Antituberculous Drugs - An Overview - UpToDate

4/6/2019 Antituberculous drugs: An overview - UpToDate
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Antituberculous drugs: An overview

Authors: Richard H Drew, PharmD, MS, FCCP, FIDP, Timothy R Sterling, MD
Section Editor: John Bernardo, MD
Deputy Editor: Elinor L Baron, MD, DTMH
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: May 2019. | This topic last updated: Apr 02, 2019.
INTRODUCTION
Pharmacologic agents for treatment of tuberculosis (TB) are utilized in a hierarchical fashion [1-4]. First-line agents for treatment of active
tuberculosis consist of isoniazid, a rifamycin (rifampin or [less frequently] either rifapentine or rifabutin), pyrazinamide, and ethambutol.
Presence of drug resistance, contraindication, or intolerance to first-line agents may warrant substitution with one or more second-line agents.
Categories of second-line agents are summarized in the table (table 1). Dosing for first- and second-line agents is summarized in the tables (table 2
and table 3).
Pharmacologic issues and some clinical data related to use of antituberculous drugs are reviewed here; issues related to clinical use of
antituberculous drugs in therapeutic regimens are discussed separately. (See "Treatment of drug-susceptible pulmonary tuberculosis in HIV-
uninfected adults" and "Treatment of pulmonary tuberculosis in HIV-infected adults: Initiation of therapy" and "Treatment of drug-resistant pulmonary
tuberculosis in adults".)
FIRST-LINE AGENTS
First-line antituberculous agents for treatment of susceptible TB consist of isoniazid, a rifamycin (usually rifampin), ethambutol, and pyrazinamide.
The clinical approach to use of these agents is discussed separately. (See "Treatment of drug-susceptible pulmonary tuberculosis in HIV-uninfected
adults" and "Treatment of pulmonary tuberculosis in HIV-infected adults: Initiation of therapy".)
Dosing for first-line agents is summarized in the table (table 2).
It may be possible to overcome low-level resistance to isoniazid by increasing the isoniazid dose [2]. This approach may be used for treatment of
TB caused by isolates with low-level isoniazid resistance in vitro and evidence of an inhA mutation (which is associated with low-level isoniazid
resistance) but is unlikely to be beneficial in the presence of a katG mutation (which is associated with high-level isoniazid resistance).
Issues related to isoniazid are discussed further separately. (See "Isoniazid: An overview" and "Isoniazid hepatotoxicity" and "Isoniazid (INH)
poisoning".)
Issues related to rifampin and the other rifamycins are discussed further separately. (See "Rifamycins (rifampin, rifabutin, rifapentine)".)
Issues related to ethambutol are discussed further separately. (See "Ethambutol: An overview".)
Issues related to pyrazinamide are discussed further separately. (See "Pyrazinamide: An overview".)
SECOND-LINE AGENTS
Presence of drug resistance, contraindications, or intolerance to first-line antituberculous agents warrants use of second-line agents. These agents
are so classified because of decreased activity against Mycobacterium tuberculosis, relative lack of clinical data, unfavorable or poorly
characterized pharmacokinetic profile, and/or increased incidence and severity of adverse events compared with first-line agents [4,5].
Selection of second-line antituberculous agents should be guided by in vitro susceptibility results with involvement of an expert in the treatment of
tuberculosis. In the setting of severe illness, treatment with second-line agents may need to be initiated prior to availability of drug susceptibility
results. In such cases, treatment decisions should be based on the drug susceptibility pattern of the source case to whom the patient has been
exposed, prior treatment regimens of the patient (ie, agents that have not been used previously are preferred), and the likelihood of cross-
resistance based on previous agents used. Dosing and adverse effects for second-line agents are summarized in the table (table 3).
Oral medications for treatment of multidrug-resistant (MDR)- or extensively drug resistant (XDR)-TB should be given daily, not intermittently. The
clinical approach to use of second-line agents is discussed further separately. (See "Treatment of drug-resistant pulmonary tuberculosis in adults",
section on 'Clinical approach'.)
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All patients with tuberculosis should receive directly observed therapy (DOT) as part of patient-centered case management [4]. Ideally, DOT should
occur seven days per week. If this is not possible, five-days-per-week DOT may be used for patients who are not hospitalized, with self-
administration of medications on weekends. (See "Adherence to tuberculosis treatment".)
Quinolones: levofloxacin or moxifloxacin — Fluoroquinolones have excellent activity in vitro against M. tuberculosis and represent the initial
category of second-line antituberculous agents in the setting of resistance and/or intolerance to first-line agents [6,7].
In general, levofloxacin and moxifloxacin are favored over the early-generation fluoroquinolones (specifically ciprofloxacin) for treatment of TB, due
to greater in vitro activity of levofloxacin and moxifloxacin [3,8-15]. In one study including 834 patients with suspected drug-resistant TB, mortality
rates among those treated with either moxifloxacin or levofloxacin were half those of participants not treated with any fluoroquinolone or treated only
with an earlier-generation fluoroquinolone (adjusted hazard ratio 0.46; 95% CI 0.26-0.80) [15]. Since all fluoroquinolones share a genetic target
(DNA gyrase), there is no role for simultaneous use of more than one drug in this class [10,16-18].
Cross-resistance between fluoroquinolones is common but not universal [2,19]. When fluoroquinolone resistance is detected by culture-based drug
susceptibility testing or molecular testing, a minimum inhibitory concentration (MIC) for moxifloxacin may be performed to determine whether an
increased dose may be considered. Use of "high-dose" moxifloxacin (600 mg or 800 mg orally once daily) may achieve adequate serum
concentrations in patients for whom the isolate's MIC to moxifloxacin is 1 to 2 mcg/mL; however, this approach has not been studied in clinical trials,
and the safety of such dose escalations has not been established [2].
The fluoroquinolones are generally well-tolerated. Rare complications include tenosynovitis (including reports of Achilles tendinitis and rupture) and
exacerbation of symptoms among patients with myasthenia gravis and peripheral neuropathy [20,21]. Levofloxacin is less frequently associated
with QT interval prolongation than moxifloxacin (standard dose), so levofloxacin may be preferred for patients on a regimen including other agents
associated with QT prolongation (including clofazimine and bedaquiline) (table 3). Moxifloxacin does not require dose adjustment in patients with
renal insufficiency (unlike levofloxacin), but moxifloxacin should be used with caution in patients with liver impairment.
Data supporting use of higher doses of levofloxacin (1000 mg/day) come from a small randomized trial and a pharmacokinetic study [22,23]. In a
previous trial including 182 patients with MDR-TB randomized to receive either levofloxacin (750 mg/day) or moxifloxacin (with a background drug
regimen), both drugs were associated with high rates of culture conversion at three months [9]. Prior to these studies, data on levofloxacin
administered at a lower dose (500 mg/day) suggested that levofloxacin was less effective than moxifloxacin or gatifloxacin [16].
Additional issues related to fluoroquinolones are discussed further separately. (See "Fluoroquinolones".)
Bedaquiline — Bedaquiline is an oral diarylquinoline drug with bactericidal antituberculous activity. It may be used as part of combination therapy
for treatment of pulmonary drug-resistant TB via directly observed therapy (DOT) for patients >18 years of age when an effective treatment cannot
otherwise be provided.
Bedaquiline was approved by the FDA in 2012 for treatment of MDR-TB. Provisional United States Centers for Disease Control and Prevention
(CDC) guidelines have been issued for both approved and unapproved uses [24]. The World Health Organization (WHO) has also published
recommendations regarding the use of bedaquiline [25].
The CDC issued provisional guidelines for use of bedaquiline in 2013 that extended recommendations to populations who were not included in the
clinical trials for the drug (and hence were not covered by the FDA approval), including children, pregnant women, individuals with extrapulmonary
MDR-TB, and individuals with human immunodeficiency virus (HIV) or other comorbid conditions [24]. The CDC indicated that, although safety and
effectiveness in these populations have not been determined, bedaquiline may be used on a case-by-case basis for these individuals when an
effective treatment regimen cannot otherwise be provided. Additional clinical considerations for use of bedaquiline are summarized in the table
(table 4) [24].
Bedaquiline can cause QT prolongation, which could lead to cardiac arrhythmia or death. In data submitted to the FDA, death was observed more
frequently among patients receiving treatment with bedaquiline than among those treated with background regimens only (11.4 versus 2.5 percent);
the most frequent cause of death was tuberculosis.
Cross-resistance between bedaquiline and clofazimine has been observed via mutation in the Rv0678 regulatory gene, resulting in upregulation of
an efflux pump [26,27]. Therefore, it may be prudent to avoid use of one of these drugs for patients who have previously failed a regimen with the
other drug.
Clinical trial data for bedaquiline include the following studies:
● In a retrospective study including 330 South African patients with MDR-TB, substitution of bedaquiline for second-line injectable agents in
patients unable to tolerate the injectable drug was associated with a lower proportion of unfavorable treatment outcomes (death, failure to
achieve sustained culture conversion at 12 months, or loss to follow-up; 36 versus 24 percent) [28].
● Among 440 patients with MDR-TB in two phase II clinical trials, those who received bedaquiline in combination with optimized background
regimens had faster and more frequent conversion to negative sputum culture than patients receiving the background regimens only (77.6
versus 57.6 percent) [29,30].

