Sterilizing Activity of Pyrazinamide in Combination with First-Line Drugs in a C3HeB/FeJ Mouse Model of Tuberculosis
Sterilizing Activity of Pyrazinamide in Combination with First-Line Drugs in a C3HeB/FeJ Mouse Model of Tuberculosis
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DOI：
10.1128/aac.02637-15
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发表时间：
2016-02-01
影响因子：
4.9
通讯作者：
Nuermberger, Eric
中科院分区：
文献类型：
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作者：
Lanoix, Jean-Philippe;Betoudji, Fabrice;Nuermberger, Eric
吡嗪酰胺（PZA）是一线结核病（TB）治疗方案中的关键杀菌药物，在人类感染的前2个月内完全发挥其活性。最近，我们描述了减少活动的PZA在C3 HeB/FeJ小鼠与大干酪结节由于中性pH值。在这里，我们的目的是确定的贡献PZA的一线TB方案在C3 HeB/FeJ和BALB/c小鼠的杀菌活性。比较了三种方案（组合：R，利福平; H，异烟肼; E，乙胺丁醇; Z，吡嗪酰胺;数字表示治疗持续时间，以月为单位）：2 RHEZ/4 RH、2 RHE/4 RH和2 RHEZ/4 RHZ。在治疗0个月和2个月后评估肺部CFU计数，并在治疗3个月、4.5个月和6个月后评估3个月的复发率。治疗3个月后，接受2 RHEZ/1 RH和2 RHE/1 RH的C3 HeB/FeJ小鼠的复发率分别为53%和95%，接受2 RHEZ/1 RH、2 RHE/1 RH和2 RHEZ/1 RHZ的BALB/c小鼠的复发率分别为67%、100%和80%。治疗4.5个月后，接受2 RHEZ/2.5RH、2 RHE/2.5RH和2 RHEZ/2.5RHZ的C3 HeB/FeJ小鼠的复发率分别为32%、20%和0%，而接受2 RHEZ/2.5RH和2 RHE/2.5RH的BALB/c小鼠的复发率分别为0%和67%。C3 HeB/FeJ小鼠经2 RHEZ/4 RH、2 RHE/4 RH和2 RHEZ/4 RHZ给药后6个月的复发率分别为0%、13%和0%，而BALB/c小鼠经2 RHE/4 RH给药后6个月的复发率为7%。PZA的添加缩短了预防两种小鼠品系复发所需的治疗持续时间。然而，虽然PZA的作用仅限于BALB/c小鼠治疗的前2个月，但在前2个月后继续使用PZA对C3 HeB/FeJ小鼠是有益的，可预防疾病负担最高的小鼠复发。
Pyrazinamide (PZA) is a key sterilizing drug in first-line tuberculosis (TB) regimens and exerts its activity entirely during the first 2 months in human infections. We recently described the reduced activity of PZA in C3HeB/FeJ mice with large caseous tubercles due to neutral pH. Here, we aimed to determine the contribution of PZA to the sterilizing activity of the first-line TB regimen in C3HeB/FeJ and BALB/c mice. Three regimens were compared (in combinations: R, rifampin; H, isoniazid; E, ethambutol; Z, pyrazinamide; with numbers indicating the treatment duration, in months): 2RHEZ/4RH, 2RHE/4RH, and 2RHEZ/4RHZ. Lung CFU counts were assessed after 0 and 2 months of treatment, and relapse rates were assessed 3 months after 3, 4.5, and 6 months of treatment. The relapse rates after 3 months of treatment were 53% and 95% in C3HeB/FeJ mice receiving 2RHEZ/1RH and 2RHE/1RH, respectively, and 67%, 100%, and 80% in BALB/c receiving 2RHEZ/1RH, 2RHE/1RH, and 2RHEZ/1RHZ, respectively. The relapse rates after 4.5 months of treatment were 32%, 20%, and0% in C3HeB/FeJ mice receiving 2RHEZ/2.5RH, 2RHE/2.5RH, and 2RHEZ/2.5RHZ, respectively, and 0% and 67% in BALB/c receiving 2RHEZ/2.5RH and 2RHE/2.5RH, respectively. The month-6 relapse rates were 0%, 13%, and 0% in C3HeB/FeJ mice given 2RHEZ/4RH, 2RHE/4RH, and 2RHEZ/4RHZ, respectively, and7% in BALB/c mice receiving 2RHE/4RH. The addition of PZA shortens the duration of treatment needed to prevent relapse in both mouse strains. However, while its contribution is limited to the first 2 months of treatment in BALB/c mice, continuing PZA beyond the first 2 months is beneficial in C3HeB/FeJ mice by preventing relapse among those with the highest disease burden.