Therapeutic Drug Monitoring in the Treatment of Tuberculosis
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Therapeutic drug monitoring (TDM) is a standard clinical technique used for many disease states, including many infectious diseases. As for these other conditions, the use of TDM in the setting of tuberculosis (TB) allows the clinician to make informed decisions regarding the timely adjustment of drug therapy. Such adjustments may not be required for otherwise healthy individuals who are responding to the standard, four-drug TB regimens. However, some patients are slow to respond to treatment, have drug-resistant TB, are at risk of drug-drug interactions or have concurrent disease states that significantly complicate the clinical situation. Such patients may benefit from TDM and early interventions may preclude the development of further drug resistance.
It is not possible to collect multiple blood samples in the clinical setting for logistical and financial reasons. Therefore, one typically is limited to one or two time points. When only one sample can be obtained, the 2-hour post-dose concentrations of isoniazid, rifampin, pyrazinamide and ethambutol are usually most informative. Unfortunately, low 2-hour values do not distinguish between delayed absorption (late peak, close to normal range) and malabsorption (low concentrations at all time points). A second sample, often collected at 6-hour post-dose, can differentiate between these two scenarios. The second time point can also provide some information about clearance and half-life, assuming that drug absorption was nearly completed by 2 hours. TDM requires that samples are promptly centrifuged, and that the serum is promptly harvested and frozen. Isoniazid and ethionamide, in particular, are not stable in human serum at room temperature. Rifampin is stable for more than 6 hours under these conditions.
During TB treatment, isoniazid causes the greatest early reduction in organisms and is considered to be one of the two most important TB drugs, along with rifampin. Although isoniazid is highly active against TB, low isoniazid concentrations were associated with poorer clinical and bacteriological outcomes in US Public Health Services (USPHS) TB Trial 22. Several earlier trials showed a clear dose-response for rifampin and pyrazinamide, so low concentrations for those two drugs also may correlate with poorer treatment outcomes. At least in USPHS TB Trial 22, the rifampin pharmacokinetic parameters were not predictive of the outcome variables. In contrast, low concentrations of unbound rifapentine may have been responsible, in part, for the worse-than-anticipated performance of this drug in clinical trials.
The ‘second-line’ TB drugs, including p-aminosalicylic acid, cycloserine and ethionamide, are relatively weak TB drugs. Under the best conditions, treatment with these drugs takes over 2 years, as opposed to 6 to 9 months with isoniazid- and rifampin-containing regimens. Therefore, TB centres such as National Jewish Medical and Research Center in Denver, CO, USA, measure serum concentrations of the ‘second-line’ TB drugs early in the course of treatment. That way, poor drug absorption can be dealt with in a timely manner. This helps to minimise the time that patients are sputum smear- and culture-positive with multidrug-resistant TB, and may prevent the need for even longer treatment durations.
Patients with HIV are at particular risk for drug-drug interactions. Because the published guidelines typically reflect interactions only between two drugs, these guidelines are of limited value when the patient is treated with three or more interacting drugs. Under such complicated circumstances, TDM often is the best available tool for sorting out these interactions and placing the patient the necessary doses that they require.
TDM is only one part of the care of patients with TB. In isolation, it is of limited value. However, combined with clinical and bacteriological data, it can be a decisive tool, allowing the clinician to successfully treat even the most complicated TB patients.
KeywordsRifampicin Isoniazid Therapeutic Drug Monitoring Ethambutol Pyrazinamide
The author has provided no information on sources of funding or on conflicts of interest directly relevant to the content of this review/study.
- 1.Peloquin CA, Ebert SC. Tuberculosis. In: DiPiro JT, Talbert RL, Yee GC, et al., editors. Pharmacotherapy: A pathophysiologic Approach. 4th ed. Stamford (CT): Appleton & Lange, 1999: 1717–36Google Scholar
- 2.American Thoracic Society. Targeted tuberculin skin testing and treatment of latent tuberculosis infection. Am J Respir Crit Care Med 2000; 161: S221–47Google Scholar
- 3.Verbist L. Mode of action of antituberculous drugs: I. Medikon 1974; 3: 11–23Google Scholar
- 4.Verbist L. Mode of action of antituberculous drugs: II. Medikon 1979; 3: 3–17Google Scholar
- 5.Winder FG. Mode of action of the antimycobacterial agents and associated aspects of the molecular biology of the mycobacteria. In: Rat-ledge C, Stanford J, editors. The Biology of Mycobacteria: Vol1. Physiology, Identification, and Classification. London: Academic Press, 1982: 353–438Google Scholar
- 10.Fox W, Ellard GA, Mitchison DA. Studies on the treatment of tuberculosis undertaken by the British Medical Research Council Tuberculosis Units, 1946–1986, with relevant subsequent publications. Int JTuberc Lung Dis 1999; 3: S231–79Google Scholar
