New drugs and regimens for tuberculosis

Abstract

Since standardized rifampin-based first-line regimens and fluoroquinolone-based second-line regimens were used to treat tuberculosis (TB), unfortunately without timely modification according to the drug resistance profile, TB and drug-resistant disease are still important public health threats worldwide. Although the last decade has witnessed advances in rapid diagnostic tools and use of repurposed and novel drugs for better managing drug-resistant TB, we need an appropriate TB control strategy and a well-functioning health infrastructure to ensure optimal operational use of rapid tests, judicious use of effective treatment regimens that can be rapidly tailored according to the drug resistance profile and timely management of risk factors and co-morbidities that promote infection and its progression to disease. We searched the published literature to discuss (i) standardized versus individualized therapies, including the choice between a single one-size-fit-all regimen versus different options with different key drugs determined mainly by rapid drug susceptibility testing, (ii) alternative regimens for managing drug-susceptible TB, (iii) evidence for using the World Health Organization (WHO) longer and shorter regimens for multidrug-resistant TB and (iv) evidence for using repurposed and novel drugs. We hope an easily applicable combination of biomarkers that accurately predict individual treatment outcome will soon be available to ultimately guide individualized therapy.

Contemporary Concise Review 2018: Respiratory infections and tuberculosis

“…About 3.5% of new TB cases and 18% of previously treated cases in 2017 were MDR‐/RR‐TB, while 8.5% of MDR‐TB cases were extensively drug‐resistant (XDR‐)TB . Standardized treatment regimens, while having facilitated programmatic implementation, could have inadvertently accelerated the development of MDR‐TB and XDR‐TB through progressive selection of resistant mutants . The standardized 9‐ to 12‐month shorter MDR‐TB regimen showed marginally less favourable outcome (78% vs 81%) than the conventional 18‐ to 24‐month regimen in the preliminary results of the STREAM Stage 1 Trial .…”

Malaria and tuberculosis as diseases of neglected populations: state of the art in chemotherapy and advances in the search for new drugs

“…Taking this fact into consideration, the WHO established that Direct Observation Treatment Short Course (DOTS) should be applied to new patients as a method for minimising treatment negligence, and research efforts must be employed to avoid the spread of resistance. (54,55) Currently, there are two lines of TB treatment standardised by the WHO. The first one employs four of the following: isoniazid (H), rifampicin (R), pyrazinamide (Z) , ethambutol (E) ( Table II and Fig.…”

“…Taking this fact into consideration, the WHO established that Direct Observation Treatment Short Course (DOTS) should be applied to new patients as a method for minimising treatment negligence, and research efforts must be employed to avoid the spread of resistance. 54 , 55 …”

“…Currently, there are more than fifteen clinical trials in Phase II or III, evaluating the efficacy of new tuberculostatic drugs in combination therapy regimens, alone or in association with another standard drug. 55 Several compounds are in Phase II clinical trials such as delpazolid, nitazoxanide, SQ109 , Q203, carbapenems, benzothiazinones and OPC-1677832. 112 Some of these compounds explored new targets, such as SQ109, which targets mmpL3 and inhibits the donation of mycolic acid to the cell wall, and BTZ043, which inhibits DprE1, both promoting the cell wall disruption.…”

Optimal Sampling Strategies for Therapeutic Drug Monitoring of First-Line Tuberculosis Drugs in Patients with Tuberculosis

“…Several factors, such as malabsorption, pharmacogenetics of N-acetyltransferase 2 (NAT2), intraindividual differences in pharmacokinetics (PK), or food intake, may lead to low drug exposure [4–6]. Treatment optimization can be achieved by increasing adherence [7] or studying new or repurposed drugs [8, 9]. Another option is better attainment of the pharmacokinetic/pharmacodynamic (PK/PD) parameters that best predict the efficacy of first-line anti-TB drugs, i.e.…”