A Phase 1 Pharmacokinetic and Safety Study of Extended-Duration, High-dose Cefixime for Cephalosporin-resistant Neisseria gonorrhoeae in the Pharynx

被引:20
作者
Barbee, Lindley A. [1 ,2 ]
Nayak, Seema U. [3 ]
Blumer, Jeffrey L. [4 ]
O'Riordan, Mary Ann [6 ]
Gray, Wesley [4 ]
Zenilman, Jonathan M. [3 ]
Golden, Matthew R. [1 ,2 ]
Griffiss, J. McLeod [5 ]
机构
[1] Univ Washington, Sch Med, Dept Med, Seattle, WA 98104 USA
[2] Publ Hlth Seattle & King Cty HIV STD Program, Seattle, WA USA
[3] Johns Hopkins Univ, Sch Med, Dept Med, Baltimore, MD 21205 USA
[4] Univ Toledo, Dept Pediat, Sch Med, 2801 W Bancroft St, Toledo, OH 43606 USA
[5] Clin RM Inc, Hinckley, OH USA
[6] Case Western Reserve Univ, Sch Med, Dept Pediat, Cleveland, OH 44106 USA
基金
美国国家卫生研究院;
关键词
CEFTRIAXONE; ABSORPTION; PENICILLIN; URETHRITIS; CANADA; MEN;
D O I
10.1097/OLQ.0000000000000844
中图分类号
R51 [传染病];
学科分类号
100401 ;
摘要
Background There are no fully oral recommended treatment regimens for gonorrhea. Inadequately treated pharyngeal gonococcal infections are a likely reservoir for transmission and development of antimicrobial resistance. We sought to determine an oral cefixime dosing regimen that would theoretically treat pharyngeal infections by gonococci with minimum inhibitory concentrations 0.5 g/mL. Methods We conducted an open-label, nonrandomized, phase I pharmacokinetic and safety study of cefixime in 25 healthy male and female volunteers divided into 4 dosing cohorts (cohort A, 400 mg; cohort B, 800 mg; cohort C, 1200 mg; and cohort D, 800 mg every 8 hours x 3 doses [total dose 2400 mg]) with a target serum concentration of at least 2.0 g/mL for more than 20 hours. Cefixime concentrations from serum and pharyngeal fluid were determined with use of a validated liquid chromatography-tandem mass spectrometry assay. Safety measures included laboratories, physical examinations, and symptom diaries. Results None of the single-dose regimens attained the target concentration; however, 50% of subjects in cohort D attained the target concentration. Variation in absorption and protein binding contributed to differences in concentrations. Pharyngeal fluid concentrations were negligible. The single-dose regimens were well tolerated; the multidose regimen resulted in mild to moderate gastrointestinal symptoms in 43% of subjects. Conclusions None of the dosing regimens achieved the target concentration. However, the proposed theoretical target was extrapolated from penicillin data; there are no empirically derived pharmacokinetic/pharmacodynamic criteria for pharyngeal gonorrhea. Under alternative cephalosporin-specific therapeutic goals, the multidose regimen may be effective, although the absence of cefixime in pharyngeal fluid is concerning. A clinical trial evaluating efficacy and defining pharmacokinetic/pharmacodynamic outcomes may be warranted.
引用
收藏
页码:677 / 683
页数:7
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