Clin Chest Med 26 (2005) 273 – 282 Treatment of Active Tuberculosis: Challenges and Prospects Behzad Sahbazian, DOa, Stephen E. Weis, DOb,* a John Peter Smith Hospital, Viola Pitts/Como Community Health Clinic, 4701 Bryant Irvin Road, Fort Worth, TX 76107, USA b Department of Medicine, University of North Texas Science Center, Texas College of Osteopathic Medicine, 3500 Camp Bowie Boulevard, Fort Worth, TX 76107, USA In the past 5 years, the Tuberculosis Trials Con- emerged from the first studies of drug therapy of sortium (TBTC) of the Centers for Disease Control tuberculosis initiated in the late 1940s. These studies and Prevention has completed several large studies evaluated monotherapy with streptomycin and sub- that have improved the understanding of pharmaco- sequently para-aminosalicylic acid (PAS) [7 – 9]. therapy of tuberculosis. Insights gained from these They demonstrated that drug resistance developed studies have resulted in major changes in drug frequently in persons treated with monotherapy. therapy of tuberculosis in HIV-infected and non- During 3 months of monotherapy with streptomycin, infected individuals [1 – 5]. These advances require 92% of persons who remained culture-positive that tuberculosis drug therapy now be individualized. developed streptomycin resistance . Resistance Recommended treatment regimens are based on a also developed commonly during monotherapy with patient’s risk profile that is determined by a combi- PAS and was found in approximately one third of nation of hematologic, microbiologic, clinical, and patients during 4 months of treatment . It was also radiographic findings . These studies have resulted observed that resistance was much less common in in substantial changes in the treatment guidelines. persons treated with the combination of streptomycin Although they are more complicated than the pre- and PAS, and that many more patients treated with vious guidelines, they allow treatment to be refined the two-drug regimen became bacteriologically nega- so that it can be extended in patients at high risk for tive with 4 months of therapy . Ten percent or less treatment failure and allow shorter, more convenient of persons treated simultaneously with streptomycin treatment regimens in patients who can be identified and PAS developed streptomycin resistance [7,8]. It as being at very low risk for failure . This article also was observed that development of resistance reviews the basic principles of drug treatment of was associated with a worse prognosis and with more tuberculosis, individual pharmacologic agents, cur- severe disease . From these early observations rent treatment recommendations, and several special came the principle that tuberculosis treatment must situations that clinicians are likely to encounter in include simultaneous treatment with at least two ef- medical practice. fective drugs. The microbiologic basis for these early observa- tions was not identified until the early 1960s and Axioms of chemotherapy of tuberculosis remains as important today to understand the design of current treatment regimens . Persons with cavi- Effective tuberculosis drug therapy requires not tary disease are estimated to have bacterial popu- one but at least two effective drugs. This axiom lations of approximately 108 organisms in each cavity [10,11]. During division, Mycobacterium tubercu- losis bacilli mutate from drug-susceptible to drug- * Corresponding author. resistant status spontaneously, randomly, and at a E-mail address: firstname.lastname@example.org (S.E. Weis). predictable rate . The proportion of naturally oc- 0272-5231/05/$ – see front matter D 2005 Elsevier Inc. All rights reserved. doi:10.1016/j.ccm.2005.02.011 chestmed.theclinics.com 274 sahbazian & weis curring organisms that are resistant to antituberculosis with drug-resistant tuberculosis is testimony that drugs is variable, approximately 10À5 for ethambutol, these principles are not being implemented success- 10À6 for isoniazid and streptomycin, and 10À8 for fully . rifampin . The probability of a single organism The last 50 years of tuberculosis drug treatment mutating simultaneously and becoming resistant to can be summarized succinctly. First, it was demon- two drugs is the product of individual probabilities strated that proper chemotherapy and the cooperation of mutation. It can therefore be estimated that the of the patient are the most important factors influenc- likelihood of an organism having mutations simulta- ing response to treatment . Second, it has been neously for isoniazid and rifampin is approximately proven that the social factors such as those corrected [(1 Â 10À6) Â (1 Â 10À8)] or (1 Â 10À14), and the during sanatoria treatment of tuberculosis (which pro- bacillary burden in human tuberculosis is several vided bed rest, airy accommodations, a well-balanced orders less than this . This mutation rate