Background: Antimicrobial resistance in Neisseria gonorrhoeae is threatening the gonorrhoea treatment, and optimizations of the current ceftriaxone-treatment regimens are crucial. We evaluated the pharmacodynamics of ceftriaxone single-dose therapy (0.125-1 g) against ceftriaxone-susceptible and ceftriaxone-resistant gonococcal strains, based on EUCAST ceftriaxone-resistance breakpoint (MIC > 0.
View Article and Find Full Text PDFAmikacin is an FDA-approved aminoglycoside antibiotic that is commonly used. However, validated dosage regimens that achieve clinically relevant exposure profiles in mice are lacking. We aimed to design and validate humanized dosage regimens for amikacin in immune-competent murine bloodstream and lung infection models of .
View Article and Find Full Text PDFAntimicrobial resistance in the sexually transmitted bacterium is compromising the management and control of gonorrhea globally. Optimized use and enhanced stewardship of current antimicrobials and development of novel antimicrobials are imperative. The first in class zoliflodacin (spiropyrimidinetrione, DNA Gyrase B inhibitor) is a promising novel antimicrobial in late-stage clinical development for gonorrhea treatment, i.
View Article and Find Full Text PDFPolymyxin B is a "last-line-of-defense" antibiotic approved in the 1960s. However, the population pharmacokinetics (PK) of its four main components has not been reported in infected mice. We aimed to determine the PK of polymyxin B1, B1-Ile, B2, and B3 in a murine bloodstream and lung infection model of Acinetobacter baumannii and develop humanized dosage regimens.
View Article and Find Full Text PDFThe emergence and spread of antimicrobial resistance in is seriously threatening the treatment and control of gonorrhea globally. Novel treatment options are essential, coupled with appropriate methods to pharmacodynamically examine the efficacy and resistance emergence of these novel drugs. Herein, we used our dynamic hollow fiber infection model (HFIM) to evaluate protein-unbound lefamulin, a semisynthetic pleuromutilin, against .
View Article and Find Full Text PDFAntimicrob Agents Chemother
October 2022
Mycobacterium tuberculosis (Mtb) exists in various metabolic states, including a nonreplicating persister (NRP) phenotype which may affect response to therapy. We have adopted a model-informed strategy to accelerate discovery of effective Mtb treatment regimens and previously found pretomanid (PMD), moxifloxacin (MXF), and bedaquiline (BDQ) to readily kill logarithmic- and acid-phase Mtb. Here, we studied multiple concentrations of each drug in flask-based, time-kill studies against NRP Mtb in single-, two- and three-drug combinations, including the active M2 metabolite of BDQ.
View Article and Find Full Text PDFNovel antimicrobials for effective treatment of uncomplicated gonorrhea are essential, and the first-in-class, oral spiropyrimidinetrione DNA gyrase B inhibitor zoliflodacin appears promising. Using our newly developed Hollow Fiber Infection Model (HFIM), the pharmacodynamics of zoliflodacin was examined. A clinical zoliflodacin-susceptible strain, SE600/18 (harbouring a GyrB S467N amino acid substitution; MIC = 0.
View Article and Find Full Text PDFIn recent years, clofazimine (CFZ) has been regaining prominence for the treatment of tuberculosis. However, it shows limited efficacy as a single drug and optimal combination partners have not been identified. Therefore, the objective of our analysis was to evaluate the efficacy of CFZ-containing two-drug regimens with pretomanid (PMD), bedaquiline (BDQ) or linezolid (LZD) by: (i) determining their pharmacodynamic (PD) mode of interaction against Mycobacterium tuberculosis (Mtb) strain H37Rv in log- phase and acid-phase metabolic states, and against Mtb strain 18b in a non-replicating persister (NRP) metabolic state; (ii) predicting bacterial cell kill of the drugs alone and in combination; and (iii) evaluating the relationship between the interaction mode and the extent of bacterial cell kill.
View Article and Find Full Text PDFMycobacterium tuberculosis metabolic state affects the response to therapy. Quantifying the effect of antimicrobials in the acid and nonreplicating metabolic phases of M. tuberculosis growth will help to optimize therapy for tuberculosis.
View Article and Find Full Text PDFDose range studies for polymyxin B (PMB) regimens of 0.75 to 12 mg/kg given every 12 h (q12h) were evaluated for bacterial killing and resistance prevention against an AmpC-overexpressing Pseudomonas aeruginosa and a -harboring Klebsiella pneumoniae in 10-day hollow-fiber models. An exposure-response was observed.
View Article and Find Full Text PDFAntimicrobial resistance in is threatening the treatment and control of gonorrhea globally, and new treatment options are imperative. Utilizing our dynamic hollow fiber infection model (HFIM), we examined the pharmacodynamics of the first-in-class spiropyrimidinetrione (DNA gyrase B inhibitors), zoliflodacin, against the reference strains World Health Organization F (susceptible to all relevant antimicrobials) and WHO X (extensively drug resistant, including resistance to ceftriaxone) over 7 days. Dose-range experiments with both strains, simulating zoliflodacin single oral dose regimens of 0.
View Article and Find Full Text PDFCeftazidime (CAZ)-avibactam (AVI) is a β-lactam/β-lactamase inhibitor combination with activity against type A and type C β-lactamases. Resistance emergence has been seen, with multiple mechanisms accounting for the resistance. We performed four experiments in the dynamic hollow-fiber infection model, delineating the linkage between drug exposure and both the rate of bacterial kill and resistance emergence by all mechanisms.