● Among 160 adults with smear-positive MDR-TB randomized to receive bedaquiline (400 mg once daily for 2 weeks, then 200 mg three times
weekly for 22 weeks) or placebo in addition to a second-line background regimen, the time to sputum culture conversion was shorter for the
bedaquiline group (83 versus 125 days) [31]. The bedaquiline group also had higher rates of sputum conversion at 24 weeks (79 versus 58
percent) and 120 weeks (62 versus 44 percent) but a significantly higher death rate (13 versus 2 percent); the cause was unclear.
● In one cohort including 428 patients with MDR- and XDR-TB treated with bedaquiline-containing regimens, high levels of sputum smear and
culture conversion were observed and bedaquiline was generally well tolerated [32].
● In a prospective trial including 272 patients with XDR (of whom 68 patients were treated with a bedaquiline-containing regimen), rates of
treatment failure at 24 months were lower among patients who received bedaquiline (6 versus 26 percent) [33]. Coadministration of linezolid
with bedaquiline was frequent but required discontinuation due to adverse events in 33 percent of cases.
● In a retrospective study including more than 700 patients in South Africa with MDR- or rifampicin-resistant TB and more than 270 patients with
XDR-TB treated with a bedaquiline-containing regimen, treatment with bedaquiline was associated with a reduction in the risk of all-cause
mortality in each group (hazard ratio 0.35 and 0.26, respectively), compared with standard regimens [34].
● In a retrospective study including 28 patients in South Africa with drug-resistant TB treated with a regimen including both bedaquiline and
delamanid, no additive or synergistic QT prolongation effects were observed [35].
Drug-drug interactions have been observed with bedaquiline and CYP3A4 inducers (eg, rifampin reduced bedaquiline exposure by approximately
50 percent) and CYP3A4 inhibitors (eg, ketoconazole increased bedaquiline exposure by approximately 22 percent) [24].
Linezolid — Linezolid may be used for treatment of MDR- and XDR-TB or in settings of intolerance to other drugs [36]. It should be used with
caution and close monitoring as its use is often limited by adverse effects such as bone marrow suppression, neuropathy, gastrointestinal
symptoms, and/or retinitis [37-43]. (See 'Adverse effects' below.)
Development of linezolid toxicity should prompt dose reduction (eg, from 600 to 300 mg orally once daily). In such cases, a serum drug
concentration should be measured to assure the concentration is within the therapeutic range.
Linezolid should not be administered concomitantly with selective serotonin reuptake inhibitors (SSRIs), tricyclic antidepressants (TCAs), or a diet
high in tyramine-containing foods (such as cheese, red wine, cured meats, soy sauce, and fermented foods), given the risk of serotonin syndrome.
If linezolid therapy is planned and when possible, SSRIs and TCAs should be withdrawn at least two weeks in advance (given the long half-lives of
these agents).
In one report including 41 patients with XDR-TB in South Korea, sputum cultures converted to negative after addition of linezolid in 87 percent of
cases [42]. Significant cumulative toxicity was observed, including peripheral neuropathy at low and high doses of linezolid (60 percent at 300
mg/day and 80 percent at 600 mg/day). These rates are significantly higher than those observed in patients receiving linezolid for other indications.
Clofazimine — In general, the availability of clofazimine is limited to regions where it is used for the treatment of leprosy [44]. In the United States,
use of clofazimine for treatment of drug-resistant TB requires submission of an investigational new drug (IND) application to the US Food and Drug
Administration (FDA).
Adverse effects of clofazimine include photosensitivity, skin discoloration, and gastrointestinal intolerance [45].
Cross-resistance between clofazimine and bedaquiline has been observed via mutation in the Rv0678 regulatory gene, resulting in upregulation of
an efflux pump [26,27]. Therefore, it may be prudent to avoid use of one of these drugs for patients who have failed a regimen with the other drug.
One study including 105 Chinese patients noted that the use of clofazimine for treatment of MDR-TB was associated with earlier cavity closure,
accelerated sputum culture conversion, and improved treatment success rates than control regimens without clofazimine (73 versus 53 percent,
respectively) [45].
Cycloserine — Cycloserine should be administered via dose escalation over a two-week period as summarized in the table (table 3). In addition,
serum drug concentrations should be monitored for all patients on cycloserine [2]. (See 'Serum drug concentration monitoring' below.)
Cycloserine should be used with caution for treatment of drug-resistant TB in patients with pre-existing mental health issues, since it may be
associated with significant neuropsychiatric adverse reactions. Cycloserine should be avoided in patients with a history of seizure disorder when
possible. (See 'Central nervous system toxicity' below.)
Delamanid — Delamanid is an oral nitro-dihydro-imidazo-oxazole drug that inhibits mycolic acid synthesis [46,47]. It has been conditionally
approved for use in the treatment of MDR-TB by the European Medicines Agency but has not yet received FDA approval for use in the United
States [48].
The WHO has advised that delamanid may be added to a TB treatment regimen in adults with pulmonary MDR-TB in circumstances when an
effective and reasonably well-tolerated regimen cannot be composed with conventional second-line drugs. Patients for whom delamanid may be
particularly useful include those with increased risk for poor outcomes (such as drug intolerance or contraindication, extensive or advanced disease,
resistance to fluoroquinolones and/or aminoglycosides/capreomycin, and XDR-TB) [49].

Carbapenems plus clavulanate — The combination of carbapenems (either imipenem or meropenem) with clavulanate (a beta-lactamase
inhibitor) has been shown to be bactericidal against M. tuberculosis, and some clinical efficacy has been observed in a small number of patients
[50,51]. M. tuberculosis is resistant to beta-lactam antibiotics in vitro, but resistance may be overcome in some isolates by inhibiting the beta-
lactamase with clavulanate [52]. Since clavulanate is not available as a single formulation, coadministration of amoxicillin-clavulanate is required.
The duration of carbapenem therapy is restricted to the intensive (initial two months) phase of therapy; use of carbapenems is limited by high cost,
intravenous administration, and limited clinical experience.
Ethionamide — Ethionamide may be used for treatment of drug-resistant TB if the isolate is known to be susceptible to ethionamide via
conventional in vitro testing or if molecular testing demonstrates no evidence of mutations in the inhA gene, since mutations in this gene can confer
resistance to ethionamide (in addition to isoniazid resistance) [2]. In the setting of known isoniazid resistance and in the absence of confirmed
ethionamide susceptibility, use of ethionamide should be deferred.
Ethionamide should be administered via dose escalation over a two-week period as summarized in the table (table 3).
The combination of ethionamide and para-aminosalicylic acid is likely to cause hypothyroidism as well as gastrointestinal side effects. Patients may
tolerate one of these two drugs but may not tolerate both together. (See 'Adverse effects' below.)
Para-aminosalicylic acid — Para-aminosalicylic acid is bacteriostatic; it has limited efficacy for treatment of TB and is poorly tolerated (due to
gastrointestinal and endocrine side effects [including hypothyroidism], particularly when administered in combination with ethionamide). An enteric-
coated formulation may be associated with fewer gastrointestinal side effects but is not available in the United States; therefore, para-aminosalicylic
acid granules should be mixed with food [2]. (See 'Adverse effects' below.)
Para-aminosalicylic acid should be administered via dose escalation over a two-week period as summarized in the table (table 3).
The combination of para-aminosalicylic acid and ethionamide is likely to cause hypothyroidism as well as gastrointestinal side effects. Patients may
tolerate one of these two drugs but may not tolerate both together. (See 'Adverse effects' below.)
Thioacetazone — Thioacetazone has bacteriostatic activity against TB. Toxicity is high, and its use should be restricted to cases with broad
resistance, and with close follow-up. Thioacetazone should not be administered to patients with HIV infection, who are at increased risk for drug-
induced Stevens-Johnson syndrome [53]. Thioacetazone is not available in the United States.
Injectable-only agents — Second-line injectable-only agents for treatment of tuberculosis include aminoglycosides (amikacin, kanamycin,
streptomycin) and capreomycin (a polypeptide). Kanamycin is no longer available in the United States. There is no role for use of more than one of
these injectable agents in a treatment regimen given their common mechanism of action (eg, protein synthesis inhibition) [10,17,18].
The choice of these injectable agents depends on a patient's previous injectable agent use (if any), risk of adverse events, and in vitro susceptibility
data. In general, amikacin is the preferred agent (due to general availability of the drug and serum concentration monitoring). Capreomycin should
be reserved for situations in which there is demonstrated resistance to amikacin and for patients with XDR-TB. In addition, it may be associated with
less ototoxicity than amikacin [54]. Use of streptomycin should be avoided given widespread resistance. Use of streptomycin is generally restricted
to the setting of known in vitro susceptibility, no history of prior use, and contraindication to amikacin.
Cross-resistance among the injectable-only agents has been observed and may be helpful in predicting use of alternate agents in the setting of
prior injectable exposure (pending definitive susceptibility data) [55-60]. Cross-resistance between amikacin and capreomycin is incomplete, while
streptomycin-resistant isolates are often susceptible to other aminoglycosides or capreomycin (unless they have been used previously).
Aminoglycosides and capreomycin can be given either intramuscularly or intravenously. For patients who cannot tolerate repeated intramuscular
injections, intravenous therapy may be administered. They are typically given five days per week; they should be administered seven days per week
for patients who are severely ill. The initial duration of daily therapy (referred to as the "intensive phase" of treatment) is administered until culture
conversion is documented (at least two to three months and can be up to six months). After culture conversion, three-days-per-week dosing can be
used for the remaining duration (referred to as the "continuation phase" of treatment [normally through at least 6 months and up to 18 months
beyond culture conversion]).
Serum drug concentration monitoring is warranted for all aminoglycosides and capreomycin given their potential for nephrotoxicity and consequent
electrolyte disorders [61]. In addition, the aminoglycosides can cause eighth cranial nerve damage. Renal function should be assessed regularly,
and audiometry performed on a monthly basis. (See 'Serum drug concentration monitoring' below and "Pathogenesis and prevention of
aminoglycoside nephrotoxicity and ototoxicity".)
OTHER AGENTS
Pretomanid (PA-824), a nitroimidazole, has bactericidal activity and is under clinical investigation [62-64]. It is not yet approved for treatment of
tuberculosis.
CLINICAL AND LABORATORY MONITORING FOR ADVERSE EFFECTS

Treatment of patients with tuberculosis requires careful monitoring for adverse drug effects. This is especially important when second-line agents
are used and/or when drug doses are escalated.
Patients receiving combination antituberculous therapy should undergo baseline measurement of liver function tests (serum bilirubin, alkaline
phosphatase, and transaminases). In addition, testing for hepatitis B and C should be pursued for patients with epidemiologic risk factors [65].
Counseling and testing for human immunodeficiency virus (HIV) infection should also be performed.
Other baseline tests prior to initiation of antituberculous therapy should include complete blood count, creatinine, and uric acid [4].
Patients on regimens including drugs associated with hepatotoxicity (notably isoniazid, rifampin, pyrazinamide, moxifloxacin, ethionamide, and
para-aminosalicylic acid) should be counseled to avoid use of alcohol and drugs associated with hepatotoxicity (such as acetaminophen). Patients
should be educated about the signs and symptoms of hepatic toxicity; these include anorexia, nausea, vomiting, dark urine, icterus, rash, pruritus,
fatigue, fever, abdominal discomfort (particularly right upper quadrant discomfort), easy bruising or bleeding, and arthralgias [66]. Patients should be
questioned directly at monthly visits for these symptoms and should know to immediately report any signs or symptoms that occur in the interval
between the monthly visits. Patients should also be assessed for symptoms of peripheral neuropathy. All symptomatic patients should be evaluated
clinically and have liver function tests performed.
Serial liver function measurements are not necessary for patients with normal baseline results and no risk for hepatitis. Monthly liver function tests
are warranted in the following settings:
● Abnormal baseline liver function tests