is the diet, good nursing care, and psychologic balance) basis for the observation that successful drug ther- have had no effect on outcome in persons prescribed apy requires that at least two drugs be given drug therapy and cooperating with treatment . concurrently to prevent selection of drug-resistant Third, a few new antituberculosis drugs have been organisms. If a single drug is used for treatment, developed. For the most part, however, progress has selection of the resistant organisms occurs, and the been made in learning to use available drugs more patient rapidly becomes resistant to that drug. This effectively, with treatment regimens becoming re- mutation rate is also the basis for designing regimens fined to the current treatments that are shorter, have with an intensive initial phase that uses more medi- fewer side effects, and are more convenient . cations and a less intense continuation phase that uses fewer medications. Corollaries of the treatment axiom that tubercu- losis treatment must include simultaneous treatment Pharmacology and toxicity of antimycobacterial with at least two effective drugs are important for agents designing effective tuberculosis regimens and tu- berculosis control programs. Because of the possi- The current drugs approved by the Food and Drug bility of resistance, a single drug is never added to Administration (FDA) for the treatment of tuber- a failing drug-treatment regimen. Optimal design of culosis include isoniazid, pyrazinamide, rifampin, re-treatment regimens should include at least two rifapentine, ethambutol, cycloserine, ethionamide, ca- medications to which the patient is naıve, and ¨ preomycin, PAS, and streptomycin. Drugs that com- clinicians designing initial treatment regimens must monly are recommended by expert panels for use in consider prevailing tuberculosis-susceptibility pat- the treatment of tuberculosis but are not FDA ap- terns in the community where the infection probably proved include rifabutin, the aminoglycosides includ- was acquired. It is equally important to successful ing amikacin, kanamycin, and the fluoroquinolones treatment that the patient actually take the two proba- including ciprofloxacin, moxifloxacin, and levofloxacin. bly effective drugs. The only way to ensure that a Of the approved drugs, isoniazid, rifampin, ethambu- patient actually takes drug therapy as prescribed is tol, and pyrazinamide are considered first-line anti- direct observation of therapy. If three separate drugs tuberculosis drugs. Rifapentine and rifabutin can also are prescribed for a patient with tuberculosis, the be considered first-line drugs under special condi- patient may, for many reasons, take a single drug at tions discussed later. The others are categorized as a time. Short-term single-drug therapy in a person second-line drugs, which are used when the first-line with high bacillary burden can lead to emergence drugs are unsuitable because of drug intolerance of drug resistance [7 – 9]. If a patient happens to or infection with drug-resistant tuberculosis. Addi- be initially resistant to one drug and takes a combi- tionally clarithromycin, amoxicillin/clavulanate, and nation of two drugs, including the one to which he linezolid have been used in the treatment of patients or she is resistant, drug resistance to the second with drug-resistant tuberculosis. drug will emerge. Similarly, if the patient is resistant Drug-level monitoring is not routinely an impor- to two drugs and takes these two drugs and a single tant aspect of treatment in a patient with active effective drug, resistance to the third will emerge. tuberculosis. Therapeutic drug monitoring is most Therefore, poor adherence, inadequate prescribing, useful when there is a direct relationship between or both may result in the development of multidrug serum concentrations and therapeutic response and resistance. Although these axioms may seem self- when serum concentrations serve as a surrogate for evident, the growing number of persons worldwide drug concentrations at the site of action. Therapeutic treatment of active tuberculosis 275 drug monitoring is also important when there is a Peripheral neuropathy also is associated occasion- narrow range of concentrations that are effective ally with use of isoniazid. Neuropathy occurs more and safe and when toxicity or lack of effectiveness commonly among persons who have other risks puts the patient at great risk [16,17]. Examples of for neuropathy. Persons at increased risk of periph- situations in which therapeutic drug monitoring is eral neuropathy include those who are nutritionally useful for safety include persons treated with amino- deficient, alcoholics, diabetics, pregnant women, glycosides and persons treated with ethambutol or breastfeeding mothers, and patients with renal dis- cycloserine with renal impairment. ease. Vitamin B6 (pyridoxine) supplements