Tuberculosis Treatment
Payam Nahid and Philip C Hopewell, University of California, San Francisco, CA, USA
Ó 2017 Elsevier Inc. All rights reserved.
Summary of Principles
Prompt initiation of effective chemotherapy for pulmonary
tuberculosis is the most important means by which person-
to-person transmission of Mycobacterium tuberculosis is termi-
nated; thus, treatment of tuberculosis is not only a matter of
individual health but also is an important public health
intervention (Hopewell and Pai, 2005). Consequently, all
providers who undertake treatment of patients with tubercu-
losis must recognize that not only are they treating an indi-
vidual, they are assuming an important public health
function that also entails a high level of responsibility to
the community, as well as to the individual patient. For
each individual patient, special consideration should be
given to the specific clinical and social context in which
tuberculosis treatment is being administered so as to maxi-
mize the likelihood of successful treatment completion.
Overall, the goals of antituberculosis therapy are multifac-
eted and include achieving cure without relapse of disease,
stopping transmission of M. tuberculosis, and preventing the
emergence of drug-resistant strains.
Directly observed therapy (DOT), that is, providing medica-
tions and watching the patient swallow them, is one component
of a package of comprehensive case management strategies
designed to achieve adherence and treatment completion goals.
Case management including patient education, incentives,
enablers, are recommended for all patients as it has been shown
to increase compliance and completion of therapy (see the
section titled Promoting adherence). Consequently, tuberculosis
is generally best treated through public health agencies because
of the significant infrastructure and cost of administering
these case management strategies, including DOT. Tuberculosis
treatment is generally divided into two phases: the initiation
(bactericidal) phase, which lasts for 2 months, and the continu-
ation phase, which lasts for 4–7 months for patients with
drug-susceptible disease (Nahid et al., 2016; World Health
Organization (WHO), 2010a). Antituberculosis treatment
should be administered following bacteriologic confirmation
of tuberculosis or empirically when there is a high clinical suspi-
cion for disease prior to culture confirmation and, in certain
cases, prior to the availability of acid-fast bacilli (AFB) smear
microscopy results. Tuberculosis should never be treated
with a single drug and a single drug should never be added to
a failing regimen due to the risk of acquiring drug resistance.
Thus, multidrug therapy is always required.
Treatment is generally initiated with an empiric four-drug
regimen consisting of isoniazid, rifampin, ethambutol, and
pyrazinamide (Table 1). Recommended dosages and dosing
schedules for first- and second-line antituberculosis medica-
tions are shown in Table 2.
The efficacy of treatment should be monitored by obtaining
sputum for AFB smear and culture at least monthly until two
consecutive cultures are negative. Cultures should always be
obtained after 2 months of treatment as positive cultures at
International Encyclopedia of Public Health, 2nd edition, Volume 7
this stage predict the risk of relapse and mandate prolongation
of therapy. Drug susceptibility testing should be performed on
the initial culture and again if cultures remain positive after 3 to
4 months of treatment.
Tuberculosis treatment with combination chemotherapy
can be complicated by both mild and serious adverse reactions.
Mild adverse reactions can generally be managed with conser-
vative therapy aimed at controlling symptoms, whereas with
more severe reactions the offending drug or drugs must be dis-
continued. Managing serious adverse reactions frequently
necessitates expert consultation. Although it is important to
recognize the potential for adverse effects, first-line drugs
should not be discontinued without adequate justification.
Antituberculosis Drugs
The U.S. Food and Drug Administration (FDA) has approved
11 drugs for treating tuberculosis. Several other drugs,
including levofloxacin and moxifloxacin, are not FDA
approved for tuberculosis, but are used in selected populations.
