Efflux‐Pump–Derived Multiple Drug Resistance to Ethambutol Monotherapy inMycobacterium tuberculosisand the Pharmacokinetics and Pharmacodynamics of Ethambutol

Abstract

Background In the treatment of tuberculosis, ethambutol is used in case there is isoniazid resistance. We examined for the emergence of drug resistance to ethambutol monotherapy in pharmacokinetic-pharmacodynamic studies in the hollow fiber system. Methods Dose–effect studies and dose-scheduling studies were carried out with ethambutol and log-phase growth Mycobacterium tuberculosis to identify exposures and schedules linked to optimal kill and resistance suppression. In one study, after 7 days of ethambutol 300 mg/day isoniazid was administered to each system to determine its early bactericidal activity (EBA). Results Efflux-pump blockage reduced the mutation frequency to ethambutol 64-fold. In dose-effect studies, ethambutol had a maximal EBA of 0.22 log10 CFU/ml/day, as encountered in patients. By day 7, resistance had arisen to both ethambutol and isoniazid. Prior exposure to ethambutol abolished isoniazid EBA. Daily therapy, as opposed to more intermittent therapy, was associated with the least proportion of efflux-pump driven resistance, consistent with time driven effect. Microbial kill was best explained by the ratio of area under the concentration-time curve to minimal inhibitory effect (r2=0.90). Conclusion Induction of an efflux-pump that reduces effect to multiple drugs provides an alternative pathway to sequential acquisition of mutations in the development of multiple drug resistance.

The epidemiology, pathogenesis, transmission, diagnosis, and management of multidrug-resistant, extensively drug-resistant, and incurable tuberculosis

“…Fortunately, in recent years, a better understanding that is supported by studies in standard bacteriology and pharmacology has emerged to explain M tuberculosis acquired drug resistance. [171][172][173] Consideration of resistance mechanisms beyond gene mutations has also begun. However, this pharmacological approach does not exclude the role of tuberculosis programmes; rather it emphasises that the policy for abrogating acquired drug resistance that programmes implement should continue being revised to conform to the latest scientific understanding, which would strengthen the effectiveness of these programmes.…”

“…[171][172][173]196,197 In this theory of drug resistance (figure 5) several initiating factors exist such as low drug dosage due to poor dosing practices, pharmacokinetic variability, or inadvertent monotherapy with, for example, quino lones for bacterial pneumonias and other conditions that turn out to be tuberculosis. As part of the bacterial stress reaction to the suboptimal antibiotic concentrations-and to effective monotherapy-efflux pumps in the bacilli are upregulated within hours.…”

“…380,426,419 Table 11 shows the pharmacokineticpharmacodynamic exposure and pharmacokineticpharmacodynamic index associated with the sup pression of acquired drug resistance for several drugs that are used in clinical practice; these often differ from those associated with opti mal microbial kill for the same drug. 173,180,191,192,196,380,395,417,[419][420][421][422][423][424][425][426][427][428][429][430][431] Mistakenly, many regi mens were designed for the treatment of tuberculosis with a focus on microbial kill, ignoring the problem of acquired drug resistance. The theory was that directly observing the patients swallowing the pills, and using one drug to prevent resistance to another, would solve the acquired drug resistance problem.…”

Efflux Attenuates the Antibacterial Activity of Q203 in Mycobacterium tuberculosis

“…Indeed, M. tuberculosis has one of the largest numbers of putative drug efflux pumps relative to the size of its genome (5). The induction of efflux in response to anti-TB drug treatment has been proposed as the first step in the development of drug resistance, subsequently leading to chromosomal mutation-related resistance (6,7,8). While several efflux pumps are known in M. tuberculosis, more studies are required because anti-TB drug discovery has predominantly focused on identifying new active and potent protein target inhibitors.…”

Mycobacterial Shuttle Vectors Designed for High-Level Protein Expression in Infected Macrophages

“…In summary, our new protein expression vectors and reporter cell line provide additional tools for uncovering the pathogenic mechanisms of diverse mycobacterial strains. For example, this modified vector provides investigators with an excellent tool for testing different drugs for the eradication of M. avium and/or M. tuberculosis from infected cells (41). In addition, such a vector could enhance immune responses to specific mycobacterial proteins, which may further improve the efficacy of the recently developed M. smegmatis vaccines (43).…”