● Suspected drug reaction
● Underlying liver disease (such as viral hepatitis)
● Pregnancy and the first three months postpartum
● Use of pyrazinamide in continuation phase
● Other situations that may be associated with hepatic injury (eg, some medications, alcohol or drug abuse)
Issues related to hepatoxicity associated with antituberculous drugs are discussed below and separately. (See 'Hepatotoxicity' below and
"Treatment of drug-susceptible pulmonary tuberculosis in HIV-uninfected adults", section on 'Hepatotoxicity'.)
Additional clinical and laboratory monitoring should be tailored to the treatment regimen. Examples include:
● Ethambutol or clofazimine – Monitor visual acuity and red-green color discrimination (monthly).
● Aminoglycosides or capreomycin – Monitor renal function, electrolytes (potassium, calcium, magnesium), and signs of ototoxicity monthly
(including audiology testing and evaluation for tinnitus and vestibular toxicity).
● Ethionamide or para-aminosalicylate – Monitor thyroid stimulating hormone (every three months).
● Cycloserine – Monitor for psychiatric symptoms, particularly depression and mood changes (monthly).
● Linezolid – Monitor blood counts (weekly during initial phase, then monthly) and for signs and symptoms of peripheral neuropathy and retinitis.
● Bedaquiline and fluoroquinolones (particularly moxifloxacin) – Monitor electrocardiogram (at least 2, 12, and 24 weeks following initiation of
treatment) for evidence of QTc prolongation.
SERUM DRUG CONCENTRATION MONITORING
Monitoring of serum concentrations for antituberculous therapy is warranted for select patients as summarized below (in settings where serum drug
concentrations can be obtained). Such monitoring does not assure clinical success but does provide guidance for dose adjustments to optimize
drug efficacy and safety.
Antituberculous serum drug concentration monitoring should be pursued in the following circumstances:
● Drug-resistant tuberculosis
● Lack of clinical response or relapse while on appropriate drugs administered via directly observed therapy
● Known or suspected drug malabsorption (eg, underlying diabetes mellitus with gastroparesis, alcohol use, select gastrointestinal disorders)
● Regimen with potentially significant drug-drug interactions, such as combination of rifamycins and select antiretrovirals (most notably protease
inhibitors)
● Moderate to severe renal impairment (including those receiving renal replacement therapy) for agents with significant renal clearance
● Human immunodeficiency virus (HIV) coinfection (especially those receiving antiretrovirals known to interact with antituberculous therapy)
● Use of aminoglycosides, capreomycin, or cycloserine

● Antituberculous regimen with few effective drugs (to optimize the effect of the available drugs)
● Use of antituberculous doses lower than standard therapy because of drug intolerance
Serum drug concentration monitoring should be performed following initiation of treatment or regimen adjustments, after steady-state
concentrations have been achieved. The target peak concentrations, intervals between drug administration, and serum collection times for
therapeutic monitoring of antituberculous drugs are summarized in the table (table 5) [67].
ADVERSE EFFECTS
Antituberculous drugs are associated with a broad array of adverse effects, as discussed by system in the following sections. Some adverse effects
may be managed symptomatically with continuation of the drug, some may be managed with dose adjustment and careful monitoring, and some
require drug discontinuation with broad reconsideration of the treatment regimen. Patients should be counseled regarding frequent and/or severe
adverse effects and ways to minimize such reactions. Timing of administration (relative to food or bedtime) may help to minimize some adverse
effects. Expert consultation should be sought in complex situations.
Gastrointestinal effects — A number of antituberculous agents may be associated with gastrointestinal (GI) symptoms. These include (but are not
limited to) ethionamide, para-aminosalicylic acid, linezolid, levofloxacin, moxifloxacin, clofazimine, and bedaquiline.
Patients with gastrointestinal complaints should be evaluated clinically and a differential diagnosis should be considered based on signs and
symptoms. Such diagnoses may include (but are not limited to) gastritis, hepatotoxicity, pancreatitis, peptic ulcer disease, acute kidney injury,
Clostridioides (formerly Clostridium) difficile colitis, and pregnancy.
Strategies for management of GI symptoms attributed to antituberculous drugs include judicious symptomatic management (ie, use of antiemetics,
antidiarrheals, treatment of reflux [note that antacids cannot be given within two hours of fluoroquinolones]), minimizing other GI irritants (such as
nonsteroidal anti-inflammatory agents), spacing medications during the day, administering the causative agent at bedtime, administering medication
following a light snack, and encouraging hydration.
It may be possible to make drug dose adjustments, as follows:
● Ethionamide and para-aminosalicylic acid – Ethionamide tends to cause more upper GI symptoms such as nausea and vomiting, and para-
aminosalicylic acid more lower GI symptoms such as abdominal cramping and diarrhea, though there is often overlap. Patients may tolerate
one of these two drugs but may not tolerate both together.
If either ethionamide or para-aminosalicylic acid is suspected of causing GI symptoms, both drugs may be held for three to four days; if the
symptoms improve off the medication, they may be restarted (one drug at a time) at a lower dose (often in two or three daily administrations),
and gradually increased over the next two weeks. Ethionamide may be initiated at 250 mg daily and increased to at least 500 mg daily. Para-
aminosalicylic acid may be initiated at 2 to 4 grams daily and increased to 6 to 8 grams daily. Patients may tolerate a higher dose of
ethionamide in the evening (such as 250 mg in the morning and 500 mg at bedtime). Once the titration is complete, steady-state serum drug
concentrations should be monitored to determine whether the concentration is therapeutic.
● Linezolid – If linezolid is suspected of causing GI symptoms, the dose may be reduced from 600 mg to 300 mg orally once daily. In such cases,
a serum concentration should be measured to document whether the concentration is therapeutic.
● Clofazimine – If clofazimine is suspected of causing nausea/vomiting, the dose may be reduced to 100 mg orally once daily.
Drug doses for fluoroquinolones should not be reduced; fluoroquinolones are a critical class in the treatment regimen of drug-resistant TB, and the
bactericidal effects are dose dependent. In addition, antacids containing magnesium, aluminum, or calcium may reduce fluoroquinolone absorption
and should be avoided within two to four hours of the fluoroquinolone dose.
Drug doses for bedaquiline should not be adjusted pending further data regarding this agent.
Hepatotoxicity — Gastrointestinal complaints may represent antituberculous hepatotoxicity. Antituberculous drugs associated with
hepatotoxicity include isoniazid, rifampin, pyrazinamide, moxifloxacin, and para-aminosalicylic acid. Antituberculous drugs not commonly associated
with hepatotoxicity include ethambutol, aminoglycosides, cycloserine, and levofloxacin.
Patients on regimens including drugs associated with hepatotoxicity should be counseled to avoid use of alcohol and drugs associated with
hepatotoxicity (such as acetaminophen). Risk factors for drug-induced liver injury include underlying liver disease (particularly hepatitis C) and
coadministration of antiretroviral therapy for patients with human immunodeficiency virus (HIV) infection.
The approach to management of hepatotoxicity associated with antituberculous drugs should be guided by liver function test results and the
agent(s) most suspected of causing such results (algorithm 1). In general, all hepatotoxic drugs should be discontinued if the serum bilirubin is ≥3
mg/dL (≥51 mcmol/L) or serum transaminases are more than five times the upper limit of normal.
Once liver function tests return to baseline (or fall to less than twice normal), potentially hepatotoxic drugs can be restarted one at a time with
careful monitoring between resumption of each agent. (See "Treatment of drug-susceptible pulmonary tuberculosis in HIV-uninfected adults",

section on 'Hepatotoxicity'.)
Dermatologic effects — Dermatologic reactions secondary to antituberculous therapy may range from mild local effects (not requiring treatment or
modification of therapy) to a manifestation of a severe, life-threatening reaction. Antituberculous drugs should be discontinued in the setting of
systemic symptoms, fever, mucous membrane involvement, blistering, edema of the lips or eyes, wheezing, or airway compromise.
Dermatologic reactions associated with antituberculous drugs include (see "Drug eruptions"):
● Maculopapular rash and pruritus – All antituberculous drugs may cause a maculopapular rash and/or pruritus, some of which resolve after
several weeks despite treatment continuation. Other sources of such symptoms should be explored. Mild reactions may be managed
symptomatically (with antihistamines or topical corticosteroids) with continuation of the drugs. (See "Approach to the patient with macular skin
lesions".)
● Hives (urticaria) – Hives (urticaria) may be caused by any antituberculous drug. With antituberculosis drugs, hives can occur with or without
fever. The drug that most commonly causes this type of reaction is isoniazid, followed by rifampin, pyrazinamide, ethionamide, cycloserine,
ethambutol, para-aminosalicylic acid, and streptomycin. Fluoroquinolones and bedaquiline have also been implicated, but the frequency
compared with the other drugs is not reported. In children, this presentation may occur during a coincident viral infection (eg, Epstein-Barr or
herpes simplex), and the child should be examined for other signs of viral infection and a complete blood count obtained for possible
lymphocytosis. All potentially responsible drugs should be stopped until the reaction resolves, although, if a child is found to have evidence of
viral infection, all medications can be resumed.
In all adults and in children without evidence of a viral infection, rechallenge is recommended for the purpose of identifying the drug responsible
for the reaction and resuming the other medications. Rechallenge is appropriate only if the reaction was not severe and there was no evidence
of anaphylaxis (ie, concomitant angioedema, hoarse voice, throat tightness, sudden-onset cough, wheezing, mental status change, nausea or
vomiting, lightheadedness, or hypotension) (table 6). Rechallenge is also contraindicated if the patient's reaction had features of Stevens-
Johnson syndrome, toxic epidermal necrolysis, or systemic hypersensitivity syndromes such as drug reaction with eosinophilia and systemic
symptoms (DRESS), as detailed below. (See 'Severe systemic reactions' below.)
Rechallenge should be performed with one medication at a time, at approximately four-day intervals. A protocol used in the Philadelphia
Tuberculosis Control Program is provided (table 7) [2].
● Flushing – Flushing (in the absence of rash, with or without redness and watering of the eyes) within two to three hours of drug administration
is most often associated with rifampin and pyrazinamide. The reaction is usually mild and self-limited; if bothersome, it may be managed with
an antihistamine. Flushing with or without hot flashes, palpitations, or headache two to three hours after consuming tyramine-containing foods
(such as cheese, red wine, cured meats, soy sauce, and fermented foods) may be observed in patients taking isoniazid. This can generally be
managed with avoidance of the precipitating foods.
● Photosensitivity and hyperpigmentation – Patients on pyrazinamide, clofazimine, or fluoroquinolones are at increased risk for
photosensitivity, which may persist for prolonged periods even after the causative drug is stopped. Patients receiving these agents should limit
sun exposure and use sunscreen. Rifabutin has been associated with pseudojaundice (brownish discoloration of the skin with clear sclera and
normal liver enzymes). Clofazimine-induced hyperpigmentation may also worsen with sun exposure but is usually reversible upon drug
discontinuation.
● Lichenoid reactions – Several antituberculous drugs (most notably ethambutol, isoniazid, streptomycin, and cycloserine) can cause lichenoid
reactions (pruritic, violaceous papules most commonly involve the wrists, shins, and back). Mucous membranes and scalp may also be
involved. Lesions may resolve while medication continues, and medication should not be discontinued unless an equally effective drug is
available for substitution. (See "Lichenoid drug eruption (drug-induced lichen planus)".)
● Superficial fungal infection – Cutaneous or mucocutaneous candidiasis secondary to fluoroquinolones and linezolid occurs more commonly
in diabetics and generally responds to topical antifungal therapy.
● Alopecia – Temporary alopecia has been reported in patients receiving isoniazid or ethionamide.
Antituberculous drugs should be discontinued in the setting of systemic symptoms, fever, mucous membrane involvement, blistering, edema of the
lips or eyes, wheezing, or airway compromise.
Severe systemic reactions — Severe systemic reactions associated with antituberculous drugs include:
● Anaphylaxis – Anaphylaxis is rare and presents within minutes of medication dosing as urticaria, angioedema, pruritus, hypotension, and
respiratory symptoms (table 6). (See "Anaphylaxis: Acute diagnosis".)
Drugs suspected to have caused anaphylaxis should be discontinued. Rechallenge should not be attempted. The patient should be referred to
an allergy specialist for possible desensitization utilizing facilities equipped to respond to the potential for life-threatening anaphylaxis. Skin
testing for immunoglobulin (Ig)E using the primary drug is almost never useful because the hepatic metabolism of these medications produces
neo-antigens that are not present in the original drug. Oral desensitization protocols have been published for isoniazid, rifampin, and

