NOTORIOUSLY difficult to treat, antibiotic-resistant tuberculosis (TB) would develop less frequently if there was greater optimisation of the dosing schedules used in antibiotic treatment regimens, according to a new computer model developed by Dr Elsje Pienaar and colleagues from the University of Michigan, Ann Arbor, Michigan, USA. Approximately 10 million people acquire TB each year, with 480,000 patients estimated to have developed multi-antibiotic resistant TB in 2014.
Current treatment regimens for TB recommend the use of four different antibiotics for 2 months followed by two antibiotics for the following 4 months. Unfortunately, many patients do not comply with the prescribed regimen and many stop taking the antibiotics once they begin to feel better. It can be difficult to determine whether the infection has been completely cleared because the bacteria can hide within tumour-like granulomas and can enter a latent stage in which they stop trying to reproduce; current antibiotics are ineffective against bacteria during these stages. However, the newly developed computer programme has been able to model the treatment efficacy of thousands of different antibiotic combinations.
The study found that a combined daily dose of the common antibiotics isoniazid and rifampin was more effective than other regimens involving larger doses fewer times per week or smaller daily doses. However, this optimal treatment was still predicted to be unable to clear 100% of infections due to the persistence of bacteria within granulomas. Prof Denise Kirschner from the University of Michigan highlighted this challenge: “The drugs actually have to penetrate into the core of this granuloma.” before going on to add that the passive state the bacteria can adopt also influences the effectiveness of the treatment: “If it is just sitting there, the drug is not going to have as strong an effect on it, which is why you have to treat for 6 months, you need to catch those bacteria in the few moments when they divide.”
The researchers investigated whether increasing the number of doses could raise the concentration of antibiotics within granulomas and found that nine doses per week reduced the length of time it would take to clear an infection by approximately 10 days. They also found that treatment failure would be reduced from 1% to almost 0% if isoniazid could be modified so that absorption of the drug by host cells was reduced by 20%.