Table 2 lists the drugs commonly used worldwide for drug-
susceptible and –resistant TB, available preparations, and the
doses that are recommended. In regard to newer drugs, in
December 2012, FDA granted accelerated approval for a new
drug, bedaquiline (Sirturo), as part of a combination therapy
to treat adults with multidrug-resistant pulmonary tuberculosis
when other alternatives are not available (Food and Drug
Administration). Phase 3 trials and prospective patient regis-
tries are underway to help identify optimal combination regi-
mens that include bedaquiline (see Relevant Websites;
Identifiers: NCT02333799; NCT02274389). In November
2013, a conditional marketing authorization for delaminid
was granted by the European Medicines Agency (EMA). Delam-
anid was also approved for use as part of a combination
regimen for pulmonary MDR-TB in adult patients “when an
effective treatment regimen cannot otherwise be composed
for reasons of resistance or tolerability”. Interim guidance on
the use of both delaminid and bedaquiline are provided by
the WHO. For now, Phase 3 trials are underway to define the
optimal combinations to use with delaminid and bedaquiline
for the treatment of drug-resistant TB.
Current Treatment Regimens
Newly published guidelines for the treatment of tuberculosis
(Nahid et al., 2016; WHO, 2010b) are all based on similar prin-
ciples, all recommend the same drugs, and all agree that 6
months is the minimum duration of treatment for bacteriologi-
cally confirmed drug-susceptible tuberculosis. Differences exist
between the guidelines mostly in the frequency of administra-
tion recommended (daily vs intermittent), which is primarily
determined by the availability of resources for supervision.
http://dx.doi.org/10.1016/B978-0-12-803678-5.00473-2 267
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Tuberculosis Treatment
Table 1 Drug regimens for microbiologically confirmed pulmonary tuberculosis caused by drug-susceptible organisms

Intensive phase Continuation phase

b
Interval and dose Range of Regimen
Regimen Drug a (minimum duration) Drugs Interval and dose b,c (minimum duration) total doses Comments c,d effectiveness

1 INH 7 days/week for 56 doses INH 7 days/week for 126 doses (18 weeks), or 182–130 This is the preferred regimen for patients with newly Greater
RIF (8 weeks), or RIF 5 days/week for 90 doses (18 weeks) diagnosed pulmonary tuberculosis.
PZA 5 days/week for 40 doses
EMB (8 weeks)
2 INH 7 days/week for 56 doses INH 3 times weekly for 54 doses (18 weeks) 110–94 Preferred alternative regimen in situations in which more
RIF (8 weeks), or RIF frequent DOT during continuation phase is difficult to
PZA 5 days/week for 40 doses achieve.
EMB (8 weeks)
3 INH 3 times weekly for 24 INH 3 times weekly for 54 doses (18 weeks) 78 Use regimen with caution in patients with HIV and/or
RIF doses (8 weeks) RIF cavitary disease. Missed doses can lead to treatment
PZA failure, relapse, and acquired drug resistance.
EMB
4 INH 7 days/week for 14 doses INH Twice weekly for 36 doses (18 weeks) 62 Do not use twice-weekly regimens in HIV-infected patients
RIF then twice weekly for 12 RIF or patients with smear-positive and/or cavitary disease.
PZA dosese If doses are missed, then therapy is equivalent to once
EMB weekly, which is inferior.
Lesser

Abbreviations: DOT, directly observed therapy; EMB, ethambutol; HIV, human immunodeficiency virus; INH, isoniazid; PZA, pyrazinamide; RIF, rifampin.
a
Other combinations may be appropriate in certain circumstances; additional details are provided in the section ‘Recommended Treatment Regimens’.
b
When DOT is used, drugs may be given 5 days per week and the necessary number of doses adjusted accordingly. Although there are no studies that compare 5 with 7 daily doses, extensive experience indicates this would be an effective
practice. DOT should be used when drugs are administered <7 days per week.
c
Based on expert opinion, patients with cavitation on initial chest radiograph and positive cultures at completion of 2 months of therapy should receive a 7-month (31-week) continuation phase.
d
Pyridoxine (vitamin B6), 25–50 mg day 1, is given with INH to all persons at risk of neuropathy (e.g., pregnant women; breastfeeding infants; persons with HIV; patients with diabetes, alcoholism, malnutrition, or chronic renal failure; or
patients with advanced age). For patients with peripheral neuropathy, experts recommend increasing pyridoxine dose to 100 mg day 1.
e
See Cohn et al. (1990). Alternatively, some US tuberculosis control programs have administered intensive-phase regimens 5 days per week for 15 doses (3 weeks), then twice weekly for 12 doses.