ethambutol [68,69] and can be devised for almost any drug. Issues related to drug desensitization are discussed further separately. (See
"Rapid drug desensitization for immediate hypersensitivity reactions".)
● Drug reaction with eosinophilia and systemic symptoms – DRESS is a rare but potentially life-threatening syndrome secondary to the
administration of antituberculous medications (most commonly rifampin, isoniazid, and ethambutol). Signs and symptoms (usually beginning
two to eight weeks after drug initiation) can include fever, malaise, lymphadenopathy, rash, facial edema, mucous membrane involvement, and
liver function abnormalities. Once a drug has been identified as the causative agent, it should be discontinued. Rechallenge should not be
attempted. Issues related to DRESS are discussed further separately. (See "Drug reaction with eosinophilia and systemic symptoms
(DRESS)".)
● Stevens-Johnson syndrome and toxic epidermal necrolysis – These are severe mucocutaneous reactions characterized by drug-induced
extensive necrosis and detachment of the epidermis. Once a drug has been identified as the causative agent, it should be discontinued.
Rechallenge should not be attempted. These entities are discussed separately. (See "Stevens-Johnson syndrome and toxic epidermal
necrolysis: Pathogenesis, clinical manifestations, and diagnosis" and "Stevens-Johnson syndrome and toxic epidermal necrolysis:
Management, prognosis, and long-term sequelae".)
QT prolongation — Drugs associated with QT interval prolongation include bedaquiline, clofazimine, delamanid, and fluoroquinolones (especially
moxifloxacin). Patients on these drugs should undergo baseline and monthly electrocardiogram as well as baseline electrolyte studies (with repeat
studies if QTc prolongation occurs). Issues related to use of bedaquiline are summarized in the table (table 4).
Neurotoxicity — Forms of neurotoxicity associated with antituberculous drugs include peripheral neuropathy and central nervous system toxicity
(including psychiatric effects, seizures, and serotonin syndrome).
Perioral numbness (transient, nonprogressive) has been reported in patients receiving streptomycin; it may be managed with dose and/or interval
reduction accompanied by serum drug concentration monitoring to assure target concentrations are achieved.
Peripheral neuropathy — Antituberculous drugs most commonly associated with peripheral neuropathy include isoniazid, ethionamide,
cycloserine, and linezolid. Fluoroquinolones and ethambutol have rarely been associated with peripheral neuropathy.
The likelihood of neuropathy is increased in patients with diabetes, alcoholism, HIV infection, hypothyroidism, pregnancy, and poor nutrition (with
inadequate dietary intake of pyridoxine).
If dietary intake of vitamin B6 is insufficient (less than 0.5 to 2 mg daily for children and adults), pyridoxine should be administered to patients on
regimens including isoniazid, ethionamide, cycloserine, or linezolid [70]. Patients on a standard regimen for treatment of drug-susceptible TB should
receive pyridoxine 50 mg daily. Patients on treatment for MDR-TB should receive pyridoxine 100 mg daily.
Neuropathy associated with linezolid usually occurs after four months of therapy. In some patients, symptoms may respond if linezolid doses of 600
mg once daily are reduced (to 300 or 450 mg once daily or 600 mg three to four times weekly) with serum concentration monitoring performed to
assure therapeutic concentrations are achieved.
Symptomatic treatment of peripheral neuropathy with neuroleptics (such as gabapentin, pregabalin, carbamazepine, or low-dose tricyclic
antidepressants) may facilitate the continuation of therapy in some patients.
Central nervous system toxicity — Forms of central nervous system toxicity associated with antituberculous drugs include psychiatric effects,
seizures, and serotonin syndrome.
● Psychiatric effects – Drug-induced depression can occur with cycloserine, ethionamide, and (less frequently) isoniazid or ethambutol. In
patients on cycloserine or ethionamide, depression may be severe and accompanied by suicidal ideation requiring drug discontinuation.
Patients with depression should have a serum drug concentration obtained, and the dose should be reduced if feasible (table 5).
Patients with suicidal ideation who are on isoniazid and/or ethambutol should have these drugs discontinued. Once stable, the drugs may be
restarted (isoniazid 300 mg orally daily; ethambutol 250 mg once daily followed by escalation to 500 mg once daily and 750 mg once daily if the
patient tolerates the dose escalation). Mild depression may be managed with continuation of therapy and supportive care. Antidepressants may
be used, but patients on linezolid may not take selective serotonin reuptake inhibitors (SSRIs) or tricyclic antidepressants (due to the risk of
serotonin syndrome).
Drug-induced psychosis has been reported with the use of cycloserine, fluoroquinolones, and (less frequently) isoniazid. Patients with
psychosis should be treated with pyridoxine (100 mg if not already given) along with antipsychotic therapy. Cycloserine should be discontinued
and a serum drug concentration obtained. Some patients may tolerate cycloserine with an antipsychotic drug if no other treatment options are
available. Cycloserine may be restarted at a lower dose with titration guided by serum drug concentration monitoring.
● Seizures – Drug-induced seizures can occur with cycloserine, fluoroquinolones, linezolid, isoniazid, and carbapenems. These drugs should be
discontinued in patients with seizures. Patients on cycloserine should have a serum drug concentration obtained. (See "Isoniazid (INH)
poisoning", section on 'Seizure management'.)

Patients should be treated with anticonvulsant therapy for the duration of the treatment regimen. Once seizures have resolved, medications
may be restarted one at a time. Patients with suspected isoniazid-induced seizures who resume isoniazid should take concomitant pyridoxine.
Cycloserine should be restarted only if it is absolutely essential.
● Serotonin syndrome – Serotonin syndrome may result from the coadministration of linezolid with a serotonin reuptake inhibitor, a tricyclic
antidepressant, or a diet high in tyramine-containing foods (such as cheese, wine, cured meats, soy sauce, and fermented foods). Signs and
symptoms include clonus, agitation, tremor, and/or hyperthermia. (See "Serotonin syndrome (serotonin toxicity)".)
Ototoxicity — Aminogylcosides and capreomycin can cause vestibular and auditory toxicity, even if serum drug concentrations are within the
therapeutic range. Toxicity is related to the total dose and is cumulative. (See 'Injectable-only agents' above.)
Patients receiving these agents should have monthly assessments for vestibular and auditory toxicity. Symptoms attributed to the injectable agent
(such as tinnitus, unsteadiness, or hearing loss) should prompt elimination of the entire drug class, and rechallenge should not be attempted.
For patients with fullness in the ears (which may be an early symptom of vestibular toxicity), the dosing interval may be reduced from daily to three
times a week (after three to four months of treatment with negative sputum cultures).
Nephrotoxicity — Aminoglycosides and capreomycin can cause nephrotoxicity and electrolyte disturbances. Patients receiving these drugs should
have weekly serum creatinine monitoring for the first several weeks, then at least monthly, in addition to monthly electrolyte monitoring (potassium,
calcium and magnesium) with repletion as needed. The optimal frequency of serum drug concentration monitoring for injectable agents is uncertain;
it is often performed weekly during the initial phase of treatment (while on daily therapy) and any time there are changes in serum creatinine or
following dose adjustments.
Drug dose adjustments should be made for patient with renal dysfunction (table 3).
Hematologic effects — Hematologic abnormalities associated with antituberculous drugs (notably isoniazid, rifampin, and linezolid) may involve
any cell line (table 8). It may be difficult to differentiate abnormalities due to antituberculous therapy from hematologic effects due to tuberculosis or
other underlying diseases.
Hematologic abnormalities in patients receiving treatment for TB may reflect comorbid diseases such as renal insufficiency, nutritional deficiency,
malignancy, HIV infection, or bone marrow suppression due to other drugs. They may also occur as a result of bone marrow involvement
associated with TB.
If other causes are excluded, TB drugs associated with hematologic abnormalities should be discontinued until counts have recovered; thereafter,
the drugs should restarted one at a time with close hematologic monitoring. Drug(s) associated with recurrent hematologic abnormalities should not
be continued.
When hematologic toxicity due to linezolid is mild and resolves off therapy, linezolid may be resumed at a lower dose (eg, 300 mg instead of 600
mg). In such settings, monitoring of serum concentrations is necessary to assure adequate therapeutic concentrations.
Ophthalmic toxicity — Antituberculous drugs associated with optic nerve toxicity include ethambutol, linezolid, ethionamide, and isoniazid.
Clofazimine toxicity produces a pigmentary maculopathy and generalized retinal degeneration. Ophthalmic toxicity associated with these agents
should prompt ophthalmology referral and drug discontinuation. Rifabutin can cause a pan-uveitis that is reversible with holding therapy and
resumption with dose adjustment.
Patients taking ethambutol should be monitored monthly for ophthalmic symptoms, which can be dose and duration related. Monthly visual acuity
and color discrimination evaluation is warranted for patients receiving high-dose ethambutol (≥25 mg/kg) and/or patients receiving the drug for
longer than two months.
Musculoskeletal effects — Myalgias and arthralgias are common in patients taking antituberculous therapy and may be associated with
pyrazinamide, fluoroquinolones, rifabutin, isoniazid, ethionamide, and bedaquiline. These manifestations do not warrant drug discontinuation and
may reflect drug-induced electrolyte disturbances or thyroid dysfunction.
Tendonitis and tendon rupture have been associated with fluoroquinolone use. The drug may be continued in the setting of mild tendon
inflammation but should be discontinued in the setting of significant inflammation.
Endocrine effects — Endocrine effects associated with antituberculous drugs include hypothyroidism, gynecomastia, and dysglycemia.
Hypothyroidism may develop with para-aminosalicylic acid or ethionamide; when used in combination, the incidence of hypothyroidism may be ≥40
percent [2]. Patients on these drugs should have baseline and monthly thyroid function assessment. When thyroid stimulating hormone (TSH) rises
to >1.5 times the upper limit of normal, thyroid hormone replacement should be initiated. (See "Treatment of primary hypothyroidism in adults".)
Gynecomastia can occur in patients on ethionamide; the drug may be continued and gynecomastia resolves when treatment is stopped.
Hypoglycemia has been associated with linezolid. Fluoroquinolones, particularly gatifloxacin (no longer available in the United States for this
reason), can cause hypoglycemia or hyperglycemia.
Other effects — Miscellaneous adverse effects are summarized below.