usually are given with isoniazid to prevent development of peripheral neuropathy . Isoniazid Hypersensitivity reactions including arthralgias, irritability, seizures, and lupuslike syndrome have Isoniazid is used for the treatment of both latent also been reported in patients receiving isoniazid. and active tuberculosis and works primarily by Although as many as 20% of patients treated with inhibiting cell wall synthesis. It is usually adminis- isoniazid develop a positive antinuclear antibody test, tered orally but has been given successfully intra- systemic lupus rarely occurs . muscularly or intravenously . Isoniazid is cleared Isoniazid has clinically important reactions with predominantly through the liver by acetylation. A other concomitantly used medications. Isoniazid patient’s acetylation status and the associated differ- can affect the levels of certain antiseizure medica- ences in plasma isoniazid concentrations are not as- tions, such as phenytoin and carbamazepine. Levels sociated with isoniazid-induced liver injury . of these medications must be monitored during iso- Additionally, no association was found between niazid therapy . plasma isoniazid concentrations and isoniazid-induced liver injury . Isoniazid is distributed throughout the body with peak concentrations occurring within Rifamycins 1 to 2 hours after the administration of an oral dose . The usual dose for isoniazid is 3 to 5 mg/kg The rifamycins, which include rifampin, rifabutin, body weight/day in adults with a maximum dose and rifapentine, work by interfering with RNA of 300 mg/day . synthesis, even in bacilli with minimal metabolic Isoniazid generally is well tolerated. Hepatic side activity . The rifamycins are variable inducers of effects are perhaps the best known of the untoward the cytochrome P450 system. Rifampin, rifabutin, effects associated with isoniazid use. Less well and rifapentine are each first-line drugs for the treat- known is the asymptomatic elevation of liver amino- ment of tuberculosis in different circumstances. transferases of up to five times the upper limits of Rifampin generally is given orally, but formulations normal, which occurs in approximately 20% of are available for parenteral therapy. The usual dose patients receiving isoniazid. This asymptomatic mild for rifampin in adults is 10 mg/kg to a maximum of elevation of liver aminotransferases is not progres- 600 mg daily. It is distributed well throughout the sive, is not an indication of progressive liver toxicity, body and reaches effective concentrations in all tis- and when asymptomatic does not require discon- sues . Rifampin is a necessary component of all tinuation of isoniazid treatment . Isoniazid-induced short-course regimens . hepatitis does occur, but recent studies indicate it is Rifampin is generally a well-tolerated drug. The less common than previously thought. Isoniazid- most common side effect of rifampin use is an induced hepatitis is estimated to occur in 0.15% of orange discoloration of the urine, tears, and other those starting and in 0.15% of those completing body fluids. The change in the color of the urine or treatment for latent tuberculosis infection . The other body fluids can be disconcerting to persons rate of isoniazid-induced hepatitis is higher when treated with rifampin if they are not warned. This isoniazid is combined with rifampin . It is also discoloration has been associated with discoloration more common in older persons, heavy alcohol of soft contact lenses and clothing. This staining consumers, and persons with underlying liver disease must be rare, however, because the author and col- . Based on a large survey, the risk of isoniazid- leagues have treated many contact lens wearers with induced fatal hepatitis is much lower than previously rifampin and never have had a complaint of dis- thought—0.001%—when patients are monitored rou- coloration of contacts lens, even though they rou- tinely for liver toxicity [24,25]. The risk increases tinely warn patients of this potential side effect. slightly in patients over the age of 35 years. Rifampin can also cause pruritus . Gastroin- 276 sahbazian & weis testinal upset, including diarrhea, nausea, and ab- concurrent medications must be checked for inter- dominal pains, can occur but rarely require drug actions with rifampin. discontinuation and are usually self limiting . Transient elevation of serum bilirubin may be ob- Ethambutol served during rifampin administration. Hepatitis is more common when rifampin is administered with Ethambutol is used in combination with isoniazid isoniazid . and rifampin in the initial treatment of active tuber- A more serious side effect of rifampin use is an culosis and has been proven effective in primary influenzalike syndrome. Symptoms often mistaken treatment of pulmonary tuberculosis . Ethambutol by patients and physicians for influenza, including