Table 2 Dosesa of antituberculosis drugs for adults and childrenb

Drug Preparation Population Daily Once weekly Twice weekly Thrice weekly

First-line drugs
1
Isoniazid Tablets (50, 100, 300 mg); elixir (50 mg/5 mL); Adults 5mg kg (typically 300 mg) 15 mg kg 1 (typically 15 mg kg 1 (typically 15 mg kg 1
aqueous solution (100 mg mL 1) for intravenous or 900 mg) 900 mg) (typically 900 mg)
intramuscular injection. Note: Pyridoxine (vitamin Children 10–15 mg kg 1
. 20–30 mg kg 1 .b
B6), 25–50 mg day 1, is given with INH to all
persons at risk of neuropathy (e.g., pregnant
women; breastfeeding infants; persons with HIV;
patients with diabetes, alcoholism, malnutrition, or
chronic renal failure; or patients with advanced
age). For patients with peripheral neuropathy,
experts recommend increasing pyridoxine dose to
100 mg day 1.
Rifampin Capsule (150, 300 mg). Powder may be Adultsc 10 mg kg 1
(typically 600 mg) . 10 mg kg 1 (typically 10 mg kg 1
suspended for oral administration. 600 mg) (typically 600 mg)
Aqueous solution for intravenous injection. Children 10–20 mg kg 1 . 10–20 mg kg 1 .b
Rifabutin Capsule (150 mg) Adultsd 5 mg kg 1 (typically 300 mg) . Not recommended Not recommended
Children Appropriate dosing for children is unknown. Estimated at 5 mg kg 1.
Rifapentine Tablet (150 mg film coated) Adults 10–20 mg kg 1e . .
Children Active tuberculosis: for children 12 years of age, same dosing as for adults, administered once weekly. Rifapentine is
not FDA-approved for treatment of active tuberculosis in children <12 years of age.
Pyrazinamide Tablet (500 mg scored) Adults .
Children 35 (30–40) mg kg 1 . 50 mg kg 1 .b
Ethambutol Tablet (100 mg; 400 mg) Adults .
Childrenf 20 (15–25) mg kg 1 . 50 mg kg 1 .b
Second-line drugs
Cycloserine Capsule (250 mg) Adultsg 10–15 mg kg 1 total (usually 250–500 mg There are inadequate data to support intermittent administration.
once or twice daily)
Children 15–20 mg kg 1 total (divided 1–2 times
daily)

Tuberculosis Treatment
Ethionamide Tablet (250 mg) Adultsh 15–20 mg kg 1 total (usually 250–500 mg There are inadequate data to support intermittent administration.
once or twice daily)
Children 15–20 mg kg 1 total (divided 1–2 times
daily)
Streptomycin Aqueous solution (1 g vials) for IM or IV Adults 15 mg kg 1 daily. Some clinicians prefer 25 mg kg 1 3 times weekly.
administration. Patients with decreased renal function may require the 15 mg kg 1 dose to be given only 3 times weekly to allow for drug
clearance.
Children 15–20 mg kg 1 (Schaaf et al., 2015) . 25–30 mg kg 1i .

(Continued)

269
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Tuberculosis Treatment
Table 2 Dosesa of antituberculosis drugs for adults and childrenbdcont'd

Drug Preparation Population Daily Once weekly Twice weekly Thrice weekly

Amikacin/ Aqueous solution (500 mg and 1 g vials) for Adults 15 mg kg 1 daily. Some clinicians prefer 25 mg kg 1 3 times weekly.
kanamycin IM or IV administration. Patients with decreased renal function, including older patients, may require the 15 mg kg 1 dose to be given only 3
times weekly to allow for drug clearance.
Children 15–20 mg kg 1 (Schaaf et al., 2015) . 25–30 mg kg 1i .