● Metallic taste – Metallic taste can occur in patients on ethionamide or fluoroquinolones. Patients should be encouraged to tolerate this side
effect, which resolves when treatment is stopped.
● Flu-like syndrome – Rifampin can cause a flu-like syndrome beginning one to two hours after administration and resolving six to eight hours
later. Typically, this syndrome occurs more commonly with intermittent rather than daily therapy, particularly at higher doses. This is discussed
separately. (See "Rifamycins (rifampin, rifabutin, rifapentine)", section on 'Adverse effects'.)
SOCIETY GUIDELINE LINKS
Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society
guideline links: Diagnosis and treatment of tuberculosis".)
SUMMARY
● First-line agents for treatment of tuberculosis (TB) consist of isoniazid, rifampin (or rifapentine or rifabutin in certain situations), pyrazinamide,
and ethambutol. Dosing for first-line agents is summarized in the table (table 2). (See 'First-line agents' above.)
● Presence of drug resistance or intolerance to first-line agents warrants use of second-line agents. These agents are so classified because of
relative lack of clinical data, unfavorable or poorly characterized pharmacokinetic profile, and/or increased incidence and severity of adverse
events. Categories of second-line agents are summarized in the table (table 1). Antituberculous agents should be used in combination for
active infections, guided by in vitro susceptibility results and selected with involvement of an expert in the treatment of tuberculosis. Dosing for
second-line agents is summarized in the table (table 3). (See 'Second-line agents' above.)
● In general, levofloxacin and moxifloxacin are favored over the early-generation fluoroquinolones for treatment of TB. There is no role for use of
more than one fluoroquinolone in a treatment regimen since all drugs in the class share a genetic target. Cross-resistance between
fluoroquinolones is common but not universal. (See 'Quinolones: levofloxacin or moxifloxacin' above.)
● Patients receiving antituberculous therapy should undergo baseline measurement of liver function tests (serum bilirubin, alkaline phosphatase,
and transaminases). Serial liver function measurements are not necessary for patients with normal baseline results and no risk for hepatitis;
monthly liver function tests should be obtained in the clinical settings outlined above. (See 'Clinical and laboratory monitoring for adverse
effects' above.)
● Indications for therapeutic drug monitoring include (but are not limited to) use of injectable-only agents or cycloserine, presence of renal
impairment, and regimens with potentially significant drug-drug interactions (table 5). (See 'Serum drug concentration monitoring' above.)
● Gastrointestinal symptoms may be associated with a number of antituberculous agents, including ethionamide, para-aminosalicylic acid (the
latter two particularly in combination), linezolid, levofloxacin, moxifloxacin, clofazimine, and bedaquiline. Strategies include symptomatic
management; it may be possible to make drug dose adjustments in some cases. (See 'Gastrointestinal effects' above.)
● Management of hepatotoxicity should be guided by liver function test results (algorithm 1). In general, all hepatotoxic drugs should be
discontinued if the serum bilirubin is ≥3 mg/dL (≥51 mcmol/L) or serum transaminases are more than five times the upper limit of normal.
Thereafter, once liver function tests return to baseline (or fall to less than twice normal), potentially hepatotoxic drugs can be restarted one at a
time with careful monitoring between resumption of each agent. (See 'Hepatotoxicity' above.)
● Dermatologic reactions associated with antituberculous drugs include maculopapular rash (any antituberculous drug), flushing (rifampin or
pyrazinamide), photosensitivity (pyrazinamide, clofazimine, or fluoroquinolones), lichenoid reactions (ethambutol, isoniazid, streptomycin, and
cycloserine), and hives (any antituberculous drug). Severe systemic reactions associated with antituberculous drugs include anaphylaxis, drug
reaction with eosinophilia and systemic symptoms, Stevens-Johnson syndrome, and toxic epidermal necrolysis. Antituberculous drugs should
be discontinued in the setting of systemic symptoms, fever, urticaria, mucous membrane involvement, blistering, edema of the lips or eyes,
wheezing, or airway compromise. Referral to an allergist with experience in drug allergy should be considered for more severe reactions. (See
'Dermatologic effects' above and 'Severe systemic reactions' above.)
● Drugs associated with QT interval prolongation include bedaquiline, clofazimine, delamanid, and fluoroquinolones (especially moxifloxacin).
Patients on these drugs should undergo baseline and monthly electrocardiogram as well as baseline electrolyte studies (with repeat studies if
QTc prolongation occurs). (See 'QT prolongation' above.)
● Forms of neurotoxicity associated with antituberculous drugs include peripheral neuropathy (isoniazid, ethionamide, cycloserine, and linezolid)
and central nervous system toxicity (psychiatric effects [depression can occur with cycloserine or ethionamide; psychosis can occur with
cycloserine, fluoroquinolones, or isoniazid], seizures [fluoroquinolones, linezolid, isoniazid, and carbapenems], and serotonin syndrome
[linezolid]). (See 'Neurotoxicity' above.)
● The aminoglycosides and capreomycin can cause vestibular toxicity, auditory toxicity, nephrotoxicity, and electrolyte disturbances. Patients on
these agents should have monthly assessments for vestibular and auditory toxicity, close monitoring of renal function and electrolytes, and
therapeutic drug monitoring. (See 'Ototoxicity' above and 'Nephrotoxicity' above.)
https://www.uptodate.com/contents/antituberculous-drugs-an-overview/print?search=treatment tuberculosis&source=search_result&selectedTitl… 10/21
● Hematologic abnormalities associated with antituberculous drugs may involve any cell line. The most common causes of hematologic
abnormalities among the antituberculous drugs include isoniazid, rifampin, and linezolid; these are summarized in the table (table 8). (See
'Hematologic effects' above.)
● Antituberculous drugs associated with optic nerve toxicity include ethambutol, linezolid, ethionamide, and isoniazid. Clofazimine toxicity
produces a pigmentary maculopathy and generalized retinal degeneration. Rifabutin can cause a pan-uveitis that is reversible with dose
adjustment. (See 'Ophthalmic toxicity' above.)
● Other adverse effects associated with antituberculous drugs include musculoskeletal effects, endocrine effects, and other effects. (See
'Musculoskeletal effects' above and 'Endocrine effects' above and 'Other effects' above.)
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Topic 488 Version 29.0

GRAPHICS
Antituberculous drugs for treatment of drug-resistant tuberculosis: longer, individualized regimen
Group Medicine Abbreviation
Group A: Levofloxacin OR Lfx

Include all three medicines (unless they cannot be used)
Moxifloxacin Mfx
Bedaquiline* ¶ Bdq
Linezolid Δ Lzd
Group B: Clofazimine Cfz

Add one or both medicines (unless they cannot be used)
Cycloserine OR Cs
Terizidone Trd
Group C: Ethambutol E
Add to complete the regimen and when medicines from Groups A and B cannot be used
Delamanid ¶ ◊ Dlm
Pyrazinamide § Z
Imipenem-cilastatin OR Ipm-Cln
Meropenem ¥ Mpm
Amikacin Am
(OR Streptomycin) ‡ (S)
Ethionamide †,** OR Eto
Prothionamide †,** Pto
p-aminosalicylic acid † PAS
This table is intended to guide the design of longer, individualized multidrug-resistant tuberculosis regimens. All 3 Group A agents and at least 1 Group B agent should be
included, to ensure that the intensive phase includes at least 4 drugs likely to be effective and that the continuation phase includes at least 3 effective drugs after bedaquiline
is stopped. If only 1 or 2 Group A agents are used, both Group B agents should be included. If the regimen cannot be composed with agents from Groups A and B alone,
Group C agents are added to complete it. Drugs in Group C are listed in decreasing order of preference, subject to additional considerations.
* Thus far, evidence on the safety and effectiveness of bedaquiline for >6 months and in patients <6 years of age is insufficient; extended use of bedaquiline in individual patients should
follow "off-label" use best practices.
¶ Thus far, evidence on concurrent use of bedaquiline and delamanid is insufficient.
Δ The optimal duration of linezolid use is not established. Use for at least 6 months has been shown to be highly effective, although toxicity may limit its use.
◊ Thus far, evidence on the safety and effectiveness of delamanid for >6 months and in patients <3 years of age is insufficient; extended use of delamanid in individual patients should
follow "off-label" use best practices.
§ Pyrazinamide may be counted as an effective agent only if drug susceptibility test results confirm susceptibility.
¥ Amoxicillin-clavulanic acid should be coadministered with every dose of imipenem-cilastatin or meropenem but is not counted as a separate agent and should not be used as a separate
agent.
‡ Amikacin and streptomycin are only to be considered if drug susceptibility test results confirm susceptibility and high-quality audiology monitoring for hearing loss can be performed.
Streptomycin should be considered only if amikacin cannot be used and if drug susceptibility test results confirm susceptibility (streptomycin resistance is not detectable with second-line
molecular line probe assays; phenotypic drug susceptibility testing is required). Kanamycin and capreomycin are no longer recommended for use in multidrug-resistant
tuberculosis regimens.
† Ethionamide, prothionamide, and p-aminosalicylic acid should be used only when better options to compose a regimen are not feasible.
** Ethionamide and prothionamide are not commercially available in the United States. Clinicians should contact the US Food and Drug Administration's Office of Emergency Operations
(866-300-4374 or 301-796-8240) in order to apply for a single patient investigational new drug. The drug is made available on a case-by-case basis without charge.
Reprinted from Rapid communication: Key changes to treatment of multidrug- and rifampicin-resistant tuberculosis (MDR/RR-TB). World Health Organization 2018, p. 3, copyright ©
2018. Available at: https://www.who.int/tb/publications/2018/WHO_RapidCommunicationMDRTB.pdf?ua=1 (Accessed on September 27, 2018).
Updated with information from:
1. WHO treatment guidelines for multidrug- and rifampicin-resistant tuberculosis, 2018 update. Available at: https://www.who.int/tb/publications/2018/WHO.2018.MDR-
TB.Rx.Guidelines.prefinal.text.pdf (Accessed on January 15, 2019).
Graphic 119120 Version 3.0

Dosing of first-line antituberculosis drugs in adults*
Doses
Drug Preparations
Daily 3x/week 2x/week 1x/week
First-line drugs
Isoniazid ¶ Tablets (50 mg, 100 mg, 5 mg/kg (usual maximum 15 mg/kg (usual maximum 15 mg/kg (usual maximum 15 mg/kg (usual maximum
300 mg); elixir (50 mg/5 dose 300 mg) dose 900 mg) dose 900 mg) dose 900 mg)
mL); aqueous solution (100
mg/mL) for intravenous or
intramuscular injection
Rifampin Capsules (150 mg, 300 10 mg/kg (usual maximum 10 mg/kg (usual maximum 10 mg/kg (usual maximum –
(rifampicin) Δ mg); capsule contents may dose 600 mg) dose 600 mg) dose 600 mg)
be suspended for oral
administration; aqueous
solution for intravenous
injection
Rifabutin Δ Capsule (150 mg) 5 mg/kg (usual maximum Not recommended Not recommended –
dose 300 mg)
Rifapentine Δ Tablet (150 mg, film – – – 10 to 20 mg/kg once

coated) weekly during continuation
phase of treatment ◊
Pyrazinamide Tablet (500 mg, scored) Patient weight 40 to 55 kg §
1000 mg (18.2 to 25 1500 (27.3 to 37.5 mg/kg) 2000 mg (36.4 to 50 –

mg/kg) mg/kg)
Patient weight 56 to 75 kg §
1500 mg (20 to 26.8 2500 (33.3 to 44.6 mg/kg) 3000 mg (40 to 53.6 –
mg/kg) mg/kg)
Patient weight 76 to 90kg §¥
2000 mg ‡ (22.2 to 26.3 3000 mg ‡ (33.3 to 39.5 4000 mg ‡ (44.4 to 52.6 –

mg/kg) mg/kg) mg/kg)
Ethambutol Tablets (100 mg, 400 mg) Patient weight 40 to 55kg §
800 mg (14.5 to 20 1200 mg (21.8 to 30 2000 mg (36.4 to 50 –

