared to the expression of PAO1. Results: The high-risk clones ST235 and ST111 were the most prevalent among >90 sequence types (STs). Metallo-β-lactamase (MBLs) genes were detected in 40 isolates. AmpC and MexXY were the most common genes overexpressed in approximately 50% of the 173 isolates that did not carry MBLs. Isolates overexpressing pmrA and pmrB, the norspermidine production genes speD2 and speE2, and the operon arnBCADTEF-ugd were noted among strains resistant to ceftolozane-tazobactam and ceftazidime-avibactam, despite the lack of polymyxin resistance often associated to increased expression of these genes. Overexpression of MuxABC-OpmB, OprG, and OprE proteins were associated with resistance to ceftolozane-tazobactam in addition to the usual genes involved in cephalosporin, monobactam, and carbapenem resistance. Statistical analysis identified discrete mutations in ArmZ, OprD, and AmpC that correlated to antipseudomonal β-lactam resistance. Conclusions: P. aeruginosa resistance mechanisms are complex. This analysis suggests the role of multiple genes in resistance to antipseudomonal β-lactams, including some not commonly described.
Published: 2022
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3. Vaborbactam increases meropenem susceptibility in Pseudomonas aeruginosa clinical isolates displaying MexXY and AmpC upregulation

Author: Mariana Castanheira, Timothy B. Doyle, Cory M. Hubler, Sean DeVries, and Dee Shortridge
Subjects: P. aeruginosa, β-lactam/β-lactamase inhibitor combinations, efflux, Microbiology, QR1-502
Abstract: ABSTRACT To evaluate the resistance mechanisms among Pseudomonas aeruginosa clinical isolates exhibiting meropenem (MEM) MIC values higher than meropenem-vaborbactam (MEV). P. aeruginosa clinical isolates collected in US hospitals from 2014 to 2019 were susceptibility tested. Whole-genome and transcriptome sequencing were performed. Results were analyzed for strain typing, acquired β-lactamases, and mutations in chromosomal genes; gene expression was measured for known β-lactam resistance contributors. Results were compared to a control group of 10 P. aeruginosa isolates displaying MIC values at 8 mg/L for meropenem ± vaborbactam (MEM = MEV). Out of 88 isolates displaying MEM > MEV, 33 (37.5%) isolates had reproducibly lower MIC values for meropenem-vaborbactam compared to meropenem when retested. The expression of mexX, mexY, mexZ, and ampC was significantly greater among a higher percentage of the MEM > MEV isolates. Furthermore, the association of mexXY and ampC overexpression was detected in 17/33 MEM > MEV isolates and only 1/10 MEM = MEV isolate. In addition, the Pseudomonas-derived cephalosporinase amino acid substitution R79Q was detected among 33.3% of the isolates displaying MEM > MEV, and none of the isolates displayed MEM = MEV. Other resistance mechanisms were not observed or were equally observed in both groups. In rare cases, vaborbactam plays a role in lowering the meropenem MIC values in P. aeruginosa clinical isolates likely due to the inhibition of the AmpC gene that was overexpressed in the presence of upregulation of MexXY with or without alterations in the AmpC gene. IMPORTANCE Pseudomonas aeruginosa isolates are intrinsically resistant to multiple antimicrobial agents and meropenem is an important therapeutic option to treat infections caused by this organism. Meropenem-vaborbactam activity is similar to that of meropenem alone against P. aeruginosa isolates. Isolates belonging to this species that display lower meropenem-vaborbactam compared to meropenem are rare. We initiated this study to understand the resistance mechanisms that could lead to lower meropenem-vaborbactam MIC values when compared to meropenem alone. We documented that isolates displaying lower meropenem-vaborbactam exhibited overexpression of MexXY and AmpC. In addition, isolates displaying the R79Q PDC (AmpC) mutation were more likely to display lower meropenem-vaborbactam when compared to isolates displaying the same MIC values for these agents.
Published: 2023
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4. Engineered phage with antibacterial CRISPR–Cas selectively reduce E. coli burden in mice

Author: Yilmaz Emre Gencay, Džiuginta Jasinskytė, Camille Robert, Szabolcs Semsey, Virginia Martínez, Anders Østergaard Petersen, Katja Brunner, Ana de Santiago Torio, Alex Salazar, Iszabela Cristiana Turcu, Melissa Kviesgaard Eriksen, Lev Koval, Adam Takos, Ricardo Pascal, Thea Staffeldt Schou, Lone Bayer, Tina Bryde, Katja Chandelle Johansen, Emilie Glad Bak, Frenk Smrekar, Timothy B. Doyle, Michael J. Satlin, Aurelie Gram, Joana Carvalho, Lene Jessen, Björn Hallström, Jonas Hink, Birgitte Damholt, Alice Troy, Mette Grove, Jasper Clube, Christian Grøndahl, Jakob Krause Haaber, Eric van der Helm, Milan Zdravkovic, and Morten Otto Alexander Sommer
Subjects: Biomedical Engineering, Molecular Medicine, Bioengineering, Applied Microbiology and Biotechnology, Biotechnology
Abstract: Antibiotic treatments have detrimental effects on the microbiome and lead to antibiotic resistance. To develop a phage therapy against a diverse range of clinically relevant Escherichia coli, we screened a library of 162 wild-type (WT) phages, identifying eight phages with broad coverage of E. coli, complementary binding to bacterial surface receptors, and the capability to stably carry inserted cargo. Selected phages were engineered with tail fibers and CRISPR–Cas machinery to specifically target E. coli. We show that engineered phages target bacteria in biofilms, reduce the emergence of phage-tolerant E. coli and out-compete their ancestral WT phages in coculture experiments. A combination of the four most complementary bacteriophages, called SNIPR001, is well tolerated in both mouse models and minipigs and reduces E. coli load in the mouse gut better than its constituent components separately. SNIPR001 is in clinical development to selectively kill E. coli, which may cause fatal infections in hematological cancer patients.
Published: 2023
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5. Prevalence of carbapenemase genes among carbapenem-nonsusceptible Enterobacterales collected in US hospitals in a five-year period and activity of ceftazidime/avibactam and comparator agents

Author: Mariana Castanheira, Lalitagauri M Deshpande, Rodrigo E Mendes, Timothy B Doyle, and Helio S Sader
Subjects: General Medicine
Abstract: Objectives To evaluate the prevalence of acquired β-lactamase genes and susceptibility profiles of carbapenem-nonsusceptible Enterobacterales (CNSE) clinical isolates collected in US hospitals during a 5-year period. Methods Isolates were susceptibility tested by reference broth microdilution methods. Results were interpreted using CLSI breakpoints. Isolates displaying nonsusceptible MICs for imipenem or meropenem were categorized as CNSE. CNSE isolates were screened for β-lactamase-encoding genes using whole-genome sequencing. New genes were cloned, expressed in an Escherichia coli background and susceptibility tested. Results A total of 450 (1.3%) isolates were CNSE. Klebsiella pneumoniae serine carbapenemase (KPC) production was the most common resistance mechanism among CNSE isolates: 281/450 (62.4%) carried blaKPC, including three new variants. OXA-48-like and metallo-β-lactamase (MBL) encoding genes were detected among seven and 12 isolates, respectively. Among MBL genes, blaNDM-1 was the most common, but blaNDM-5, blaVIM-1 and blaIMP-27 were also identified. 169 (37.6% of the CNSE) isolates did not produce carbapenemases. Ceftazidime/avibactam was the most active agent (95.0% to 100.0% susceptible) against CNSE isolates from all carbapenemase groups except MBL-producing isolates. Ceftazidime/avibactam, meropenem/vaborbactam and imipenem/relebactam inhibited 100.0%, 97.6% and 92.3% of the non-carbapenemase CNSE isolates, respectively. Among the three new blaKPC variants, one conferred resistance to ceftazidime/avibactam and low meropenem MIC results while the other two had profiles similar to blaKPC-2 or blaKPC-3. Conclusions A decline in carbapenemase production was noticed in US hospitals in the 5-year period analysed in this study. New β-lactam/β-lactamase inhibitor combinations tested had good activity against CNSE isolates.
Published: 2022
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6. Investigation of mechanisms responsible for decreased susceptibility of aztreonam/avibactam activity in clinical isolates of Enterobacterales collected in Europe, Asia and Latin America in 2019

Author: Rodrigo E. Mendes, Jennifer M. Streit, Timothy B Doyle, Helio S. Sader, Francis F. Arhin, and Mariana Castanheira
Subjects: Microbiology (medical), Penicillin binding proteins, Sequence analysis, Klebsiella pneumoniae, Avibactam, Microbial Sensitivity Tests, Aztreonam, medicine.disease_cause, Ceftazidime, beta-Lactamases, Microbiology, chemistry.chemical_compound, Escherichia coli, medicine, AcademicSubjects/MED00740, Pharmacology (medical), Original Research, Pharmacology, biology, biology.organism_classification, Anti-Bacterial Agents, Drug Combinations, AcademicSubjects/MED00290, Latin America, Infectious Diseases, chemistry, AcademicSubjects/MED00230, Azabicyclo Compounds, Enterobacter cloacae, Bacteria
Abstract: Background The combination aztreonam/avibactam is currently under Phase 3 trials for the treatment of serious infections caused by Gram-negative bacteria including those with MBLs. Objectives To investigate the resistance mechanisms in Enterobacterales exhibiting aztreonam/avibactam MICs of ≥4 mg/L. Methods Among 8787 Enterobacterales, 17 (0.2%) isolates exhibited an aztreonam/avibactam MIC of ≥4 mg/L. Isolates were sequenced and screened for β-lactamases. Sequences of porins, penicillin-binding protein 3 (PBP3) and expression levels of AmpC and AcrA were evaluated. Results Eleven (11/4154 isolates; 0.26%) Escherichia coli, three (3/1981; 0.15%) Klebsiella pneumoniae and three (3/628; 0.5%) Enterobacter cloacae were identified. All E. coli showed either an ‘YRIK’ or ‘YRIN’ insertion in PBP3. In general, these isolates carried blaCMY and/or blaCTX-M variants, except for one isolate from Korea that also produced NDM-5 and one isolate from Turkey that produced OXA-48. Two DHA-1-producing K. pneumoniae overexpressed acrA and had a premature stop codon in either OmpK35 or OmpK36, whereas a third K. pneumoniae carried blaPER-2 and had a premature stop codon in OmpK35. All three E. cloacae expressed AmpC at levels ≥570-fold, but sequence analysis did not reveal known amino acid alterations associated with decreased avibactam binding or increased hydrolysis of β-lactams. Minor amino acid polymorphisms within OmpC, OmpF and PBP3 were noted among the E. cloacae. Conclusions A small number of isolates (0.2%) met the inclusion criteria. E. coli showed altered PBP3 as the most relevant resistance mechanism, whereas K. pneumoniae had multiple resistance mechanisms. Further investigations are needed to clarify resistance in E. cloacae.
Published: 2021
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7. Antimicrobial Activity of Ceftazidime-Avibactam, Ceftolozane-Tazobactam and Comparators Tested Against Pseudomonas aeruginosa and Klebsiella pneumoniae Isolates from United States Medical Centers in 2016–2018

Author: Helio S. Sader, Cecilia G Carvalhaes, Mariana Castanheira, Timothy B Doyle, and Jennifer M. Streit
Subjects: Microbiology (medical), Klebsiella pneumoniae, medicine.drug_class, Immunology, Cephalosporin, medicine.disease_cause, Microbiology, Meropenem, 03 medical and health sciences, polycyclic compounds, Medicine, 030304 developmental biology, Pharmacology, 0303 health sciences, biology, 030306 microbiology, business.industry, Pseudomonas aeruginosa, Broth microdilution, biochemical phenomena, metabolism, and nutrition, bacterial infections and mycoses, Ceftazidime/avibactam, biology.organism_classification, Antimicrobial, Amikacin, business, medicine.drug
Abstract: Very few antimicrobial agents remain active against Pseudomonas aeruginosa and Klebsiella pneumoniae in some geographic regions. We evaluated the in vitro activity of ceftazidime-avibactam, ceftolozane-tazobactam, and comparator agents against 6,210 P. aeruginosa and 6,041 K. pneumoniae isolates consecutively collected from 85 U.S. medical centers across 37 states in 2016-2018. Antimicrobial susceptibility was determined by reference broth microdilution method. K. pneumoniae isolates found to have elevated MICs for broad-spectrum cephalosporins were submitted to whole-genome sequencing analysis to detect resistance genes. Ceftazidime-avibactam (97.1% susceptible [S]) and ceftolozane-tazobactam (97.0%S) were the most active compounds against P. aeruginosa and retained activity against meropenem-nonsusceptible (88.5-89.0%S), piperacillin-tazobactam-nonsusceptible (86.6-87.0%S), and other resistant subsets of isolates. The most active agents against K. pneumoniae per CLSI criteria were ceftazidime-avibactam (>99.9%S), amikacin (98.4%S), and meropenem (97.1%S). Ceftolozane-tazobactam was active against 95.3% of K. pneumoniae but showed limited activity against extended-spectrum β-lactamase and carbapenemase producers (82.9% and 0.0%S, respectively).
Published: 2021
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8. 1078. Optimization of a 96-well Plate Format Assay to Evaluate Concentration-Dependent Activity of a Monoclonal Antibody Against the O Antigen O25b from ST131-H30 Escherichia coli