- 16.Iseman MD. A clinician’s guide to tuberculosis. Philadelphia: Lippencott Williams & Wilkins, 2000: 271–321Google Scholar
- 17.American Thoracic Society. Treatment of tuberculosis and tuberculosis infection in adults and children. Am J Respir Crit Care Med 1994; 149: 1359–74Google Scholar
- 23.Vernon A, for the TB Trials Consortium. TBTC Study 22 (Rifapentine Trial): Preliminary Results in HIV-negative Patients [abstract]. Am J Respir Crit Care Med 2000; 161: A252Google Scholar
- 27.Weiner M, Khan A, Benator D, et al. Low isoniazid levels are associated with tuberculosis treatment failure or relapse with once-weekly rifapentine and isoniazid [abstract]. Proceedings of the 97th American Lung Association / American Thoracic Society International Conference; 2001 May 18–23; San Francisco (CA). Am J Respir Crit Care Med 2001; 163: A–498Google Scholar
- 28.Peloquin CA, Benator D, Hayden K, et al. Low rifapentine, rifampin, & isoniazid plasma levels are not predicted by clinical and demographic features [abstract]. Proceedings of the 97th American Lung Association / American Thoracic Society International Conference; 2001 May 18–23; San Francisco (CA). Am J Respir Crit Care Med 2001; 163: A–498Google Scholar
- 33.Peloquin CA. Antituberculosis drugs: pharmacokinetics. In: Heifets L, editor. Drug susceptibility in the chemotherapy of mycobacterial infections. Boca Raton: CRC Press; 1991: 59–88Google Scholar
- 34.Steil CF. Diabetes mellitus. In: DiPiro JT, Talbert RL, Yee GC, et al., editors. Pharmacotherapy: a pathophysiologic approach. 4th ed. Stamford (CT): Appleton & Lange, 1999: 1219–43Google Scholar
- 36.Kotier DP, Gaetz HP, Lange M, et al. Enteropathy associated with the acquired immunodeficiency syndrome. Ann Intern Med 1984; 101: 421–8Google Scholar
- 42.Colborn D, Lewis R, Narang P. HIV disease does not influence rifabutin absorption [abstract no. A42]. Proceedings of the 34th Interscience Conference on Antimicrobial Agents and Chemotherapy; 1994 Oct 4–7; Orlando (FL)Google Scholar
- 52.Perlman DC, Remmel R, Brundage R, et al., for the ACTG 309 Protocol Team. Pharmacokinetics of antituberculous agents in persons with HIV-related tuberculosis [abstract no. 619]. Proceedings of the Infectious Diseases Society 37th Annual Meeting; 1999 Nov 18–21; Philadelphia (PA). Clin Infect Dis 1999; 29: 1070Google Scholar
- 55.CDC. Prevention and treatment of tuberculosis among patients infected with human Immunodeficiency Virus: principles of therapy and revised recommendations. Morb Mortal Wkly Rep 1998; 47(RR-20): 1–58Google Scholar
- 56.CDC. Updated guidelines for the use of rifabutin or rifampin for the treatment and prevention of tuberculosis among HIV-infected patients taking protease inhibitors on nonnucleoside reverse transcriptase inhibitors. Morb Mortal Wkly Rep 2000; 49: 185–9Google Scholar
- 59.Piscitell SC. The value of drug levels: the plot thickens. Medscape.com 2001 [online]. Available from URL: http://id.medscape.com/medscape/cno/2001/RETRO/story.cfm?.story_id=2055 [Accessed 2002 Sep 3]
- 63.Cuss FMC, Carmichael DJS, Linington A, et al. Tuberculosis in renal failure: a high incidence in patients born in the third world. Clin Nephrology 1986; 25: 129–33Google Scholar
- 69.Peloquin CA, Jaresko GS, Yong CL, et al. Population Pharmacokinetic Modeling of Isoniazid, Rifampin, and Pyrazinamide. Antimicrobial Agents Chemother 1997; 41: 2670–9Google Scholar
- 71.Weiner M, Khan A, Benator D, et al., and the TB Trials Consortium. Low Isoniazid (INH) Levels Are Associated with TB Treatment Failure/Relapse with Once-Weekly Rifapentine (RPT) and INH [abstract]. Am J Respir Crit Care Med 2001; 163: A498Google Scholar
- 75.McEvoy GK, editor. AHFS Drug Information. Bethesda (MD): American Soc Health-Systems Pharmacists, 2002: 482–527Google Scholar
- 77.Kucers A, Bennett N. The use of antibiotics. 4th ed. Philadelphia: J.B. Lippencott Company, 1987: 914–70Google Scholar
- 79.Tarn CM, Chan SL, Kam KM, et al. Rifapentine and isoniazid in the continuation phase of a 6-month regimen. Interim report: no activity of isoniazid in the continuation phase. Int J Tuberc Lung Dis 2000; 4: 262–7Google Scholar
- 81.Bock N, Sterling T, Pachucki C, et al. for the TB Trials Consortium. Tolerability of once-weekly rifapentine 900 mg plus INH vs once-weekly rifapentine 600 mg plus INH during continuation phase treatment of pan-susceptible tuberculosis in HIV-negative adults [abstract + poster]. Am J Respir Crit Care Med 2001; 163: A497Google Scholar
- 91.Peloquin CA, Bulpitt AE, Jaresko GS, et al. Pharmacokinetics of ethambutol under fasting conditions, with food, and with antacids. Antimicrobial Agents Chemother 1999, 43; 568–72Google Scholar
- 94.Demczar DJ, Nafziger AN, Bertino JS Jr. Pharmacokinetics of gentamicin at traditional versus high doses: implications for once-daily aminoglycoside dosing. Antimicrobial Agents Chemother 1997; 41: 1115–9Google Scholar
- 98.Berning SE, Peloquin CA. Antimycobacterial agents: Cycloserine. In: Yu VL, Merigan TC, Barriere S, White NJ, editors. Antimicrobial chemotherapy and vaccines. Baltimore (MD): Williams and Wilkins, 1998: 638–42Google Scholar
- 100.Berning SE, Peloquin CA. Antimycobacterial agents: Ethionamide. In: Yu VL, Merigan TC, Barriere S, White NJ, editors. Antimicrobial chemotherapy and vaccines. Baltimore (MD): Williams and Wilkins, 1998: 650–4Google Scholar
- 102.Garrelts JC. Clofazimine: a review of its use in leprosy and Mycobacterium avium complex infection. DICP Ann Pharmacother 1991; 25: 525–31Google Scholar