1200 mg (16 to 21.4 2000 mg (26.7 to 35.7 2800 mg (37.3 to 50 –

1600 mg ‡ (17.8 to 21.1 2400 mg ‡ (26.7 to 31.6 4000 mg ‡ (44.4 to 52.6 –

Adult dosing listed in this table is used in patients ≥15 years old or weighing >40 kg.
Antituberculous agents are used in multidrug combination regimens of varying duration, which are described in detail in a separate table (refer to the UpToDate table on
regimens for treatment of drug-susceptible tuberculosis) and in the accompanying text.
* Dosing based on actual weight is acceptable in patients who are not obese. For obese patients (>20% above ideal body weight [IBW]), dosing based on IBW may be preferred for initial
doses. Some clinicians prefer a modified IBW (IBW + [0.40 × (actual weight – IBW)]) as is done for initial aminoglycoside doses. Because tuberculosis drug dosing for obese patients has
not been established, therapeutic drug monitoring may be considered for such patients.
¶ Pyridoxine (vitamin B6; 25 to 50 mg/day) is given with isoniazid to individuals at risk for neuropathy (eg, pregnant women, breastfeeding infants, and individuals with HIV infection,
diabetes, alcoholism, malnutrition, chronic renal failure, or advanced age). For patients with peripheral neuropathy, experts recommend increasing pyridoxine dose to 100 mg/day.
Δ Rifabutin dose may need to be adjusted when there is concomitant use of protease inhibitors or nonnucleoside reverse transcriptase inhibitors. Refer to the UpToDate topic on
treatment of pulmonary tuberculosis in HIV-infected adults for specific dose adjustments.
◊ Rarely used in practice; it may be an alternative in the continuation phase of treatment in a once-weekly regimen to facilitate directly observed therapy. For further details, refer to the
UpToDate topic on rifamycins.
§ Based on estimated lean body weight.
¥ Patients >90 kg should have serum concentration monitoring. In obese patients, weight-based dosing is likely best based on measurements of ideal (versus total) body weight.
‡ Maximum dose regardless of weight.
Data adapted from:

1. Nahid P, Dorman SE, Alipanah N, et al. Official American Thoracic Society/Centers for Disease Control and Prevention/Infectious Diseases Society of American clinical practice
guidelines: Treatment of drug-susceptible tuberculosis. Clin Infect Dis 2016. Epub ahead of print.
2. Curry International Tuberculosis Center and California Department of Public Health, 2016: Drug-Resistant Tuberculosis: A Survival Guide for Clinicians, Third Edition.

Dosing of second-line antituberculosis drugs in adults
Main and rare but serious

Drug Adult dose* Pregnancy
adverse effects
Amikacin ¶Δ◊ 15 mg/kg IM or IV once daily (usual Ototoxicity, vestibular toxicity, Avoid
maximum 1 g) adjusted according to nephrotoxicity, electrolyte disturbances,
serum concentrations local pain with IM injection
Amoxicillin-clavulanate 2000 mg amoxicillin/125 mg clavulanate GI toxicity May be used

orally every 8 to 12 hours
Bedaquiline 400 mg orally once daily for 2 weeks, QT prolongation, hepatitis, GI toxicity, May be used
followed by 200 mg 3 times weekly others
(maximum duration studied 24 weeks)
Capreomycin Δ◊ 15 mg/kg IM or IV once daily (usual Ototoxicity, vestibular toxicity, Avoid

serum concentrations local pain with IM injections
Clofazimine (not commercially available in 100 to 200 mg orally once daily Red discoloration of skin, eyes, body Avoid
the United States) § fluids; GI toxicity; photosensitivity; others
Cycloserine ¥‡† 10 to 15 mg/kg orally in 2 divided doses CNS toxicity (psychiatric symptoms, Potential choice when there are no suitable
(usually 250 mg twice daily, maximum 500 seizures usually occur at peak alternatives
mg twice daily) adjusted according to concentrations >35 mcg/mL but may occur
serum concentrations in the normal therapeutic range),
peripheral neuropathy, dermatologic
effects include serious cutaneous
hypersensitivity reactions
Administration of pyridoxine 50 mg (oral
once per day) for every 250 mg of
cycloserine may be useful in preventing or
reducing neurotoxicity
Delamanid 100 mg orally twice daily with food GI toxicity, QT prolongation Avoid
(maximum duration studied 26 weeks)
Ethionamide ¥,‡,** 15 to 20 mg/kg orally (usually 500 to 750 GI toxicity (antiemetic premedication is Potential choice when there are no suitable
mg per day) as a single daily dose or 2 often helpful), hepatic toxicity, metallic alternatives
divided doses (maximum 1 g per day) taste, neurotoxicity including optic neuritis
(administer with pyridoxine 100 mg per
day), endocrine effects including
hypothyroidism (treat with thyroid
replacement)
Imipenem-cilastatin 1000 mg IV every 12 hours; must be GI toxicity, seizures Potential choice when there are no suitable
given with clavulanate 125 mg orally every alternatives
8 to 12 hours (available as amoxicillin-
clavulanate; refer to above)
Isoniazid, high dose ‡ 900 to 1500 mg orally, IM, or IV twice or 3 Hepatitis, peripheral neuropathy May be used
times weekly (administer with pyridoxine),
hypersensitivity, others
Kanamycin ¶Δ◊ 15 mg/kg IM or IV once daily (usual Ototoxicity, vestibular toxicity, Avoid
maximum 1 g) adjusted according to nephrotoxicity, electrolyte disturbances
serum concentrations
Levofloxacin 750 to 1000 mg orally or IV once daily ¶¶ GI toxicity, CNS effects, rash, dysglycemia, Potential choice when there are no suitable
tendonitis, tendon rupture, QT alternatives
prolongation
Linezolid ‡ 600 mg orally or IV once daily Myelosuppression, GI toxicity, neuropathy Avoid (limited data)
(optic and peripheral); pyridoxine 50 to
100 mg per day may be useful in
preventing or reducing peripheral
neuropathy
Meropenem 2000 mg IV every 8 to 12 hours (based on GI toxicity, seizures Potential choice when there are no suitable
published study); 1000 mg every 12 hours alternatives
may be sufficient (based on
pharmacokinetic data); must be given with
clavulanate 125 mg orally every 8 to 12
hours (available as amoxicillin-clavulanate;
refer to above)
Moxifloxacin 400 mg orally or IV once daily (doses up GI toxicity, CNS effects, rash, dysglycemia, Potential choice when there are no suitable
to 800 mg once daily have been used) tendonitis, tendon rupture, QT alternatives
prolongation, hepatotoxicity
Para-aminosalicylic acid ¥ 8 to 12 g orally in 2 or 3 divided doses GI toxicity, hepatotoxicity, hypothyroidism Potential choice when there are no suitable
(treat with thyroid replacement) alternatives
Streptomycin Δ◊ 15 mg/kg IM or IV once daily (usual Ototoxicity, vestibular toxicity, Avoid

serum concentrations local pain with IM injections
Thioacetazone (not available in the United 150 mg once daily GI toxicity, myelosuppression, hepatitis, Potential choice when there are no suitable
States) ΔΔ peripheral neuropathy, serious cutaneous alternatives
hypersensitivity reactions
Antituberculous agents are used in multidrug combination regimens of varying duration, which are described in detail in a separate table (refer to the UpToDate table on
regimens for treatment of drug-susceptible tuberculosis) and in the accompanying text.
IM: intramuscular; IV: intravenous; GI: gastrointestinal; CNS: central nervous system.
* Dose may need to be adjusted for renal impairment. Dosing of oral medications for treatment of multidrug-resistant tuberculosis (MDR-TB) or extensively drug-resistant tuberculosis
(XDR-TB) should be daily, not intermittent.
¶ For patients who are overweight or obese, dose is based on ideal body weight or dosing weight (a calculator is available in UpToDate). Adjust dose based on serum concentration
monitoring for target trough <1 mcg/mL and target peak of 56 to 64 mcg/mL for once-daily administration.
Δ Injectable agents (ie, aminoglycosides and capreomycin) are typically given 5 days per week; injectable agents should be administered 7 days per week for patients who are severely
ill. The initial duration of therapy is at least 2 to 3 months (and until culture conversion is documented). After documentation of culture conversion, 3-days-per-week dosing can be used
for the remaining duration of injectable use (normally through at least 6 months beyond culture conversion).
◊ For patients over 59 years of age, some favor administering a lower dose (10 mg/kg), with standard target drug levels.
§ Clofazimine is not commercially available in the United States; its use requires application to the US Food and Drug Administration, Division of Anti-infective Products (telephone 301-

796-1400).
¥ Administration of cycloserine, para-aminosalicylic acid, and ethionamide should be via dose escalation (drug ramping) over a 2-week period. The initial dose of cycloserine should
be 250 mg orally once daily for 3 to 4 days, followed by 250 mg orally twice daily for 3 to 4 days, followed by 250 mg orally in the morning and 500 mg orally in the evening; the goal
peak serum cycloserine level is <35 mcg/mL. The initial dose of para-aminosalicylic acid is 2 g orally twice daily for 3 to 4 days, followed by 2 g orally in the morning and 4 g orally in the
evening for 3 to 4 days, followed by 4 g orally twice daily. The initial dose of ethionamide is 250 mg orally daily for 3 to 4 days, followed by 250 mg orally twice daily for 3 to 4 days,
followed by 250 mg orally in the morning and 500 mg orally in the evening.
‡ Patients on regimens including high-dose isoniazid, ethionamide, cycloserine, or linezolid should receive oral pyridoxine (100 mg daily) for prevention of neurotoxicity.
† Clinicians experienced with using cycloserine suggest starting with 250 mg once daily and gradually increasing as tolerated. Serum concentrations often are useful in determining the
appropriate dose for a given patient. Few patients tolerate 500 mg twice daily.
** Ethionamide can be given at bedtime or with a main meal in an attempt to reduce nausea. Clinicians experienced with using ethionamide suggest starting with 250 mg once daily and
gradually increasing as tolerated. Serum concentrations may be useful in determining the appropriate dose for a given patient. Few patients tolerate 500 mg twice daily.
¶¶ Greater efficacy has been observed with administration of 1000 mg (compared with 500 mg) for treatment of MDR-TB. For treatment of contacts to MDR-TB: 500 mg/day if ≤45.5 kg
and 750 mg/day if >45.5 kg.
ΔΔ Thioacetazone should not be administered to HIV-infected patients.
References:
2. Nahid P, Dorman SE, Alipanah N, et al. Official American Thoracic Society/Centers for Disease Control and Prevention/Infectious Diseases Society of America Clinical Practice
Guidelines: Treatment of Drug-Susceptible Tuberculosis. Clin Infect Dis 2016; 63:e147.
3. Treatment Guidelines from The Medical Letter, April 2012; Vol. 10 (116):29. www.medicalletter.org.
4. Centers for Disease Control and Prevention. Treatment of Tuberculosis. American Thoracic Society, CDC, and Infectious Diseases Society of America. MMWR Recomm Rep 2003;
52:3.