Author: Jill Lindley, Timothy B Doyle, Brian D VanScoy, Christopher M Rubino, Sujata M Bhavnani, Paul G Ambrose, and Mariana Castanheira
Subjects: Infectious Diseases, Oncology
Abstract: Background Escherichia coli ST131 is a major challenge for global human health. Among ST131 isolates, the H30 type is prevalent and displays multiple drug resistance to classes. A monoclonal antibody (mAb) specific for the O antigen, O25b, which is conserved in ST131-H30 clonal lineage, was developed for diagnostic and prophylactic therapy. We optimized a 96-well plate assay to test different concentrations of the mAb against E. coli clinical isolates. Methods Initial growth curves were performed against 69 ST131-O25b, 9 ST131-O25a, 32 ST131 non-O25, and 29 non-ST131 E. coli isolates in 40% active human serum (HS). Additional conditions evaluated for growth inhibition by the mAb included 3 media types, 3 HS sources, pH variations, addition of polysorbate 80 (P80), inoculum concentration, length of incubation, and varying calcium and magnesium concentrations. Once optimal parameters were established, the assay was miniaturized into a 96-well format and 12 ST131-O25b and 5 non-ST131 were tested. Fluorescence and visual reading using alamarBlue (AB), a cell metabolism indicator, were performed at 8 and 10h in addition to plating for viable colonies. Results After 10h incubation, only 36/69 (52.2%) ST131-O25b isolates exhibited visible growth in BHI plus 40% HS. A 2-part growth inhibition assay using BHI plus 50% HS and BHI with 25% HS without the addition of P80, calcium, or magnesium was considered the optimal growth condition for EC strains to test the effect of the mAb. By 10 hours, all ST131-O25b strains displayed a visual inhibition of growth between 0.3-5 mg/L of α-ST131 mAb and zero non-ST131 strains were inhibited (Figure). While reading AB on a fluorometer was more sensitive and less subjective than visual interpretation, both reading methods allow for endpoint determinations. Additionally, panels were able to go through one freeze-thaw cycle and still retain α-ST131:O25b mAb activity. Conclusion Concentration-dependent activity of a α-ST131:O25b mAb can be measured in vitro in a microtiter format; however, the growth inhibition by HS, while still providing enough complement for complement-mediated mAb killing, might be an obstacle. Additionally, assay reproducibility may be difficult without a consistent source of active HS. Figure Disclosures Jill Lindley, Bravos Biosciences (Research Grant or Support)ContraFect Corporation (Research Grant or Support)Pfizer, Inc. (Research Grant or Support)Qpex Biopharma (Research Grant or Support) Timothy B. Doyle, AbbVie (formerly Allergan) (Research Grant or Support)Bravos Biosciences (Research Grant or Support)GlaxoSmithKline (Research Grant or Support)Melinta Therapeutics, Inc. (Research Grant or Support)Pfizer, Inc. (Research Grant or Support)Shionogi (Research Grant or Support)Spero Therapeutics (Research Grant or Support) Brian D. VanScoy, B.S., 3-V Biosciences (Grant/Research Support)Achogen (Grant/Research Support)Amplyx Pharmaceuticals, Inc. (Grant/Research Support)Arixa Pharmaceuticals (Grant/Research Support)Arsanis Inc. (Grant/Research Support)B. Braun Medical Inc. (Grant/Research Support)Basilea Pharmaceutica (Grant/Research Support)BLC USA (Grant/Research Support)Boston Pharmaceuticals (Grant/Research Support)Bravos Biosciences, LLC (Grant/Research Support)Cidara Therapeutics Inc. (Grant/Research Support)Cipla, USA (Grant/Research Support)Corcept Therapeutics (Grant/Research Support)Cumberland Pharmaceuticals (Grant/Research Support)Debiopharm International SA (Grant/Research Support)Discuva Limited (Grant/Research Support)Emerald Lake Technologies (Grant/Research Support)Enhanced Pharmacodynamics (Grant/Research Support)Entasis Therapeutics (Grant/Research Support)E-Scape Bio (Grant/Research Support)Genentech (Grant/Research Support)Geom Therapeutics, Inc. (Grant/Research Support)GlaxoSmithKline (Grant/Research Support)Hoffmann-La Roche (Grant/Research Support)Horizon Orphan LLC (Grant/Research Support)ICPD Biosciences, LLC (Grant/Research Support)Indalo Therapeutics (Grant/Research Support)Insmed Inc. (Grant/Research Support)Institute for Clinical Pharmacodynamics (Employee)Iterum (Grant/Research Support)KBP Biosciences USA (Grant/Research Support)Kyoto Biopharma, Inc. (Grant/Research Support)Matinas (Grant/Research Support)Meiji Seika Pharma Co., Ltd. (Grant/Research Support)Melinta Therapeutics (Grant/Research Support)Menarini Ricerche S.p.A. (Grant/Research Support)Merck & Co., Inc (Grant/Research Support)Mutabilis (Grant/Research Support)Nabriva Therapeutics AG (Grant/Research Support)Naeja-RGM Pharmaceuticals (Grant/Research Support)Nosopharm SAS (Grant/Research Support)Novartis Pharmaceuticals Corp. (Grant/Research Support)NuCana Biomed (Grant/Research Support)Paratek Pharmaceuticals, Inc. (Grant/Research Support)Polyphor, Ltd. (Grant/Research Support)Prothena Corporation (Grant/Research Support)PTC Therapeutics (Grant/Research Support)Rempex Pharmaceuticals (Grant/Research Support)Roche TCRC (Grant/Research Support)Sagimet (Grant/Research Support)scPharmaceuticals Inc. (Grant/Research Support)Scynexis (Grant/Research Support)Spero Therapeutics (Grant/Research Support)TauRx Therapeutics (Grant/Research Support)Tetraphase Pharmaceuticals (Grant/Research Support)Theravance Biopharma Pharmaceutica (Grant/Research Support)USCAST (Grant/Research Support)VenatoRx (Grant/Research Support)Vical Incorporated (Grant/Research Support)Wockhardt Bio AG (Grant/Research Support)Zavante Therapeutics (Grant/Research Support)Zogenix International (Grant/Research Support) Christopher M. Rubino, Pharm.D., 3-V Biosciences (Grant/Research Support)Achogen (Grant/Research Support)Amplyx Pharmaceuticals, Inc. (Grant/Research Support)Arixa Pharmaceuticals (Grant/Research Support)Arsanis Inc. (Grant/Research Support)B. Braun Medical Inc. (Grant/Research Support)Basilea Pharmaceutica (Grant/Research Support)BLC USA (Research Grant or Support)Boston Pharmaceuticals (Grant/Research Support)Bravos Biosciences, LLC (Grant/Research Support, Other Financial or Material Support, member/owner)Cidara Therapeutics Inc. (Grant/Research Support)Cipla, USA (Grant/Research Support)Corcept Therapeutics (Grant/Research Support)Cumberland Pharmaceuticals (Grant/Research Support)Debiopharm International SA (Grant/Research Support)Discuva Limited (Grant/Research Support)Emerald Lake Technologies (Grant/Research Support)Enhanced Pharmacodynamics (Grant/Research Support)Entasis Therapeutics (Grant/Research Support)E-Scape Bio (Grant/Research Support)Genentech (Grant/Research Support)Geom Therapeutics, Inc. (Grant/Research Support)GlaxoSmithKline (Grant/Research Support)Hoffmann-La Roche (Grant/Research Support)Horizon Orphan LLC (Grant/Research Support)ICPD Biosciences, LLC (Grant/Research Support, Other Financial or Material Support, member/owner)Indalo Therapeutics (Grant/Research Support)Insmed Inc. (Grant/Research Support)Institute for Clinical Pharmacodynamics (Employee)Iterum (Grant/Research Support)KBP Biosciences USA (Grant/Research Support)Kyoto Biopharma, Inc. (Grant/Research Support)Matinas (Grant/Research Support)Meiji Seika Pharma Co., Ltd. (Grant/Research Support)Melinta Therapeutics (Grant/Research Support)Menarini Ricerche S.p.A. (Grant/Research Support)Merck & Co., Inc (Grant/Research Support)Mutabilis (Grant/Research Support)Nabriva Therapeutics AG (Grant/Research Support)Naeja-RGM Pharmaceuticals (Grant/Research Support)Nosopharm SAS (Grant/Research Support)Novartis Pharmaceuticals Corp. (Grant/Research Support)NuCana Biomed (Grant/Research Support)Paratek Pharmaceuticals, Inc. (Grant/Research Support)Polyphor, Ltd. (Grant/Research Support)Prothena Corporation (Grant/Research Support)PTC Therapeutics (Grant/Research Support)Rempex Pharmaceuticals (Grant/Research Support)Roche TCRC (Grant/Research Support)Sagimet (Grant/Research Support)scPharmaceuticals Inc. (Grant/Research Support)Scynexis (Grant/Research Support)Spero Therapeutics (Grant/Research Support)TauRx Therapeutics (Grant/Research Support)Tetraphase Pharmaceuticals (Grant/Research Support)Theravance Biopharma Pharmaceutica (Grant/Research Support)USCAST (Grant/Research Support)VenatoRx (Grant/Research Support)Vical Incorporated (Grant/Research Support)Wockhardt Bio AG (Grant/Research Support)Zavante Therapeutics (Grant/Research Support)Zogenix International (Grant/Research Support) Sujata M. Bhavnani, Pharm.D., M.S., FIDSA, 3-V Biosciences (Grant/Research Support)Achogen (Grant/Research Support)Amplyx Pharmaceuticals, Inc. (Grant/Research Support)Arixa Pharmaceuticals (Grant/Research Support)Arsanis Inc. (Grant/Research Support)B. Braun Medical Inc. (Grant/Research Support)Basilea Pharmaceutica (Grant/Research Support)BLC USA (Grant/Research Support)Boston Pharmaceuticals (Grant/Research Support)Bravos Biosciences, LLC (Grant/Research Support, Other Financial or Material Support, member/owner)Cidara Therapeutics Inc. (Grant/Research Support)Cipla, USA (Grant/Research Support)Corcept Therapeutics (Grant/Research Support)Cumberland Pharmaceuticals (Grant/Research Support)Debiopharm International SA (Grant/Research Support)Discuva Limited (Grant/Research Support)Emerald Lake Technologies (Grant/Research Support)Enhanced Pharmacodynamics (Grant/Research Support)Entasis Therapeutics (Grant/Research Support)E-Scape Bio (Grant/Research Support)Genentech (Grant/Research Support)Geom Therapeutics, Inc. (Grant/Research Support)GlaxoSmithKline (Grant/Research Support)Hoffmann-La Roche (Grant/Research Support)Horizon Orphan LLC (Grant/Research Support)ICPD Biosciences, LLC (Grant/Research Support, Other Financial or Material Support, member/owner)Indalo Therapeutics (Grant/Research Support)Insmed Inc. (Grant/Research Support)Institute for Clinical Pharmacodynamics (Employee)Iterum (Grant/Research Support)KBP Biosciences USA (Grant/Research Support)Kyoto Biopharma, Inc. (Grant/Research Support)Matinas (Grant/Research Support)Meiji Seika Pharma Co., Ltd. (Grant/Research Support)Melinta Therapeutics (Grant/Research Support)Menarini Ricerche S.p.A. (Grant/Research Support)Merck & Co., Inc (Grant/Research Support)Mutabilis (Grant/Research Support)Nabriva Therapeutics AG (Grant/Research Support)Naeja-RGM Pharmaceuticals (Grant/Research Support)Nosopharm SAS (Grant/Research Support)Novartis Pharmaceuticals Corp. (Grant/Research Support)NuCana Biomed (Grant/Research Support)Paratek Pharmaceuticals, Inc. (Grant/Research Support)Polyphor, Ltd. (Grant/Research Support)Prothena Corporation (Grant/Research Support)PTC Therapeutics (Grant/Research Support)Rempex Pharmaceuticals (Grant/Research Support)Roche TCRC (Grant/Research Support)Sagimet (Grant/Research Support)scPharmaceuticals Inc. (Grant/Research Support)Scynexis (Grant/Research Support)Spero Therapeutics (Grant/Research Support)TauRx Therapeutics (Grant/Research Support)Tetraphase Pharmaceuticals (Grant/Research Support)Theravance Biopharma Pharmaceutica (Grant/Research Support)USCAST (Grant/Research Support)VenatoRx (Grant/Research Support)Vical Incorporated (Grant/Research Support)Wockhardt Bio AG (Grant/Research Support)Zavante Therapeutics (Grant/Research Support)Zogenix International (Grant/Research Support) Paul G. Ambrose, Pharm.D., FIDSA, 3-V Biosciences (Grant/Research Support)Achogen (Grant/Research Support)Amplyx Pharmaceuticals, Inc. (Grant/Research Support)Arixa Pharmaceuticals (Grant/Research Support)Arsanis Inc. (Grant/Research Support)B. Braun Medical Inc. (Grant/Research Support)Basilea Pharmaceutica (Grant/Research Support)BLC USA (Grant/Research Support)Boston Pharmaceuticals (Grant/Research Support)Bravos Biosciences, LLC (Grant/Research Support, Other Financial or Material Support, member/owner)Cidara Therapeutics Inc. (Grant/Research Support)Cipla, USA (Grant/Research Support)Corcept Therapeutics (Grant/Research Support)Cumberland Pharmaceuticals (Grant/Research Support)Debiopharm International SA (Grant/Research Support)Discuva Limited (Research Grant or Support)Emerald Lake Technologies (Grant/Research Support)Enhanced Pharmacodynamics (Grant/Research Support)Entasis Therapeutics (Grant/Research Support)E-Scape Bio (Grant/Research Support)Genentech (Grant/Research Support)Geom Therapeutics, Inc. (Grant/Research Support)GlaxoSmithKline (Grant/Research Support)Hoffmann-La Roche (Grant/Research Support)Horizon Orphan LLC (Grant/Research Support)ICPD Biosciences, LLC (Grant/Research Support, Other Financial or Material Support, member/owner)Indalo Therapeutics (Grant/Research Support)Insmed Inc. (Grant/Research Support)Institute for Clinical Pharmacodynamics (Employee)Iterum (Grant/Research Support)KBP Biosciences USA (Grant/Research Support)Kyoto Biopharma, Inc. (Grant/Research Support)Matinas (Grant/Research Support)Meiji Seika Pharma Co., Ltd. (Grant/Research Support)Melinta Therapeutics (Grant/Research Support)Menarini Ricerche S.p.A. (Grant/Research Support)Merck & Co., Inc (Grant/Research Support)Mutabilis (Grant/Research Support)Nabriva Therapeutics AG (Grant/Research Support)Naeja-RGM Pharmaceuticals (Grant/Research Support)Nosopharm SAS (Grant/Research Support)Novartis Pharmaceuticals Corp. (Grant/Research Support)NuCana Biomed (Grant/Research Support)Paratek Pharmaceuticals, Inc. (Grant/Research Support)Polyphor, Ltd. (Grant/Research Support)Prothena Corporation (Grant/Research Support)PTC Therapeutics (Grant/Research Support)Rempex Pharmaceuticals (Grant/Research Support)Roche TCRC (Grant/Research Support)Sagimet (Grant/Research Support)scPharmaceuticals Inc. (Grant/Research Support)Scynexis (Grant/Research Support)Spero Therapeutics (Grant/Research Support)TauRx Therapeutics (Grant/Research Support)Tetraphase Pharmaceuticals (Grant/Research Support)Theravance Biopharma Pharmaceutica (Grant/Research Support)USCAST (Grant/Research Support)VenatoRx (Grant/Research Support)Vical Incorporated (Grant/Research Support)Wockhardt Bio AG (Grant/Research Support)Zavante Therapeutics (Grant/Research Support)Zogenix International (Grant/Research Support) Mariana Castanheira, PhD, AbbVie (formerly Allergan) (Research Grant or Support)Bravos Biosciences (Research Grant or Support)Cidara Therapeutics, Inc. (Research Grant or Support)Cipla Therapeutics (Research Grant or Support)Cipla USA Inc. (Research Grant or Support)GlaxoSmithKline (Research Grant or Support)Melinta Therapeutics, Inc. (Research Grant or Support)Melinta Therapeutics, LLC (Research Grant or Support)Pfizer, Inc. (Research Grant or Support)Qpex Biopharma (Research Grant or Support)Shionogi (Research Grant or Support)Spero Therapeutics (Research Grant or Support) Mariana Castanheira, PhD, Affinity Biosensors (Individual(s) Involved: Self): Research Grant or Support; Allergan (Individual(s) Involved: Self): Research Grant or Support; Amicrobe, Inc (Individual(s) Involved: Self): Research Grant or Support; Amplyx Pharma (Individual(s) Involved: Self): Research Grant or Support; Artugen Therapeutics USA, Inc. (Individual(s) Involved: Self): Research Grant or Support; Astellas (Individual(s) Involved: Self): Research Grant or Support; Basilea (Individual(s) Involved: Self): Research Grant or Support; Beth Israel Deaconess Medical Center (Individual(s) Involved: Self): Research Grant or Support; BIDMC (Individual(s) Involved: Self): Research Grant or Support; bioMerieux Inc. (Individual(s) Involved: Self): Research Grant or Support; BioVersys Ag (Individual(s) Involved: Self): Research Grant or Support; Bugworks (Individual(s) Involved: Self): Research Grant or Support; Cidara (Individual(s) Involved: Self): Research Grant or Support; Cipla (Individual(s) Involved: Self): Research Grant or Support; Contrafect (Individual(s) Involved: Self): Research Grant or Support; Cormedix (Individual(s) Involved: Self): Research Grant or Support; Crestone, Inc. (Individual(s) Involved: Self): Research Grant or Support; Curza (Individual(s) Involved: Self): Research Grant or Support; CXC7 (Individual(s) Involved: Self): Research Grant or Support; Entasis (Individual(s) Involved: Self): Research Grant or Support; Fedora Pharmaceutical (Individual(s) Involved: Self): Research Grant or Support; Fimbrion Therapeutics (Individual(s) Involved: Self): Research Grant or Support; Fox Chase (Individual(s) Involved: Self): Research Grant or Support; GlaxoSmithKline (Individual(s) Involved: Self): Research Grant or Support; Guardian Therapeutics (Individual(s) Involved: Self): Research Grant or Support; Hardy Diagnostics (Individual(s) Involved: Self): Research Grant or Support; IHMA (Individual(s) Involved: Self): Research Grant or Support; Janssen Research & Development (Individual(s) Involved: Self): Research Grant or Support; Johnson & Johnson (Individual(s) Involved: Self): Research Grant or Support; Kaleido Biosceinces (Individual(s) Involved: Self): Research Grant or Support; KBP Biosciences (Individual(s) Involved: Self): Research Grant or Support; Luminex (Individual(s) Involved: Self): Research Grant or Support; Matrivax (Individual(s) Involved: Self): Research Grant or Support; Mayo Clinic (Individual(s) Involved: Self): Research Grant or Support; Medpace (Individual(s) Involved: Self): Research Grant or Support; Meiji Seika Pharma Co., Ltd. (Individual(s) Involved: Self): Research Grant or Support; Melinta (Individual(s) Involved: Self): Research Grant or Support; Menarini (Individual(s) Involved: Self): Research Grant or Support; Merck (Individual(s) Involved: Self): Research Grant or Support; Meridian Bioscience Inc. (Individual(s) Involved: Self): Research Grant or Support; Micromyx (Individual(s) Involved: Self): Research Grant or Support; MicuRx (Individual(s) Involved: Self): Research Grant or Support; N8 Medical (Individual(s) Involved: Self): Research Grant or Support; Nabriva (Individual(s) Involved: Self): Research Grant or Support; National Institutes of Health (Individual(s) Involved: Self): Research Grant or Support; National University of Singapore (Individual(s) Involved: Self): Research Grant or Support; North Bristol NHS Trust (Individual(s) Involved: Self): Research Grant or Support; Novome Biotechnologies (Individual(s) Involved: Self): Research Grant or Support; Paratek (Individual(s) Involved: Self): Research Grant or Support; Pfizer (Individual(s) Involved: Self): Research Grant or Support; Prokaryotics Inc. (Individual(s) Involved: Self): Research Grant or Support; QPEX Biopharma (Individual(s) Involved: Self): Research Grant or Support; Rhode Island Hospital (Individual(s) Involved: Self): Research Grant or Support; RIHML (Individual(s) Involved: Self): Research Grant or Support; Roche (Individual(s) Involved: Self): Research Grant or Support; Roivant (Individual(s) Involved: Self): Research Grant or Support; Salvat (Individual(s) Involved: Self): Research Grant or Support; Scynexis (Individual(s) Involved: Self): Research Grant or Support; SeLux Diagnostics (Individual(s) Involved: Self): Research Grant or Support; Shionogi (Individual(s) Involved: Self): Research Grant or Support; Specific Diagnostics (Individual(s) Involved: Self): Research Grant or Support; Spero (Individual(s) Involved: Self): Research Grant or Support; SuperTrans Medical LT (Individual(s) Involved: Self): Research Grant or Support; T2 Biosystems (Individual(s) Involved: Self): Research Grant or Support; The University of Queensland (Individual(s) Involved: Self): Research Grant or Support; Thermo Fisher Scientific (Individual(s) Involved: Self): Research Grant or Support; Tufts Medical Center (Individual(s) Involved: Self): Research Grant or Support; Universite de Sherbrooke (Individual(s) Involved: Self): Research Grant or Support; University of Iowa (Individual(s) Involved: Self): Research Grant or Support; University of Iowa Hospitals and Clinics (Individual(s) Involved: Self): Research Grant or Support; University of Wisconsin (Individual(s) Involved: Self): Research Grant or Support; UNT System College of Pharmacy (Individual(s) Involved: Self): Research Grant or Support; URMC (Individual(s) Involved: Self): Research Grant or Support; UT Southwestern (Individual(s) Involved: Self): Research Grant or Support; VenatoRx (Individual(s) Involved: Self): Research Grant or Support; Viosera Therapeutics (Individual(s) Involved: Self): Research Grant or Support; Wayne State University (Individual(s) Involved: Self): Research Grant or Support
Published: 2021
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9. In Vitro Selection of Enterobacter cloacae with Cefepime, Meropenem, and Ceftazidime-Avibactam Generates Diverse Resistance Mechanisms

Author: Mariana Castanheira, Jill Lindley, Timothy B. Doyle, Andrew P. Davis, and Helio S. Sader
Subjects: Microbiology (medical), Infectious Diseases, Pharmacology (medical), General Medicine
Abstract: We submitted 5 E. cloacae isolates to 10-day serial passage in broth microdilution with cefepime, meropenem, or ceftazidime-avibactam to evaluate MIC increases and resistance mechanisms after exposure. Post-exposure isolates displaying2-fold changes from the parent isolate were analyzed alongside their parent isolate. Overall increase is MIC results of 4- to 256-fold (median: 16-fold) were noted after cefepime exposure, 16- to 128-fold (64-fold) after meropenem, and 2- to 32-fold (8-fold) after ceftazidime-avibactam. Post-exposure isolates had diverse mechanisms identified using a combination of short- and long-whole genome sequencing. All agents selected for AmpC alterations in one isolate set. OmpC and TetA/AcrR regulator alterations were noted in meropenem and ceftazidime-avibactam post-exposure isolates of the same set. Other mutations in AmpC were noted when isolates were exposed to cefepime or ceftazidime-avibactam. A premature stop codon in the cell division inhibitor protein MioC was observed when one parent isolate was exposed to any of the agents, suggesting a cell persistence mechanism. Mutations in less common transporter systems and protein synthesis components were also noted. Cross-resistance to other β-lactams occurred with all agents and resistance mechanisms were diverse with some not usually associated with β-lactam resistance in Enterobacterales. This initial evaluation suggests that cefepime and meropenem select for isolates with higher MIC values when compared to ceftazidime-avibactam. Further studies evaluating these findings should be performed for other species for which the primary β-lactam resistance mechanism is not gene acquisition. These studies should evaluate these observations in vivo to evaluate their translation into patient treatment policies.
Published: 2023
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10. Characterization of Enterobacter cloacae and Citrobacter freundii species complex isolates with decreased susceptibility to cephalosporins from United States hospitals and activity of ceftazidime/avibactam and comparator agents

Author: Andrew P. Davis, Helio S. Sader, Rodrigo E. Mendes, Timothy B Doyle, and M Castanheira
Subjects: biology, Avibactam, Cefepime, Broth microdilution, Ceftazidime, biochemical phenomena, metabolism, and nutrition, Ceftazidime/avibactam, biology.organism_classification, bacterial infections and mycoses, Microbiology, Citrobacter freundii, chemistry.chemical_compound, AcademicSubjects/MED00290, chemistry, Amikacin, medicine, bacteria, AcademicSubjects/MED00740, Original Article, AcademicSubjects/MED00230, Enterobacter cloacae, medicine.drug
Abstract: Objectives To evaluate the antimicrobial susceptibility and resistance mechanisms to β-lactams among Enterobacter cloacae and Citrobacter freundii from United States medical centres. Methods 2571 E. cloacae and 1008 C. freundii species complex isolates were consecutively collected from 77 medical centres and susceptibility tested by broth microdilution method. Isolates displaying MIC values ≥16 mg/L for ceftazidime or ≥2 mg/L for cefepime (n = 914) were tested for β-lactamase-encoding genes using whole genome sequencing. Results Overall susceptibility to ceftazidime and cefepime were 73.9% and 91.2% among E. cloacae and 74.2% and 93.5% among C. freundii, respectively. Sixty-three isolates harboured a carbapenemase gene, including 56 blaKPC, 2 blaNMC-A, and 5 metallo-β-lactamase genes. Among non-carbapenemase producers, 121 isolates had at least one ESBL-encoding gene, mainly blaSHV (81) or blaCTX-M (61), and 15 had a transferable AmpC gene, mainly blaDHA-1 (8) or blaFOX-5 (6). Carbapenemase, ESBL, or transferable AmpC-encoding genes were not identified among 718 of 914 (78.6%) isolates sequenced. The most active agents against isolates with a decreased susceptibility to ceftazidime and/or cefepime were ceftazidime/avibactam (MIC50/90, 0.5/1 mg/L; 99.3% susceptible), amikacin (MIC50/90, 1/4 mg/L; 99.5% susceptible), and meropenem (MIC50/90, 0.06/0.5 mg/L; 92.9% susceptible). The isolates resistant to ceftazidime/avibactam were the five MBL producers and one E. cloacae isolate with a reduced expression of OmpF and overexpression of AcrAB-TolC. Conclusions Hyperproduction of chromosomal AmpC appears to be the most common mechanism of resistance to ceftazidime and/or cefepime in E. cloacae and C. freundii. Ceftazidime/avibactam remained highly active against most isolates showing decreased susceptibility to ceftazidime and/or cefepime.
Published: 2021

11. Antimicrobial activity of ceftazidime/avibactam, ceftolozane/tazobactam and comparator agents against Pseudomonas aeruginosa from cystic fibrosis patients

Author: M Castanheira, Leonard R. Duncan, Timothy B Doyle, and Helio S. Sader
Subjects: business.industry, Avibactam, Ceftazidime, Ceftazidime/avibactam, Tazobactam, Meropenem, Microbiology, chemistry.chemical_compound, chemistry, Piperacillin/tazobactam, polycyclic compounds, medicine, Ceftolozane, business, medicine.drug, Piperacillin
Abstract: Objectives To evaluate the antimicrobial susceptibility patterns of Pseudomonas aeruginosa isolates collected from the lower respiratory tract of cystic fibrosis (CF) patients. Methods We susceptibility tested 273 contemporary P. aeruginosa isolates from 39 hospitals worldwide (17 countries) by the reference broth microdilution method. Results Ceftazidime/avibactam [MIC50/90, 2/8 mg/L; 96.0% susceptible (S)] was the most active agent, followed by ceftolozane/tazobactam (MIC50/90, 1/4 mg/L; 90.5% S), ceftazidime (MIC50/90, 2/>32 mg/L; 80.6% S), piperacillin/tazobactam (MIC50/90, 4/128 mg/L; 80.2% S) and tobramycin (MIC50/90, 2/>16 mg/L; 76.6% S). Ceftazidime/avibactam retained activity against P. aeruginosa isolates non-susceptible to meropenem (86.5% S to ceftazidime/avibactam), piperacillin/tazobactam (85.2% S to ceftazidime/avibactam) or ceftazidime (79.2% S to ceftazidime/avibactam). MDR phenotype was observed among 36.3% of isolates, and 88.9% and 73.7% of MDR isolates were susceptible to ceftazidime/avibactam and ceftolozane/tazobactam, respectively. Against isolates non-susceptible to meropenem, piperacillin/tazobactam and ceftazidime, susceptibility rates were 78.9% for ceftazidime/avibactam and 47.4% for ceftolozane/tazobactam. Ceftazidime/avibactam was active against 65.4% of ceftolozane/tazobactam-non-susceptible isolates and ceftolozane/tazobactam was active against 18.2% of ceftazidime/avibactam-non-susceptible isolates. Conclusions Ceftazidime/avibactam and ceftolozane/tazobactam exhibited potent and broad-spectrum activity against P. aeruginosa isolated from CF patients worldwide, but higher susceptibility rates for ceftazidime/avibactam compared with ceftolozane/tazobactam were observed among the resistant subsets. Ceftazidime/avibactam and ceftolozane/tazobactam represent valuable options to treat CF pulmonary exacerbations caused by P. aeruginosa.
Published: 2021
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12. 1218. Activity of Meropenem-Vaborbactam and Comparator Agents Against Carbapenemase-Negative, Carbapenem-Resistant Enterobacterales from US Hospitals