1 1
Capreomycin Aqueous solution (1 g vials) for IM or IV Adults 15 mg kg daily. Some clinicians prefer 25 mg kg 3 times weekly.
administration. Patients with decreased renal function, including older patients, may require the 15 mg kg 1 dose to be given only 3
times weekly to allow for drug clearance.
Children 15–20 mg kg 1 (Schaaf et al., 2015) 25–30 mg kg 1i
Para-amino Granules (4 g packets) can be mixed in and ingested Adults 8–12 g total (usually 4000 mg 2–3 times There are inadequate data to support intermittent administration.
salicylic acid with soft food (granules should not be chewed). daily)
Tablets (500 mg) are still available in some Children 200–300 mg kg 1 total (usually divided
countries, but not in the United States. A solution 100 mg kg 1 given 2 to 3 times daily)
for IV administration is available in Europe.
Levofloxacin Tablets (250, 500, 750 mg); aqueous solution (500 Adults 500–1000 mg daily There are inadequate data to support intermittent administration.
mg vials) for IV injection.
Children The optimal dose is not known, but clinical data suggest 15–20 mg kg 1 (Schaaf et al., 2015)
Moxifloxacin Tablets (400 mg); aqueous solution (400 mg/250 mL) Adults 400 mg daily There are inadequate data to support intermittent administration.j
for IV injection. Children The optimal dose is not known. Some experts use 10 mg kg 1 daily dosing, though lack of formulations makes such
titration challenging. Aiming for serum concentrations of 3–5 mL mL 1 2 h postdose is proposed by experts as
a reasonable target.

Abbreviations: FDA, US Food and Drug Administration; HIV, human immunodeficiency virus; IM, intramuscular; INH, isoniazid; IV, intravenous.
a
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.
b
For purposes of this document, adult dosing begins at age 15 years or at a weight of >40 kg in younger children. The optimal doses for thrice-weekly therapy in children and adolescents have not been established. Some experts use in
adolescents the same doses as recommended for adults, and for younger children the same doses as recommended for twice-weekly therapy.
c
Higher doses of rifampin, currently as high as 35 mg kg 1, are being studied in clinical trials.
d
Rifabutin dose may need to be adjusted when there is concomitant use of protease inhibitors or nonnucleoside reverse transcriptase inhibitors.
e
TBTC Study 22 used rifapentine (RPT) dosage of 10 mg kg 1 in the continuation phase of treatment for active disease (Benator et al., 2002). However, RIFAQUIN and PREVENT TB safely used higher dosages of RPT, administered once weekly
(Jindani et al., 2014; Sterling et al., 2011). Daily doses of 1200 mg RPT are being studied in clinical trials for active tuberculosis disease.
f
As an approach to avoiding ethambutol (EMB) ocular toxicity, some clinicians use a 3-drug regimen (INH, rifampin, and pyrazinamide) in the initial 2 months of treatment for children who are HIV-uninfected, have no prior tuberculosis
treatment history, are living in an area of low prevalence of drug-resistant tuberculosis, and have no exposure to an individual from an area of high prevalence of drug-resistant tuberculosis. However, because the prevalence of and risk for drug-
resistant tuberculosis can be difficult to ascertain, the American Academy of Pediatrics and most experts include EMB as part of the intensive-phase regimen for children with tuberculosis.
g
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.
h
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.
i
Modified from adult intermittent dose of 25 mg kg 1, and accounting for larger total body water content and faster clearance of injectable drugs in most children. Dosing can be guided by serum concentrations.
j
RIFAQUIN trial studied a 6-month regimen. Daily isoniazid was replaced by daily moxifloxacin 400 mg for the first 2 months, followed by once-weekly doses of moxifloxacin 400 mg and RPT 1200 mg for the remaining 4 months. Two hundred
twelve patients were studied (each dose of RPT was preceded by a meal of two hard-boiled eggs and bread). This regimen was shown to be noninferior to a standard daily administered 6-month regimen (Jindani et al., 2014).

