Zoliflodacin: An Oral Spiropyrimidinetrione Antibiotic for the Treatment of Neisseria gonorrheae, Including Multi-Drug-Resistant Isolates.
ACS Infect Dis
; 6(6): 1332-1345, 2020 06 12.
Article
em En
| MEDLINE
| ID: mdl-32329999
ABSTRACT
The Centers for Disease Control and the World Health Organization have issued a list of priority pathogens for which there are dwindling therapeutic options, including antibiotic-resistant Neisseria gonorrheae, for which novel oral agents are urgently needed. Zoliflodacin, the first in a new class of antibacterial agents called the spiropyrimidinetriones, is being developed for the treatment of gonorrhea. It has a unique mode of inhibition against bacterial type II topoisomerases with binding sites in bacterial gyrase that are distinct from those of the fluoroquinolones. Zoliflodacin is bactericidal, with a low frequency of resistance and potent antibacterial activity against N. gonorrheae, including multi-drug-resistant strains (MICs ranging from ≤0.002 to 0.25 µg/mL). Although being developed for the treatment of gonorrhea, zoliflodacin also has activity against Gram-positive, fastidious Gram-negative, and atypical pathogens. A hollow-fiber infection model using S. aureus showed that that pharmacokinetic/pharmacodynamic index of fAUC/MIC best correlated with efficacy in in vivo neutropenic thigh models in mice. This data and unbound exposure magnitudes derived from the thigh models were subsequently utilized in a surrogate pathogen approach to establish dose ranges for clinical development with N. gonorrheae. In preclinical studies, a wide safety margin supported progression to phase 1 studies in healthy volunteers, which showed linear pharmacokinetics, good oral bioavailability, and no significant safety findings. In a phase 2 study, zoliflodacin was effective in treating gonococcal urogenital and rectal infections. In partnership with the Global Antibiotic Research Development Program (GARDP), zoliflodacin is currently being studied in a global phase 3 clinical trial. Zoliflodacin represents a promising new oral therapy for drug-resistant infections caused by N. gonorrheae.
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Texto completo:
1
Coleções:
01-internacional
Contexto em Saúde:
2_ODS3
Base de dados:
MEDLINE
Assunto principal:
Preparações Farmacêuticas
/
Antibacterianos
Tipo de estudo:
Prognostic_studies
Limite:
Animals
Idioma:
En
Revista:
ACS Infect Dis
Ano de publicação:
2020
Tipo de documento:
Article