Author: Mariana Castanheira, Timothy B Doyle, Valerie Kantro, Rodrigo E Mendes, and Dee Shortridge
Subjects: Infectious Diseases, AcademicSubjects/MED00290, Oncology, education, Poster Abstracts, health care economics and organizations
Abstract: Background Meropenem-vaborbactam (MVB) is an important addition to the armamentarium to treat infections caused by carbapenem-resistant Enterobacterales (CREs). Carbapenemase-negative (CN) CRE isolates have been reported, but the activity of newer agents against these isolates is still not well understood. We evaluated the activity of MVB against CN-CRE collected during 6 years of surveillance in US hospitals. Methods A total of 27,968 Enterobacterales isolates collected in US hospitals from 2014-2019 were susceptibility tested by reference broth microdilution methods. Results were interpreted using CLSI 2020 breakpoints. CRE isolates were submitted to PCR/sequencing (2014-2015) or whole genome sequencing (WGS; 2016-2019) for characterization of carbapenemase genes. Isolates from 2016-2019 were evaluated for other beta-lactam resistance mechanisms. Results Among 357 (1.3% of all isolates) CRE isolates identified during 6 years of surveillance, 48 (13.4% of the CRE) isolates did not produce known carbapenemases. The CN-CRE collection included 7 bacterial, species, or species complex. The top four most common species in the collection were K. pneumoniae (16 isolates) followed by E. cloacae (9), E. coli (8), and K. aerogenes (8). MVB was the most active agent tested against these isolates, inhibiting 47/48 (97.9%) of the isolates tested. The only isolate displaying a resistant MIC for MVB was a P. mirabilis (MIC, 16 mg/L) collected in 2015. Meropenem alone inhibited only 2.1% of the isolates. Other beta-lactams inhibited 4.2 to 14.6% of the isolates. Among non-beta-lactam comparator agents, tigecycline and amikacin inhibited 93.8 and 91.7% of the isolates, respectively, when applying CLSI or US FDA breakpoints. A total of 89.6% of the isolates had intermediate colistin MIC values. Among the 27 isolates collected from 2016-2019 that were submitted to WGS, 15 harbored CTX-M encoding genes. K. aerogenes and E. cloacae isolates (3 each) overexpressed AmpC. OmpC/K36 was disrupted in 20 isolates and OmpF/K35 was disrupted in 8 isolates. Conclusion MVB displayed good activity against CN-CRE isolates from US hospitals. This combination agent could be a good option to treat infections caused by these isolates. Disclosures Mariana Castanheira, PhD, AbbVie (formerly Allergan) (Research Grant or Support)Bravos Biosciences (Research Grant or Support)Cidara Therapeutics, Inc. (Research Grant or Support)Cipla Therapeutics (Research Grant or Support)Cipla USA Inc. (Research Grant or Support)GlaxoSmithKline (Research Grant or Support)Melinta Therapeutics, Inc. (Research Grant or Support)Melinta Therapeutics, LLC (Research Grant or Support)Pfizer, Inc. (Research Grant or Support)Qpex Biopharma (Research Grant or Support)Shionogi (Research Grant or Support)Spero Therapeutics (Research Grant or Support) Mariana Castanheira, PhD, Affinity Biosensors (Individual(s) Involved: Self): Research Grant or Support; Allergan (Individual(s) Involved: Self): Research Grant or Support; Amicrobe, Inc (Individual(s) Involved: Self): Research Grant or Support; Amplyx Pharma (Individual(s) Involved: Self): Research Grant or Support; Artugen Therapeutics USA, Inc. (Individual(s) Involved: Self): Research Grant or Support; Astellas (Individual(s) Involved: Self): Research Grant or Support; Basilea (Individual(s) Involved: Self): Research Grant or Support; Beth Israel Deaconess Medical Center (Individual(s) Involved: Self): Research Grant or Support; BIDMC (Individual(s) Involved: Self): Research Grant or Support; bioMerieux Inc. (Individual(s) Involved: Self): Research Grant or Support; BioVersys Ag (Individual(s) Involved: Self): Research Grant or Support; Bugworks (Individual(s) Involved: Self): Research Grant or Support; Cidara (Individual(s) Involved: Self): Research Grant or Support; Cipla (Individual(s) Involved: Self): Research Grant or Support; Contrafect (Individual(s) Involved: Self): Research Grant or Support; Cormedix (Individual(s) Involved: Self): Research Grant or Support; Crestone, Inc. (Individual(s) Involved: Self): Research Grant or Support; Curza (Individual(s) Involved: Self): Research Grant or Support; CXC7 (Individual(s) Involved: Self): Research Grant or Support; Entasis (Individual(s) Involved: Self): Research Grant or Support; Fedora Pharmaceutical (Individual(s) Involved: Self): Research Grant or Support; Fimbrion Therapeutics (Individual(s) Involved: Self): Research Grant or Support; Fox Chase (Individual(s) Involved: Self): Research Grant or Support; GlaxoSmithKline (Individual(s) Involved: Self): Research Grant or Support; Guardian Therapeutics (Individual(s) Involved: Self): Research Grant or Support; Hardy Diagnostics (Individual(s) Involved: Self): Research Grant or Support; IHMA (Individual(s) Involved: Self): Research Grant or Support; Janssen Research & Development (Individual(s) Involved: Self): Research Grant or Support; Johnson & Johnson (Individual(s) Involved: Self): Research Grant or Support; Kaleido Biosceinces (Individual(s) Involved: Self): Research Grant or Support; KBP Biosciences (Individual(s) Involved: Self): Research Grant or Support; Luminex (Individual(s) Involved: Self): Research Grant or Support; Matrivax (Individual(s) Involved: Self): Research Grant or Support; Mayo Clinic (Individual(s) Involved: Self): Research Grant or Support; Medpace (Individual(s) Involved: Self): Research Grant or Support; Meiji Seika Pharma Co., Ltd. (Individual(s) Involved: Self): Research Grant or Support; Melinta (Individual(s) Involved: Self): Research Grant or Support; Menarini (Individual(s) Involved: Self): Research Grant or Support; Merck (Individual(s) Involved: Self): Research Grant or Support; Meridian Bioscience Inc. (Individual(s) Involved: Self): Research Grant or Support; Micromyx (Individual(s) Involved: Self): Research Grant or Support; MicuRx (Individual(s) Involved: Self): Research Grant or Support; N8 Medical (Individual(s) Involved: Self): Research Grant or Support; Nabriva (Individual(s) Involved: Self): Research Grant or Support; National Institutes of Health (Individual(s) Involved: Self): Research Grant or Support; National University of Singapore (Individual(s) Involved: Self): Research Grant or Support; North Bristol NHS Trust (Individual(s) Involved: Self): Research Grant or Support; Novome Biotechnologies (Individual(s) Involved: Self): Research Grant or Support; Paratek (Individual(s) Involved: Self): Research Grant or Support; Pfizer (Individual(s) Involved: Self): Research Grant or Support; Prokaryotics Inc. (Individual(s) Involved: Self): Research Grant or Support; QPEX Biopharma (Individual(s) Involved: Self): Research Grant or Support; Rhode Island Hospital (Individual(s) Involved: Self): Research Grant or Support; RIHML (Individual(s) Involved: Self): Research Grant or Support; Roche (Individual(s) Involved: Self): Research Grant or Support; Roivant (Individual(s) Involved: Self): Research Grant or Support; Salvat (Individual(s) Involved: Self): Research Grant or Support; Scynexis (Individual(s) Involved: Self): Research Grant or Support; SeLux Diagnostics (Individual(s) Involved: Self): Research Grant or Support; Shionogi (Individual(s) Involved: Self): Research Grant or Support; Specific Diagnostics (Individual(s) Involved: Self): Research Grant or Support; Spero (Individual(s) Involved: Self): Research Grant or Support; SuperTrans Medical LT (Individual(s) Involved: Self): Research Grant or Support; T2 Biosystems (Individual(s) Involved: Self): Research Grant or Support; The University of Queensland (Individual(s) Involved: Self): Research Grant or Support; Thermo Fisher Scientific (Individual(s) Involved: Self): Research Grant or Support; Tufts Medical Center (Individual(s) Involved: Self): Research Grant or Support; Universite de Sherbrooke (Individual(s) Involved: Self): Research Grant or Support; University of Iowa (Individual(s) Involved: Self): Research Grant or Support; University of Iowa Hospitals and Clinics (Individual(s) Involved: Self): Research Grant or Support; University of Wisconsin (Individual(s) Involved: Self): Research Grant or Support; UNT System College of Pharmacy (Individual(s) Involved: Self): Research Grant or Support; URMC (Individual(s) Involved: Self): Research Grant or Support; UT Southwestern (Individual(s) Involved: Self): Research Grant or Support; VenatoRx (Individual(s) Involved: Self): Research Grant or Support; Viosera Therapeutics (Individual(s) Involved: Self): Research Grant or Support; Wayne State University (Individual(s) Involved: Self): Research Grant or Support Timothy B. Doyle, AbbVie (formerly Allergan) (Research Grant or Support)Bravos Biosciences (Research Grant or Support)GlaxoSmithKline (Research Grant or Support)Melinta Therapeutics, Inc. (Research Grant or Support)Pfizer, Inc. (Research Grant or Support)Shionogi (Research Grant or Support)Spero Therapeutics (Research Grant or Support) Valerie Kantro, n/a, Melinta Therapeutics, Inc. (Research Grant or Support) Rodrigo E. Mendes, PhD, AbbVie (Research Grant or Support)AbbVie (formerly Allergan) (Research Grant or Support)Cipla Therapeutics (Research Grant or Support)Cipla USA Inc. (Research Grant or Support)ContraFect Corporation (Research Grant or Support)GlaxoSmithKline, LLC (Research Grant or Support)Melinta Therapeutics, Inc. (Research Grant or Support)Melinta Therapeutics, LLC (Research Grant or Support)Nabriva Therapeutics (Research Grant or Support)Pfizer, Inc. (Research Grant or Support)Shionogi (Research Grant or Support)Spero Therapeutics (Research Grant or Support) Dee Shortridge, PhD, AbbVie (formerly Allergan) (Research Grant or Support)Melinta Therapeutics, Inc. (Research Grant or Support)Melinta Therapeutics, LLC (Research Grant or Support)Shionogi (Research Grant or Support)
Published: 2021

13. Increasing frequency of OXA-48-producing Enterobacterales worldwide and activity of ceftazidime/avibactam, meropenem/vaborbactam and comparators against these isolates

Author: Rodrigo E. Mendes, Helio S. Sader, Mariana Castanheira, Timothy D Collingsworth, and Timothy B Doyle
Subjects: Microbiology (medical), Klebsiella pneumoniae, Avibactam, Cefepime, Ceftazidime, Aztreonam, Microbial Sensitivity Tests, Biology, Meropenem, beta-Lactamases, Microbiology, chemistry.chemical_compound, Heterocyclic Compounds, 1-Ring, Enterobacteriaceae, medicine, polycyclic compounds, AcademicSubjects/MED00740, Pharmacology (medical), Original Research, Pharmacology, Broth microdilution, biochemical phenomena, metabolism, and nutrition, Ceftazidime/avibactam, biology.organism_classification, Boronic Acids, Anti-Bacterial Agents, Drug Combinations, Infectious Diseases, AcademicSubjects/MED00290, chemistry, bacteria, AcademicSubjects/MED00230, Azabicyclo Compounds, medicine.drug, Multilocus Sequence Typing
Abstract: Objectives To investigate the increase in the rates of OXA-48-like-producing isolates during 3 years of global surveillance. Methods Among 55?>162 Enterobacterales isolates, 354 carbapenem-resistant isolates carried genes encoding OXA-48-like enzymes. Isolates were susceptibility tested for ceftazidime/avibactam and comparators by broth microdilution methods. Analysis of β-lactam resistance mechanisms and MLST was performed in silico using WGS data. Results OXA-48-like-producing isolates increased from 0.5% (94/18 656) in 2016 to 0.9% (169/18?>808) in 2018. OXA-48 was the most common variant; isolates primarily were Klebsiella pneumoniae (318/354 isolates) from Europe and adjacent countries. MLST analysis revealed a diversity of STs, but K. pneumoniae belonging to ST395, ST23 and ST11 were observed most frequently. Thirty-nine isolates harboured MBLs and were resistant to most agents tested. The presence of blaCTX-M-15 (258 isolates), OmpK35 nonsense mutations (232) and OmpK36 alterations (316) was common among OXA-48 producers. Ceftazidime, cefepime and aztreonam susceptibility rates, when applying CLSI breakpoints, were 12%–15% lower for isolates carrying ESBLs alone and with either or both OmpK35 stop codons and OmpK36 alterations. Meropenem and, remarkably, meropenem/vaborbactam were affected by specific OmpK36 alterations when a deleterious mutation also was observed in OmpK35. These mechanisms caused a decrease of 12%–42% in the susceptibility rates for meropenem and meropenem/vaborbactam. Ceftazidime/avibactam susceptibility rates were >98.9%, regardless of the presence of additional β-lactam resistance mechanisms. Conclusions Guidelines for the treatment of infections caused by OXA-48-producing isolates are scarce and, as the dissemination of these isolates continues, studies are needed to help physicians understand treatment options for these infections.
Published: 2021

14. Antimicrobial activity of ceftazidime/avibactam, ceftolozane/tazobactam and comparator agents against

Author: Helio S, Sader, Leonard R, Duncan, Timothy B, Doyle, and Mariana, Castanheira
Subjects: AcademicSubjects/MED00290, Brief Report, polycyclic compounds, AcademicSubjects/MED00740, biochemical phenomena, metabolism, and nutrition, bacterial infections and mycoses, AcademicSubjects/MED00230
Abstract: Objectives To evaluate the antimicrobial susceptibility patterns of Pseudomonas aeruginosa isolates collected from the lower respiratory tract of cystic fibrosis (CF) patients. Methods We susceptibility tested 273 contemporary P. aeruginosa isolates from 39 hospitals worldwide (17 countries) by the reference broth microdilution method. Results Ceftazidime/avibactam [MIC50/90, 2/8 mg/L; 96.0% susceptible (S)] was the most active agent, followed by ceftolozane/tazobactam (MIC50/90, 1/4 mg/L; 90.5% S), ceftazidime (MIC50/90, 2/>32 mg/L; 80.6% S), piperacillin/tazobactam (MIC50/90, 4/128 mg/L; 80.2% S) and tobramycin (MIC50/90, 2/>16 mg/L; 76.6% S). Ceftazidime/avibactam retained activity against P. aeruginosa isolates non-susceptible to meropenem (86.5% S to ceftazidime/avibactam), piperacillin/tazobactam (85.2% S to ceftazidime/avibactam) or ceftazidime (79.2% S to ceftazidime/avibactam). MDR phenotype was observed among 36.3% of isolates, and 88.9% and 73.7% of MDR isolates were susceptible to ceftazidime/avibactam and ceftolozane/tazobactam, respectively. Against isolates non-susceptible to meropenem, piperacillin/tazobactam and ceftazidime, susceptibility rates were 78.9% for ceftazidime/avibactam and 47.4% for ceftolozane/tazobactam. Ceftazidime/avibactam was active against 65.4% of ceftolozane/tazobactam-non-susceptible isolates and ceftolozane/tazobactam was active against 18.2% of ceftazidime/avibactam-non-susceptible isolates. Conclusions Ceftazidime/avibactam and ceftolozane/tazobactam exhibited potent and broad-spectrum activity against P. aeruginosa isolated from CF patients worldwide, but higher susceptibility rates for ceftazidime/avibactam compared with ceftolozane/tazobactam were observed among the resistant subsets. Ceftazidime/avibactam and ceftolozane/tazobactam represent valuable options to treat CF pulmonary exacerbations caused by P. aeruginosa.
Published: 2021

15. 1068. Antimicrobial Activity of Aztreonam-Avibactam and Comparator Agents against Gram-Negative Bacteria Isolated from Bloodstream and Complicated Urinary Tract Infections in Europe, Asia, and Latin America (2019-2020)

Author: Helio S Sader, Rodrigo E Mendes, Cecilia G Carvalhaes, Timothy B Doyle, and Mariana Castanheira
Subjects: Infectious Diseases, Oncology
Abstract: Background Aztreonam (ATM) is a monobactam stable to hydrolysis by metallo-β-lactamases (MBLs). Avibactam (AVI) is a non-β-lactam β-lactamase inhibitor that inhibits serine β-lactamases (BLs) such as ESBLs, KPCs, AmpC, and some OXAs. ATM-AVI is under clinical development for the treatment of serious infections caused by gram-negative bacteria (GNB), including MBL-producers. We evaluated ATM-AVI activity against GNB causing bloodstream (BSI) and complicated urinary tract infections (cUTI). Methods 10,103 GNB isolates (5,314 from BSI and 4,789 from cUTI) were consecutively collected (1/patient) from 66 medical centers located in Western Europe (W-EU; n=5,238; 25 centers in 10 countries), Eastern Europe (E-EU; n=1,729; 13 centers in 10 countries), the Asia-Pacific region (APAC; n=1,817; 17 centers in 9 countries), and Latin America (LATAM; n=1,319; 11 centers in 7 countries) in 2019 (n=5,030) and 2020 (n=5,073). Susceptibility (S) testing was performed by reference broth microdilution methods in a central laboratory. Results Overall, 99.9% of Enterobacterales (ENT; MIC50/90, ≤0.03/0.12 mg/L), including 99.7% of carbapenem-resistant ENT (CRE; MIC50/90, 0.25/0.5 mg/L), were inhibited at an ATM-AVI MIC of ≤8 mg/L (Table). CRE rates among BSI/cUTI isolates were 2.3%/0.6% in W-EU, 9.5%/6.1% in E-EU, 3.3%/2.8% in APAC, and 8.1%/5.2% in LATAM (4.2%/2.7% overall). ATM-AVI was very active against MDR (MIC50/90, 0.06/0.5 mg/L; 99.6% inhibited at ≤8 mg/L) and XDR (MIC50/90, 0.25/0.5 mg/L; highest MIC, 2 mg/L) ENT. Among P. aeruginosa, the percentage of isolates inhibited at ≤8 mg/L of ATM-AVI (78.3%) was similar to the S rates for piperacillin-tazobactam (78.8%), meropenem (79.1%), and ceftazidime (80.6%). Among S. maltophilia isolates, 100.0% were inhibited at ≤8mg/L of ATM-AVI and 95.4% were S to cotrimoxazole. ATM-AVI was highly active against Aeromonas spp. (highest MIC, 0.25 mg/L) and showed good activity against B. cepacia (MIC50/90, 4/16 mg/L). Conclusion ATM-AVI exhibited potent and consistent activity against ENT (including CRE, MDR, and XDR isolates) from W-EU, E-EU, APAC, and LATAM. Our results support clinical development of ATM-AVI to treat BSI and cUTI caused by ENT, P. aeruginosa, S. maltophilia, B. cepacia and Aeromonas spp. Table Disclosures Helio S. Sader, MD, PhD, FIDSA, AbbVie (formerly Allergan) (Research Grant or Support)Basilea Pharmaceutica International, Ltd. (Research Grant or Support)Cipla Therapeutics (Research Grant or Support)Cipla USA Inc. (Research Grant or Support)Department of Health and Human Services (Research Grant or Support, Contract no. HHSO100201600002C)Melinta Therapeutics, LLC (Research Grant or Support)Nabriva Therapeutics (Research Grant or Support)Pfizer, Inc. (Research Grant or Support)Shionogi (Research Grant or Support)Spero Therapeutics (Research Grant or Support) Rodrigo E. Mendes, PhD, AbbVie (Research Grant or Support)AbbVie (formerly Allergan) (Research Grant or Support)Cipla Therapeutics (Research Grant or Support)Cipla USA Inc. (Research Grant or Support)ContraFect Corporation (Research Grant or Support)GlaxoSmithKline, LLC (Research Grant or Support)Melinta Therapeutics, Inc. (Research Grant or Support)Melinta Therapeutics, LLC (Research Grant or Support)Nabriva Therapeutics (Research Grant or Support)Pfizer, Inc. (Research Grant or Support)Shionogi (Research Grant or Support)Spero Therapeutics (Research Grant or Support) Cecilia G. Carvalhaes, MD, PhD, AbbVie (formerly Allergan) (Research Grant or Support)Cidara Therapeutics, Inc. (Research Grant or Support)Cipla Therapeutics (Research Grant or Support)Cipla USA Inc. (Research Grant or Support)Melinta Therapeutics, LLC (Research Grant or Support)Pfizer, Inc. (Research Grant or Support) Timothy B. Doyle, AbbVie (formerly Allergan) (Research Grant or Support)Bravos Biosciences (Research Grant or Support)GlaxoSmithKline (Research Grant or Support)Melinta Therapeutics, Inc. (Research Grant or Support)Pfizer, Inc. (Research Grant or Support)Shionogi (Research Grant or Support)Spero Therapeutics (Research Grant or Support) Mariana Castanheira, PhD, AbbVie (formerly Allergan) (Research Grant or Support)Bravos Biosciences (Research Grant or Support)Cidara Therapeutics, Inc. (Research Grant or Support)Cipla Therapeutics (Research Grant or Support)Cipla USA Inc. (Research Grant or Support)GlaxoSmithKline (Research Grant or Support)Melinta Therapeutics, Inc. (Research Grant or Support)Melinta Therapeutics, LLC (Research Grant or Support)Pfizer, Inc. (Research Grant or Support)Qpex Biopharma (Research Grant or Support)Shionogi (Research Grant or Support)Spero Therapeutics (Research Grant or Support) Mariana Castanheira, PhD, Affinity Biosensors (Individual(s) Involved: Self): Research Grant or Support; Allergan (Individual(s) Involved: Self): Research Grant or Support; Amicrobe, Inc (Individual(s) Involved: Self): Research Grant or Support; Amplyx Pharma (Individual(s) Involved: Self): Research Grant or Support; Artugen Therapeutics USA, Inc. (Individual(s) Involved: Self): Research Grant or Support; Astellas (Individual(s) Involved: Self): Research Grant or Support; Basilea (Individual(s) Involved: Self): Research Grant or Support; Beth Israel Deaconess Medical Center (Individual(s) Involved: Self): Research Grant or Support; BIDMC (Individual(s) Involved: Self): Research Grant or Support; bioMerieux Inc. (Individual(s) Involved: Self): Research Grant or Support; BioVersys Ag (Individual(s) Involved: Self): Research Grant or Support; Bugworks (Individual(s) Involved: Self): Research Grant or Support; Cidara (Individual(s) Involved: Self): Research Grant or Support; Cipla (Individual(s) Involved: Self): Research Grant or Support; Contrafect (Individual(s) Involved: Self): Research Grant or Support; Cormedix (Individual(s) Involved: Self): Research Grant or Support; Crestone, Inc. (Individual(s) Involved: Self): Research Grant or Support; Curza (Individual(s) Involved: Self): Research Grant or Support; CXC7 (Individual(s) Involved: Self): Research Grant or Support; Entasis (Individual(s) Involved: Self): Research Grant or Support; Fedora Pharmaceutical (Individual(s) Involved: Self): Research Grant or Support; Fimbrion Therapeutics (Individual(s) Involved: Self): Research Grant or Support; Fox Chase (Individual(s) Involved: Self): Research Grant or Support; GlaxoSmithKline (Individual(s) Involved: Self): Research Grant or Support; Guardian Therapeutics (Individual(s) Involved: Self): Research Grant or Support; Hardy Diagnostics (Individual(s) Involved: Self): Research Grant or Support; IHMA (Individual(s) Involved: Self): Research Grant or Support; Janssen Research & Development (Individual(s) Involved: Self): Research Grant or Support; Johnson & Johnson (Individual(s) Involved: Self): Research Grant or Support; Kaleido Biosceinces (Individual(s) Involved: Self): Research Grant or Support; KBP Biosciences (Individual(s) Involved: Self): Research Grant or Support; Luminex (Individual(s) Involved: Self): Research Grant or Support; Matrivax (Individual(s) Involved: Self): Research Grant or Support; Mayo Clinic (Individual(s) Involved: Self): Research Grant or Support; Medpace (Individual(s) Involved: Self): Research Grant or Support; Meiji Seika Pharma Co., Ltd. (Individual(s) Involved: Self): Research Grant or Support; Melinta (Individual(s) Involved: Self): Research Grant or Support; Menarini (Individual(s) Involved: Self): Research Grant or Support; Merck (Individual(s) Involved: Self): Research Grant or Support; Meridian Bioscience Inc. (Individual(s) Involved: Self): Research Grant or Support; Micromyx (Individual(s) Involved: Self): Research Grant or Support; MicuRx (Individual(s) Involved: Self): Research Grant or Support; N8 Medical (Individual(s) Involved: Self): Research Grant or Support; Nabriva (Individual(s) Involved: Self): Research Grant or Support; National Institutes of Health (Individual(s) Involved: Self): Research Grant or Support; National University of Singapore (Individual(s) Involved: Self): Research Grant or Support; North Bristol NHS Trust (Individual(s) Involved: Self): Research Grant or Support; Novome Biotechnologies (Individual(s) Involved: Self): Research Grant or Support; Paratek (Individual(s) Involved: Self): Research Grant or Support; Pfizer (Individual(s) Involved: Self): Research Grant or Support; Prokaryotics Inc. (Individual(s) Involved: Self): Research Grant or Support; QPEX Biopharma (Individual(s) Involved: Self): Research Grant or Support; Rhode Island Hospital (Individual(s) Involved: Self): Research Grant or Support; RIHML (Individual(s) Involved: Self): Research Grant or Support; Roche (Individual(s) Involved: Self): Research Grant or Support; Roivant (Individual(s) Involved: Self): Research Grant or Support; Salvat (Individual(s) Involved: Self): Research Grant or Support; Scynexis (Individual(s) Involved: Self): Research Grant or Support; SeLux Diagnostics (Individual(s) Involved: Self): Research Grant or Support; Shionogi (Individual(s) Involved: Self): Research Grant or Support; Specific Diagnostics (Individual(s) Involved: Self): Research Grant or Support; Spero (Individual(s) Involved: Self): Research Grant or Support; SuperTrans Medical LT (Individual(s) Involved: Self): Research Grant or Support; T2 Biosystems (Individual(s) Involved: Self): Research Grant or Support; The University of Queensland (Individual(s) Involved: Self): Research Grant or Support; Thermo Fisher Scientific (Individual(s) Involved: Self): Research Grant or Support; Tufts Medical Center (Individual(s) Involved: Self): Research Grant or Support; Universite de Sherbrooke (Individual(s) Involved: Self): Research Grant or Support; University of Iowa (Individual(s) Involved: Self): Research Grant or Support; University of Iowa Hospitals and Clinics (Individual(s) Involved: Self): Research Grant or Support; University of Wisconsin (Individual(s) Involved: Self): Research Grant or Support; UNT System College of Pharmacy (Individual(s) Involved: Self): Research Grant or Support; URMC (Individual(s) Involved: Self): Research Grant or Support; UT Southwestern (Individual(s) Involved: Self): Research Grant or Support; VenatoRx (Individual(s) Involved: Self): Research Grant or Support; Viosera Therapeutics (Individual(s) Involved: Self): Research Grant or Support; Wayne State University (Individual(s) Involved: Self): Research Grant or Support
Published: 2021
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16. 1232. In Vitro Activity of Cefiderocol and Comparator Agents against Molecularly characterized Carbapenem-resistant Enterobacterales Clinical Isolates Causing Infection in United States Hospitals (2020)