is used with isoniazid and rifampin to prevent fevers, chills, faintness, headaches, myalgia, and ar- selecting resistant organisms when resistance to thralgia, occur alone or in combination. This hyper- one of the primary drugs is present. Like isoniazid, sensitivity syndrome seems to be immune mediated ethambutol inhibits cell wall synthesis. It is available and develops primarily when rifampin is given only in the oral form. Because it is secreted through intermittently or in larger doses than are currently the kidneys, it can accumulate in patients with renal recommended. It most commonly develops after 3 to insufficiency. The usual dose for ethambutol is 15 to 6 months but can occur at any time during treatment 20 mg/kg/day or 50 mg/kg two times per week. . Among persons receiving once-weekly rifampin Ethambutol generally is very well tolerated, but, as part of the antituberculosis regimen, 35% to 57% rarely, it can cause retrobulbar neuritis. This syn- of persons who received 1200 to 1800 mg rifampin drome first manifests as decreased red-green color developed a flulike syndrome; the rates were 22% to discrimination and visual acuity. Although it can 31% among those receiving 900 mg/week and 10% result in irreversible vision loss, recognition of the among persons taking 600 mg/week . In contrast, symptoms and prompt discontinuation of the drug for persons who received twice-weekly rifampin, a usually results in return of normal vision. Reducing flulike syndrome was reported in 8% of those the dose of ethambutol to 15 mg/kg/day can minimize receiving 900 mg/week and in 4% of those receiving the risk . 600 mg/week. Symptoms usually appear 1 to 2 hours after administration of the drug and last up to 8 hours Fluoroquinolones [31,32]. The hypersensitivity syndrome can be ac- companied by other manifestations that may be Levofloxacin, moxifloxacin, and gatifloxacin severe and, rarely, life threatening. The incidence all are active against mycobacterium tuberculosis of individual adverse drug reactions included in [37,38]. Although they are not approved by the the hypersensitivity syndrome is not well described FDA for the treatment of tuberculosis, they are for persons treated for tuberculosis. A study of used frequently in treating drug-resistant tubercu- 20,667 patients treated for leprosy with rifampin, losis or when patients are intolerant of first-line 600 mg/day for 3 months, noted the following agents [39,40]. The adult dose for levofloxacin is incidence rates: rash (0.07%), acute renal failure 500 to 1000 mg/day orally. Moxifloxacin is admin- (0.1%), thrombocytopenia (0.01%), and hypotension istered at 400 mg/day. Central nervous system (CNS) (0.01%) . Rifabutin use is also associated with concentrations of fluoroquinolones have been found rare immune-related reactions. These reactions tend to be around 16% to 20% of serum after admin- to be hematologic, such as leukopenia and thrombo- istration of a standard dose of levofloxacin . cytopenia [33,34]. Microbial resistance to fluoroquinolones is common Rifampin can interact with a large number of in the community setting; therefore it is imperative medications because it is a potent inducer of several that fluoroquinolones be used only when appropriate. enzymes. Rifampin induction of hepatic enzymes can The most common side effects reported with the use reduce serum concentrations of oral contraceptives, of this group of antimicrobials are gastrointestinal resulting in pregnancy, and women relying on hor- symptoms such as nausea, anorexia, dyspepsia, ab- monal methods of contraception need to use addi- dominal pain, followed by CNS disturbances (head- tional means of contraception. Rifampin can increase ache, dizziness, drowsiness, abnormal vision) and the metabolism of methadone and glucocorticoids, liver enzyme abnormalities . Fluoroquinolones resulting in narcotic withdrawal syndrome and ad- were not developed with the expectation that they renal insufficiency or exacerbation of the illness would be used for months; however most experts in being treated by glucocorticoid. The interactions of the field of TB have reported a good safety profile rifampin with other drugs are so extensive that all and tolerability with long-term use. Controlled stud- treatment of active tuberculosis 277 ies are in progress by CDC/TBTC to look at fluo- Box 1. Infectious Diseases Society of roquinolones as there is a dearth of information on America/United States Public Health the efficacy of long-term fluoroquinolone treatment Service rating system for treatment (either daily or intermittently) as is required for multi- recommendations based on quality of drug resistant TB. evidence Pyrazinamide Strength of the recommendation Pyrazinamide is the primary drug used in the ini- A. Preferred; should generally be tial intensive phase of active tuberculosis therapy offered to reduce the