Concentration-Dependent Mycobacterium tuberculosis Killing and Prevention of Resistance by Rifampin

Abstract

Rifampin is a cornerstone of modern antituberculosis therapy. However, rifampin's half-life of 3 h is believed to limit its utility for intermittent therapy, so new congeners with long half-lives are being developed. Using an in vitro pharmacokinetic-pharmacodynamic model of tuberculosis, we examined the relationships between rifampin exposure, microbial killing of log-phase-growth Mycobacterium tuberculosis, and suppression of resistance. Rifampin's microbial killing was linked to the area under the concentration-time curve-to-MIC ratio. The suppression of resistance was associated with the free peak concentration (C max )-to-MIC ratio and not the duration that the rifampin concentration was above MIC. Rifampin prevented resistance to itself at a free C max /MIC ratio of >175. The postantibiotic effect duration was >5.2 days and was most closely related to the C max /MIC ratio (r 2 ‫؍‬ 0.96). To explain rifampin's concentration-dependent effect, we examined the kinetics of rifampin entry into M. tuberculosis. Rifampin achieved concentration-dependent intracellular steady-state concentrations within 15 min. Our results suggest that doses of rifampin higher than those currently employed would optimize the effect of rifampin, if patients could tolerate them. Another major implication is that in the design of new rifampin congeners for intermittent therapy, the important properties may include (i) the efficient entry of the rifamycin into M. tuberculosis, (ii) the achievement of a free C max /MIC of >175 that can be tolerated by patients, and (iii) a long postantibiotic effect duration.Tuberculosis (TB) is arguably the most important infectious disease to have confronted humankind. Currently, Mycobacterium tuberculosis infects 2 billion of the 6 billion people worldwide (50). The discovery of rifampin 40 years ago (31) was revolutionary in allowing the creation of potent combination drug regimens against this ancient nemesis. Rifampin is the backbone of modern anti-TB chemotherapy by virtue of being active against M. tuberculosis in exponential growth phase as well as possessing activity against nonreplicating persistent bacilli. Major limitations to rifampin use are believed to include its short half-life (t 1/2 ), which allows cycles of M. tuberculosis regrowth and resistance emergence.It has been the belief for almost half a century that if a drug such as rifampin was given once a week in the initial phase of therapy, its short serum t 1/2 of 3 h would allow short periods of microbial killing followed by regrowth between doses (33, 37). The inference is that the length of time that rifampin is above a certain threshold concentration is the most important index associated with M. tuberculosis killing and the prevention of resistance. Thus, one of the strategic goals of the World Health Organization, the pharmaceutical industry, and research scientists has been to develop rifampin congeners with long t 1/2 s, such as rifapentine, which would make intermittent dosing more effective (3,9,24,26).It is widely believed...

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

“…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.…”

“…More data about drug exposure targets that would minimise therapy failure is available. Most data about acquired drug resistance was collected from preclinical models, 380,419,420,[426][427][428][429][430][431] except for one analysis of clinical studies in which all acquired drug resistance was preceded by low drug concentrations. 191,426 Drug concentrations are also likely to be lower than the optimal concentration in some anatomical compartments, such as the meninges and pericardial fluid, because of poor penetration of drugs into those compartments.…”

Tuberculous Meningitis in Adults: A Review of a Decade of Developments Focusing on Prognostic Factors for Outcome

“…Levels of rifampicin in the CSF are approximately 10-20% of those in plasma, depending on the severity of blood-brain barrier disruption [80]. The antimycobacterial activity of rifampicin is exposure-and concentration-dependent [81]. A relatively modest increase in administered doses of rifampicin (from 10mg/kg to 13 mg/kg) resulted in a significant increase (65%) in mean plasma area under the curve 0-24 h (AUC 0-24 h ) and 49% increase in plasma C max without a significant increase in the rate of adverse events [82,83].…”

In vitro activity of various combinations of antimicrobials against carbapenem-resistant Acinetobacter species in Singapore

“…20 Rifampicin was tested at 2 mg ml À1 , which represented a free peak concentration arising from a 600 mg, daily oral dose to maximize the use of the drug. 21 The concentrations of polymyxin B and tigecycline were tested at 0.5Â MIC to yield attainable experimental end points.…”