Author: Rodrigo E Mendes, Timothy B Doyle, Dee Shortridge, Helio S Sader, Jennifer M Streit, and Mariana Castanheira
Subjects: Infectious Diseases, Oncology
Abstract: Background Cefiderocol (CFDC) represents a new addition to the antimicrobial armamentarium with broad activity against Gram-negative bacteria (GNB). CFDC remains stable to hydrolysis in the presence of serine β-lactamases (ESBLs, KPC and OXA-type carbapenemases) and metallo-β-lactamases. The CFDC and comparator activities were analyzed against Enterobacterales (ENT), including molecularly characterized carbapenem-resistant isolates (CRE), as a part of the SENTRY Antimicrobial Surveillance Program in the USA. Methods 4,053 ENT were collected from 31 sites in 2020. Susceptibility testing was performed by broth microdilution and CFDC testing used iron-depleted media. CLSI/FDA breakpoints were used. Isolates displaying MIC values ≥4 µg/mL for imipenem (excluded for P. mirabilis, P. penneri and indole-positive Proteus) or meropenem (MER) were subjected to genome sequencing and screening of β-lactamase genes. Results A total of 36 (0.9%) CRE were detected, and represented mostly by isolates carrying blaKPC (75.0%; 27/36; Table). A small number of ENT (11.1%; 4/36) carried other carbapenemase genes (1 each of blaNDM-1, blaNDM-5, blaOXA-232, and blaSME-2), whereas 13.9% (5/36) of isolates did not carry any known carbapenemases. CFDC (99.8% susceptible [S]), imipenem-relebactam (IMR; 99.7-99.9%S), meropenem-vaborbactam (MEV; 99.9-100%S), ceftazidime-avibactam (CZA; 99.9-100%S), and MER (99.1-99.9%S) were active against all ENT and the non-CRE subset. CFDC (MIC50/90, 0.5/4 µg/mL; 97.2%S) and CZA (MIC50/90, 1/8 µg/mL; 94.4%S) were the most active agents against CRE, whereas CFDC, IMR, MEV and CZA were active (100%S) against the KPC subset. Finally, CFDC (MIC, 0.5-4 µg/mL; 100%S) was the most active agent against ENT carrying genes other than blaKPC, whereas CZA (1-8 µg/mL; 100%S) was most active against CRE with no known carbapenemases, followed by CFDC (0.5-8 µg/mL; 80.0%S). Conclusion The CFDC activity was consistent, regardless of phenotypes or genotypes, including against isolates carrying genes other than blaKPC, where approved β-lactam/β-lactamase inhibitor combinations showed limited activity. These data confirm CFDC as an important option for the treatment of infections caused by ENT and resistant subsets. Table Disclosures Rodrigo E. Mendes, PhD, AbbVie (Research Grant or Support)AbbVie (formerly Allergan) (Research Grant or Support)Cipla Therapeutics (Research Grant or Support)Cipla USA Inc. (Research Grant or Support)ContraFect Corporation (Research Grant or Support)GlaxoSmithKline, LLC (Research Grant or Support)Melinta Therapeutics, Inc. (Research Grant or Support)Melinta Therapeutics, LLC (Research Grant or Support)Nabriva Therapeutics (Research Grant or Support)Pfizer, Inc. (Research Grant or Support)Shionogi (Research Grant or Support)Spero Therapeutics (Research Grant or Support) Timothy B. Doyle, AbbVie (formerly Allergan) (Research Grant or Support)Bravos Biosciences (Research Grant or Support)GlaxoSmithKline (Research Grant or Support)Melinta Therapeutics, Inc. (Research Grant or Support)Pfizer, Inc. (Research Grant or Support)Shionogi (Research Grant or Support)Spero Therapeutics (Research Grant or Support) Dee Shortridge, PhD, AbbVie (formerly Allergan) (Research Grant or Support)Melinta Therapeutics, Inc. (Research Grant or Support)Melinta Therapeutics, LLC (Research Grant or Support)Shionogi (Research Grant or Support) Helio S. Sader, MD, PhD, FIDSA, AbbVie (formerly Allergan) (Research Grant or Support)Basilea Pharmaceutica International, Ltd. (Research Grant or Support)Cipla Therapeutics (Research Grant or Support)Cipla USA Inc. (Research Grant or Support)Department of Health and Human Services (Research Grant or Support, Contract no. HHSO100201600002C)Melinta Therapeutics, LLC (Research Grant or Support)Nabriva Therapeutics (Research Grant or Support)Pfizer, Inc. (Research Grant or Support)Shionogi (Research Grant or Support)Spero Therapeutics (Research Grant or Support) Jennifer M. Streit, BS, GlaxoSmithKline, LLC (Research Grant or Support)Melinta Therapeutics, LLC (Research Grant or Support)Shionogi (Research Grant or Support)Spero Therapeutics (Research Grant or Support) Mariana Castanheira, PhD, AbbVie (formerly Allergan) (Research Grant or Support)Bravos Biosciences (Research Grant or Support)Cidara Therapeutics, Inc. (Research Grant or Support)Cipla Therapeutics (Research Grant or Support)Cipla USA Inc. (Research Grant or Support)GlaxoSmithKline (Research Grant or Support)Melinta Therapeutics, Inc. (Research Grant or Support)Melinta Therapeutics, LLC (Research Grant or Support)Pfizer, Inc. (Research Grant or Support)Qpex Biopharma (Research Grant or Support)Shionogi (Research Grant or Support)Spero Therapeutics (Research Grant or Support) Mariana Castanheira, PhD, Affinity Biosensors (Individual(s) Involved: Self): Research Grant or Support; Allergan (Individual(s) Involved: Self): Research Grant or Support; Amicrobe, Inc (Individual(s) Involved: Self): Research Grant or Support; Amplyx Pharma (Individual(s) Involved: Self): Research Grant or Support; Artugen Therapeutics USA, Inc. (Individual(s) Involved: Self): Research Grant or Support; Astellas (Individual(s) Involved: Self): Research Grant or Support; Basilea (Individual(s) Involved: Self): Research Grant or Support; Beth Israel Deaconess Medical Center (Individual(s) Involved: Self): Research Grant or Support; BIDMC (Individual(s) Involved: Self): Research Grant or Support; bioMerieux Inc. (Individual(s) Involved: Self): Research Grant or Support; BioVersys Ag (Individual(s) Involved: Self): Research Grant or Support; Bugworks (Individual(s) Involved: Self): Research Grant or Support; Cidara (Individual(s) Involved: Self): Research Grant or Support; Cipla (Individual(s) Involved: Self): Research Grant or Support; Contrafect (Individual(s) Involved: Self): Research Grant or Support; Cormedix (Individual(s) Involved: Self): Research Grant or Support; Crestone, Inc. (Individual(s) Involved: Self): Research Grant or Support; Curza (Individual(s) Involved: Self): Research Grant or Support; CXC7 (Individual(s) Involved: Self): Research Grant or Support; Entasis (Individual(s) Involved: Self): Research Grant or Support; Fedora Pharmaceutical (Individual(s) Involved: Self): Research Grant or Support; Fimbrion Therapeutics (Individual(s) Involved: Self): Research Grant or Support; Fox Chase (Individual(s) Involved: Self): Research Grant or Support; GlaxoSmithKline (Individual(s) Involved: Self): Research Grant or Support; Guardian Therapeutics (Individual(s) Involved: Self): Research Grant or Support; Hardy Diagnostics (Individual(s) Involved: Self): Research Grant or Support; IHMA (Individual(s) Involved: Self): Research Grant or Support; Janssen Research & Development (Individual(s) Involved: Self): Research Grant or Support; Johnson & Johnson (Individual(s) Involved: Self): Research Grant or Support; Kaleido Biosceinces (Individual(s) Involved: Self): Research Grant or Support; KBP Biosciences (Individual(s) Involved: Self): Research Grant or Support; Luminex (Individual(s) Involved: Self): Research Grant or Support; Matrivax (Individual(s) Involved: Self): Research Grant or Support; Mayo Clinic (Individual(s) Involved: Self): Research Grant or Support; Medpace (Individual(s) Involved: Self): Research Grant or Support; Meiji Seika Pharma Co., Ltd. (Individual(s) Involved: Self): Research Grant or Support; Melinta (Individual(s) Involved: Self): Research Grant or Support; Menarini (Individual(s) Involved: Self): Research Grant or Support; Merck (Individual(s) Involved: Self): Research Grant or Support; Meridian Bioscience Inc. (Individual(s) Involved: Self): Research Grant or Support; Micromyx (Individual(s) Involved: Self): Research Grant or Support; MicuRx (Individual(s) Involved: Self): Research Grant or Support; N8 Medical (Individual(s) Involved: Self): Research Grant or Support; Nabriva (Individual(s) Involved: Self): Research Grant or Support; National Institutes of Health (Individual(s) Involved: Self): Research Grant or Support; National University of Singapore (Individual(s) Involved: Self): Research Grant or Support; North Bristol NHS Trust (Individual(s) Involved: Self): Research Grant or Support; Novome Biotechnologies (Individual(s) Involved: Self): Research Grant or Support; Paratek (Individual(s) Involved: Self): Research Grant or Support; Pfizer (Individual(s) Involved: Self): Research Grant or Support; Prokaryotics Inc. (Individual(s) Involved: Self): Research Grant or Support; QPEX Biopharma (Individual(s) Involved: Self): Research Grant or Support; Rhode Island Hospital (Individual(s) Involved: Self): Research Grant or Support; RIHML (Individual(s) Involved: Self): Research Grant or Support; Roche (Individual(s) Involved: Self): Research Grant or Support; Roivant (Individual(s) Involved: Self): Research Grant or Support; Salvat (Individual(s) Involved: Self): Research Grant or Support; Scynexis (Individual(s) Involved: Self): Research Grant or Support; SeLux Diagnostics (Individual(s) Involved: Self): Research Grant or Support; Shionogi (Individual(s) Involved: Self): Research Grant or Support; Specific Diagnostics (Individual(s) Involved: Self): Research Grant or Support; Spero (Individual(s) Involved: Self): Research Grant or Support; SuperTrans Medical LT (Individual(s) Involved: Self): Research Grant or Support; T2 Biosystems (Individual(s) Involved: Self): Research Grant or Support; The University of Queensland (Individual(s) Involved: Self): Research Grant or Support; Thermo Fisher Scientific (Individual(s) Involved: Self): Research Grant or Support; Tufts Medical Center (Individual(s) Involved: Self): Research Grant or Support; Universite de Sherbrooke (Individual(s) Involved: Self): Research Grant or Support; University of Iowa (Individual(s) Involved: Self): Research Grant or Support; University of Iowa Hospitals and Clinics (Individual(s) Involved: Self): Research Grant or Support; University of Wisconsin (Individual(s) Involved: Self): Research Grant or Support; UNT System College of Pharmacy (Individual(s) Involved: Self): Research Grant or Support; URMC (Individual(s) Involved: Self): Research Grant or Support; UT Southwestern (Individual(s) Involved: Self): Research Grant or Support; VenatoRx (Individual(s) Involved: Self): Research Grant or Support; Viosera Therapeutics (Individual(s) Involved: Self): Research Grant or Support; Wayne State University (Individual(s) Involved: Self): Research Grant or Support
Published: 2021
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17. 1272. Cefiderocol In Vitro Activity Against Molecularly Characterized Acinetobacter baumannii-calcoaceticus Complex and Pseudomonas aeruginosa Clinical Isolates Causing Infection in United States Hospitals (2020)

Author: Rodrigo E Mendes, Timothy B Doyle, Dee Shortridge, Helio S Sader, Jennifer M Streit, and Mariana Castanheira
Subjects: Infectious Diseases, Oncology
Abstract: Background Cefiderocol (CFDC) is a novel siderophore-conjugated cephalosporin with broad activity against aerobic, nonfastidious Gram-negative bacteria. CFDC and comparator activities were analyzed against molecularly characterized A. baumannii-calcoaceticus complex (ACB) and P. aeruginosa (PSA), as a part of the SENTRY Antimicrobial Surveillance Program in the USA. Methods 248 ACB and 1,069 PSA were consecutively collected from 30 sites in 2020. Susceptibility was performed by broth microdilution and CFDC testing used iron-depleted media. FDA and CLSI breakpoints were used for CFDC. CLSI criteria were applied to comparators, except for imipenem-relebactam (IMR) that used FDA breakpoints. ACB and PSA with imipenem and/or meropenem (MER) MIC ≥4 μg/mL or ceftazidime (CAZ) and/or cefepime MIC ≥16 μg/mL were subjected to next-generation genome sequencing for screening for acquired extended-spectrum β-lactamase (ESBL) and carbapenemase genes. Results 33.0% of PSA met the MIC screening criteria, and ESBL or carbapenemase genes were not detected among these isolates, except for 1 strain with blaIMP-1. CFDC (97.7-100% susceptible [S]) had similar MIC50 (0.12 μg/mL) and MIC90 (0.25-0.5 μg/mL) values against both PSA populations, as did IMR (91.8-100%S). An MIC of 1 μg/mL was noted for CFDC against the single blaIMP-1-carrying isolate, whereas other agents had MIC values >8 μg/mL (Table). CFDC (MIC50/90, 0.25/2 μg/mL) had the lowest MIC against ACB that met the MIC screening criteria, whereas CFDC, IMR, MER and CAZ were active (99.2-100%S) against MIC screen negative ACB. CFDC (MIC50/90, 0.25/2 μg/mL; 86.7-96.7%S) and IMR (MIC50/90, 0.25/1 μg/mL; 90.0%S) were the most active agents against ACB where only blaOXA-51 and variant genes were noted. CFDC was the only agent active (93.9-100%S; CLSI criteria) against ACB carrying blaOXA-23 (MIC50/90, 0.5/4 μg/mL), blaOXA-24 (MIC50/90, 0.25/1 μg/mL) or other genes (MIC50, 1 μg/mL). Conclusion Acquired ESBL and carbapenemase genes remained rare among multidrug-resistant PSA in USA hospitals, whereas acquired blaOXA carbapenemase were prevalent among ACB. CFDC showed potent activity against PSA subsets, as well as across molecularly characterized subsets of ACB, where treatment options were limited. Disclosures Rodrigo E. Mendes, PhD, AbbVie (Research Grant or Support)AbbVie (formerly Allergan) (Research Grant or Support)Cipla Therapeutics (Research Grant or Support)Cipla USA Inc. (Research Grant or Support)ContraFect Corporation (Research Grant or Support)GlaxoSmithKline, LLC (Research Grant or Support)Melinta Therapeutics, Inc. (Research Grant or Support)Melinta Therapeutics, LLC (Research Grant or Support)Nabriva Therapeutics (Research Grant or Support)Pfizer, Inc. (Research Grant or Support)Shionogi (Research Grant or Support)Spero Therapeutics (Research Grant or Support) Timothy B. Doyle, AbbVie (formerly Allergan) (Research Grant or Support)Bravos Biosciences (Research Grant or Support)GlaxoSmithKline (Research Grant or Support)Melinta Therapeutics, Inc. (Research Grant or Support)Pfizer, Inc. (Research Grant or Support)Shionogi (Research Grant or Support)Spero Therapeutics (Research Grant or Support) Dee Shortridge, PhD, AbbVie (formerly Allergan) (Research Grant or Support)Melinta Therapeutics, Inc. (Research Grant or Support)Melinta Therapeutics, LLC (Research Grant or Support)Shionogi (Research Grant or Support) Helio S. Sader, MD, PhD, FIDSA, AbbVie (formerly Allergan) (Research Grant or Support)Basilea Pharmaceutica International, Ltd. (Research Grant or Support)Cipla Therapeutics (Research Grant or Support)Cipla USA Inc. (Research Grant or Support)Department of Health and Human Services (Research Grant or Support, Contract no. HHSO100201600002C)Melinta Therapeutics, LLC (Research Grant or Support)Nabriva Therapeutics (Research Grant or Support)Pfizer, Inc. (Research Grant or Support)Shionogi (Research Grant or Support)Spero Therapeutics (Research Grant or Support) Jennifer M. Streit, BS, GlaxoSmithKline, LLC (Research Grant or Support)Melinta Therapeutics, LLC (Research Grant or Support)Shionogi (Research Grant or Support)Spero Therapeutics (Research Grant or Support) Mariana Castanheira, PhD, AbbVie (formerly Allergan) (Research Grant or Support)Bravos Biosciences (Research Grant or Support)Cidara Therapeutics, Inc. (Research Grant or Support)Cipla Therapeutics (Research Grant or Support)Cipla USA Inc. (Research Grant or Support)GlaxoSmithKline (Research Grant or Support)Melinta Therapeutics, Inc. (Research Grant or Support)Melinta Therapeutics, LLC (Research Grant or Support)Pfizer, Inc. (Research Grant or Support)Qpex Biopharma (Research Grant or Support)Shionogi (Research Grant or Support)Spero Therapeutics (Research Grant or Support) Mariana Castanheira, PhD, Affinity Biosensors (Individual(s) Involved: Self): Research Grant or Support; Allergan (Individual(s) Involved: Self): Research Grant or Support; Amicrobe, Inc (Individual(s) Involved: Self): Research Grant or Support; Amplyx Pharma (Individual(s) Involved: Self): Research Grant or Support; Artugen Therapeutics USA, Inc. (Individual(s) Involved: Self): Research Grant or Support; Astellas (Individual(s) Involved: Self): Research Grant or Support; Basilea (Individual(s) Involved: Self): Research Grant or Support; Beth Israel Deaconess Medical Center (Individual(s) Involved: Self): Research Grant or Support; BIDMC (Individual(s) Involved: Self): Research Grant or Support; bioMerieux Inc. (Individual(s) Involved: Self): Research Grant or Support; BioVersys Ag (Individual(s) Involved: Self): Research Grant or Support; Bugworks (Individual(s) Involved: Self): Research Grant or Support; Cidara (Individual(s) Involved: Self): Research Grant or Support; Cipla (Individual(s) Involved: Self): Research Grant or Support; Contrafect (Individual(s) Involved: Self): Research Grant or Support; Cormedix (Individual(s) Involved: Self): Research Grant or Support; Crestone, Inc. (Individual(s) Involved: Self): Research Grant or Support; Curza (Individual(s) Involved: Self): Research Grant or Support; CXC7 (Individual(s) Involved: Self): Research Grant or Support; Entasis (Individual(s) Involved: Self): Research Grant or Support; Fedora Pharmaceutical (Individual(s) Involved: Self): Research Grant or Support; Fimbrion Therapeutics (Individual(s) Involved: Self): Research Grant or Support; Fox Chase (Individual(s) Involved: Self): Research Grant or Support; GlaxoSmithKline (Individual(s) Involved: Self): Research Grant or Support; Guardian Therapeutics (Individual(s) Involved: Self): Research Grant or Support; Hardy Diagnostics (Individual(s) Involved: Self): Research Grant or Support; IHMA (Individual(s) Involved: Self): Research Grant or Support; Janssen Research & Development (Individual(s) Involved: Self): Research Grant or Support; Johnson & Johnson (Individual(s) Involved: Self): Research Grant or Support; Kaleido Biosceinces (Individual(s) Involved: Self): Research Grant or Support; KBP Biosciences (Individual(s) Involved: Self): Research Grant or Support; Luminex (Individual(s) Involved: Self): Research Grant or Support; Matrivax (Individual(s) Involved: Self): Research Grant or Support; Mayo Clinic (Individual(s) Involved: Self): Research Grant or Support; Medpace (Individual(s) Involved: Self): Research Grant or Support; Meiji Seika Pharma Co., Ltd. (Individual(s) Involved: Self): Research Grant or Support; Melinta (Individual(s) Involved: Self): Research Grant or Support; Menarini (Individual(s) Involved: Self): Research Grant or Support; Merck (Individual(s) Involved: Self): Research Grant or Support; Meridian Bioscience Inc. (Individual(s) Involved: Self): Research Grant or Support; Micromyx (Individual(s) Involved: Self): Research Grant or Support; MicuRx (Individual(s) Involved: Self): Research Grant or Support; N8 Medical (Individual(s) Involved: Self): Research Grant or Support; Nabriva (Individual(s) Involved: Self): Research Grant or Support; National Institutes of Health (Individual(s) Involved: Self): Research Grant or Support; National University of Singapore (Individual(s) Involved: Self): Research Grant or Support; North Bristol NHS Trust (Individual(s) Involved: Self): Research Grant or Support; Novome Biotechnologies (Individual(s) Involved: Self): Research Grant or Support; Paratek (Individual(s) Involved: Self): Research Grant or Support; Pfizer (Individual(s) Involved: Self): Research Grant or Support; Prokaryotics Inc. (Individual(s) Involved: Self): Research Grant or Support; QPEX Biopharma (Individual(s) Involved: Self): Research Grant or Support; Rhode Island Hospital (Individual(s) Involved: Self): Research Grant or Support; RIHML (Individual(s) Involved: Self): Research Grant or Support; Roche (Individual(s) Involved: Self): Research Grant or Support; Roivant (Individual(s) Involved: Self): Research Grant or Support; Salvat (Individual(s) Involved: Self): Research Grant or Support; Scynexis (Individual(s) Involved: Self): Research Grant or Support; SeLux Diagnostics (Individual(s) Involved: Self): Research Grant or Support; Shionogi (Individual(s) Involved: Self): Research Grant or Support; Specific Diagnostics (Individual(s) Involved: Self): Research Grant or Support; Spero (Individual(s) Involved: Self): Research Grant or Support; SuperTrans Medical LT (Individual(s) Involved: Self): Research Grant or Support; T2 Biosystems (Individual(s) Involved: Self): Research Grant or Support; The University of Queensland (Individual(s) Involved: Self): Research Grant or Support; Thermo Fisher Scientific (Individual(s) Involved: Self): Research Grant or Support; Tufts Medical Center (Individual(s) Involved: Self): Research Grant or Support; Universite de Sherbrooke (Individual(s) Involved: Self): Research Grant or Support; University of Iowa (Individual(s) Involved: Self): Research Grant or Support; University of Iowa Hospitals and Clinics (Individual(s) Involved: Self): Research Grant or Support; University of Wisconsin (Individual(s) Involved: Self): Research Grant or Support; UNT System College of Pharmacy (Individual(s) Involved: Self): Research Grant or Support; URMC (Individual(s) Involved: Self): Research Grant or Support; UT Southwestern (Individual(s) Involved: Self): Research Grant or Support; VenatoRx (Individual(s) Involved: Self): Research Grant or Support; Viosera Therapeutics (Individual(s) Involved: Self): Research Grant or Support; Wayne State University (Individual(s) Involved: Self): Research Grant or Support
Published: 2021
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18. Antimicrobial Activity of Ceftazidime-Avibactam, Ceftolozane-Tazobactam and Comparators Tested Against