The treatment regimens that are recommended by the new
American Thoracic Society (ATS), Centers for Disease Control
and Prevention (CDC), and the Infectious Diseases Society of
America (IDSA) are shown in Table 1. These recommenda-
tions are intended to guide treatment in areas where mycobac-
terial culture, drug susceptibility testing, chest radiography,
and second-line drugs are available routinely. The treatment
recommendations of the World Health Organization
(WHO, 2003) are directed toward resource-limited countries
in which the above facilities may not be available routinely.
The basic treatment regimen recommended by the ATS,
CDC, IDSA, and WHO for previously untreated patients
with either pulmonary or extrapulmonary tuberculosis
consists of an initial phase of isoniazid, rifampin, pyrazina-
mide, and ethambutol for 2 months, followed by 4 months
of isoniazid and rifampin (Nahid et al., 2016; World Health
Organization (WHO), 2010a). The recommendation of
a four-drug initial phase is based, in part, on findings of the
British Medical Research Council (Mitchison and Nunn,
1986), and strongly suggests that where the prevalence of
initial resistance to isoniazid is likely to be high, treatment
regimens should include an initial 2-month, 4-drug initial
phase, and rifampin plus isoniazid should be given for
a 4-month continuation phase. The results of this regimen
are nearly as good in the presence of resistance to isoniazid
as for fully susceptible organisms.
Variations in the pattern of administration of the basic
regimen do exist and are designed primarily to enable observa-
tion of medication ingestion (Table 1).
Treatment of Tuberculosis in Patients with HIV
Infection
Both the CDC and WHO recommend routine HIV testing
and counseling to all patients with presumptive and diag-
nosed tuberculosis. Treatment of tuberculosis in patients
with HIV infection has several important differences
compared with treatment of patients who do not have HIV
infection. These differences include the need for antiretrovi-
ral therapy (ART), the potential for drug–drug interactions,
especially between the rifamycins and ARTs, paradoxical
reactions that may be interpreted as clinical worsening, and
the potential for developing resistance to rifamycins when
using intermittent tuberculosis therapy. Critically important
to improved survival, decreased frequency of AIDS-defining
illnesses and TB outcomes is that ARTs are initiated during
tuberculosis treatment. Data from numerous trials clearly
show that patients with HIV should begin treatment with
ART during TB treatment, as compared to waiting until after
TB therapy is completed (Nahid et al., 2016). There is
a paucity of data on the optimal duration of tuberculosis
treatment for HIV-infected patients receiving highly active
antiretroviral therapy (HAART),though it is widely believed
that the standard 6-month regimen is effective and achieves
tuberculosis cure rates comparable to those reported for
HIV-uninfected patients. However, in the uncommon situa-
tion in which an HIV-infected patient does NOT receive
ART during tuberculosis treatment, guidelines suggest
extending the continuation phase with INH and RIF for an
Tuberculosis Treatment 271
additional 3 months (ie, a continuation 2075 phase of 7
months in duration, corresponding to a total of 9 months
of therapy) for treatment of drug-susceptible pulmonary
tuberculosis (Nahid et al., 2016).
Patients with HIV infection and tuberculosis are at
increased risk of developing paradoxical worsening of symp-
toms, signs, or clinical manifestations of tuberculosis after
beginning antituberculosis and antiretroviral treatments
(Nahid et al., 2016). These reactions presumably develop
as a consequence of reconstitution of immune responsive-
ness brought about by ART, and are designated as the
immune reconstitution inflammatory syndrome (IRIS).
Such findings, however, are attributed to IRIS only after
excluding other possible causes, especially tuberculosis treat-
ment failure from drug-resistant tuberculosis or another
opportunistic disease, such as non-Hodgkin lymphoma or
infection. Management of IRIS is usually symptomatic,
though for patients with worsening pleural effusions or
abscesses, drainage may be necessary (Nahid et al., 2016).
For more severe cases of IRIS, treatment with corticosteroids
is effective.