total length of therapy. It has a steril- B. Alternative; acceptable to offer izing effect and helps eliminate potential persisters C. Offer when preferred or alternative and consequently is used in the first two months of regimens cannot be given intensive therapy to reduce the total length of ther- D. Should generally not be offered apy . It is administered orally and is first broken E. Should never be offered down by the liver. The remaining metabolites are excreted through the kidney . It is more hepa- totoxic than isoniazid; therefore, liver function tests Quality of evidence supporting the should be monitored. It can exacerbate gout and recommendation arthralgias by elevating serum uric acid levels . The adult dose for pyrazinamide, based on estimated I. At least one properly randomized lean body weight, is 25 mg/kg for daily oral ad- trial with clinical end points ministration orally, 37.5 mg/kg for trice-weekly II. Clinical trials that either were not administration, and 50 mg/kg for twice-weekly ad- randomized or were conducted in ministration . other populations III. Expert opinion Aminoglycosides From Gross PA, Barrett TL, Dellinger EP, Amikacin , kanamycin , and capreomycin et al. Purpose of quality standards for in- are three aminoglycosides that are second-line agents fectious diseases. Infectious Diseases So- used in treatment of patients who have resistant ciety of America. Clin Infect Dis 1994;18: tuberculosis. They are available for both intramus- 421; with permission. cular and intravenous administration. All three are administered at 15 mg/kg/day (maximum, 1.0 g/day). Sensitivity tests have shown incomplete cross- resistance between amikacin and capreomycin but United States Public Health Service and the Infec- complete cross-resistance between amikacin and tious Diseases Society of America (Box 1) . kanamycin . Adverse effects most commonly The guidelines recommend four regimens for associated with the use of these drugs are ototoxicity treating persons with drug-susceptible tuberculosis and nephrotoxicity. Patients receiving these medica- . These regimens contain recommendations for tions should have regular audiograms, vestibular and regimen modification under circumstances deter- Romberg testing, and monitoring of renal function. mined by a combination of hematologic, microbio- logic, clinical, and radiographic findings . Each regimen has an initial intensive phase of 2 months Treatment guidelines followed by several options for the continuation phase of 4 or 7 months’ duration. These regimens, Tuberculosis treatment guidelines for the United together with the number of doses specified by the States have been prepared by and endorsed by the regimen, are described in Table 1. The initial phases American Thoracic Society, the Infectious Diseases are denoted by a number (1, 2, 3, or 4), and the con- Society of America, and the Centers for Disease tinuation phases associated with the initial phase are Control and Prevention. These regimens are, for the denoted by the number of the initial phase plus a letter most part, evidence based. These guidelines rate designation for the continuation phase (a, b, or c). treatments according to the strength of the evidence The continuation phase can be given daily, two supporting their use, using a system developed by the times per week, or three times per week with iso- 278 Table 1 Drug regimens for culture-positive pulmonary tuberculosis caused by drug-susceptible organisms Ratinga Initial phase Continuation phase Range of total doses (evidence)b Regimen Drugs Interval and dosesc (minimal duration) Regimen Drugs Interval and dosesc,d (minimal duration) (minimal duration) HIVÀ HIV+ 1 INH 7 d/wk for 56 doses (8 wk) or 5 d/wk 1a INH/RIF 7 d/wk for 128 doses (18 wk) or 182 – 130 (26 wk) A (I) A (II) RIF for 40 doses (8 wk)e 5 d/wk for 90 doses (18 wk)c PZA 1b INH/RIF 2Â/wk for 36 doses (18 wk) 92 – 76 (26 wk) A (I) A (II)f EMB 1cg INH/RPT 1Â/wk for 18 doses (18 wk) 74 – 68 (26 wk) B (I) E (I) 2 INH 7 d/wk for 14 doses (2 wk), then 2a INH/RIF 2Â/wk for 36 doses (18 wk) 62 – 68 (26 wk) A (II) B (II)f RIF 2Â/wk for 12 doses (6 wk) or 5 d/wk 2bg INH/RPT 1Â/wk for 18 doses (18 wk) 44 – 40 (26 wk) B (I) E (I) PZA for 10 doses (2 wk)e then 2Â/wk for EMB 12 doses (8 wk) sahbazian 3 INH 3Â/wk for 24 doses (8 wk) 3a INH/RIF 3Â/wk for 54 doses (18 wk) 78 (26 wk) B (I) B (II) RIF PZA EMB & 4 INH 7 d/wk for 56 doses (8 wk) or 5 d/wk 4a INH/RIF 7 d/wk for 217 doses (31 wk) or 273 – 195 (39 wk) C (I) C (II) weis RIF for 40 doses (8 wk)e 5 d/wk for 156 doses (31 wk)c EMB 4b INH/RIF 2Â/wk for 62 doses (31 wk) 118 – 102 (39 wk) C (I) C (II) Abbreviations: EMB, Ethambutol; HIVÀ, HIV-negative; HIV+, HIV-positive; INH, isoniazid; PZA, pyrazinamide; RIF, rifampin; RPT, rifapentine. a Definitions of evidence ratings: A, preferred; B, acceptable alternative; C, offer when A and B cannot be