Author: Helio S, Sader, Cecilia G, Carvalhaes, Jennifer M, Streit, Timothy B, Doyle, and Mariana, Castanheira
Subjects: Tazobactam, Whole Genome Sequencing, Meropenem, Microbial Sensitivity Tests, Ceftazidime, United States, beta-Lactam Resistance, Anti-Bacterial Agents, Cephalosporins, Drug Combinations, Klebsiella pneumoniae, Phenotype, Piperacillin, Tazobactam Drug Combination, Drug Resistance, Multiple, Bacterial, Pseudomonas aeruginosa, Humans, Amikacin, Azabicyclo Compounds
Abstract: Very few antimicrobial agents remain active against
Published: 2020

19. Correction for Castanheira et al., 'Meropenem-Vaborbactam Activity against Carbapenem-Resistant

Author: Mariana, Castanheira, Timothy B, Doyle, Valerie, Kantro, Rodrigo E, Mendes, and Dee, Shortridge
Subjects: Enterobacterales, Susceptibility, CRE, outer membrane protein
Abstract: The activities of meropenem-vaborbactam and comparators against 152 (1.1%) carbapenem-resistant Enterobacterales (CRE) isolates identified among 13,929 Enterobacterales isolates collected from U.S. hospitals during 2016 to 2018 were evaluated. CRE rates were higher in the Middle Atlantic census division (3.5%) than in the other divisions (range, 0.0% for the West North Central division to 1.4% for the West South Central division)., The activities of meropenem-vaborbactam and comparators against 152 (1.1%) carbapenem-resistant Enterobacterales (CRE) isolates identified among 13,929 Enterobacterales isolates collected from U.S. hospitals during 2016 to 2018 were evaluated. CRE rates were higher in the Middle Atlantic census division (3.5%) than in the other divisions (range, 0.0% for the West North Central division to 1.4% for the West South Central division). Among the CRE isolates, 134 carried carbapenemase genes, and these included 72 isolates carrying blaKPC-3, 51 isolates carrying blaKPC-2, 4 isolates carrying blaNDM-1, 3 isolates carrying blaSME-4, 2 isolates carrying blaVIM-1, 1 isolate carrying blaOXA-232, and 1 isolate carrying blaKPC-4. Meropenem-vaborbactam was active against 95.4% of the CRE isolates and 94.8% of the carbapenem-producing Enterobacterales (CPE) isolates when applying the CLSI breakpoints. All isolates producing serine carbapenemases were inhibited by meropenem-vaborbactam at ≤8 mg/liter. One Citrobacter freundii isolate carrying blaKPC-3 had a meropenem-vaborbactam MIC of 8 mg/liter and was resistant according to CLSI breakpoints (the isolate was susceptible when the EUCAST criterion of an MIC of ≤8 mg/liter for susceptible was applied), had disrupted OmpC and OmpF sequences, and overexpressed AcrAB-TolC. All carbapenemase-negative CRE isolates (n = 18) were inhibited by meropenem-vaborbactam at ≤4 mg/liter, and the MIC values of this combination ranged from 0.25 to 4 mg/liter. Among 7 isolates carrying metallo-β-lactamases and/or oxacillinases with carbapenemase activity, meropenem-vaborbactam susceptibility was 14.3% and 57.1% when applying CLSI and EUCAST breakpoints, respectively. CRE isolates were resistant to many comparator agents, and the most active agents were tigecycline, colistin, and amikacin (to which 63.2% to 96.7% of the isolates were susceptible). Understanding the epidemiology of CRE isolates in U.S. hospitals and the resistance mechanisms among these isolates is important to form guidelines for the treatment of infections caused by these organisms, which have high mortality rates.
Published: 2020

20. Correction for Castanheira et al., 'Meropenem-Vaborbactam Activity against Carbapenem-Resistant Enterobacterales Isolates Collected in U.S. Hospitals during 2016 to 2018'

Author: Dee Shortridge, Valerie Kantro, Timothy B Doyle, Mariana Castanheira, and Rodrigo E. Mendes
Subjects: Pharmacology, medicine.medical_specialty, Infectious Diseases, Carbapenem resistant, business.industry, Enterobacterales, Internal medicine, Medicine, Meropenem+Vaborbactam, Pharmacology (medical), business
Published: 2020
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21. 1081. Antimicrobial Activity of Ceftibuten-Avibactam against Clinical Isolates of Enterobacterales Producing Clinically Relevant Beta-Lactamases

Author: Helio S Sader, Jill Lindley, Lalitagauri M Deshpande, Timothy B Doyle, and Mariana Castanheira
Subjects: Infectious Diseases, Oncology
Abstract: Background Ceftibuten (CTB) is an oral cephalosporin active against Enterobacterales approved by the US Food and Drug Administration in 1995. Avibactam (AVI) is a potent inhibitor of extended-spectrum β-lactamases (ESBLs), serine carbapenemases and AmpC that can be administered orally. We evaluated the in vitro activity of CTB-AVI against molecularly characterized Enterobacterales that produced the most common β-lactamases (BLs) and assessed the AVI concentration to be combined with CTB for susceptibility testing. Methods The organism collection (n=71) included Enterobacterales producing ESBLs (28; CTX-M, SHV, and TEM), KPCs (8), MBLs (7; NDM, VIM, and IMP), AmpC derepressed (3), plasmid AmpC (3), OXA-48-like (2), and SME (2) as well as isolates with porin alterations (5) and wild-type organisms (13). Resistance mechanisms were evaluated by whole genome sequencing. MIC values were determined by broth microdilution of CTB with fixed concentrations (2, 4, and 8 mg/L) and ratios (1:1 and 2:1) of AVI. Results The fixed AVI concentration of 4 mg/L best separated CTB-AVI-susceptible from CTB-AVI-resistant isolates. CTB-AVI (fixed 4 mg/L) was very active against Enterobacterales producing ESBL (MIC50/90, 0.03/0.12 mg/L), including CTX-M-15 (MIC50/90, 0.03/0.12 mg/L), KPC (MIC50, 0.06 mg/L), derepressed AmpC (MIC range, 1-2 mg/L), plasmidic AmpC (MIC range, 0.12-0.5 mg/L), SME (MIC range, 0.06-0.12 mg/L), and OXA-48-like (MIC range, 0.5-4 mg/L), but it showed limited activity against MBL-producers (MIC50, >128 mg/L) and isolates with porin alterations (MIC50, 32 mg/L; Table). CTB was very active against SME-producers (MIC, 0.12-0.25 mg/L) and showed some activity against KPC-producers (MIC50, 4 mg/L; MIC range, 2-16 mg/L) and ESBL-producers (MIC50/90, 4/64 mg/L), but it exhibited very limited activity against MBL, AmpC derepressed, plasmidic AmpC, and OXA-48-like producers (MIC50 values of 128 to >128 mg/L). Conclusion CTB-AVI showed potent in vitro activity against Enterobacterales producing most clinically relevant BLs, including ESBLs, KPCs, OXA-48-like, and AmpC, for which limited oral treatment options are available. These in vitro results support further clinical development of CTB-AVI. Disclosures Helio S. Sader, MD, PhD, FIDSA, AbbVie (formerly Allergan) (Research Grant or Support)Basilea Pharmaceutica International, Ltd. (Research Grant or Support)Cipla Therapeutics (Research Grant or Support)Cipla USA Inc. (Research Grant or Support)Department of Health and Human Services (Research Grant or Support, Contract no. HHSO100201600002C)Melinta Therapeutics, LLC (Research Grant or Support)Nabriva Therapeutics (Research Grant or Support)Pfizer, Inc. (Research Grant or Support)Shionogi (Research Grant or Support)Spero Therapeutics (Research Grant or Support) Jill Lindley, Bravos Biosciences (Research Grant or Support)ContraFect Corporation (Research Grant or Support)Pfizer, Inc. (Research Grant or Support)Qpex Biopharma (Research Grant or Support) Lalitagauri M. Deshpande, PhD, AbbVie (formerly Allergan) (Research Grant or Support)Pfizer, Inc. (Research Grant or Support) Timothy B. Doyle, AbbVie (formerly Allergan) (Research Grant or Support)Bravos Biosciences (Research Grant or Support)GlaxoSmithKline (Research Grant or Support)Melinta Therapeutics, Inc. (Research Grant or Support)Pfizer, Inc. (Research Grant or Support)Shionogi (Research Grant or Support)Spero Therapeutics (Research Grant or Support) Mariana Castanheira, PhD, AbbVie (formerly Allergan) (Research Grant or Support)Bravos Biosciences (Research Grant or Support)Cidara Therapeutics, Inc. (Research Grant or Support)Cipla Therapeutics (Research Grant or Support)Cipla USA Inc. (Research Grant or Support)GlaxoSmithKline (Research Grant or Support)Melinta Therapeutics, Inc. (Research Grant or Support)Melinta Therapeutics, LLC (Research Grant or Support)Pfizer, Inc. (Research Grant or Support)Qpex Biopharma (Research Grant or Support)Shionogi (Research Grant or Support)Spero Therapeutics (Research Grant or Support) Mariana Castanheira, PhD, Affinity Biosensors (Individual(s) Involved: Self): Research Grant or Support; Allergan (Individual(s) Involved: Self): Research Grant or Support; Amicrobe, Inc (Individual(s) Involved: Self): Research Grant or Support; Amplyx Pharma (Individual(s) Involved: Self): Research Grant or Support; Artugen Therapeutics USA, Inc. (Individual(s) Involved: Self): Research Grant or Support; Astellas (Individual(s) Involved: Self): Research Grant or Support; Basilea (Individual(s) Involved: Self): Research Grant or Support; Beth Israel Deaconess Medical Center (Individual(s) Involved: Self): Research Grant or Support; BIDMC (Individual(s) Involved: Self): Research Grant or Support; bioMerieux Inc. (Individual(s) Involved: Self): Research Grant or Support; BioVersys Ag (Individual(s) Involved: Self): Research Grant or Support; Bugworks (Individual(s) Involved: Self): Research Grant or Support; Cidara (Individual(s) Involved: Self): Research Grant or Support; Cipla (Individual(s) Involved: Self): Research Grant or Support; Contrafect (Individual(s) Involved: Self): Research Grant or Support; Cormedix (Individual(s) Involved: Self): Research Grant or Support; Crestone, Inc. (Individual(s) Involved: Self): Research Grant or Support; Curza (Individual(s) Involved: Self): Research Grant or Support; CXC7 (Individual(s) Involved: Self): Research Grant or Support; Entasis (Individual(s) Involved: Self): Research Grant or Support; Fedora Pharmaceutical (Individual(s) Involved: Self): Research Grant or Support; Fimbrion Therapeutics (Individual(s) Involved: Self): Research Grant or Support; Fox Chase (Individual(s) Involved: Self): Research Grant or Support; GlaxoSmithKline (Individual(s) Involved: Self): Research Grant or Support; Guardian Therapeutics (Individual(s) Involved: Self): Research Grant or Support; Hardy Diagnostics (Individual(s) Involved: Self): Research Grant or Support; IHMA (Individual(s) Involved: Self): Research Grant or Support; Janssen Research & Development (Individual(s) Involved: Self): Research Grant or Support; Johnson & Johnson (Individual(s) Involved: Self): Research Grant or Support; Kaleido Biosceinces (Individual(s) Involved: Self): Research Grant or Support; KBP Biosciences (Individual(s) Involved: Self): Research Grant or Support; Luminex (Individual(s) Involved: Self): Research Grant or Support; Matrivax (Individual(s) Involved: Self): Research Grant or Support; Mayo Clinic (Individual(s) Involved: Self): Research Grant or Support; Medpace (Individual(s) Involved: Self): Research Grant or Support; Meiji Seika Pharma Co., Ltd. (Individual(s) Involved: Self): Research Grant or Support; Melinta (Individual(s) Involved: Self): Research Grant or Support; Menarini (Individual(s) Involved: Self): Research Grant or Support; Merck (Individual(s) Involved: Self): Research Grant or Support; Meridian Bioscience Inc. (Individual(s) Involved: Self): Research Grant or Support; Micromyx (Individual(s) Involved: Self): Research Grant or Support; MicuRx (Individual(s) Involved: Self): Research Grant or Support; N8 Medical (Individual(s) Involved: Self): Research Grant or Support; Nabriva (Individual(s) Involved: Self): Research Grant or Support; National Institutes of Health (Individual(s) Involved: Self): Research Grant or Support; National University of Singapore (Individual(s) Involved: Self): Research Grant or Support; North Bristol NHS Trust (Individual(s) Involved: Self): Research Grant or Support; Novome Biotechnologies (Individual(s) Involved: Self): Research Grant or Support; Paratek (Individual(s) Involved: Self): Research Grant or Support; Pfizer (Individual(s) Involved: Self): Research Grant or Support; Prokaryotics Inc. (Individual(s) Involved: Self): Research Grant or Support; QPEX Biopharma (Individual(s) Involved: Self): Research Grant or Support; Rhode Island Hospital (Individual(s) Involved: Self): Research Grant or Support; RIHML (Individual(s) Involved: Self): Research Grant or Support; Roche (Individual(s) Involved: Self): Research Grant or Support; Roivant (Individual(s) Involved: Self): Research Grant or Support; Salvat (Individual(s) Involved: Self): Research Grant or Support; Scynexis (Individual(s) Involved: Self): Research Grant or Support; SeLux Diagnostics (Individual(s) Involved: Self): Research Grant or Support; Shionogi (Individual(s) Involved: Self): Research Grant or Support; Specific Diagnostics (Individual(s) Involved: Self): Research Grant or Support; Spero (Individual(s) Involved: Self): Research Grant or Support; SuperTrans Medical LT (Individual(s) Involved: Self): Research Grant or Support; T2 Biosystems (Individual(s) Involved: Self): Research Grant or Support; The University of Queensland (Individual(s) Involved: Self): Research Grant or Support; Thermo Fisher Scientific (Individual(s) Involved: Self): Research Grant or Support; Tufts Medical Center (Individual(s) Involved: Self): Research Grant or Support; Universite de Sherbrooke (Individual(s) Involved: Self): Research Grant or Support; University of Iowa (Individual(s) Involved: Self): Research Grant or Support; University of Iowa Hospitals and Clinics (Individual(s) Involved: Self): Research Grant or Support; University of Wisconsin (Individual(s) Involved: Self): Research Grant or Support; UNT System College of Pharmacy (Individual(s) Involved: Self): Research Grant or Support; URMC (Individual(s) Involved: Self): Research Grant or Support; UT Southwestern (Individual(s) Involved: Self): Research Grant or Support; VenatoRx (Individual(s) Involved: Self): Research Grant or Support; Viosera Therapeutics (Individual(s) Involved: Self): Research Grant or Support; Wayne State University (Individual(s) Involved: Self): Research Grant or Support
Published: 2021
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22. Activity of ceftazidime/avibactam, meropenem/vaborbactam and imipenem/relebactam against carbapenemase-negative carbapenem-resistant Enterobacterales isolates from US hospitals

Author: Rodrigo E. Mendes, Lalitagauri M. Deshpande, Helio S. Sader, Mariana Castanheira, and Timothy B Doyle
Subjects: Microbiology (medical), Imipenem, Klebsiella pneumoniae, Avibactam, Ceftazidime, Microbial Sensitivity Tests, Meropenem, beta-Lactamases, Microbiology, Heterocyclic Compounds, 1-Ring, chemistry.chemical_compound, Bacterial Proteins, Drug Resistance, Multiple, Bacterial, Enterobacter cloacae, Escherichia coli, medicine, Humans, Pharmacology (medical), biology, Enterobacter aerogenes, General Medicine, biochemical phenomena, metabolism, and nutrition, biology.organism_classification, Ceftazidime/avibactam, Boronic Acids, Proteus mirabilis, United States, Anti-Bacterial Agents, Drug Combinations, Carbapenem-Resistant Enterobacteriaceae, Infectious Diseases, chemistry, beta-Lactamase Inhibitors, Azabicyclo Compounds, medicine.drug
Abstract: We investigated the prevalence, resistance mechanisms and activity of ceftazidime/avibactam, meropenem/vaborbactam, imipenem/relebactam and comparator agents against carbapenem-resistant Enterobacterales (CRE) that did not carry carbapenemase genes. Among 304 CRE isolates collected in US hospitals during 2016–2018 (1.1% of the overall Enterobacterales), 45 (14.8%) isolates did not carry carbapenemases. These isolates were mainly Klebsiella aerogenes (n = 11), Enterobacter cloacae (n = 11) and Klebsiella pneumoniae (n = 10). Isolates harboured one to six β-lactam resistance mechanisms (median, three mechanisms). Acquired β-lactamase genes were detected in 21 isolates; blaCTX-M-15 was the most common acquired β-lactamase gene found (14 isolates). All 11 K. aerogenes and 6 E. cloacae isolates overexpressed AmpC. Only one isolate belonging to these species carried acquired β-lactamase genes. Disruptions or reduced expression of both outer membrane proteins (ompC/ompK36 and ompF/ompK35) were detected among 20 isolates. AcrAB–TolC was modestly expressed or overexpressed among 19 isolates from six species. One E. coli isolate produced a CTX-M-15 variant that displayed an increased meropenem minimum inhibitory concentration (MIC) when expressed in a clean background. Most β-lactam agents had limited activity against CRE isolates that did not carry carbapenemases. Ceftazidime/avibactam inhibited all isolates, while imipenem/relebactam and meropenem/vaborbactam inhibited 93.0% (88.9% if Proteus mirabilis is included) and 93.3% of tested isolates at current breakpoints. The resistance mechanisms among CRE isolates that did not produce carbapenemases are complex; β-lactam/β-lactamase inhibitor combinations might have different activity against these isolates depending on their resistance mechanisms and the bacterial species.
Published: 2021
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23. 26. in Vitro selection Of enterobacter Cloacae with Cefepime, Meropenem, and Ceftazidime-avibactam Generate Diverse Resistance Mechanism