Initial Susceptibility Testing
Where quality-assured laboratory facilities are available, drug
susceptibility testing against first-line medication should be
performed. This is of particular importance in areas of high
prevalence of drug resistance or among persons in whom
epidemiological circumstances indicate a risk of drug resis-
tance. If resistance is identified, regimens can be tailored to
suit the specific pattern. In certain situations, expert consulta-
tion may be needed to guide empiric selection of an expanded
treatment regimen for individuals suspected of having drug-
resistant tuberculosis, even before susceptibility results are
available.
Promoting Adherence
The successful treatment of tuberculosis requires not only
the selection of an appropriate regimen (prescribed in appro-
priate doses and for appropriate durations) but also assid-
uous efforts in assisting patient to adhere and complete the
prescribed regimen.
The reasons for poor adherence to treat tuberculosis are
complex and numerous, and prediction of who will be adherent
and who will not is unreliable (Burkhart and Sabate, 2003).
Numerous factors including challenges in safety, tolerability of
medications, as well as cultural and linguistic barriers lifestyle
circumstances, such as homelessness and substance abuse,
among a variety of other issues, can interfere with adherence
(Nahid et al., 2016; Moss et al., 2000). It is clear that there is
no single approach to management that is effective for all
patients, conditions, and settings. Consequently, interventions
that target adherence must be tailored or customized to the
particular situation of a given patient (Nahid et al., 2016), but
should always be patient-centered using strategies that are devel-
oped in consultation with the patient. Some approaches include
setting clinic hours to suit the patient’s schedule; providing
272 Tuberculosis Treatment
treatment support in alternative settings outside the clinic, such
as the patient’s home, place of work, or other locations; and
offering incentives and enablers, such as transportation reim-
bursements. This patient-centered, individualized approach
toward treatment support is a core element of all tuberculosis
care and control efforts. Education and improving treatment
literacy in patients with tuberculosis is a core element of opti-
mizing treatment completion and success.
One component of a package of interventions to improve
adherence includes administering tuberculosis medications
under DOT (Nahid et al., 2016). Use of DOT has been shown
to be associated with improved treatment success and two
month culture conversion across systematic reviews conducted
in support of new guidelines (Nahid et al., 2016) Patient-
centered approaches using the full range of accepted measures
to ensure medication ingestion are central to the ATS/CDC/
IDSA guidelines, the International Standards for Tuberculosis
Care (Hopewell, see Relevant websites) as well as the WHO’s
global tuberculosis control strategy.
Predictors of Outcome
The optimal surrogate marker for predicting poor outcome
has yet to be identified, however, several factors have been
found to be associated with poor outcomes, namely treatment
failure (culture-positive tuberculosis after 4 months of treat-
ment) or relapse (a second episode of tuberculosis after
attaining culture-negative cure at completion of treatment)
(Nahid et al., 2016; Benator et al., 2002; Mitchison, 1993).
Culture status at the end of the initiation phase is currently
the most validated marker for risk of poor treatment outcome
(Perrin et al., 2007). The U.S. Public Health Service Study 22
found that sputum culture positivity at the time of comple-
tion of the initial phase of treatment in combination with
the presence of cavitation on the initial chest film were highly
predictive of either treatment failure or relapse (Benator et al.,
2000). For this reason, patients with cavitation on the initial
chest film who have positive sputum cultures at the end of the
initial phase of treatment should have the continuation phase
of treatment extended from 4 to 7 months, making a total of
9 months as recommended by the ATS/CDC/IDSA treatment
guidelines (Nahid et al., 2016). Additional factors to be
considered in deciding to prolong treatment in patients with
either cavitation or a positive culture at 2 months (but not
both) might include being >10% below ideal body weight;
being a smoker; having diabetes, HIV infection not being
treated with antiretroviral therapies, or other immunosup-
pressing condition; or having extensive disease on chest radio-
graph (Nahid et al., 2016).
