Department of Immunology, Faculty of Health Sciences, University of Pretoria, Pretoria, South Africa.
Department of Immunology, Faculty of Health Sciences, University of Pretoria, Pretoria, South Africa; Department of Medical Microbiology, Faculty of Health Sciences, University of Pretoria, Pretoria, South Africa.
J Glob Antimicrob Resist. 2022 Jun;29:343-352. doi: 10.1016/j.jgar.2022.03.008. Epub 2022 Mar 23.
The chemotherapeutic regimens of patients with drug-susceptible (DS)- tuberculosis (TB) comprise four primary anti-TB drugs: rifampicin (RMP), isoniazid (INH), ethambutol (EMB) and pyrazinamide (PZA), administered for six-to-nine months. These drug regimens target the various microbial populations that include actively replicating (AR), slow-replicating (SR) and non-replicating (NR) organisms. Clofazimine (CFZ) has showed benefit in shortening DS-TB treatment in vivo from six to four months when used in combination with this regimen in murine models of experimental infection. However, its antimicrobial efficacy when used in combination with the primary drugs against the various microbial populations of Mycobacterium tuberculosis has not been demonstrated.
In the current in vitro study, the inhibitory and bactericidal activities of CFZ in combination with the primary anti-TB drugs, RMP, INH and EMB against the AR and SR organisms in planktonic and biofilm-forming cultures, respectively, were evaluated by fractional inhibitory concentration index (FICI) and fractional bactericidal concentration index (FBCI) determinations, using the Loewe Additivity Model.
In planktonic cultures, CFZ demonstrated synergistic growth inhibitory activity in combination with RMP and INH individually and collectively. With respect to bactericidal activity, CFZ exhibited synergistic activity only in a two-drug combination with RMP. However, in biofilm-forming cultures, all CFZ-containing anti-TB drug combinations exhibited synergistic inhibitory and bactericidal effects, particularly in combination with RIF and INH.
Clofazimine exhibited synergistic effects in combination with primary anti-TB drugs against both planktonic and biofilm-forming cultures, showing potential benefit in augmenting treatment outcome when used during standard TB chemotherapy.
耐多药（DS）结核病（TB）患者的化疗方案包括四种主要的抗 TB 药物：利福平（RMP）、异烟肼（INH）、乙胺丁醇（EMB）和吡嗪酰胺（PZA），治疗期为 6 至 9 个月。这些药物方案针对包括活跃复制（AR）、缓慢复制（SR）和非复制（NR）在内的各种微生物群。氯法齐明（CFZ）在实验感染的鼠模型中与该方案联合使用时，已显示出可将 DS-TB 治疗时间从 6 个月缩短至 4 个月，从而带来益处。然而，当与针对结核分枝杆菌各种微生物群的主要药物联合使用时，CFZ 的抗菌功效尚未得到证实。
在当前的体外研究中，通过分数抑菌浓度指数（FICI）和分数杀菌浓度指数（FBCI）测定，使用 Loewe 加性模型，评估 CFZ 与主要抗 TB 药物利福平（RMP）、异烟肼（INH）和乙胺丁醇（EMB）联合使用时，对浮游和生物膜形成培养物中的 AR 和 SR 生物的抑制和杀菌活性。
在浮游培养物中，CFZ 与 RMP 和 INH 单独和联合使用时表现出协同的生长抑制活性。关于杀菌活性，CFZ 仅与 RMP 联合使用时表现出协同活性。然而，在生物膜形成培养物中，所有包含 CFZ 的抗 TB 药物联合均表现出协同的抑制和杀菌作用，尤其是与 RIF 和 INH 联合使用时。
氯法齐明与主要抗 TB 药物联合使用时，对浮游和生物膜形成培养物均表现出协同作用，在标准 TB 化疗中使用时，可能有助于提高治疗效果。