Author: Helio S. Sader, Jill Lindley, Timothy B Doyle, Brieanna M. Roth, Mariana Castanheira, and Andrew P. Davis
Subjects: biology, business.industry, Cefepime, education, Antimicrobial, biology.organism_classification, Ceftazidime/avibactam, Meropenem, In vitro, Microbiology, Infectious Diseases, AcademicSubjects/MED00290, Oncology, Oral Abstracts, AVIBACTAM/CEFTAZIDIME, medicine, business, Enterobacter cloacae, health care economics and organizations, medicine.drug, Protein overexpression
Abstract: Background Acquired β-lactamases are not a common β-lactam resistance mechanism in E. cloacae. In this species, porin mutations decreasing β-lactams permeability are associated with overexpression of the constitutive AmpC with or without increased efflux contributing to β-lactam resistance. We subjected 6 E. cloacae isolates to 10-day serial passage with cefepime (FEP), meropenem (MER), and ceftazidime-avibactam (CAZ-AVI) to evaluate resistance level and mechanism in the mutant strains. Methods Serial passaging was performed in broth microdilution (BMD). Isolated colonies growing in the highest antimicrobial concentrations were submitted to short-read whole genome sequencing (WGS) and analyzed for β-lactam resistance mechanisms. Final mutants displaying > 2-fold changes from the baseline and baseline isolates were sequenced using long-read WGS for single nucleotide polymorphism (SNP) analysis. Results After 10-day passaging, 3 (50.0%) isolates displayed FEP resistance, but only 1 (15.0%) displayed resistance to MER or CAZ-AVI (Table). MIC changes were 4 to 64-fold for FEP, 16 to 64-fold for MER and 2 to 32-fold for CAZ-AVI. SNP analysis demonstrated that final resistant mutants had diverse mechanisms. MER and CAZ-AVI selected for AmpC mutants E61V, G213D, and V303E. OmpC and AcrA regulator alterations were noted in MER and CAZ-AVI mutants for 1 isolate. Mutations in the ABC transporter UrtB and the cell division inhibitor MioC were observed when 1 isolate was exposed to any of the 3 agents. Mutants for 1 isolate had deletion of OmpC (PCR confirmed). Mutations in the upstream region of various genes and gene regulators were observed. The highest CAZ-AVI MIC values were noted in an isolate displaying a mutation in an RND transported permease. Table Conclusion FEP displayed more resistant mutants when compared to MER and CAZ-AVI. Despite the low MIC values of the mutant isolates for MER, the fold changes for this agent were higher than in FEP and CAZ-AVI. Resistance mechanisms in the mutants were complex. Only a few isolates had alterations in the genes usually associated with β-lactam resistance in E. cloacae. Further studies should be performed to evaluate if the mutations observed in vitro are present in clinical isolates resistant to these agents. Disclosures Mariana Castanheira, PhD, 1928 Diagnostics (Research Grant or Support)A. Menarini Industrie Farmaceutiche Riunite S.R.L. (Research Grant or Support)Allergan (Research Grant or Support)Allergan (Research Grant or Support)Amplyx Pharmaceuticals (Research Grant or Support)Cidara Therapeutics (Research Grant or Support)Cidara Therapeutics (Research Grant or Support)Cipla Ltd. (Research Grant or Support)Cipla Ltd. (Research Grant or Support)Fox Chase Chemical Diversity Center (Research Grant or Support)GlaxoSmithKline (Research Grant or Support)Melinta Therapeutics, Inc. (Research Grant or Support)Melinta Therapeutics, Inc. (Research Grant or Support)Melinta Therapeutics, Inc. (Research Grant or Support)Merck (Research Grant or Support)Merck (Research Grant or Support)Merck & Co, Inc. (Research Grant or Support)Merck & Co, Inc. (Research Grant or Support)Paratek Pharma, LLC (Research Grant or Support)Pfizer (Research Grant or Support)Qpex Biopharma (Research Grant or Support) Jill Lindley, Allergan (Research Grant or Support)Qpex Biopharma (Research Grant or Support) Brieanna Roth, n/a, Allergan (Research Grant or Support) Timothy B. Doyle, Allergan (Research Grant or Support)Allergan (Research Grant or Support)Cipla Ltd. (Research Grant or Support)Melinta Therapeutics, Inc. (Research Grant or Support)Pfizer (Research Grant or Support)Qpex Biopharma (Research Grant or Support) Helio S. Sader, MD, PhD, A. Menarini Industrie Farmaceutiche Riunite S.R.L. (Research Grant or Support)Allergan (Research Grant or Support)Allergan (Research Grant or Support)Allergan (Research Grant or Support)Cipla Ltd. (Research Grant or Support)Cipla Ltd. (Research Grant or Support)Melinta (Research Grant or Support)Merck (Research Grant or Support)Merck (Research Grant or Support)Paratek Pharma, LLC (Research Grant or Support)Pfizer (Research Grant or Support)
Published: 2020

24. 1454. Plazomicin Activity against Enterobacterales Isolates Producing Extended-Spectrum β-Lactamases (ESBLs), Carbapenemases, and Aminoglycoside-Modifying Enzymes (AMEs) from United States (US) Hospitals

Author: Timothy B Doyle, Jaideep Gogtay, Helio S. Sader, Sandhya Das, Rodrigo E. Mendes, Valerie Kantro, and Mariana Castanheira
Subjects: Aminoglycoside modifying enzymes, business.industry, β lactamases, Plazomicin, Microbiology, chemistry.chemical_compound, AcademicSubjects/MED00290, Infectious Diseases, Oncology, chemistry, Enterobacterales, Poster Abstracts, Medicine, business
Abstract: Background Limited therapeutic options are available for the treatment of multidrug resistant (MDR) organisms. Plazomicin (PLZ) is an aminoglycoside developed to overcome common aminoglycoside-resistance mechanisms. We evaluated the activity of PLZ and comparators against Enterobacterales isolates collected in 2018-2019 carrying genes encoding ESBLs, carbapenemases, and AMEs. Methods Among 3,899 Enterobacterales isolates from US hospitals susceptibility (S) tested using reference broth microdilution method, 619 isolates from selected species displaying elevated MIC values for cephalosporins, carbapenems and/or resistance (CLSI criteria) to amikacin (AMK), gentamicin (GEN) and tobramycin (TOB) were submitted to whole genome sequencing for detection of resistance genes. Results Most isolates producing ESBLs (n= 418) carried blaCTX-M (n= 386). The activity of PLZ (99.3% susceptible [S]) was comparable to that of colistin and higher than other comparators against ESBL isolates (Figure). AMK inhibited 96.4% of the isolates and GEN and TOB inhibited 57.9% and 43.5%, respectively. Only 34 isolates produced carbapenemases, including 19 KPC-2, 10 KPC-3, 1 each with VIM-1, OXA-181, NDM-5 and KPC-2-like plus 1 isolate carrying the genes encoding NDM-1 and OXA-232. These isolates displayed higher resistance rates to comparators and only PLZ, and tigecycline inhibited >90% of these isolates. AMK and GEN inhibited 67.6% and 55.9% of these isolates, respectively. PLZ was active against 97.7% of isolates carrying AME genes (n= 306) that carried aac(6’)-Ib-cr (n =177), aac(3)-IIa (n = 159) and aac(3)-IId (n =81), among others. Most of these isolates were resistant to GEN and TOB (only 10.8-14.1% S), but 92.8% were S to AMK. Three K. pneumoniae isolates carried 16S rRNA methyltransferases, 1 armA (also harboring NDM-1) and 2 rmtB1. Conclusion The activity of PLZ against Enterobacteriaceae isolates carrying AMEs, ESBLs, and carbapenemases was greater than the activity of other aminoglycosides tested and comparable to those of tigecycline and colistin against carbapenemase-producing organisms. Isolates carrying genes encoding ESBLs, AMEs and carbapenemases are usually MDR and PLZ had activity against these organisms collected in the US. Figure 1 Disclosures Mariana Castanheira, PhD, 1928 Diagnostics (Research Grant or Support)A. Menarini Industrie Farmaceutiche Riunite S.R.L. (Research Grant or Support)Allergan (Research Grant or Support)Allergan (Research Grant or Support)Amplyx Pharmaceuticals (Research Grant or Support)Cidara Therapeutics (Research Grant or Support)Cidara Therapeutics (Research Grant or Support)Cipla Ltd. (Research Grant or Support)Cipla Ltd. (Research Grant or Support)Fox Chase Chemical Diversity Center (Research Grant or Support)GlaxoSmithKline (Research Grant or Support)Melinta Therapeutics, Inc. (Research Grant or Support)Melinta Therapeutics, Inc. (Research Grant or Support)Melinta Therapeutics, Inc. (Research Grant or Support)Merck (Research Grant or Support)Merck (Research Grant or Support)Merck & Co, Inc. (Research Grant or Support)Merck & Co, Inc. (Research Grant or Support)Paratek Pharma, LLC (Research Grant or Support)Pfizer (Research Grant or Support)Qpex Biopharma (Research Grant or Support) Rodrigo E. Mendes, PhD, A. Menarini Industrie Farmaceutiche Riunite S.R.L. (Research Grant or Support)Allergan (Research Grant or Support)Allergan (Research Grant or Support)Basilea Pharmaceutica International, Ltd (Research Grant or Support)Cipla Ltd. (Research Grant or Support)Department of Health and Human Services (Research Grant or Support)GlaxoSmithKline (Research Grant or Support)Melinta Therapeutics, Inc. (Research Grant or Support)Merck (Research Grant or Support)Merck (Research Grant or Support)Pfizer (Research Grant or Support) Timothy B. Doyle, Allergan (Research Grant or Support)Allergan (Research Grant or Support)Cipla Ltd. (Research Grant or Support)Melinta Therapeutics, Inc. (Research Grant or Support)Pfizer (Research Grant or Support)Qpex Biopharma (Research Grant or Support) Valerie Kantro, n/a, Cipla Ltd. (Research Grant or Support) Helio S. Sader, MD, PhD, A. Menarini Industrie Farmaceutiche Riunite S.R.L. (Research Grant or Support)Allergan (Research Grant or Support)Allergan (Research Grant or Support)Allergan (Research Grant or Support)Cipla Ltd. (Research Grant or Support)Cipla Ltd. (Research Grant or Support)Melinta (Research Grant or Support)Merck (Research Grant or Support)Merck (Research Grant or Support)Paratek Pharma, LLC (Research Grant or Support)Pfizer (Research Grant or Support) Jaideep Gogtay, n/a, Cipla Ltd. (Employee) Sandhya Das, n/a, Cipla Ltd. (Research Grant or Support)
Published: 2020
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25. 166. Activity of a Novel β-lactamase Inhibitor QPX7728 Combined With β-lactams Against st258 klebsiella Pneumoniae and st131 escherchia Coli Isolates Producing β-lactamases

Author: Andrew P. Davis, Olga Lomovskaya, Jill Lindley, Mariana Castanheira, and Timothy B Doyle
Subjects: biology, business.industry, Klebsiella pneumoniae, β lactamases, education, biology.organism_classification, Microbiology, AcademicSubjects/MED00290, Infectious Diseases, Oncology, β lactamase inhibitor, Poster Abstracts, β lactams, Medicine, business, health care economics and organizations
Abstract: Background ST258 K. pneumoniae and ST131 E. coli clones are considered vectors for the global spread of multidrug resistance. We evaluated the activity of β-lactams in combination with QPX7728, a novel β-lactamase inhibitor active against all β-lactamase classes, against a collection of 210 isolates belonging to these clones collected from a worldwide surveillance study. Methods A total of 118 ST258 K. pneumoniae and 92 ST131 E. coli (single loci variant also included) were susceptibility tested by reference broth microdilution against various β-lactams ± QPX7728 and comparator agents. All isolates were screened for β-lactamases using whole genome sequencing analysis. Results All β-lactam agents had limited activity against 118 ST258 K. pneumoniae (1.7–7.6% susceptible). Among these, 104 carried carbapenemase-encoding genes: 66 KPC variants, 20 NDM and 17 OXA-48-like. One isolate carried 2 carbapenemases. The addition of QPX7728 at 4 mg/L or 8 mg/L lowered the MICs for cefepime (MIC50/90, 0.25/1 mg/L and MIC50/90, 0.12/0.5 mg/L), ceftolozane (MIC50/90, 0.5/ > 32 mg/L and MIC50/90, 0.25/16 mg/L), ertapenem (MIC50/90, 0.12/2 mg/L and MIC50/90, 0.06/0.5 mg/L), and meropenem (MIC50/90, 0.06/0.5 mg/L and MIC50/90, 0.03/0.12 mg/L; Table). QPX7728 at 4 mg/L reduced the ceftibuten (MIC50/90, 0.25/8 mg/L) or tebipenem (MIC50/90, 0.12/2 mg/L) MICs for ST258 isolates. E. coli ST131 carried mainly CTX-M variant (85 isolates), but 6 isolates harbored carbapenemases. Carbapenems were the only β-lactams displaying > 80.0% activity against ST131 E. coli, followed by piperacillin-tazobactam (79.3% susceptible). Only 5.4%and 41.3% ST131 isolates were susceptible to cefepime and ceftibuten, respectively. MIC50/MIC90 values for these agents with QPX7728 were ≤ 0.015/≤ 0.015 mg/L for cefepime and ≤ 0.015/0.06 mg/L for ceftolozane with the inhibitor at 8 mg/L and ≤ 0.015/0.03 mg/L for ceftibuten with the inhibitor at 4 mg/L. Conclusion QPX7728 lowered the MICs for all agents tested to clinically achievable levels when tested against isolates multidrug resistant belonging to important clones responsible to the dissemination of KPC, CTX variants, and metallo-β-lactamases. The development of this broad β-lactamase inhibitor should be pursued. Table 1 Disclosures Mariana Castanheira, PhD, 1928 Diagnostics (Research Grant or Support)A. Menarini Industrie Farmaceutiche Riunite S.R.L. (Research Grant or Support)Allergan (Research Grant or Support)Allergan (Research Grant or Support)Amplyx Pharmaceuticals (Research Grant or Support)Cidara Therapeutics (Research Grant or Support)Cidara Therapeutics (Research Grant or Support)Cipla Ltd. (Research Grant or Support)Cipla Ltd. (Research Grant or Support)Fox Chase Chemical Diversity Center (Research Grant or Support)GlaxoSmithKline (Research Grant or Support)Melinta Therapeutics, Inc. (Research Grant or Support)Melinta Therapeutics, Inc. (Research Grant or Support)Melinta Therapeutics, Inc. (Research Grant or Support)Merck (Research Grant or Support)Merck (Research Grant or Support)Merck & Co, Inc. (Research Grant or Support)Merck & Co, Inc. (Research Grant or Support)Paratek Pharma, LLC (Research Grant or Support)Pfizer (Research Grant or Support)Qpex Biopharma (Research Grant or Support) Jill Lindley, Allergan (Research Grant or Support)Qpex Biopharma (Research Grant or Support) Timothy B. Doyle, Allergan (Research Grant or Support)Allergan (Research Grant or Support)Cipla Ltd. (Research Grant or Support)Melinta Therapeutics, Inc. (Research Grant or Support)Pfizer (Research Grant or Support)Qpex Biopharma (Research Grant or Support) Olga Lomovskaya, PhD, Qpex Biopharma (Employee)
Published: 2020
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26. Meropenem-Vaborbactam Activity against Carbapenem-Resistant Enterobacterales Isolates Collected in U.S. Hospitals during 2016 to 2018

Author: Dee Shortridge, Valerie Kantro, Mariana Castanheira, Rodrigo E. Mendes, and Timothy B Doyle
Subjects: Pharmacology, 0303 health sciences, Carbapenem resistant, biology, 030306 microbiology, High mortality, Meropenem+Vaborbactam, Tigecycline, biochemical phenomena, metabolism, and nutrition, bacterial infections and mycoses, biology.organism_classification, Microbiology, Citrobacter freundii, 03 medical and health sciences, 0302 clinical medicine, Infectious Diseases, Amikacin, Enterobacterales, polycyclic compounds, medicine, Colistin, Pharmacology (medical), 030212 general & internal medicine, medicine.drug
Abstract: The activities of meropenem-vaborbactam and comparators against 152 (1.1%) carbapenem-resistant Enterobacterales (CRE) isolates identified among 13,929 Enterobacterales isolates collected from U.S. hospitals during 2016 to 2018 were evaluated. CRE rates were higher in the Middle Atlantic census division (3.5%) than in the other divisions (range, 0.0% for the West North Central division to 1.4% for the West South Central division). Among the CRE isolates, 134 carried carbapenemase genes, and these included 72 isolates carrying bla KPC-3, 51 isolates carrying bla KPC-2, 4 isolates carrying bla NDM-1, 3 isolates carrying bla SME-4, 2 isolates carrying bla VIM-1, 1 isolate carrying bla OXA-232, and 1 isolate carrying bla KPC-4 Meropenem-vaborbactam was active against 95.4% of the CRE isolates and 94.8% of the carbapenem-producing Enterobacterales (CPE) isolates when applying the CLSI breakpoints. All isolates producing serine carbapenemases were inhibited by meropenem-vaborbactam at ≤8 mg/liter. One Citrobacter freundii isolate carrying bla KPC-3 had a meropenem-vaborbactam MIC of 8 mg/liter and was resistant according to CLSI breakpoints (the isolate was susceptible when the EUCAST criterion of an MIC of ≤8 mg/liter for susceptible was applied), had disrupted OmpC and OmpF sequences, and overexpressed AcrAB-TolC. All carbapenemase-negative CRE isolates (n = 18) were inhibited by meropenem-vaborbactam at ≤4 mg/liter, and the MIC values of this combination ranged from 0.25 to 4 mg/liter. Among 7 isolates carrying metallo-β-lactamases and/or oxacillinases with carbapenemase activity, meropenem-vaborbactam susceptibility was 14.3% and 57.1% when applying CLSI and EUCAST breakpoints, respectively. CRE isolates were resistant to many comparator agents, and the most active agents were tigecycline, colistin, and amikacin (to which 63.2% to 96.7% of the isolates were susceptible). Understanding the epidemiology of CRE isolates in U.S. hospitals and the resistance mechanisms among these isolates is important to form guidelines for the treatment of infections caused by these organisms, which have high mortality rates.
Published: 2020
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27. Media for colistin susceptibility testing does not improve the detection of Klebsiella pneumoniae isolates carrying MgrB disruption and other mutation driven colistin resistance mechanisms

Author: Brieanna M. Roth, Cecilia G Carvalhaes, Timothy B Doyle, Rodrigo E. Mendes, Paul R. Rhomberg, and Mariana Castanheira
Subjects: 0301 basic medicine, Microbiology (medical), Susceptibility testing, Klebsiella pneumoniae, medicine.drug_class, Polymyxin, 030106 microbiology, Microbial Sensitivity Tests, Biology, medicine.disease_cause, Colistin resistance, Microbiology, 03 medical and health sciences, 0302 clinical medicine, Bacterial Proteins, Enterobacterales, Drug Resistance, Multiple, Bacterial, medicine, Humans, 030212 general & internal medicine, Polymyxins, Mutation, Colistin, Broth microdilution, General Medicine, biology.organism_classification, Anti-Bacterial Agents, Culture Media, Klebsiella Infections, Infectious Diseases, medicine.drug
Abstract: We evaluated different susceptibility testing media against 200 Klebsiella pneumoniae isolates that have been genetically characterized for the presence of polymyxin resistance mechanisms. The media evaluated included calcium enriched media that was described to promote separation of mcr-carrying Enterobacterales isolates and standard cation-adjusted Mueller-Hinton broth with and without polysorbate 80. The testing conditions evaluated did not show improvement in the separation of isolates carrying MgrB alterations and other mutation-driven polymyxin resistance mechanisms.
Published: 2019

28. Ceftazidime-avibactam activity against a challenge set of carbapenem-resistant Enterobacterales: Ompk36 L3 alterations and β-lactamases with ceftazidime hydrolytic activity lead to elevated MIC values

Author: Timothy B Doyle, Cory Hubler, Helio S. Sader, Mariana Castanheira, and Rodrigo E. Mendes
Subjects: 0301 basic medicine, Microbiology (medical), Klebsiella pneumoniae, Phenylalanine, 030106 microbiology, Ceftazidime, Porins, Microbial Sensitivity Tests, Enterobacter aerogenes, Genome, beta-Lactamases, Microbiology, 03 medical and health sciences, 0302 clinical medicine, Bacterial Proteins, Drug Resistance, Multiple, Bacterial, medicine, Humans, Pharmacology (medical), 030212 general & internal medicine, Gene, Polymyxin B, biology, Membrane Transport Proteins, General Medicine, biology.organism_classification, Ceftazidime/avibactam, Anti-Bacterial Agents, Drug Combinations, Infectious Diseases, Carbapenem-Resistant Enterobacteriaceae, Multilocus sequence typing, Bacterial outer membrane, beta-Lactamase Inhibitors, Azabicyclo Compounds, medicine.drug, Bacterial Outer Membrane Proteins, Multilocus Sequence Typing
Abstract: Introduction This study examined ceftazidime-avibactam activity against carbapenem-resistant Enterobacterales (CRE) clinical isolates and resistance mechanisms among non-metallo β-lactamase (MBL) producers displaying ceftazidime-avibactam MIC values at 4 mg/L. Methods CRE isolates (286 of 8161 Enterobacterales) collected in Asia-Pacific, Europe and Latin America during 2016 were screened for carbapenemase genes. Selected isolates were susceptibility tested for ceftazidime-avibactam in the presence or absence of phenylalanine-arginyl β-naphthylamide (PAβN) and polymyxin B nonapeptide (PMBN). Genome sequences were investigated for the integrity of outer membrane protein (OMP) genes and multilocus sequence typing. qRT-PCR assays were conducted to determine expression of acrA, ampC, and OMP genes. Results Ceftazidime-avibactam inhibited 99.2% of the Enterobacterales, 22 (78.7%) of the 286 CRE and 226 (100%) non-MBL producers. Among carbapenemase producers (85.3%; 244 of 286), the most common gene was blaKPC (76 blaKPC-3 and 46 blaKPC-2), followed by blaOXA-48-like (60 isolates) and blaNDM (37). Ceftazidime-avibactam MIC values at 4 mg/L were noted among 14 Klebsiella pneumoniae (13 carrying blaKPC and 1 blaCTX-M-15) mostly from Italy and Brazil and 1 Klebsiella aerogenes overexpressing ampC. PAβN did not significantly decrease ceftazidime-avibactam results, but adding PMBN did significantly decrease the MIC results for the combination. All K. pneumoniae isolates had a premature stop codon at OmpK35 and most isolates had L3 alterations of OmpK36, low expression of this gene, or OmpC disruption (K. aerogenes). Nine K. pneumoniae isolates belonged to clonal complex 258 and displayed intrahospital clonality. Conclusion Ceftazidime-avibactam is an important addition to the armamentarium against multidrug-resistant organisms, and elevated MIC results for this combination seem to be associated with L3 OmpK36 alterations and β-lactamases able to hydrolyze ceftazidime.
Published: 2019

