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Editor's Pick Mechanisms of ResistanceRepeated Isolation of Extended-Spectrum-β-Lactamase-Positive Escherichia coli Sequence Types 648 and 131 from Community Wastewater Indicates that Sewage Systems Are Important Sources of Emerging Clones of Antibiotic-Resistant BacteriaAntibiotic resistance in bacteria is an emerging problem globally. Resistant bacteria are found in human and animal microbiota, as well as in the environment. Wastewater receives bacteria from all these sources and thus can provide a measurement of abundance and diversity of antibiotic-resistant bacteria circulating in communities. In this study, water samples were collected from a wastewater pump station in a Norwegian suburban...
MinireviewPast and Present Perspectives on β-Lactamasesβ-Lactamases, the major resistance determinant for β-lactam antibiotics in Gram-negative bacteria, are ancient enzymes whose origins can be traced back millions of years ago. These well-studied enzymes, currently numbering almost 2,800 unique proteins, initially emerged from environmental sources, most likely to protect a producing bacterium from attack by naturally occurring β-lactams.
Experimental TherapeuticsIn Vivo Pharmacodynamic Study of Cefiderocol, a Novel Parenteral Siderophore Cephalosporin, in Murine Thigh and Lung Infection ModelsThe pharmacokinetic (PK) and pharmacodynamic (PD) parameters which correlated with the in vivo efficacy of cefiderocol were evaluated using neutropenic murine thigh and lung infection models in which the infections were caused by a variety of Gram-negative bacilli.
Clinical TherapeuticsSafety, Tolerability, Pharmacokinetics, and Drug Interaction Potential of SPR741, an Intravenous Potentiator, after Single and Multiple Ascending Doses and When Combined with β-Lactam Antibiotics in Healthy SubjectsSPR741 is a novel polymyxin B derivative, with minimal intrinsic antibacterial activity and reduced nonclinical nephrotoxicity compared to levels with polymyxin B, that interacts with the outer membrane of Gram-negative bacteria, enhancing penetration of coadministered antibiotics.
Mechanisms of ResistanceAcquisition of Cross-Resistance to Bedaquiline and Clofazimine following Treatment for Tuberculosis in PakistanWe report on the first six cases of acquired resistance to bedaquiline in Pakistan. Seventy sequential isolates from 30 drug-resistant-tuberculosis patients on bedaquiline-containing regimens were retrospectively tested for bedaquiline resistance by MIC testing and by the detection of mutations in relevant genes. We documented cases failing therapy that developed specific mutations in Rv0678 and had increased MICs associated...
PharmacologyPharmacokinetics and Pharmacodynamics of the Nitroimidazole DNDI-0690 in Mouse Models of Cutaneous LeishmaniasisThe nitroimidazole DNDI-0690 is a clinical drug candidate for visceral leishmaniasis (VL) that also shows potent in vitro and in vivo activity against cutaneous leishmaniasis (CL). To support further development of this compound into a patient-friendly oral or topical formulation for the treatment of CL, we investigated the free drug exposure at the dermal site of infection and subsequent elimination of the causative...
Clinical TherapeuticsPharmacokinetics, Safety, and Tolerability of Intravenous Durlobactam and Sulbactam in Subjects with Renal Impairment and Healthy Matched Control SubjectsSulbactam-durlobactam is being developed for the treatment of infections caused by Acinetobacter baumannii, including those caused by multidrug- and carbapenem-resistant isolates. This was a phase 1 study to evaluate the effects of various degrees of renal impairment, including subjects with end-stage renal disease (ESRD) on hemodialysis (HD), on the pharmacokinetics...
Mechanisms of ResistanceMolecular Basis of Class A β-Lactamase Inhibition by Relebactamβ-Lactamase production is the major β-lactam resistance mechanism in Gram-negative bacteria. β-Lactamase inhibitors (BLIs) efficacious against serine β-lactamase (SBL) producers, especially strains carrying the widely disseminated class A enzymes, are required. Relebactam, a diazabicyclooctane (DBO) BLI, is in phase 3 clinical trials in combination with imipenem for the treatment of infections by multidrug-resistant...
Mechanisms of Action: Physiological EffectsWatching DNA Replication Inhibitors in Action: Exploiting Time-Lapse Microfluidic Microscopy as a Tool for Target-Drug Interaction Studies in MycobacteriumSpreading resistance to antibiotics and the emergence of multidrug-resistant strains have become frequent in many bacterial species, including mycobacteria, which are the causative agents of severe diseases and which have profound impacts on global health.
PharmacologyPopulation Pharmacokinetics of Unbound Ceftolozane and Tazobactam in Critically Ill Patients without Renal DysfunctionEvaluation of dosing regimens for critically ill patients requires pharmacokinetic data in this population. This prospective observational study aimed to describe the population pharmacokinetics of unbound ceftolozane and tazobactam in critically ill patients without renal impairment and to assess the adequacy of recommended dosing regimens for treatment of systemic infections. Patients received 1.5 or 3.0 g ceftolozane-tazobactam...