given; E, should never be given. b Definitions of evidence ratings: I, randomized clinical trial; II, data from clinical trials that were not randomized or were conducted in other populations; III, expert opinion. c When directly observed therapy is used, drugs may be given 5 d/wk and the necessary number of doses adjuated accordingly. Although there are no studies that compare five with seven daily doses, extensive experience indicates this would be an effective practice. d Patients with cavitation on initial chest radiograph and positive cultures at completion of 2 months of therapy should receive a 7-month (31 wk; either 217 doses [7Â/wk] or 62 doses [2Â/wk]) continuation phase. e Five d/wk administration is always given by DOT. Rating for 5 d/wk regimens is A III. f Not recommended for HIV-infected patients with CD4+ cell counts <100 cells/ml. g Options 1c and 2b should be used only in HIV-negative patients who have negative sputum smears at the time of completion of 2 months of therapy and who do not have cavitation on initial chest radiograph (see text). For patients started on this regimen and found to have a positive culture from 2-month specimen, treatment should be extended an extra 3 months. From American Thoracic Society, Centers for Disease Control and Prevention, and Infectious Diseases Society of America. Treatment of tuberculosis. MMWR Recomm Rep 2003; 52(RR-11):3. treatment of active tuberculosis 279 niazid and rifampin. It can also be given, more con- therapy group. There was no demonstrable improve- veniently for patients and staff, once weekly using ment in the broader prespecified combined end points isoniazid and rifapentine in patients with tuberculo- of death or severe disability after 9 months . sis without cavitation on the chest radiograph. This There have been many reports of an increased risk group is estimated to represent 40% of persons with of tuberculosis in patients receiving tumor necrosis tuberculosis in the United States . Persons who factor- alpha (TNF-a) antagonists [53,54]. These have cavitation on the initial or follow-up chest agents, which include infliximab, etanercept, and radiograph or who are culture positive at the end adalimumab, are used for the treatment of an ex- of initial phase of therapy (usually completed after panding group of diseases and work by blocking 2 months) have an unacceptably high risk of treat- TNF-a; an inflammatory cytokine. TNF-a is ex- ment failure [3,6]. For these patients, the continuation pressed by activating macrophages, T cells, and other phase should be extended for an additional 3 months immune cells and is an important part of the host . It is critically important to have sputum cultures response against M. tuberculosis and other intra- at the time of completion of the initial phase of treat- cellular organisms. Current expert opinion on this ment to identify patients at increased risk of relapse. emerging problem in tuberculosis treatment is that The treatment of tuberculosis in persons with HIV the TNF-a antagonist should be discontinued if is discussed elsewhere in this issue. tuberculosis develops during TNF-a antagonist ther- Treatment of tuberculosis may be delayed for apy. The optimal time for resuming TNF-a antagonist many reasons. The current treatment guidelines de- therapy is undetermined. It is recommended that fined completion of adequate therapy by the number TNF-a antagonist therapy be withheld at least until of doses ingested as well as by the duration of treatment with the tuberculosis regimen has been treatment administration . The minimum goal for started, and the patient’s condition has improved . adequate therapy is delivery of the full number of Tuberculosis occurring in pregnancy is a danger to doses in no more than 150% of the expected delivery the pregnant woman and her child, and treatment duration . should not be delayed because of the pregnancy. In- fants born to women with untreated tuberculosis may Special situations be of lower birth weight than those born to women without tuberculosis and can acquire congenital Central nervous system tuberculosis is one of the tuberculosis [55 – 57]. Of the first-line medications, most devastating presentations of human tuberculo- pyrazinamide is not recommended for general use in sis. Disability and death occur despite antitubercu- pregnant women in the United States because of losis therapy . The best antimicrobial agents for insufficient data to determine safety. Aminoglyco- the treatment of central nervous system tuberculosis sides should not be used to treat tuberculosis in preg- have not been validated by well-designed, random- nancy, because they are associated with birth defects ized, clinical trials. Isoniazid and pyrazinamide pene- . There is little information about the safety of trate the meninges in all stages of inflammation. second-line antituberculosis drugs during