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Pharmacodynamic eva...
Pharmacodynamic evaluation of lefamulin in the treatment of gonorrhea using a hollow fiber infection model simulating Neisseria gonorrhoeae infections
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- Jacobsson, Susanne, 1974- (författare)
- Örebro universitet,Institutionen för medicinska vetenskaper,Region Örebro län,WHO Collaborating Centre for Gonorrhoea and Other STIs, National Reference Laboratory for Sexually Transmitted Infections, Department of Laboratory Medicine
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- Golparian, Daniel, 1984- (författare)
- Örebro universitet,Institutionen för medicinska vetenskaper,WHO Collaborating Centre for Gonorrhoea and Other STIs, National Reference Laboratory for Sexually Transmitted Infections, Department of Laboratory Medicine, Faculty of Medicine and Health, Örebro University, Örebro, Sweden
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- Oxelbark, Joakim, 1970- (författare)
- Örebro universitet,Institutionen för hälsovetenskaper,Region Örebro län,Division of Clinical Chemistry, Department of Laboratory Medicine
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- Wicha, Wolfgang W. (författare)
- Nabriva Therapeutics GmbH, Vienna, Austria
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- da Costa, Renata Maria Augusto (författare)
- Global Antibiotic Research and Development Partnership (GARDP), Geneva, Switzerland
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- Franceschi, Francois (författare)
- Global Antibiotic Research and Development Partnership (GARDP), Geneva, Switzerland
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- Brown, David (författare)
- Institute for Therapeutic Innovation, College of Medicine, University of Florida, Orlando, FL, United States
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- Louie, Arnold (författare)
- Institute for Therapeutic Innovation, College of Medicine, University of Florida, Orlando, FL, United States
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- Gelone, Steven P. (författare)
- Nabriva Therapeutics US Inc., Fort Washington, PA, United States
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- Drusano, George (författare)
- Institute for Therapeutic Innovation, College of Medicine, University of Florida, Orlando, FL, United States
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- Unemo, Magnus, 1970- (författare)
- Örebro universitet,Institutionen för medicinska vetenskaper,Region Örebro län,WHO Collaborating Centre for Gonorrhoea and Other STIs, National Reference Laboratory for Sexually Transmitted Infections, Department of Laboratory Medicine, Faculty of Medicine and Health, Örebro University, Örebro, Sweden; Institute for Global Health, University College London (UCL), London, United Kingdom
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(creator_code:org_t)
- 2022-11-14
- 2022
- Engelska.
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Ingår i: Frontiers in Pharmacology. - : Frontiers Media S.A.. - 1663-9812. ; 13
- Relaterad länk:
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https://doi.org/10.3...
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https://urn.kb.se/re...
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https://doi.org/10.3...
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Abstract
Ämnesord
Stäng
- The emergence and spread of antimicrobial resistance in Neisseria gonorrhoeae 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 in vitro hollow fiber infection model (HFIM) to evaluate protein-unbound lefamulin, a semisynthetic pleuromutilin, against N. gonorrhoeae. Dose-range and dose-fractionation experiments with N. gonorrhoeae reference strains: WHO F (susceptible to all relevant antimicrobials), WHO X (extensively drug-resistant, including ceftriaxone resistance), and WHO V (high-level azithromycin resistant, and highest gonococcal MIC of lefamulin (2 mg/l) reported), were performed to examine lefamulin gonococcal killing and resistance development during treatment. The dose-range experiments, simulating a single oral dose of lefamulin based on human plasma concentrations, indicated that ≥1.2 g, ≥2.8 g, and ≥9.6 g of lefamulin were required to eradicate WHO F, X, and V, respectively. Dose-fractionation experiments, based on human lefamulin plasma concentrations, showed that WHO X was eradicated with ≥2.8 g per day when administered as q12 h (1.4 g twice a day) and with ≥3.6 g per day when administered as q8 h (1.2 g thrice a day), both for 7 days. However, when simulating the treatment with 5-10 times higher concentrations of free lefamulin in relevant gonorrhea tissues (based on urogenital tissues in a rat model), 600 mg every 12 h for 5 days (approved oral treatment for community-acquired bacterial pneumonia) eradicated all strains, and no lefamulin resistance emerged in the successful treatment arms. In many arms failing single or multiple dose treatments for WHO X, lefamulin-resistant mutants (MIC = 2 mg/l), containing an A132V amino acid substitution in ribosomal protein L3, were selected. Nevertheless, these lefamulin-resistant mutants demonstrated an impaired biofitness. In conclusion, a clinical study is warranted to elucidate the clinical potential of lefamulin as a treatment option for uncomplicated gonorrhea (as well as several other bacterial STIs).
Ämnesord
- MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin -- Infektionsmedicin (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Clinical Medicine -- Infectious Medicine (hsv//eng)
Nyckelord
- Neisseria gonorrhoeae
- antimicrobial treatment
- gonorrhea
- hollow fiber infection model
- lefamulin
- pharmacodynamics
- pharmacokinetics
Publikations- och innehållstyp
- ref (ämneskategori)
- art (ämneskategori)
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Jacobsson, Susan ...
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Golparian, Danie ...
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Oxelbark, Joakim ...
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Wicha, Wolfgang ...
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da Costa, Renata ...
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Franceschi, Fran ...
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Brown, David
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Louie, Arnold
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Gelone, Steven P ...
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Drusano, George
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Unemo, Magnus, 1 ...
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- MEDICIN OCH HÄLSOVETENSKAP
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Frontiers in Pha ...
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Örebro universitet