In vitro activity of the siderophore monosulfactam BAL30072 against contemporary Gram-negative pathogens from New York City,including multidrug-resistant isolates |
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| Affiliation: | 1. Department of Medicine, Mayo Clinic, Rochester, MN;2. Division of Clinical Microbiology, Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN;3. Department of Surgery, Mayo Clinic, Rochester, MN;4. Center for Individualized Medicine, Mayo Clinic, Rochester, MN;5. Department of Health Sciences Research, Mayo Clinic, Rochester, MN;6. Division of Infectious Diseases, Mayo Clinic, Rochester, MN;7. Institute for Genome Biology, University of Illinois at Urbana-Champaign, Urbana;1. College of Life Sciences, Zhejiang University, Hangzhou, Zhejiang 310058, China,;2. Key Laboratory of Microbial Biochemistry and Metabolism Engineering of Zhejiang Province, Hangzhou, Zhejiang 310058, China;1. Assistance Publique – Hôpitaux de Paris, Service de Médecine Interne et Immunologie Clinique, Hôpital Universitaire Bicêtre, 94275 Le Kremlin-Bicêtre Cedex, France;2. Université Paris Sud XI, 63 rue Gabriel Péri, 94276 Le Kremlin-Bicêtre Cedex, France;3. Assistance Publique – Hôpitaux de Paris, Service de Mycologie et Parasitologie, Hôpital Universitaire Bicêtre, 94275 Le Kremlin-Bicêtre Cedex, France;4. Assistance Publique – Hôpitaux de Paris, Service d’Immuno-hématologie pédiatrique, Hôpital Universitaire Necker-Enfants Malades, 75014 Paris, France;5. Université Paris Descartes, Assistance Publique – Hôpitaux de Paris, Service de Maladies Infectieuses et Tropicales, Hôpital Universitaire Necker-Enfants Malades, Centre d’Infectiologie Necker-Pasteur, 75014 Paris, France;6. Institut Pasteur, Centre National de Référence Mycoses Invasives et Antifongiques, CNRS URA3012, 75015 Paris, France;7. Assistance Publique – Hôpitaux de Paris, Centre hépato-biliaire, Hôpital Universitaire Paul Brousse, 94800 Villejuif, France;8. Assistance Publique – Hôpitaux de Paris, Service d’anatomopathologie, Hôpital Universitaire Bicêtre, 94275 Le Kremlin-Bicêtre Cedex, France;9. Assistance Publique – Hôpitaux de Paris, Service d’hématologie biologique, Hôpital Universitaire Bicêtre, 94275 Le Kremlin-Bicêtre Cedex, France;1. Department of Infectious Diseases, MD Anderson Cancer Center, Houston, TX 77030, USA;2. Department of Laboratory Medicine, MD Anderson Cancer Center, Houston, TX 77030, USA;3. Department of Genomic Medicine, MD Anderson Cancer Center, Houston, TX 77030, USA;1. Department of Pharmaceutical Sciences, College of Pharmacy, University of Tennessee Health Science Center, 881 Madison Avenue, Memphis, TN 38163, USA;2. Division of Chemistry and Chemical Engineering, California Institute of Technology, 1200 E. California Bld., Pasadena, CA 91125, USA |
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| Abstract: | The in vitro activity of BAL30072 was assessed against clinical isolates from NYC hospitals, including isolates from a citywide surveillance study and a collection of isolates with well-characterised resistance mechanisms. BAL30072 was the most active β-lactam against Pseudomonas aeruginosa (MIC50/90, 0.25/1 μg/mL), Acinetobacter baumannii (MIC50/90, 4/>64 μg/mL) and KPC-possessing Klebsiella pneumoniae (MIC50/90, 4/>64 μg/mL). Combining BAL30072 with meropenem resulted in a ≥4-fold decrease in the BAL30072 MIC90 both for A. baumannii and K. pneumoniae. For isolates with a BAL30072 MIC > 4 μg/mL, addition of a sub-MIC concentration of colistin resulted in a four-fold decrease in the BAL30072 MIC in 44% of P. aeruginosa, 82% of A. baumannii and 23% of K. pneumoniae. Using sub-MIC concentrations, BAL30072 plus colistin was bactericidal against 4 of 11 isolates in time–kill studies. BAL30072 MICs were frequently lower for P. aeruginosa and K. pneumoniae when tested using Mueller–Hinton agar versus Iso-Sensitest agar or Mueller–Hinton broth. Against the well-characterised isolates, reduced susceptibility to BAL30072 correlated with mexA and mexX expression (P. aeruginosa), adeB expression (A. baumannii) and presence of SHV-type ESBLs (A. baumannii and K. pneumoniae). BAL30072 shows promising activity against contemporary Gram-negatives, including MDR P. aeruginosa, A. baumannii and K. pneumoniae. Enhanced activity was often present when BAL30072 was combined with meropenem or colistin. BAL30072 MICs were influenced by the testing method, particularly for P. aeruginosa and K. pneumoniae. Further in vivo studies are warranted to determine the potential clinical utility of BAL30072 alone and combined with other agents. |
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| Keywords: | Multidrug-resistant |
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