Monitoring Response
Sputum cultures should have converted to negative within
2–3 months of chemotherapy in 75–90% of patients taking
a regimen that includes isoniazid and rifampin. Failure of the
sputum cultures to become negative by this time should
prompt further investigation, and may indicate that either the
patient is not taking the drugs or the organisms are resistant
to the drugs being used. Patients who continue to have
M. tuberculosis in their sputum after 2–3 months of treatment
should be started on DOT, if not already being supervised in
this manner, and should have drug susceptibility tests per-
formed. If resistance is found, the regimen should be modified
based on the results. If sputum samples are still positive after
4 months of therapy, the regimen should be considered to
have failed and a new regimen begun, ideally, based on recent
drug susceptibility test results (Nahid et al., 2016).
Management of Relapse
Most relapses occur within 6–12 months after completion of
therapy (Nunn et al., 2010). In general, the management of
patients who experience relapse despite the completion of a
DOT regimen that contained isoniazid and rifampin involves
reinstituting the same regimen previously used until suscepti-
bility results are available. This approach is possible because
organisms known at the outset of treatment to be sensitive
to the first-line antituberculosis drugs commonly retain full
drug susceptibility when isoniazid and rifampin were part
of the original regimen. However, if the patient is severely
ill, at least three new agents should be added to the regimen
for the possibility of drug resistance. Drug susceptibility
testing should be performed and the regimen modified if
resistance is detected. In addition, retreatment should be
given under DOT.
Patients who experience relapse after completing a regimen
that did not contain rifampin should be considered to harbor
organisms that are resistant to the drugs that were used, at least
until susceptibility is proven. The likelihood of resistance is
directly related to the duration of previous treatment (Costello
et al., 1980; Suwanogool et al., 1984). The likelihood of resis-
tance to isoniazid increases approximately 4% per month of
prior treatment and resistance to streptomycin increases at
approximately 2.5% per month of prior treatment.
Drug-Resistant Tuberculosis
Drug resistance can be present de novo in the initial isolate or
acquired during treatment. Features known to be associated
with the acquisition of drug resistance while on treatment
include the initial size of the bacillary population (i.e., pres-
ence of pulmonary cavities), the drug regimen prescribed
(i.e., inappropriate drugs, insufficient dosage) and noncom-
pliance of an otherwise adequate regimen (Nahid et al.,
2016). If drug-resistant organisms are suspected or confirmed
by susceptibility testing, assistance should be sought from
a clinician who has appropriate expertise in such situations.
The basic principle of treatment for patients whose organ-
isms demonstrate resistance to one or more of the first-line
drugs, but not both to isoniazid and rifampin (see section
titled Multidrug – resistant and extensively drug-resistant
tuberculosis) is to administer a regimen that consists of
any remaining effective first-line drugs plus generally two
to four agents to which there is demonstrated susceptibility
(Curry International Tuberculosis Center and California
Department of Public Health, 2016).

Multidrug-Resistant and Extensively Drug-Resistant
Tuberculosis
Multidrug-resistant (MDR) tuberculosis (MDRTB) is defined
by the presence of resistance to both isoniazid and rifampin.
Extensively drug-resistant (XDR) tuberculosis (XDRTB) is
defined as MDRTB that is also resistant to a fluoroquinolone
and at least one of the three injectable second-line drugs,
amikacin, capreomycin, or kanamycin. It is estimated that
worldwide there are 400 000 incident cases of MDRTB and
XDRTB identified each year (Raviglione and Smith, 2007).
Since 1994, the WHO and the International Union Against
Tuberculosis and Lung Disease have been conducting drug
surveillance monitoring in 35 countries through a network
of Supranational Reference Laboratories that aid National
Reference Laboratories in conducting quality-assured drug
susceptibility testing. These surveys have shown that drug
resistance in general is ubiquitous (Aziz and Wright,
2005). The surveys are being repeated every 3–5 years to
determine trend and in certain areas of the world rates of
multidrug resistance continue to be alarmingly high (Aziz
and Wright, 2005; Espinal et al., 2001; Pablos-Mendez
et al., 1998). These so-called hotspots include Latvia, the
Delhi region in India, Estonia, the Dominican Republic,
and Argentina.