View Article and Find Full Text PDFMultidrug-resistant bacteria are causing a serious global health crisis. A dramatic decline in antibiotic discovery and development investment by pharmaceutical industry over the last decades has slowed the adoption of new technologies. It is imperative that we create new mechanistic insights based on latest technologies, and use translational strategies to optimize patient therapy.
View Article and Find Full Text PDFThe repurposed agent moxifloxacin has become an important addition to the physician's armamentarium for the therapy of When a drug is administered, we need to have metrics for success. As for most antimicrobial chemotherapy, we contend that for therapy, these metrics should be a decline in the susceptible bacterial burden and the suppression of amplification of less-susceptible populations. To achieve optimal outcomes relative to these metrics, a dose and schedule of administration need to be chosen.
View Article and Find Full Text PDFAntimicrob Agents Chemother
January 2021
The drug discovery effort has generated a substantial number of new/repurposed drugs for therapy for this pathogen. The arrival of these drugs is welcome, but another layer of difficulty has emerged. Single agent therapy is insufficient for patients with late-stage tuberculosis because of resistance emergence.
View Article and Find Full Text PDFcauses serious infections that often require over 18 months of antibiotic combination therapy. There is no standard regimen for the treatment of infections, and the multitude of combinations that have been used clinically have had low success rates and high rates of toxicities. With β-lactam antibiotics being safe, double β-lactam and β-lactam/β-lactamase inhibitor combinations are of interest for improving the treatment of infections and minimizing toxicity.
View Article and Find Full Text PDFAntimicrob Agents Chemother
November 2020
Preclinical animal models of infection are employed to develop new agents but also to screen among molecules to rank them. There are often major differences between human pharmacokinetic (PK) profiles and those developed by animal models of infection, and these may lead to substantial differences in efficacy relative to that seen in humans. Linezolid is a repurposed agent employed to great effect for therapy of In this study, we used the hollow-fiber infection model (HFIM) to evaluate the impact of different pharmacokinetic profiles of mice and nonhuman primates (NHP) versus humans on bacterial cell kill as well as resistance suppression.
View Article and Find Full Text PDFAntimicrob Agents Chemother
October 2020
Multidrug therapy is often required. Examples include antiviral therapy, nosocomial infections, and, most commonly, anti- therapy. Our laboratory previously identified a mathematical approach to identify 2-drug regimens with a synergistic or additive interaction using a full factorial study design.
View Article and Find Full Text PDFNon-human primates (NHP) are thought to be a good preclinical animal model for tuberculosis because they develop disease characteristics that are similar to humans. The objective of the current study was to determine if NHPs can also be used to reliably predict the exposure of tedizolid, sutezolid, and its biologically active metabolite sutezolid-M1 in humans. The prodrug tedizolid phosphate and sutezolid were administered orally to NHPs either once or twice daily for up to eight days.
View Article and Find Full Text PDFPoor penetration through the outer membrane (OM) of Gram-negative bacteria is a major barrier of antibiotic development. While β-lactam antibiotics are commonly used against and , there are limited data on OM permeability especially in Here, we developed a novel cassette assay, which can simultaneously quantify the OM permeability to five β-lactams in carbapenem-resistant and Both clinical isolates harbored a and several other β-lactamases. The OM permeability of each antibiotic was studied separately ("discrete assay") and simultaneously ("cassette assay") by determining the degradation of extracellular β-lactam concentrations via multiplex liquid chromatography-tandem mass spectrometry analyses.
View Article and Find Full Text PDF(), the etiological agent of melioidosis, is a Gram-negative bacterium with additional concern as a biothreat pathogen. The mortality rate from varies depending on the type of infection and extent of available health care, but in the case of septicemia left untreated it can range from 50 - 90%. Current therapy for melioidosis is biphasic, consisting of parenteral acute-phase treatment for two weeks or longer, followed by oral eradication-phase treatment lasting several months.
View Article and Find Full Text PDFIn 2017, the WHO identified Acinetobacter baumannii as the top priority for the development of new antibiotics. Despite the need for new antibiotics, there remains a lack of well validated preclinical tools for A. baumannii.
View Article and Find Full Text PDFCeftazidime-avibactam (CAZ/AVI) combines ceftazidime with a diazabicyclooctane non-β-lactam β-lactamase inhibitor. This has potent inhibitory activity against KPC-type enzymes. We studied activity of clinically relevant regimens of CAZ/AVI against two KPC-2-bearing isolates (sequence type 258 recovered sequentially from the same patient) with and without K36 mutations in a hollow fiber infection model.
View Article and Find Full Text PDFThere is a great need for efficacious therapies against Gram-negative bacteria. Double β-lactam combination(s) (DBL) are relatively safe, and preclinical data are promising; however, their clinical role has not been well defined. We conducted a metaanalysis of the clinical and microbiological efficacy of DBL compared to β-lactam plus aminoglycoside combinations (BLAG).
View Article and Find Full Text PDFIn June 2017, the National Institute of Allergy and Infectious Diseases, part of the National Institutes of Health, organized a workshop entitled "Pharmacokinetics-Pharmacodynamics (PK/PD) for Development of Therapeutics against Bacterial Pathogens." The aims were to discuss details of various PK/PD models and identify sound practices for deriving and utilizing PK/PD relationships to design optimal dosage regimens for patients. Workshop participants encompassed individuals from academia, industry, and government, including the United States Food and Drug Administration.
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