29. Meropenem-Vaborbactam Activity against Carbapenem-Resistant

Author: Mariana, Castanheira, Timothy B, Doyle, Valerie, Kantro, Rodrigo E, Mendes, and Dee, Shortridge
Subjects: Enterobacteriaceae Infections, Porins, Meropenem, Microbial Sensitivity Tests, Boronic Acids, United States, beta-Lactamases, Anti-Bacterial Agents, Carbapenem-Resistant Enterobacteriaceae, Bacterial Proteins, Carbapenems, Humans, beta-Lactamase Inhibitors, Author Correction
Abstract: The activities of meropenem-vaborbactam and comparators against 152 (1.1%) carbapenem-resistant
Published: 2019

30. Comparative Activities of Ceftazidime-Avibactam and Ceftolozane-Tazobactam against Enterobacteriaceae Isolates Producing Extended-Spectrum β-Lactamases from U.S. Hospitals

Author: Rodrigo E. Mendes, Helio S. Sader, Mariana Castanheira, and Timothy B Doyle
Subjects: Tazobactam, medicine.drug_class, Klebsiella pneumoniae, Cephalosporin, Tigecycline, Microbial Sensitivity Tests, medicine.disease_cause, Ceftazidime, Microbiology, Epidemiology and Surveillance, 03 medical and health sciences, 0302 clinical medicine, Enterobacteriaceae, medicine, polycyclic compounds, Escherichia coli, Pharmacology (medical), 030212 general & internal medicine, Pharmacology, 0303 health sciences, biology, 030306 microbiology, Colistin, biochemical phenomena, metabolism, and nutrition, biology.organism_classification, Ceftazidime/avibactam, bacterial infections and mycoses, Anti-Bacterial Agents, Cephalosporins, Drug Combinations, Infectious Diseases, bacteria, Enterobacter cloacae, Azabicyclo Compounds, medicine.drug
Abstract: The activities of ceftazidime-avibactam, ceftolozane-tazobactam, and comparators were evaluated for 733 isolates displaying resistance to broad-spectrum cephalosporins and carrying extended-spectrum β-lactamase (ESBL) genes detected by whole-genome sequencing analysis. Isolates were collected during 2017 in U.S. hospitals. The ESBL producers were 486 Escherichia coli, 190 Klebsiella pneumoniae, and 42 Enterobacter cloacae isolates and isolates from 3 other species. The most common groups of ESBL-encoding genes were bla(CTX-M-15)-like (n = 491 isolates) and bla(CTX-M-15) alone (n = 168) or plus bla(OXA-1) (n = 260), followed by bla(CTX-M-14)-like (n = 162), which included bla(CTX-M-27) and bla(CTX-M-14) (104 and 51 isolates, respectively), and bla(SHV-12) and bla(SHV-7) (48 and 22 isolates, respectively). ESBL producers carried other β-lactamases, including 1 E. cloacae harboring bla(KPC-3). All ESBL-producing isolates were susceptible to ceftazidime-avibactam, and 90.2/83.9% (CLSI/EUCAST breakpoints) were susceptible to ceftolozane-tazobactam. Tigecycline (98.1/95.8% susceptible) and colistin (99.2%) were comparators that displayed the greatest activity against these isolates. Ceftolozane-tazobactam inhibited 91.4/83.9% of isolates carrying bla(CTX-M-15)-like and 97.5/95.1% of isolates carrying bla(CTX-M-14)-like, and its activity was more limited against the 91 isolates carrying bla(SHV) (66.7/61.1% susceptible). Ceftolozane-tazobactam inhibited 95.5% of the E. coli isolates but only 83.0%, 64.3%, and 80.0% of K. pneumoniae, E. cloacae, and other species harboring ESBL-encoding genes (CLSI breakpoints), respectively. Outer membrane protein sequences for ceftolozane-tazobactam-nonsusceptible isolates did not exhibit significant differences compared to those in genetically related ceftolozane-tazobactam-susceptible isolates. Ceftazidime-avibactam was more active than other agents tested, including ceftolozane-tazobactam, and the activity of this combination was stable regardless of species or ESBL gene carried.
Published: 2019

31. Low Prevalence of Gram-Positive Isolates Showing Elevated Lefamulin MIC Results during the SENTRY Surveillance Program for 2015–2016 and Characterization of Resistance Mechanisms

Author: Robert K. Flamm, Steven P Gelone, Rodrigo E. Mendes, Timothy B Doyle, Susanne Paukner, and Helio S. Sader
Subjects: Staphylococcus aureus, Microbial Sensitivity Tests, Biology, medicine.disease_cause, Pneumococcal Infections, Streptococcus agalactiae, Microbiology, 03 medical and health sciences, Bacterial Proteins, Mechanisms of Resistance, Streptococcus pneumoniae, medicine, Humans, Polycyclic Compounds, Pharmacology (medical), 030304 developmental biology, Gram, Pharmacology, 0303 health sciences, 030306 microbiology, cons, Staphylococcal Infections, Anti-Bacterial Agents, Infectious Diseases, Sentry, Thioglycolates, ATP-Binding Cassette Transporters, Diterpenes
Abstract: This study investigated the molecular mechanisms possibly associated with non-wild-type MICs for lefamulin among staphylococci and streptococci included in the lefamulin surveillance program from 2015 to 2016. A total of 2,919 Staphylococcus aureus, 276 coagulase-negative staphylococci (CoNS), 3,923 Streptococcus pneumoniae, 389 β-hemolytic, and 178 viridans group streptococci isolates were included in the surveillance studies. Eleven (0.3% of all S. aureus) S. aureus isolates with lefamulin MICs above the staphylococcal epidemiological cutoff (ECOFF) value (>0.25 μg/ml) were selected for this study. Eight (72.7%) S. aureus (lefamulin MIC, 0.5 to 4 μg/ml) isolates carried vga(A or E), one isolate (MIC, 32 μg/ml) carried lsa(E), one isolate (MIC, 16 μg/ml) had an alteration in L4, and one strain (MIC, 0.5 μg/ml) did not carry any of the investigated resistance mechanisms. A total of 14 (5.1% of all CoNS) CoNS isolates had lefamulin MICs (0.5 to >32 μg/ml) above the ECOFF. Similar to S. aureus, 8 (57.1%) CoNS (lefamulin MIC, 1 to 8 μg/ml) isolates carried vga(A or B), while 2 isolates (MIC, 4 to 32 μg/ml) carried cfr. High genetic diversity was observed among staphylococci, although 3 S. aureus isolates belonged to sequence type 398 (ST398). Among the 3 Streptococcus agalactiae and 3 viridans group streptococci (0.1% of all streptococci surveyed) isolates selected for additional characterization, all but 1 isolate carried lsa(E). This study documents a low occurrence of surveillance isolates exhibiting a non-wild-type MIC for lefamulin, and among these isolates, vga and lsa(E) prevailed in staphylococci and streptococci, respectively.
Published: 2019
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32. 1261. Antimicrobial Activity of Aztreonam-Avibactam against Gram-negative Bacteria Isolated from Patients Hospitalized with Pneumonia in Europe, Latin America, and Asia in 2019

Author: Rodrigo E. Mendes, Cecilia G Carvalhaes, Timothy B Doyle, Mariana Castanheira, and Helio S. Sader
Subjects: Gram-negative bacteria, biology, business.industry, Avibactam, Ceftazidime, Aztreonam, Antimicrobial, biology.organism_classification, medicine.disease, Meropenem, Microbiology, Pneumonia, chemistry.chemical_compound, Infectious Diseases, AcademicSubjects/MED00290, Oncology, chemistry, Piperacillin/tazobactam, Poster Abstracts, Medicine, business, medicine.drug
Abstract: Background Aztreonam (ATM) is a monobactam stable to hydrolysis by metallo-β-lactamases (MBL). Avibactam (AVI) is a non-β-lactam β-lactamase inhibitor that inhibits serine carbapenemases (CPEs), such as ESBLs, KPCs, AmpC, and some OXAs. ATM-AVI is under clinical development for treatment of serious infections caused by Gram-negative bacteria (GNB), including MBL-producers. Methods 2,582 GNB (1,630 Enterobacterales [ENT] and 952 nonfermentative-GNB) were consecutively collected (1/patient) from 56 medical centers located in Western Europe (W-EU; 22 centers in 10 nations), Eastern Europe (E-EU; 12 centers in 9 nations), Latin America (LATAM; 10 centers 6 nations), and the Asia-Pacific region (APAC; 12 centers in 8 nations) in 2019 and susceptibility (S) tested against ATM-AVI and comparators at a central laboratory by reference broth microdilution methods. Results Overall, 99.9% of ENT (MIC50/90, 0.06/0.25 mg/L), including 99.1% of carbapenem-resistant ENT (CRE; MIC50/90, 0.25/0.5 mg/L), were inhibited at an ATM-AVI MIC of ≤ 8 mg/L (Table). CRE rates were 1.4%, 23.7%, 6.3%, and 9.6% in W-EU, E-EU, LATAM, and APAC, respectively (6.9% overall). A CPE was identified in 95 of 113 CRE isolates (84.1%). These CPEs included NDM-like (31.0% of CRE), KPC-like (26.5%), OXA-48-like (24.8%), and VIM-like (7.1%). Six isolates produced 2 CPEs. The highest ATM-AVI MIC value among MBL-producers (n=43; MIC50/90, 0.12/0.5 mg/L) was 4 mg/L. Among P. aeruginosa, 75.1% were inhibited at ≤ 8 mg/L of ATM-AVI; S to meropenem (MEM), piperacillin-tazobactam, and ceftazidime were 69.4%, 72.5%, and 75.7%, respectively, and ranged from 64.3% in E-EU to 82.0% in W-EU. MEM non-S P. aeruginosa varied from 22.2% in W-EU to 54.8% in E-EU. ATM-AVI was highly active against S. maltophilia, inhibiting 95.0%, 100.0%, 100.0%, and 90.0% of isolates from W-EU, E-EU, LATAM, and APAC, respectively, at ≤8 mg/L. S. maltophilia S to cotrimoxazole were 90.0%, 97.7%, 85.7%, and 100.0% in W-EU, E-EU, LATAM, and APAC, respectively. ATM-AVI also was very active against Burkholderia spp. (highest MIC, 8 mg/L). Conclusion Our results support clinical development of ATM-AVI to treat pneumonia caused by ENT (including MBL-producers), P. aeruginosa, S. maltophilia, and Burkholderia spp. Table 1 Disclosures Helio S. Sader, MD, PhD, A. Menarini Industrie Farmaceutiche Riunite S.R.L. (Research Grant or Support)Allergan (Research Grant or Support)Allergan (Research Grant or Support)Allergan (Research Grant or Support)Cipla Ltd. (Research Grant or Support)Cipla Ltd. (Research Grant or Support)Melinta (Research Grant or Support)Merck (Research Grant or Support)Merck (Research Grant or Support)Paratek Pharma, LLC (Research Grant or Support)Pfizer (Research Grant or Support) Mariana Castanheira, PhD, 1928 Diagnostics (Research Grant or Support)A. Menarini Industrie Farmaceutiche Riunite S.R.L. (Research Grant or Support)Allergan (Research Grant or Support)Allergan (Research Grant or Support)Amplyx Pharmaceuticals (Research Grant or Support)Cidara Therapeutics (Research Grant or Support)Cidara Therapeutics (Research Grant or Support)Cipla Ltd. (Research Grant or Support)Cipla Ltd. (Research Grant or Support)Fox Chase Chemical Diversity Center (Research Grant or Support)GlaxoSmithKline (Research Grant or Support)Melinta Therapeutics, Inc. (Research Grant or Support)Melinta Therapeutics, Inc. (Research Grant or Support)Melinta Therapeutics, Inc. (Research Grant or Support)Merck (Research Grant or Support)Merck (Research Grant or Support)Merck & Co, Inc. (Research Grant or Support)Merck & Co, Inc. (Research Grant or Support)Paratek Pharma, LLC (Research Grant or Support)Pfizer (Research Grant or Support)Qpex Biopharma (Research Grant or Support) Cecilia G. Carvalhaes, MD, PhD, A. Menarini Industrie Farmaceutiche Riunite S.R.L. (Research Grant or Support)Allergan (Research Grant or Support)Cidara Therapeutics (Research Grant or Support)Cipla Ltd. (Research Grant or Support)Fox Chase Chemical Diversity Center (Research Grant or Support)Melinta Therapeutics, Inc. (Research Grant or Support)Merck (Research Grant or Support)Merck (Research Grant or Support)Merck & Co, Inc. (Research Grant or Support)Pfizer (Research Grant or Support) Timothy B. Doyle, Allergan (Research Grant or Support)Allergan (Research Grant or Support)Cipla Ltd. (Research Grant or Support)Melinta Therapeutics, Inc. (Research Grant or Support)Pfizer (Research Grant or Support)Qpex Biopharma (Research Grant or Support) Rodrigo E. Mendes, PhD, A. Menarini Industrie Farmaceutiche Riunite S.R.L. (Research Grant or Support)Allergan (Research Grant or Support)Allergan (Research Grant or Support)Basilea Pharmaceutica International, Ltd (Research Grant or Support)Cipla Ltd. (Research Grant or Support)Department of Health and Human Services (Research Grant or Support)GlaxoSmithKline (Research Grant or Support)Melinta Therapeutics, Inc. (Research Grant or Support)Merck (Research Grant or Support)Merck (Research Grant or Support)Pfizer (Research Grant or Support)
Published: 2020

33. 1443. Activity of Ceftazidime-Avibactam against Carbapemenase-negative Carbapenem-resistant Enterobacterales (CRE) Isolates from US Hospitals

Author: Rodrigo E. Mendes, Timothy B Doyle, Cory Hubler, Mariana Castanheira, and Helio S. Sader
Subjects: biology, Carbapenem resistant, business.industry, Klebsiella pneumoniae, education, Tigecycline, Ceftazidime/avibactam, biology.organism_classification, Meropenem, Microbiology, AcademicSubjects/MED00290, Infectious Diseases, Oncology, Amikacin, Enterobacterales, Poster Abstracts, Medicine, business, Enterobacter cloacae, health care economics and organizations, medicine.drug
Abstract: Background Most CRE isolates in US hospitals produce KPC enzymes, but some do not carry carbapenemases. We investigated the prevalence, resistance mechanisms and activity of ceftazidime-avibactam and comparator agents against CRE that did not carry carbapenemase genes from US hospitals. Additionally, meropenem-resistant isolates were tested for meropenem-vaborbactam. Methods A total of 28,904 Enterobacterales isolates were collected in 70 US hospitals during 2016-2018, and susceptibility tested by reference broth microdilution. Meropenem-vaborbactam was tested using lyophilized panels following the manufacturer’s instructions. CRE isolates were submitted to whole genome sequencing for the screening of b-lactamase genes, multilocus sequence typing, changes in outer membrane protein (OMP) genes and AmpC expression levels. Results A total of 304 (1.1%) CREs were observed in the study period and 45 (14.8%) isolates did not carry carbapenemases. These isolates were mainly Klebsiella aerogenes, Enterobacter cloacae and Klebsiella pneumoniae (11, 11 and 10 isolates, respectively), but also included 5 other species. Acquired b-lactamase genes were detected among 17 isolates and blaCTX-M-15 was the most common (13 isolates). All K. aerogenes and 10 E. cloacae did not carry acquired b-lactamase genes. Ceftazidime-avibactam (100% susceptible) inhibited all isolates at the current breakpoint, followed by tigecycline and amikacin (> 80% susceptible). Other comparators were not active against non-carbapenemase-producing CRE. Nine of 35 meropenem-resistant isolates displayed meropenem-vaborbactam MIC values of ≥ 8 mg/L (nonsusceptible). Further analysis showed that 23 isolates had disruption of OmpC/OmpK36, 4 had disrupted OmpF/OmpK35 and 13 had both OMP genes disrupted. Additionally, 7 isolates had elevated AmpC expression among 17 isolates tested. Among 7 E. coli, 4 were ST131 and only 2 of 10 K. pneumoniae were clonal complex 11. Conclusion Therapy options for treatment of infections caused by CRE were very limited until recent approval of new agents with activity against these isolates. Ceftazidime-avibactam demonstrated full in vitro activity against all carbapenemase-negative CRE carrying multiple resistance mechanisms. Disclosures Mariana Castanheira, PhD, 1928 Diagnostics (Research Grant or Support)A. Menarini Industrie Farmaceutiche Riunite S.R.L. (Research Grant or Support)Allergan (Research Grant or Support)Allergan (Research Grant or Support)Amplyx Pharmaceuticals (Research Grant or Support)Cidara Therapeutics (Research Grant or Support)Cidara Therapeutics (Research Grant or Support)Cipla Ltd. (Research Grant or Support)Cipla Ltd. (Research Grant or Support)Fox Chase Chemical Diversity Center (Research Grant or Support)GlaxoSmithKline (Research Grant or Support)Melinta Therapeutics, Inc. (Research Grant or Support)Melinta Therapeutics, Inc. (Research Grant or Support)Melinta Therapeutics, Inc. (Research Grant or Support)Merck (Research Grant or Support)Merck (Research Grant or Support)Merck & Co, Inc. (Research Grant or Support)Merck & Co, Inc. (Research Grant or Support)Paratek Pharma, LLC (Research Grant or Support)Pfizer (Research Grant or Support)Qpex Biopharma (Research Grant or Support) Timothy B. Doyle, Allergan (Research Grant or Support)Allergan (Research Grant or Support)Cipla Ltd. (Research Grant or Support)Melinta Therapeutics, Inc. (Research Grant or Support)Pfizer (Research Grant or Support)Qpex Biopharma (Research Grant or Support) Cory Hubler, Allergan (Research Grant or Support) Rodrigo E. Mendes, PhD, A. Menarini Industrie Farmaceutiche Riunite S.R.L. (Research Grant or Support)Allergan (Research Grant or Support)Allergan (Research Grant or Support)Basilea Pharmaceutica International, Ltd (Research Grant or Support)Cipla Ltd. (Research Grant or Support)Department of Health and Human Services (Research Grant or Support)GlaxoSmithKline (Research Grant or Support)Melinta Therapeutics, Inc. (Research Grant or Support)Merck (Research Grant or Support)Merck (Research Grant or Support)Pfizer (Research Grant or Support) Helio S. Sader, MD, PhD, A. Menarini Industrie Farmaceutiche Riunite S.R.L. (Research Grant or Support)Allergan (Research Grant or Support)Allergan (Research Grant or Support)Allergan (Research Grant or Support)Cipla Ltd. (Research Grant or Support)Cipla Ltd. (Research Grant or Support)Melinta (Research Grant or Support)Merck (Research Grant or Support)Merck (Research Grant or Support)Paratek Pharma, LLC (Research Grant or Support)Pfizer (Research Grant or Support)
Published: 2020
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34. Combination of MexAB-OprM overexpression and mutations in efflux regulators, PBPs and chaperone proteins is responsible for ceftazidime/avibactam resistance in Pseudomonas aeruginosa clinical isolates from US hospitals

Author: Rodrigo E. Mendes, Mariana Castanheira, Timothy B Doyle, Helio S. Sader, and Caitlin J. Smith
Subjects: Microbiology (medical), Avibactam, Ceftazidime, Drug resistance, Microbial Sensitivity Tests, Biology, medicine.disease_cause, beta-Lactam Resistance, Microbiology, Bacterial genetics, chemistry.chemical_compound, Bacterial Proteins, Drug Resistance, Bacterial, Operon, medicine, Humans, Pharmacology (medical), Pseudomonas Infections, Pharmacology, Mutation, Pseudomonas aeruginosa, Membrane Transport Proteins, Ceftazidime/avibactam, Hospitals, Anti-Bacterial Agents, Drug Combinations, Infectious Diseases, chemistry, Efflux, Azabicyclo Compounds, medicine.drug, Bacterial Outer Membrane Proteins, Molecular Chaperones
Abstract: ObjectivesTo evaluate ceftazidime/avibactam resistance mechanisms among Pseudomonas aeruginosa clinical isolates and compare with isolates susceptible to this combination.MethodsDuring 2015, 2548 P. aeruginosa isolates were collected in 106 US hospitals and 46 (1.8%) were resistant to ceftazidime/avibactam. These isolates were matched with 109 ceftazidime/avibactam-susceptible isolates resistant to other antipseudomonal agents and were evaluated for the presence of β-lactam resistance mechanisms using WGS analysis and quantitative real-time PCR. Results were analysed using logistic regression comparing the isolate groups to understand the mechanisms of ceftazidime/avibactam resistance.ResultsTwo isolates carried the MBLs blaVIM-1 and blaVIM-2 and another three had unique alterations or deletions in the chromosomal AmpC Ω-loop associated with ceftazidime/avibactam resistance. Overexpression of mexA (+27.4%), disruptions in ampP (+21.7%), mexR (+17.1%) and mexZ (+14.6%) and alterations in ctpA (+13.0%), dnaK (+17.8%) and ftsI (+20.8%) were significantly more prevalent among ceftazidime/avibactam-resistant isolates when compared with their susceptible counterparts independently or in combination. The combination of dnaK alterations and mexA overexpression was more common among ceftazidime/avibactam-resistant by 82×; mexR disruptions and mexA overexpression by 45×; and other two- or three-genotype interactions that included alterations/disruptions in dnaK, ftsI, nalD, mexR, mexZ and mexA overexpression by 6.5× to 34×.ConclusionsResistance to ceftazidime/avibactam among P. aeruginosa clinical isolates has been shown to be a complex interplay of resistance mechanisms that can affect ceftazidime and/or avibactam and some similar findings were reported in laboratory isolates exposed to ceftazidime ± avibactam.
Published: 2019

