Treatment of Active Pulmonary Tuberculosis in Adults: Current Standards and Recent Advances

Abstract

Tuberculosis is a global pandemic, with 9 million new cases of the disease and approximately 2 million deaths each year. More than 98% of patients treated for tuberculosis in the United States between 1993 and 2007 had drug-susceptible strains. The standard treatment regimen for drugsusceptible tuberculosis has not changed in decades and was developed on the basis of empiric observations of different treatment regimens. Only recently has the veracity of the scientific basis for standard therapy been examined. The backbone of therapy is still isoniazid, rifampin, and pyrazinamide, although fluoroquinolones are being investigated as a replacement for isoniazid. Recent population pharmacokinetic studies have demonstrated the importance of individualized dosing of isoniazid, pyrazinamide, and rifampin. Isoniazid serum clearance differs depending on the patient's number of N-acetyltransferase 2 gene *4 (NAT2*4) alleles. Pyrazinamide serum clearance has been shown to increase with increases in body weight. Rifampin's volume of distribution, clearance, and absorption have wide between-patient and within-patient variability. Microbial pharmacokinetic-pharmacodynamic (PK-PD) indexes and targets to optimize microbial killing and minimize resistance have been identified for rifampin, isoniazid, pyrazinamide, and the fluoroquinolones. These PK-PD indexes suggest that different doses and dosing schedules than those currently recommended could optimize therapy and perhaps shorten duration of therapy. Efflux pump inhibition is also being investigated to enhance first-line antituberculosis drug therapy. Comorbid conditions such as diabetes mellitus and genetically determined iron overload syndromes have been associated with significantly worse patient outcomes. Therapy for these and other patient groups needs further improvement. These patient factors, the covariates for pharmacokinetic variability, and PK-PD factors suggest the need to individualize therapy for patients with tuberculosis in order to optimize outcomes and reduce the duration of therapy. Keywords Treatment of Drug-Susceptible Tuberculosis Scientific Basis for Current Therapeutic RegimensCurrent drug regimens grew out of empiric observations and failure of early clinical strategies.Treating tuberculosis with streptomycin, isoniazid, or pyrazinamide monotherapy in the 1950s and 1960s led to an initial favorable response that was quickly abolished by the emergence of resistance. [5][6][7] Use of combination therapy led to reduction in the emergence of drug resistance and became the standard for antituberculosis therapy. [8][9][10] A related rationale has been a belief that in cavitary tuberculosis, there are thought to be three populations of Mycobacterium tuberculosis: bacilli in log-phase growth, slowly replicating bacilli under acidic conditions, and nonreplicating bacilli under hypoxic conditions. 11 Drugs such as rifampin, isoniazid, and pyrazinamide are thought to have selective action on each of these populations, making it necessary to use multiple...

The pharmacokinetics of enteral antituberculosis drugs in patients requiring intensive care

“…[18] Of the four first-line drugs, only rifampicin is available as an IV injection in much of the developing world. The pharmacokinetic profile of anti-TB drugs has been extensively investigated outside the intensive care environment.…”

Analysis of combined anti-tuberculous drug induced neurotoxicity in the cerebral cortex of adult Wistar rats by immunohistochemistry

“…Given the prolonged and occasionally arduous nature of anti-tuberculous treatment for patients, we face an increasing incidence of multidrug-resistant tuberculosis (MDR-TB), defined as infection with M. tuberculosis that is resistant to both rifampicin and isoniazid. Resistance to multiple antituberculous drugs has arisen for a number of reasons; however, it can be argued that the principle reasons for these are the indiscriminate or poorly managed use of antibiotics, coupled with a lack of drug susceptibility testing in regions where it is most needed (Conde et al, 2009;Hall et al, 2009).…”

“…Second-line agents are used in cases of intolerance or some other contraindication to the firstline antituberculosis agents (rifampin, isoniazid, pyrazinamide, and ethambutol) and consist of cycloserine, ethionamide, p-minosalicylic acid (PAS), capreomycin, and the aminoglycosides. Fluoroquinolones are recommended as second-line agents but are being tested in multicenter trials as first-line agents (Hall et al, 2009). Several clinical trials are testing the possibility of replacing isoniazid with moxifloxacin, in an attempt to reduce duration of therapy to 4 months (Hall et al, 2009;Connell et al, 2011).…”

“…Fluoroquinolones are recommended as second-line agents but are being tested in multicenter trials as first-line agents (Hall et al, 2009). Several clinical trials are testing the possibility of replacing isoniazid with moxifloxacin, in an attempt to reduce duration of therapy to 4 months (Hall et al, 2009;Connell et al, 2011).…”

In vitro antimicrobial efficacy of a fixed-dose combination of RHZE against M. tuberculosis

“…Currently, several authors have reported synthetic or natural substances that are able to inhibit the growth of M. tuberculosis, but more studies are needed so that they become a viable alternative in the treatment of patients Boligon et al, 2012;Gising et al, Nielsen et al, 2012;Pucci et al, 2010;Vilchèze et al, 2011). Further clinical trials, probably not complete studies on new drugs against TB in the next 10 years, are urgently needed for the rational and adequate use of rifampicin and isoniazid once its use as monotherapy induces primary resistance (Hall, Leff, Gumbo, 2009). …”