Acquisition of Rifampin Resistance in Pulmonary Tuberculosis

Abstract

Mycobacterium tuberculosis strains with spontaneous mutations conferring resistance to rifampin (RIF) are exceedingly rare, and fixed drug combinations typically prevent augmentation of resistance to single drugs. Fourteen newly diagnosed tuberculosis patients were treated with RIF alone for 14 days, and bacterial loads, including mutation frequencies, were determined. A statistical model estimated that 1% of the remaining viable mycobacteria could be RIF resistant after 30 days of monotherapy. This indicates that temporal and spatial windows of RIF monotherapy due to uneven drug distribution within lung lesions could contribute to the acquisition of resistance to RIF.KEYWORDS tuberculosis, rifampin, treatment, resistance D rug resistance is a peculiarity of Mycobacterium tuberculosis in which resistance to antibiotics is genetically encoded. Resistant M. tuberculosis can be transmitted from one person to another, but resistance cannot be transmitted from one bacterium to another (1). Mycobacteria with spontaneous resistance mutations are naturally present in every population of M. tuberculosis (2, 3). The mutation rate, i.e., the probability that a resistance-conferring mutation occurs spontaneously in a bacterium, is very low for rifampin (RIF), the cornerstone of current treatment regimens, with 3.32 ϫ 10 Ϫ9 for M. tuberculosis strain H37Rv (4). However, Beijing strains, which are more prevalent in the Eastern and Western Cape provinces, South Africa, were found to acquire drug resistance in vitro faster than other strains (5-7).It is generally accepted that clinical drug resistance, i.e., the failure of antibiotic treatment to control tuberculosis (TB) in a patient, can emerge through augmentation of a small initial population of resistant mycobacteria that become dominant when susceptible bacteria are eliminated by antibiotic treatment (1, 8). Thus, antibiotic treatment combining different agents can prevent the possibility that a mutant which is resistant to a single antibiotic is able to become clinically relevant, and an effective combination has been shown to provide cure within 6 to 8 months, also in an outpatient setting (9-11). In the absence of a better explanation, patient noncompliance with the prescribed treatment has been blamed for drug resistance, but other lines of evidence, such as the hollow fiber model, have confirmed that noncompliance alone is unlikely to create drug resistance when a fixed-dose combination is used (12). A more convincing theory is pharmacokinetic and pharmacodynamic variability between patients and within patients, referring to differences in drug absorption and metabolism, uneven drug distribution, and bacterial subpopulations that are not equally susceptible. All these factors could conspire to create pockets or temporal windows of monotherapy within patients' lungs where resistance develops (13). Recently published work by Prideaux and coauthors appears to confirm this theory, with

Extreme Drug Tolerance of Mycobacterium tuberculosis in Caseum

“…Our results provide the first experimental evidence that M. tuberculosis bacteria present in caseum are largely slowly replicating or nonreplicating and display extreme drug tolerance, in support of the persistent-bacillus theory. This new factor may conspire with the factors of interindividual PK variability and suboptimal drug distribution into caseous lesions to create pockets of inadequate drug coverage, leading to relapse or emergence of drug resistance ( 3 , 22 ). Together with our recent measurements of drug concentrations in various lesion types ( 7 ), the present results and associated assay will enable the calculation of true lesion-centered PK-PD parameters.…”

The evolving biology of Mycobacterium tuberculosis drug resistance

“…Additionally, mutation, and therefore resistance, can be induced under drug pressure. For example, the mutation frequency to RIF was found to increase more than a thousand-fold during 14-days of monotherapy ( Kayigire et al., 2017 ).…”

Acquired rifampicin resistance during first TB treatment: magnitude, relative importance, risk factors and keys to control in low-income settings

“…A too low drug dosage with a too low concentration at the infection site (which may vary between and within patients) and poor adherence (particularly repeated periods of irregular intake and being on and off the drug) are generally seen as the common causes of ADR. 5 , 6 Still, at population level these factors may have less impact than a lack of careful implementation of appropriate standard regimens for mass treatment by national treatment programmes (NTPs). Considering the diversity and frequency of problems NTPs and their patients are faced with, regimens should not only reach close to 100% treatment success in clinical trials, but also be highly successful under difficult field conditions.…”