pregnancy. Rifampin, ethambutol, and aminoglycosides pene- The recommended initial treatment regimen in preg- trate the blood – brain barrier in the presence of men- nancy should consist of isoniazid, rifampin, and ingeal inflammation but poorly in its absence. The ethambutol . If the organism is confirmed to be use of glucocorticoids in an attempt to reduce mor- susceptible to isoniazid and rifampin, the ethambutol tality and morbidity has been controversial . may be discontinued and isoniazid and rifampin con- Recently, a large trial of dexamethasone adjunct tinued for a minimum of 9 months . It is recom- therapy for persons 14 years of age and older with mended that pregnant women receiving isoniazid also tuberculous meningitis has clarified the role of glu- be given pyridoxine (25 mg/day) . Breastfeeding cocorticoids . Dexamethasone treatment was should not be discouraged for women being treated started as soon as possible after starting antituber- with first-line agents, because the small concentra- culosis treatment. Patients were stratified by Glasgow tions of these drugs in breast milk do not produce Coma Scale and given intravenous dexamethasone toxic effects in the nursing infant . for 4 weeks for severe disease and for 2 weeks for Renal insufficiency increases the risk for devel- mild disease. Subsequently, all patients were given oping tuberculosis, and treatment of the two con- tapering doses of dexamethasone orally for an addi- ditions concurrently is a complex and common tional 4 weeks. Dexamethasone adjunctive treatment situation. Isoniazid and rifampin are metabolized in improved survival. Adverse and severe adverse events the liver, and dosages need not be changed in persons were reduced significantly in the dexamethasone- with chronic renal failure [59 – 61]. Metabolites of 280 sahbazian & weis pyrazinamide are excreted renally and can accumu- mens in patients who can be identified as being at late in patients with renal insufficiency . Approxi- very low risk for failure . mately 80% of ethambutol is cleared by the kidneys, so ethambutol may accumulate in patients with renal insufficiency [59,61]. Reducing the dosage may avoid Acknowledgments toxicity, but the peak serum concentrations achieved may be too low to be effective. Therefore increasing The authors acknowledge Thaddeus Miller’s work the dosing interval is recommended . For patients in editing this article. undergoing hemodialysis, administering all drugs for tuberculosis after dialysis is a way to facilitate di- rectly observed treatment and simultaneously to References avoid removal of drugs such as pyrazinamide . To avoid toxicity, it is important to monitor serum  Vernon A, Burman W, Benator D, et al. Relapse with drug concentrations in persons with renal failure who rifamycin mono-resistant tuberculosis in HIV-infected are taking aminoglycosides, cycloserine, or etham- patients treated with supervised once-weekly rifapen- butol . Data are unavailable for the effect of tine and isoniazid. Lancet 1999;353:1843 – 7. peritoneal dialysis on the clearance of antitubercu-  Centers for Disease Control and Prevention. Acquired losis drugs. rifamycin resistance in persons with advanced HIV disease being treated for active tuberculosis with The challenges facing patients with tuberculosis intermittent rifamycin-based regimens. MMWR Morb and underlying liver disease are great. Clinicians Mortal Wkly Rep 2002;51:214 – 5. must choose antituberculosis agents that, with a few  Benator D, Bhattacharya M, Bozeman L, et al. exceptions, are metabolized by the liver and can po- Tuberculosis Trials Consortium. Rifapentine and iso- tentially cause additional liver damage [62 – 64]. This niazid once a week versus rifampicin and isoniazid damage can be life threatening for a person with twice a week for treatment of drug-susceptible pul- marginal hepatic function [62 – 65]. Hepatic dysfunc- monary tuberculosis in HIV-negative patients: a ran- tion can also alter absorption and distribution of domised clinical trial. Lancet 2002;360:528 – 34. drugs that are metabolized or excreted by the liver  Weiner M, Burman W, Vernon A, et al. Tuberculosis . In the setting of severe liver disease, it is Trials Consortium. Low isoniazid concentrations and outcome of tuberculosis treatment with once-weekly reasonable to include fewer hepatotoxic medications isoniazid and rifapentine. Am J Respir Crit Care Med and to extend the period of treatment [6,65]. This 2003;167:1341 – 7. change can be accomplished using a single hepato-  Weiner M, Bock N, Peloquin CA. Tuberculosis Trials toxic drug, generally rifampin, in combination with Consortium. Pharmacokinetics of rifapentine at 600, ethambutol, a quinolone, and an aminoglycoside. 900, and 1,200 mg during once-weekly tuberculosis Isoniazid can be substituted for rifampin, if rifampin therapy. 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