Use of bedaquiline in adults
Treatment of multidrug-resistant tuberculosis (MDR-TB) should be provided in consultation with an expert in the management of MDR-TB. Bedaquiline should be used only for
patients who have no other treatment options.
Dosing consists of 400 mg orally once daily for two weeks, followed by 200 mg orally three times weekly taken with food (to maximize absorption) for a total treatment duration of
24 weeks. Patients should be advised to avoid drinking alcohol.
If a dose is missed during the first two weeks of treatment, patients should not make up the missed dose but continue the usual dosing schedule. If a dose is missed from the third
week onward, patients should take the missed dose as soon as possible and then resume the established regimen.
The use of bedaquiline with rifamycins or other drugs that induce or suppress CYP3A4 should be avoided if possible. A separate table of CYP3A4 inhibitors/inducers is available. If
bedaquiline is administered with these drugs, monitoring of serum drug levels should be performed; the United States Centers for Disease Control and Prevention (CDC) may be
contacted for assistance.
Bedaquiline has a very long terminal half-life (four to five months); providers should consider discontinuation of bedaquiline four to five months before scheduled discontinuation of
other drugs to avoid an extended period of exposure to low levels of bedaquiline as a single drug.
Bedaquiline should be administered only by directly observed therapy (DOT) as part of a case management strategy. Patients should be monitored weekly for nausea, headache,
hemoptysis, chest pain, arthralgia, and rash.
Bedaquiline should be avoided in patients with severe hepatic impairment (Child-Pugh C) but may be administered to patients with mild to moderate impairment (Child-Pugh A or
B). Serum aminotransferases should be monitored at baseline, monthly, and if symptomatic. An increase to more than three times the upper limit of normal should be managed as
discussed separately.* More frequent aminotransferase monitoring should be considered in patients receiving other hepatotoxic drugs or in those with underlying liver disease.
Bedaquiline should be administered with caution in patients with severe renal impairment requiring dialysis. Dose adjustment is not required in patients with mild to moderate renal
impairment.
An electrocardiogram (ECG) should be obtained at baseline and repeated at least 2, 12, and 24 weeks after starting treatment, as well as in the setting of syncope. Serum
potassium, calcium, and magnesium should be obtained at baseline and monitored until fully corrected. Weekly ECGs are warranted in patients with persistent low electrolyte
concentrations, patients taking other QTc prolonging drugs ¶, and patients with history of torsade de pointes, congenital long QT syndrome, hypothyroidism and bradyarrhythmia, or
uncompensated heart failure.
Discontinuation of bedaquiline is warranted in the setting of clinically significant ventricular arrhythmia or QTc F >500 ms.
A registry for individuals treated with bedaquiline in the United States is being established by the manufacturer through its United States distributor to track its use and patient
outcomes. Serious adverse events that may be attributed to bedaquiline should be reported to the US Food and Drug Administration (FDA) Medwatch
(http://www.fda.gov/Safety/MedWatch or 1-800-332-1088) and the CDC (1-770-488-7100).
* Refer to the UpToDate topic review on the treatment of pulmonary tuberculosis in HIV-negative patients.
¶ QTc prolonging drugs include fluoroquinolones, macrolides, and clofazimine. For additional information, refer to the UpToDate topic review on acquired long QT syndrome.
Division of Tuberculosis Elimination, National Center for HIV/AIDS, Viral Hepatitis, STD, and TB Prevention, CDC. Provisional CDC Guidelines for the Use and Safety Monitoring of
Bedaquiline Fumarate (Sirturo) for the Treatment of Multidrug-Resistant Tuberculosis. MMWR Recomm Rep 2013; 62:1. (Available at: http://www.cdc.gov/mmwr/pdf/rr/rr6209.pdf).

Therapeutic serum concentration monitoring of antituberculous drugs in adults
Time for additional sampling

Time from administration to peak to assess for delayed absorption or
Drug name Target peak concentration
concentration malabsorption of orally
administered drug ¶
Amikacin Intramuscular: 2 and 6 hours Target for calculated peak concentration:* Not applicable
Intravenous: 2 and 6 hours after completion of a 35 to 45 mcg/mL (for 15 mg/kg once daily dose)
30 to 60 minute infusion* 65 to 80 mcg/mL (for 25 mg/kg twice weekly
dose)
Capreomycin Intramuscular: 2 and 6 hours Target for calculated peak concentration:* Not applicable
Intravenous: 2 and 6 hours after completion of a 35 to 45 mcg/mL (for 15 mg/kg daily dose)
dose)
Clarithromycin Oral: 2 to 3 hours 2 to 7 mcg/mL (for 500 mg twice daily dose) 6 to 7 hours
Clofazimine Oral: 2 to 3 hours (fasting), 4 to 8 hours (when 0.5 to 2 mcg/mL 6 to 7 hours (fasting only)
given with food)
Cycloserine Oral: 2 hours 20 to 35 mcg/mL Δ 6 hours
Ethambutol Oral: 2 to 3 hours 2 to 6 mcg/mL (for 15 to 25 mg/kg daily dose) 6 to 7 hours

4 to 12 mcg/mL (for 50 mg/kg thrice or twice Delayed or erratic absorption occurs frequently
weekly dose)
Ethionamide Oral: 2 hours 1 to 5 mcg/mL 6 hours

Delayed or erratic absorption occurs frequently
Isoniazid Oral: 2 hours (fasting); some also check 6-hour 3 to 5 mcg/mL (for 5 mg/kg up to 300 mg daily 6 hours
levels dose)
9 to 15 mcg/mL (for 15 to 25 mg/kg twice
weekly dose)
Kanamycin Intramuscular: 2 and 6 hours Target for calculated peak concentration:* Not applicable
dose)
Levofloxacin Oral: 2 hours 8 to 12 mcg/mL 6 hours
Linezolid Oral: 2 hours 12 to 24 mcg/mL Not generally performed

Intravenous: 30 minutes after completion of
infusion
Moxifloxacin Oral: 2 hours ¶ 3 to 5 mcg/mL 6 hours
Para-aminosalicylic Oral: 6 hours (enteric-coated sustained release 20 to 60 mcg/mL Not applicable

acid PASER formulation)
Pyrazinamide ◊ Oral: 2 hours 20 to 40 mcg/mL (for 25 mg/kg daily dose) 6 hours

60 to 80 mcg/mL (for 50 mg/kg thrice or twice
weekly dose)
Rifabutin § Oral: 3 hours 0.45 to 0.9 mcg/mL 7 hours
Rifampin (rifampicin) Oral: 2 hours 8 to 24 mcg/mL 6 hours

We routinely perform 6-hour levels in all patients
receiving rifampin to assess for delayed
absorption or malabsorption ¶
Streptomycin Intramuscular: 2 and 6 hours Target for calculated peak concentration:* Not applicable
dose)
Therapeutic drug monitoring (TDM) is warranted for the injectable antituberculous agents (amikacin, streptomycin, kanamycin, and capreomycin), especially in patients with
renal impairment, and for oral antituberculous agents when needed to assess for delayed or malabsorption. For specific recommendations on other clinical situations in which
drug concentration monitoring should be pursued, refer to the accompanying UpToDate text. Serum concentration monitoring should be performed after the patient has
received therapy for three to five half-lives of the drug, typically after two or three maintenance doses at a fixed-dose interval.
* Serum levels of aminoglycosides (amikacin, streptomycin, kanamycin) and capreomycin obtained less than 2 hours after an intramuscular dose or completion of an intravenous infusion
may be falsely elevated due to incomplete distribution of drug to body tissues. To avoid misinterpretation, two post-distribution concentrations should be drawn and the peak
concentration determined by pharmacokinetic calculation using linear regression to 1 hour post-intramuscular dose or end of intravenous infusion. These calculations are usually
performed by pharmacists skilled in aminoglycoside clinical pharmacokinetics. Trough concentrations (target <5 mcg/mL to undetectable) may also be evaluated to confirm drug
clearance following a 24-hour dose. Refer to the UpToDate topic review of aminoglycosides dosing and administration for detail.
¶ To assess for delayed or malabsorption, a second sample should be collected approximately 6 to 7 hours after an oral dose (depending on the drug as noted above). This is particularly
important for patients with a history of diabetes mellitus, gastrointestinal disorders, HIV, cystic fibrosis, or alcohol abuse and in all patients receiving ethambutol or ethionamide. In
delayed absorption, the 6- or 7-hour concentration is similar to or higher than 2-hour values. If both values are beneath the expected peak, malabsorption should be suspected.
Δ Central nervous system toxicity is associated with cycloserine concentrations >35 mcg/mL but may occur at even lower concentrations. Some experts prefer to maintain the
concentration <30 mcg/mL.
◊ An elevated uric acid is an expected additional finding in patients on pyrazinamide. If not present, it may indicate that the patient is not taking the drug or there is malabsorption.
§ Rifabutin is absorbed more slowly than most other oral agents. On the day of sampling only, rifabutin can be given 1 hour before the other drugs, so that rifabutin sample times match
the 2- and 6-hour times for other drugs. This limits the collection to two venipunctures.
References:
1. Nahid P, Dorman S, Alipanah N, et al. Official American Thoracic Society/Centers for Disease Control and Prevention/Infectious Diseases Society of America Clinical Practice
Guidelines: Treatment of Drug-Susceptible Tuberculosis. Clin Infect Dis 2016; 63:e147.
2. Alsultan A, Peloquin CA. Therapeutic drug monitoring in the treatment of tuberculosis: An update. Drugs 2014; 74:839.
3. Curry International Tuberculosis Center and California Department of Public Health. Drug-Resistant Tuberculosis: A Survival Guide for Clinicians, Third Edition. 2016. Available at
http://www.currytbcenter.ucsf.edu/products/cover-pages/drug-resistant-tuberculosis-survival-guide-clinicians-3rd-edition.