35. Evaluation of the Revised Ceftaroline Disk Diffusion Breakpoints When Testing a Challenge Collection of Methicillin-Resistant Staphylococcus aureus Isolates

Author: Timothy B Doyle, Rodrigo E. Mendes, Robert K. Flamm, Helio S. Sader, and Paul R. Rhomberg
Subjects: 0301 basic medicine, Microbiology (medical), Methicillin-Resistant Staphylococcus aureus, disk diffusion, food.ingredient, Serial dilution, 030106 microbiology, Microbial Sensitivity Tests, MRSA, Biology, medicine.disease_cause, Microbiology, 03 medical and health sciences, food, medicine, Agar, Humans, Penicillin-Binding Proteins, Agar diffusion test, Diffusion methods, Broth microdilution, Bacteriology, Reference Standards, Staphylococcal Infections, Methicillin-resistant Staphylococcus aureus, Anti-Bacterial Agents, Cephalosporins, Staphylococcus aureus, Mutation, ceftaroline
Abstract: We assessed ceftaroline disk diffusion breakpoints for Staphylococcus aureus when applying revised Clinical and Laboratory Standards Institute (CLSI) ceftaroline MIC breakpoints. Disk-MIC correlation was evaluated by testing a challenge collection (n = 158) of methicillin-resistant S. aureus (MRSA) isolates composed of 106 randomly selected isolates plus 52 isolates with decreased susceptibility to ceftaroline (MIC, 1 to 16 μg/ml)., We assessed ceftaroline disk diffusion breakpoints for Staphylococcus aureus when applying revised Clinical and Laboratory Standards Institute (CLSI) ceftaroline MIC breakpoints. Disk-MIC correlation was evaluated by testing a challenge collection (n = 158) of methicillin-resistant S. aureus (MRSA) isolates composed of 106 randomly selected isolates plus 52 isolates with decreased susceptibility to ceftaroline (MIC, 1 to 16 μg/ml). Disk diffusion was performed with 30-μg disks and Mueller-Hinton agar from 2 manufacturers each. Revised CLSI susceptible (S)/susceptible dose-dependent (SDD)/resistant (R) MIC breakpoints of ≤1/2 to 4/≥8 μg/ml were applied. The disk breakpoints that provided the lowest error rates were CLSI S/R breakpoints of ≥25 mm/≤19 mm, with no very major (VM) or major (Ma) errors and with minor (Mi) error rates of 0.0% for ≥2 doubling dilutions above the I or SDD (≥I + 2), 22.1% for I or SDD plus or minus 1 doubling dilution (I ± 1), and 2.3% for ≤2 doubling dilutions below the I or SDD ≤I − 2 (overall Mi error rate, 16.5%). No mutation in the penicillin-binding protein 2a (PBP2a) was observed in 5 of 15 isolates with a ceftaroline MIC of 2 μg/ml; 3 of 11 isolates with a ceftaroline MIC of 1 μg/ml exhibited mutations in the penicillin-binding domain (PBD; 1 isolate) or in the non-PBD (2 isolates). All isolates except 1, with a ceftaroline MIC of ≥4 μg/ml, showed ≥1 mutation in the PBD and/or non-PBD. In summary, results from the disk diffusion method showed a good correlation with those from the reference broth microdilution method. Our results also showed that the ceftaroline MIC distribution of isolates with no mutations in the PBP2a goes up to 4 μg/ml, and reference broth microdilution and disk diffusion methods do not properly separate wild-type from non-wild-type isolates.
Published: 2018

36. 600. β-Lactam Resistance Mechanisms in Pseudomonas aeruginosa Isolates Analyzed Using Whole-Genome Sequencing (WGS) and Transcriptions Analysis and Their Impact in Resistance to New β-Lactam/β-Lactamase Inhibitors

Author: Rodrigo E. Mendes, Matthew Healy, Caitlin J. Smith, Cory Hubler, Timothy B Doyle, and Mariana Castanheira
Subjects: Whole genome sequencing, Mutation, Pseudomonas aeruginosa, business.industry, Avibactam, Ceftazidime, medicine.disease_cause, Microbiology, chemistry.chemical_compound, Abstracts, Infectious Diseases, Oncology, chemistry, Poster Abstracts, Lactam, Colistin, medicine, business, Gene, medicine.drug
Abstract: Background Ceftazidime–avibactam (CAZ-AVI) and ceftolozane-tazobactam (C-T) display excellent antipseudomonal activity, but Pseudomonas aeruginosa (PSA) susceptibility against these agents can be affected by acquired resistance genes and mutations. We evaluated resistance mechanisms against these agents among 109 PSA isolates using WGS and messenger (m)RNA-sequencing. Methods PSA clinical isolates from Europe (n = 62), Asia-Pacific (n = 22), and Latin America (n = 25) in 2017 were susceptibility tested using reference methods and 109 were randomly selected for WGS and total mRNA-sequencing. Data were analyzed using custom software and logistic regression. Results Isolates carrying metallo-β-lactamases (MBLs) (n = 24) were resistant to all β-lactams, including CAZ-AVI and C-T. The only compound inhibiting >50% of the isolates was colistin. ESBL genes (blaVEB-1 or blaVEB-9), some oxacillinases, and PDC variants caused resistance to CAZ-AVI and C-T, but the presence of blaPER-1, blaGES-6, and PDC-97 led to resistance to C-T, but not to CAZ-AVI. Disruptions of ampR (PDC regulator) and glnD (nitrogen metabolism) were associated with resistance to CAZ-AVI and C-T, but armZ (anti-repressor of mexZ) disruption was only associated with C-T resistance. The combination of wild-type sequences of various genes was negatively associated with resistance to CAZ-AVI and C-T, but alterations in dnaJ (chaperone) and oprM were only related to C-T resistance. mRNA-sequencing data did not show strong correlations with CAZ-AVI or C-T resistance or with expression of genes involved in β-lactam resistance, but further analyses will expand the genes analyzed. Interestingly, among 14 isolates overexpressing MexAB-OprM that extrude CAZ, only 6 had CAZ-AVI MICs >8 mg/L. Conclusion Resistance mechanisms against CAZ-AVI and C-T remain poorly understood beyond MBL acquisition. In this study, resistance mechanisms statistically associated with CAZ-AVI resistance in PSA were noted among C-T-resistant isolates, but some mechanisms were only observed among C-T-resistant isolates. The richness of results employing these 2 methodologies requires further investigations that are being performed to evaluate sequences and expression alterations. Disclosures All authors: No reported disclosures.
Published: 2019

37. 1444. Trends in Antimicrobial Non-susceptibility of PCV13-Type Streptococcus pneumoniae Pneumonia in Adults in the United States During 2009–2017

Author: Timothy B Doyle, Leah N. Woosley, Jose A Suaya, Bradford D Gessner, Raul E Isturiz, Rodrigo E. Mendes, and Robert K. Flamm
Subjects: Abstracts, Infectious Diseases, Oncology, B. Poster Abstracts, business.industry, Medicine, Antimicrobial, business, Microbiology, Streptococcus pneumoniae pneumonia
Abstract: Background The routine use of 13-valent pneumococcal conjugate vaccination (PCV13) was implemented in children in 2010 and in adults (≥65 years of age) in 2014 in the United States. Trends in rates of penicillin G (PEN) antimicrobial nonsusceptibility (NS) for PCV13-type S. pneumoniae from adult pneumonia patients were assessed by age group. Methods Isolates were consecutively collected from pneumonia patients in 105 US sites in 40 states during 2009–2017. Isolates were identified by biochemical algorithms and/or PCR; susceptibility testing and interpretation used CLSI Methods. The cpsB sequence was obtained by PCR or whole-genome sequencing for serotype (ST) determinations. Multiplex PCR and/or Quellung reactions were also performed, as needed. Results Of 7,254 analyzed S. pneumoniae isolates, 63.6 and 36.4% were obtained from pneumonia patients aged 18–64 and ≥65 years, respectively. S. pneumoniae recovered from both age groups (18–64 and ≥65 years of age) showed a reduction in PEN-NS rates (from 12.9–14.5% in 2009 to 2.8–4.3% in 2017). The PEN-NS rates among PCV13 STs from both age groups rose to 37.7–39.9% from 2009 to 2011, decreasing in subsequent years (2012–2017) to 11.8–16.4% (Figure 1). Similar results were observed for PEN-NS rates against the STs included in PCV13 but not PCV7 (Figure 2). PEN-NS rates against PCV13 and PCV13-non-PCV7 STs from patients age 18–64 years plateaued or increased in 2015–2017, while PCV13 and PCV13-non-PCV7 STs from patients age ≥65 years declined continuously after 2012. Conclusion The decrease in PEN-NS rates among PCV13 and PCV13-non-PCV7 STs may be associated with the herd effect from PCV13 vaccination in children, an effect that may have occurred as early as 2 years after PCV13 implementation. The modest differences in PEN-NS trends between age groups during 2015–2017 may reflect the US recommendation to directly vaccinate adults age ≥65 but not 18–64 years; however, this hypothesis requires further data for confirmation. Disclosures R. E. Mendes, T. B. Doyle, L. N. Woosley, R. K. Flamm, Pfizer Inc: Research Contractor, Research support. J. A. Suaya, Pfizer: Employee and Shareholder, Benefits and stock and Salary. B. D. Gessner, Pfizer Inc.: Employee and Shareholder, Salary. R. E. Isturiz, Pfizer, Inc: Employee and Shareholder, Salary and Stock & Stock Options.
Published: 2018

38. A Novel Indole Compound That Inhibits Pseudomonas aeruginosa Growth by Targeting MreB Is a Substrate for MexAB-OprM

Author: Khisimuzi E. Mdluli, Leonard R. Duncan, Qun Du, A. Simon Lynch, Gregory T. Robertson, and Timothy B Doyle
Subjects: Indoles, Cell division, Molecular Sequence Data, Mutant, Genetics and Molecular Biology, Microbial Sensitivity Tests, Biology, medicine.disease_cause, Microbiology, MreB, Bacterial Proteins, medicine, Microscopy, Phase-Contrast, Amino Acid Sequence, Molecular Biology, Actin, Mutation, Microbial Viability, Molecular Structure, Sequence Homology, Amino Acid, Pseudomonas aeruginosa, Membrane Transport Proteins, Anti-Bacterial Agents, Microscopy, Electron, Biochemistry, Efflux, Bacterial outer membrane, Bacterial Outer Membrane Proteins, Plasmids
Abstract: Drug efflux systems contribute to the intrinsic resistance of Pseudomonas aeruginosa to many antibiotics and biocides and hamper research focused on the discovery and development of new antimicrobial agents targeted against this important opportunistic pathogen. Using a P. aeruginosa PAO1 derivative bearing deletions of opmH , encoding an outer membrane channel for efflux substrates, and four efflux pumps belonging to the resistance nodulation/cell division class including mexAB-oprM , we identified a small-molecule indole-class compound (CBR-4830) that is inhibitory to growth of this efflux-compromised strain. Genetic studies established MexAB-OprM as the principal pump for CBR-4830 and revealed MreB, a prokaryotic actin homolog, as the proximal cellular target of CBR-4830. Additional studies establish MreB as an essential protein in P. aeruginosa , and efflux-compromised strains treated with CBR-4830 transition to coccoid shape, consistent with MreB inhibition or depletion. Resistance genetics further suggest that CBR-4830 interacts with the putative ATP-binding pocket in MreB and demonstrate significant cross-resistance with A22, a structurally unrelated compound that has been shown to promote rapid dispersion of MreB filaments in vivo. Interestingly, however, ATP-dependent polymerization of purified recombinant P. aeruginosa MreB is blocked in vitro in a dose-dependent manner by CBR-4830 but not by A22. Neither compound exhibits significant inhibitory activity against mutant forms of MreB protein that bear mutations identified in CBR-4830-resistant strains. Finally, employing the strains and reagents prepared and characterized during the course of these studies, we have begun to investigate the ability of analogues of CBR-4830 to inhibit the growth of both efflux-proficient and efflux-compromised P. aeruginosa through specific inhibition of MreB function.
Published: 2007
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39. In vitro evaluation of CBR-2092, a novel rifamycin-quinolone hybrid antibiotic: studies of the mode of action in Staphylococcus aureus

Author: Gregory T. Robertson, Qun Du, Timothy B Doyle, Eric J. Bonventre, Timothy W. Morris, Leonard R. Duncan, Dalai Yan, A. Simon Lynch, and Eric D. Roche
Subjects: DNA Topoisomerase IV, DNA, Bacterial, Staphylococcus aureus, medicine.drug_class, Rifamycins, Microbial Sensitivity Tests, Biology, Quinolones, medicine.disease_cause, DNA gyrase, Microbiology, Bacterial Proteins, Drug Resistance, Bacterial, medicine, polycyclic compounds, Topoisomerase II Inhibitors, Pharmacology (medical), Enzyme Inhibitors, Mechanisms of Action: Physiological Effects, Antibacterial agent, Pharmacology, DNA synthesis, Molecular Structure, Rifamycin, DNA-Directed RNA Polymerases, Quinolone, Anti-Bacterial Agents, RNA, Bacterial, Infectious Diseases, Mutation, Efflux
Abstract: Rifamycins have proven efficacy in the treatment of persistent bacterial infections. However, the frequency with which bacteria develop resistance to rifamycin agents restricts their clinical use to antibiotic combination regimens. In a program directed toward the synthesis of rifamycins with a lower propensity to elicit resistance development, a series of compounds were prepared that covalently combine rifamycin and quinolone pharmacophores to form stable hybrid antibacterial agents. We describe mode-of-action studies with Staphylococcus aureus of CBR-2092, a novel hybrid that combines the rifamycin SV and 4 H -4-oxo-quinolizine pharmacophores. In biochemical studies, CBR-2092 exhibited rifampin-like potency as an inhibitor of RNA polymerase, was an equipotent (balanced) inhibitor of DNA gyrase and DNA topoisomerase IV, and retained activity against a prevalent quinolone-resistant variant. Macromolecular biosynthesis studies confirmed that CBR-2092 has rifampin-like effects on RNA synthesis in rifampin-susceptible strains and quinolone-like effects on DNA synthesis in rifampin-resistant strains. Studies of mutant strains that exhibited reduced susceptibility to CBR-2092 further substantiated RNA polymerase as the primary cellular target of CBR-2092, with DNA gyrase and DNA topoisomerase IV being secondary and tertiary targets, respectively, in strains exhibiting preexisting rifampin resistance. In contrast to quinolone comparator agents, no strains with altered susceptibility to CBR-2092 were found to exhibit changes consistent with altered efflux properties. The combined data indicate that CBR-2092 may have potential utility in monotherapy for the treatment of persistent S. aureus infections.
Published: 2008

40. In Vitro Evaluation of CBR-2092, a Novel Rifamycin-Quinolone Hybrid Antibiotic: Microbiology Profiling Studies with Staphylococci and Streptococci ▿

Author: Qun Du, Timothy B Doyle, Eric J. Bonventre, Timothy W. Morris, Leonard R. Duncan, Dalai Yan, A. Simon Lynch, Gregory T. Robertson, and Eric D. Roche
Subjects: Staphylococcus aureus, Micrococcaceae, medicine.drug_class, Staphylococcus, Antibiotics, Drug resistance, Microbial Sensitivity Tests, Biology, In Vitro Techniques, Quinolones, medicine.disease_cause, Microbiology, Drug Resistance, Bacterial, medicine, Staphylococcus epidermidis, Humans, Pharmacology (medical), Pharmacology, Minimum bactericidal concentration, Rifamycin, Streptococcus, Quinolone, Antimicrobial, biology.organism_classification, Rifamycins, Anti-Bacterial Agents, Infectious Diseases, Phenotype, Susceptibility, Mutation
Abstract: We present data from antimicrobial assays performed in vitro that pertain to the potential clinical utility of a novel rifamycin-quinolone hybrid antibiotic, CBR-2092, for the treatment of infections mediated by gram-positive cocci. The MIC 90 s for CBR-2092 against 300 clinical isolates of staphylococci and streptococci ranged from 0.008 to 0.5 μg/ml. Against Staphylococcus aureus , CBR-2092 exhibited prolonged postantibiotic effects (PAEs) and sub-MIC effects (SMEs), with values of 3.2, 6.5, and >8.5 h determined for the PAE (3× MIC), SME (0.12× MIC), and PAE-SME (3× MIC/0.12× MIC) periods, respectively. Studies of genetically defined mutants of S. aureus indicate that CBR-2092 is not a substrate for the NorA or MepA efflux pumps. In minimal bactericidal concentration and time-kill studies, CBR-2092 exhibited bactericidal activity against staphylococci that was retained against rifampin- or intermediate quinolone-resistant strains, with apparent paradoxical cidal characteristics against rifampin-resistant strains. In spontaneous resistance studies, CBR-2092 exhibited activity consistent with balanced contributions from its composite pharmacophores, with a mutant prevention concentration of 0.12 μg/ml and a resistance frequency of −12 determined at 1 μg/ml in agar for S. aureus . Similarly, CBR-2092 suppressed the emergence of preexisting rifamycin resistance in time-kill studies undertaken at a high cell density. In studies of the intracellular killing of S. aureus , CBR-2092 exhibited prolonged bactericidal activity that was superior to the activities of moxifloxacin, rifampin, and a cocktail of moxifloxacin and rifampin. Overall, CBR-2092 exhibited promising activity in a range of antimicrobial assays performed in vitro that pertain to properties relevant to the effective treatment of serious infections mediated by gram-positive cocci.
Published: 2008

41. Further exploration of antimicrobial ketodihydronicotinic acid derivatives by multiple parallel syntheses

Author: Lester A. Mitscher, Timothy B. Doyle, Sunil A. David, Rajalakshmi Balakrishna, Yibin Zeng, John Nielsen, Torsten Haack, Srinivas Pusuluri, Zhunkun Ma, and Jane B. Laursen
Subjects: Magnetic Resonance Spectroscopy, Pyridones, Microbial Sensitivity Tests, medicine.disease_cause, Gas Chromatography-Mass Spectrometry, Anti-Infective Agents, Drug Discovery, Spectroscopy, Fourier Transform Infrared, medicine, Potency, Mode of action, Escherichia coli, biology, Chemistry, Organic Chemistry, Nicotinic Acids, General Medicine, Antimicrobial, biology.organism_classification, In vitro, Computer Science Applications, Ciprofloxacin, Biochemistry, Spectrophotometry, Ultraviolet, Bacteria, Polymyxin B, medicine.drug
Abstract: A synthetic reexamination of a series of ketodihydronicotinic acid class antibacterial agents was undertaken in an attempt to improve their therapeutic potential. A convenient new synthesis was developed involving hetero Diels-Alder chemistry producing 74 new analogs in a multiple parallel synthetic manner and these were examined in vitro for their antimicrobial potential. Several compounds demonstrated significant broad-spectrum activity against clinically derived bacterial strains but previously known 1-(2,4-difluorophenyl)-6-(4-dimethylaminophenyl)-4-pyridone-3-carboxylic acid (7) remained the most potent compound in this class. Cross-resistance with ciprofloxacin supported a commonality of mode of action. Permiabilization of Escherichia coli cells by polymyxin B significantly enhanced potency with these agents suggesting that poor cellular uptake was primarily responsible for the disappointing activity against bacteria that some of the analogs exhibited.
Published: 2006

42. New C25 carbamate rifamycin derivatives are resistant to inactivation by ADP-ribosyl transferases

Author: Eric D. Roche, Dalai Yan, Eric J. Bonventre, Anthony Simon Lynch, Timothy B Doyle, Daniel Denton, Gregory T. Robertson, Keith D. Combrink, Katrina Chapo, Susan Harran, and Zhenkun Ma
Subjects: Carbamate, Staphylococcus aureus, Magnetic Resonance Spectroscopy, Stereochemistry, medicine.medical_treatment, Clinical Biochemistry, Mycobacterium smegmatis, Pharmaceutical Science, Rifamycins, Microbial Sensitivity Tests, medicine.disease_cause, Biochemistry, Structure-Activity Relationship, Drug Discovery, Drug Resistance, Bacterial, polycyclic compounds, medicine, Escherichia coli, Transferase, Molecular Biology, chemistry.chemical_classification, ADP Ribose Transferases, biology, Chemistry, Organic Chemistry, Rifamycin, biology.organism_classification, Anti-Bacterial Agents, Enzyme, Pseudomonas aeruginosa, Molecular Medicine, Rifampin, Pentosyltransferases
Abstract: A novel series of 3-morpholino rifamycins in which the C25 acetate group was replaced by a carbamate group were prepared and found to exhibit significantly improved antimicrobial activity than rifampin against Mycobacterium smegmatis. Further characterization of such compounds suggests that relatively large groups attached to the rifamycin core via a C25 carbamate linkage prevent inactivation via ribosylation of the C23 alcohol as catalyzed by the endogenous rifampin ADP-ribosyl transferase of M. smegmatis. SAR studies of the C25 carbamate rifamycin series against M. smegmatis and other bacteria are reported.
Published: 2006

43. Use of an efflux-deficient streptococcus pneumoniae strain panel to identify ABC-class multidrug transporters involved in intrinsic resistance to antimicrobial agents

Author: Timothy B Doyle, Gregory T. Robertson, and A. Simon Lynch
Subjects: Pharmacology, Strain (chemistry), ATP-binding cassette transporter, Transporter, Microbial Sensitivity Tests, Biology, Streptococcaceae, biology.organism_classification, Antimicrobial, medicine.disease_cause, Drug Resistance, Multiple, Microbiology, Infectious Diseases, Streptococcus pneumoniae, Bacterial Proteins, Mechanisms of Resistance, Drug Resistance, Bacterial, medicine, Pharmacology (medical), ATP-Binding Cassette Transporters, Efflux, Bacteria
Abstract: Thirteen derivatives of the Streptococcus pneumoniae TIGR4 strain in which putative drug efflux pumps were genetically inactivated were constructed and characterized. The results indicate that two linked genes encoding the ABC-type transporters SP2073 and SP2075 function together to confer intrinsic resistance to a series of structurally unrelated compounds, including certain fluoroquinolones.
Published: 2005

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