The Dysbiosis Triggered by First-Line Tuberculosis Antibiotics Fails to Reduce Their Bioavailability.

Abstract:

Antituberculosis therapy (ATT) causes a rapid and distinct alteration in the composition of the intestinal microbiota that is long lasting in both mice and humans. This observation raised the question of whether such antibiotic-induced changes in the microbiome might affect the absorption or gut metabolism of the tuberculosis (TB) drugs themselves. To address this issue, we utilized a murine model of antibiotic-induced dysbiosis to assay the bioavailability of rifampicin, moxifloxacin, pyrazinamide, and isoniazid in mouse plasma over a period of 12 h following individual oral administration. We found that 4-week pretreatment with a regimen of isoniazid, rifampicin, and pyrazinamide (HRZ), a drug combination used clinically for ATT, failed to reduce the exposure of any of the four antibiotics assayed. Nevertheless, mice that received a pretreatment cocktail of the broad-spectrum antibiotics vancomycin, ampicllin, neomycin, and metronidazole (VANM), which are known to deplete the intestinal microbiota, displayed a significant decrease in the plasma concentration of rifampicin and moxifloxacin during the assay period, an observation that was validated in germfree animals. In contrast, no major effects were observed when similarly pretreated mice were exposed to pyrazinamide or isoniazid. Thus, the data from this animal model study indicate that the dysbiosis induced by HRZ does not reduce the bioavailability of the drugs themselves. Nevertheless, our observations suggest that more extreme alterations of the microbiota, such as those occurring in patients on broad-spectrum antibiotics, could directly or indirectly affect the exposure of important TB drugs and thereby potentially influencing treatment outcome. Previous studies have shown that treatment of Mycobacterium tuberculosis infection with first-line antibiotics results in a long-lasting disruption of the host microbiota. Since the microbiome has been shown to influence the host availability of other drugs, we employed a mouse model to ask whether the dysbiosis resulting from either tuberculosis (TB) chemotherapy or a more aggressive course of broad-spectrum antibiotics might influence the pharmacokinetics of the TB antibiotics themselves. While drug exposure was not reduced in animals previously described as exhibiting the dysbiosis triggered by conventional TB chemotherapy, we found that mice with other alterations in the microbiome, such as those triggered by more intensive antibiotic treatment, displayed decreased availability of rifampicin and moxifloxacin, which in turn could impact their efficacy. The above findings are relevant not only to TB but also to other bacterial infections treated with these two broader spectrum antibiotics.