Approach to hepatotoxicity caused by first-line antituberculous drugs in adults*
* First-line antituberculous drugs include isoniazid, rifampin, pyrazinamide, and ethabutol. Isoniazid, rifampin, and pyrazinamide are potentially hepatotoxic; ethambutol is not hepatotoxic.
¶ Liver function tests include measurement of serum bilirubin, alkaline phosphatase, and hepatocellular enzymes (alanine aminotransferase and aspartate aminotransferase).
Δ Alternative causes of elevated liver function tests include alcohol, acetaminophen, viral hepatitis, gallstones, biliary obstruction, and others.
◊ Signs and symptoms of hepatotoxicity include nausea, vomiting, malaise, low-grade fever, and anorexia. Refer to the UpToDate topic on drug-induced liver injury for further discussion.
§ The approach to subsequent monitoring depends on clinical circumstances; some favor checking liver function tests weekly until on a stable regimen, then every two to four weeks
thereafter.
¥ There is overlap in the pattern of liver injury caused by rifampin, isoniazid, and pyrazinamide; all individually or in combination may contribute to hepatotoxicity.
‡ Intervals of treatment interruption warranting resumption of therapy from the beginning vary between initiation and continuation phases; refer to text for further discussion.
† Refer to UpToDate content on treatment of tuberculosis for further discussion.
References
2. Nahid P, Dorman SE, Alipanah N, et al. Official American Thoracic Society/Centers for Disease Control and Prevention/Infectious Diseases Society of America Clinical Practice
Guidelines: Treatment of Drug-Susceptible Tuberculosis. Clin Infect Dis 2016.

Symptoms and signs of anaphylaxis
Skin
Feeling of warmth, flushing (erythema), itching, urticaria, angioedema, and "hair standing on end" (pilor erection)
Oral
Itching or tingling of lips, tongue, or palate
Edema of lips, tongue, uvula, metallic taste
Respiratory
Nose - Itching, congestion, rhinorrhea, and sneezing
Laryngeal - Itching and "tightness" in the throat, dysphonia, hoarseness, stridor
Lower airways - Shortness of breath (dyspnea), chest tightness, cough, wheezing, and cyanosis
Gastrointestinal
Nausea, abdominal pain, vomiting, diarrhea, and dysphagia (difficulty swallowing)
Cardiovascular
Feeling of faintness or dizziness; syncope, altered mental status, chest pain, palpitations, tachycardia, bradycardia or other dysrhythmia, hypotension, tunnel vision, difficulty
hearing, urinary or fecal incontinence, and cardiac arrest
Neurologic
Anxiety, apprehension, sense of impending doom, seizures, headache and confusion; young children may have sudden behavioral changes (cling, cry, become irritable, cease to
play)
Ocular
Periorbital itching, erythema and edema, tearing, and conjunctival erythema
Other
Uterine cramps in women and girls
Original figure modified for this publication. Simons FER. Anaphylaxis. J Allergy Clin Immunol 2010; 125:S161. Table used with the permission of Elsevier Inc. All rights reserved.

Dosing for oral* rechallenges with antituberculosis drugs following nonanaphylactic allergic reactions (adults)
Drug Dose – Day 1 Dose – Day 2 ¶ Dose – Day 3
Isoniazid 50 mg 300 mg Usual daily dose Δ
Rifampin 75 mg ◊ 300 mg 600 mg
Pyrazinamide 250 mg 1g Usual daily dose Δ
Ethionamide 125 mg 375 mg 500 to 750 mg
Cycloserine 125 mg § 250 mg 500 to 750 mg
Ethambutol 100 mg 400 mg Usual daily dose Δ
Para-aminosalicylic acid 1 g¥ 4g 6 to 8 g
Streptomycin* 125 mg 500 mg Usual daily dose Δ
Doses for the following drugs were not supplied by the Philadelphia program but have been extrapolated (based on the doses above) to the following:
Amikacin* 125 mg 500 mg Usual daily dose Δ
Capreomycin* 125 mg 500 mg Usual daily dose Δ
Levofloxacin 50 mg ‡ 200 to 250 mg Usual daily dose Δ
Reintroducing antituberculosis drugs (rechallenge) should only be considered in patients who have experienced a nonanaphylactic reaction, such as isolated hives
(urticaria) or rash without systemic symptoms or organ involvement. Reintroduction would not be appropriate for a patient who had symptoms of possible anaphylaxis (ie,
the rapid onset of some combination of hives, angioedema, airway compromise, bronchospasm, nausea and vomiting, hypotension) or of a more serious systemic
hypersensitivity reaction, such as Stevens-Johnson syndrome or toxic epidermal necrolysis (ie, blistering or peeling of the skin, high fever, flu-like symptoms, or
involvement of mucous membranes).
Drugs should be reintroduced one at a time. If the patient was taking several drugs at the time of the reaction and all were stopped, the most important one should be
reintroduced first. If the first drug causes no adverse reaction, then it is continued and challenge to the second drug is performed, etc, until the patient is again taking all
the required meds and/or the drug causing the reaction is identified.
The patient can be premedicated with oral diphenhydramine 25 mg with or without a small dose of oral glucocorticoid (eg, prednisone 10 to 20 mg) given 30 minutes
before the first dose. If the initial dose is well-tolerated, give diphenhydramine 30 minutes before the second dose, without the prednisone. If that is well-tolerated, give
the third dose without premedication.
Premedication may not prevent cutaneous symptoms entirely but typically makes the reaction less severe. Patients who develop a mild rash as a result of reintroduction
may benefit from a short course of low-dose glucocorticoids, allowing the drug to be continued.
* All rechallenge regimens are based upon oral administration except for streptomycin, amikacin, capreomycin which may be administered intramuscularly.
¶ If the day 2 dose is less than the normal recommended dose based on the patient's weight, increase the day 3 dose to the correct weight-based dose (eg, dose of ethambutol for a 70
kg patient: day 1 = 100 mg, day 2 = 500 mg, and day 3 = 1000 mg).
Δ Usual daily dose means the daily dose that the individual patient in question will require, which may vary by regimen and patient characteristics.
◊ Rifampin is available in 150 mg capsules. Empty capsule contents into a small amount of applesauce or jelly and administer one-half.
§ Cycloserine comes in 250 mg capsules. Empty capsule contents into a small amount of no sugar added chocolate pudding or grape jelly and administer one-half.
¥ Para-aminosalicylic acid comes in 4 gram packets. Suspended in orange juice and administer one-quarter.
‡ Levofloxacin is available in an oral solution of 25 mg/mL.
Adapted from: Curry International Tuberculosis Center and California Department of Public Health, 2016: Drug-Resistant Tuberculosis: A Survival Guide for Clinicians, Third Edition, p.
255.
Additional data from:
1. Philadelphia Tuberculosis Control Program, Lawrence Flick Memorial Tuberculosis Clinic. Guidelines for the Management of Adverse Drug Effects of Antimycobacterial Agents.
Philadelphia: Philadelphia Tuberculosis Control Program, 1998.
2. Peloquin CA, Durbin D, Childs J, et al. Stability of antituberculosis drugs mixed in food. Clin Infect Dis 2007; 45:521.

Hematologic abnormalities associated with anti-tuberculosis drugs
Red DIC or
Hemolytic Aplastic
Drug WBC ↓ WBC ↑ PMN ↓ Eosinophil ↑ Hemoglobin ↓ anemia
cell
anemia
Platelet ↓ Platelet ↑ coagulation
aplasia abnormal
Amikacin X
Amoxicillin- X X X X X X X
clavulanate
Capreomycin X X X X
Clofazimine X X X X
Cycloserine X
Ethambutol X X X X
Ethionamide X X
Imipenem X X X X X X X X X
Isoniazid X X X X X X X X X
Kanamycin
Levofloxacin X X X X X X X
Linezolid X X X X
Moxifloxacin X X X X X X X X X
Para- X X
aminosalicylic
acid
Pyrazinamide X X
Rifabutin X X
Rifampin X X X X X X X X
Streptomycin X X X X X
WBC: white blood cell; PMN: polymorphonuclear leukocytes; DIC: disseminated intravascular coagulation.
Modified with permission from: Curry International Tuberculosis Center and California Department of Public Health, 2016: Drug-Resistant Tuberculosis: A Survival Guide for Clinicians,
Third Edition, p. 260. Copyright © 2016 Curry International Tuberculosis Center.

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Antituberculous drugs: An overview

Dosing for first-line agents is summarized in the table (table 2).

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Clinical trial data for bedaquiline include the following studies:

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CLINICAL AND LABORATORY MONITORING FOR ADVERSE EFFECTS

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● Abnormal baseline liver function tests

● Ethionamide or para-aminosalicylate – Monitor thyroid stimulating hormone (every three months).

SERUM DRUG CONCENTRATION MONITORING

● Use of aminoglycosides, capreomycin, or cycloserine

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It may be possible to make drug dose adjustments, as follows:

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Other effects — Miscellaneous adverse effects are summarized below.

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SOCIETY GUIDELINE LINKS

Use of UpToDate is subject to the Subscription and License Agreement.

Topic 488 Version 29.0

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Antituberculous drugs for treatment of drug-resistant tuberculosis: longer, individualized regimen

Group Medicine Abbreviation

Group A: Levofloxacin OR Lfx

Group B: Clofazimine Cfz

(OR Streptomycin) ‡ (S)

Ethionamide †,** OR Eto

Prothionamide †,** Pto

p-aminosalicylic acid † PAS

Graphic 119120 Version 3.0

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Dosing of first-line antituberculosis drugs in adults*

Rifapentine Δ Tablet (150 mg, film – – – 10 to 20 mg/kg once

Pyrazinamide Tablet (500 mg, scored) Patient weight 40 to 55 kg §

1000 mg (18.2 to 25 1500 (27.3 to 37.5 mg/kg) 2000 mg (36.4 to 50 –

Patient weight 76 to 90kg §¥

2000 mg ‡ (22.2 to 26.3 3000 mg ‡ (33.3 to 39.5 4000 mg ‡ (44.4 to 52.6 –

Ethambutol Tablets (100 mg, 400 mg) Patient weight 40 to 55kg §

800 mg (14.5 to 20 1200 mg (21.8 to 30 2000 mg (36.4 to 50 –

1200 mg (16 to 21.4 2000 mg (26.7 to 35.7 2800 mg (37.3 to 50 –

1600 mg ‡ (17.8 to 21.1 2400 mg ‡ (26.7 to 31.6 4000 mg ‡ (44.4 to 52.6 –

Data adapted from:

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Dosing of second-line antituberculosis drugs in adults

Main and rare but serious

Amoxicillin-clavulanate 2000 mg amoxicillin/125 mg clavulanate GI toxicity May be used

Capreomycin Δ◊ 15 mg/kg IM or IV once daily (usual Ototoxicity, vestibular toxicity, Avoid

Streptomycin Δ◊ 15 mg/kg IM or IV once daily (usual Ototoxicity, vestibular toxicity, Avoid

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Use of bedaquiline in adults

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Therapeutic serum concentration monitoring of antituberculous drugs in adults

Time for additional sampling

Cycloserine Oral: 2 hours 20 to 35 mcg/mL Δ 6 hours

Ethambutol Oral: 2 to 3 hours 2 to 6 mcg/mL (for 15 to 25 mg/kg daily dose) 6 to 7 hours