Relationship between Gepotidacin Exposure and Prevention of On-Therapy Resistance Amplification in a Neisseria gonorrhoeae Hollow-Fiber In Vitro Infection Model
| Autor: | Sujata M. Bhavnani, Sharon Min, Nicole E. Scangarella-Oman, Karen A. Ingraham, Haley Conde, Jianzhong Huang, Paul G. Ambrose, Brian VanScoy, Steven Fikes |
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| Rok vydání: | 2020 |
| Předmět: |
Pharmacology
Drug 0303 health sciences Gepotidacin 030306 microbiology business.industry media_common.quotation_subject Gonorrhea Liter medicine.disease medicine.disease_cause Microbiology Ciprofloxacin 03 medical and health sciences Regimen 0302 clinical medicine Infectious Diseases medicine Neisseria gonorrhoeae Ceftriaxone Pharmacology (medical) 030212 general & internal medicine business medicine.drug media_common |
| Zdroj: | Antimicrobial Agents and Chemotherapy. 64 |
| ISSN: | 1098-6596 0066-4804 |
| Popis: | Multidrug-resistant Neisseria gonorrhoeae has emerged as a threat to global health. The relationship between gepotidacin exposure and prevention of on-therapy amplification of drug-resistant N. gonorrhoeae was examined using a 7-day hollow-fiber in vitro infection model. The study design included both inactive (no-treatment and ciprofloxacin) and active (ceftriaxone) control regimens. Study drug concentration-time profiles were simulated in the in vitro system for a single oral 0.5 g ciprofloxacin dose, a single intramuscular 0.25 g ceftriaxone dose, and single or two (8 to 12 h apart) oral gepotidacin doses ranging from 0.75 to 12 g. The initial bacterial burden inoculated in the model was 106 CFU/ml. The gepotidacin, ciprofloxacin, and ceftriaxone broth MIC values for the challenge isolate (N. gonorrhoeae GSK #8) were 0.5, 2, and 0.002 mg/liter, respectively. Samples were collected for enumeration of total and drug-resistant bacterial populations and drug concentrations. The no-treatment control reached a bacterial density greater than 108 CFU/ml over 24 h and remained consistent over the 7-day study period. The bacterial density in the model system of the ciprofloxacin regimen matched that of the growth control throughout the study duration, while the ceftriaxone regimen sterilized the model system by the end of day 1. For gepotidacin, a full dose-response relationship was observed. While failure was observed for the 0.75-, 1.5-, and 3-g single-dose regimens, all gepotidacin single- or divided-dose regimens totaling at least 4.5 g prevented resistance amplification and sterilized the model system. These data are useful to provide gepotidacin dose selection support for treating patients with gonorrhea infections. |
| Databáze: | OpenAIRE |
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