A recent analysis of 17 690 isolates from 49 countries by the
CDC and WHO found that 2% of the isolates met the defini-
tion of XDRTB (Centers for Disease Control and Prevention,
2006). Moreover, XDRTB was identified in all regions. For Lat-
via and the United States, where drug susceptibility results were
available for all the tuberculosis cases, 4% and 19% of their
MDR cases also met the XDR definition, respectively. As part
of these projects, an outbreak of HIV-associated XDRTB was
reported in 2006 from the KwaZulu-Natal Province of South
Africa. Of 221 MDRTB cases identified, 53 (23%) were also
resistant to a fluoroquinalone (ciprofloxacin) and an
injectable (kanamycin) (Gandhi et al., 2006). Only half
reported a prior history of treatment for tuberculosis. HIV test
results were available in 44 patients and all were found to be
seropositive, and mortality was alarmingly high with 52 of
the 53 patients dying within a median of 16 days from the
initial sputum collection.
Treatment of MDR and XDR Tuberculosis
In general, the outcome of treatment depends largely on the
number of agents to which the organisms are susceptible, the
promptness and appropriateness of therapy, the number of
previous courses of therapy, and the HIV status of the patient.
Consequently, the outcome of treatment in persons with tuber-
culosis caused by MDR organisms is less good than that of
treatment of disease caused by susceptible organisms. Treat-
ment of XDR organisms is even more complex and is estimated
to cost more than $500 000 per case. Consultation with an
expert is strongly advised in treating patients with MDRTB
and XDRTB. The regimen selected represents the last best
chance for cure and must be implemented correctly. The
regimen should be based on the results of drug susceptibility
tests, however, the results are often not known until several
Tuberculosis Treatment 273
weeks after therapy is started. In such instances, treatment
should be empirically determined on the basis of the patient’s
history of prior therapy, avoiding reliance on agents taken
previously and on the prevailing resistance patterns in the
community or subpopulation of which the patient is a member.
A recent prospective cohort study of MDR-TB patients
confirmed that treatment success increases stepwise from
41.6% to 92.3% as the number of drugs proven effective in
the regimen increased up to 5 drugs. Conversely, increasing
drug resistance was associated in a logical stepwise manner
with poor treatment outcomes (Cegielski, 2016).
Treatment of Extrapulmonary Tuberculosis
Tuberculosis can involve virtually any organ or tissue in the
body. Nonpulmonary sites tend to be more common among
children and persons with impaired immunity. To establish
the diagnosis of extrapulmonary tuberculosis, appropriate spec-
imens including pleural fluid; pericardial or peritoneal fluid;
pleural, pericardial, and peritoneal biopsy specimens; lymph
node tissue; and bone marrow, bone, blood, urine, brain, or cere-
brospinal fluid should be obtained for AFB staining, mycobacte-
rial culture, and drug susceptibility testing (Nahid et al., 2016).
Central Nervous System Tuberculosis
Tuberculous meningitis is the most severe form of extrapul-
monary tuberculosis (Thwaites, 2009). The clinical presenta-
tion can be nonspecific making early diagnosis difficult.
Moreover, conventional approaches such as AFB smear and
culture from cerebrospinal fluid for speciation and suscepti-
bility testing are often nondiagnostic. In view of the cata-
strophic consequences and high incidence of mortality in
poorly treated tuberculous meningitis, the potential for resis-
tant organisms should be taken into account when treatment
is initiated. If there are no epidemiological indicators of
possible resistance, a regimen of isoniazid, rifampin, pyrazi-
namide, and ethambutol should be effective. The recommen-
ded length of the continuation phase is 7 months for a total
treatment duration of 9–12 months, although there are no
clinical trials that serve to define the optimum treatment
duration (Nahid et al., 2016). Isoniazid penetrates the
blood–brain barrier readily, and although data are limited,
in the presence of meningeal inflammation, rifampin, pyrazi-
namide, and streptomycin enter the cerebrospinal fluid in
concentrations sufficient to inhibit growth of the organism.
Ethambutol penetrates poorly, and doses of 25 mg kg 1
body weight produce subinhibitory concentrations.
Corticosteroid treatment has a significant beneficial effect
on survival in patients with tuberculous meningitis (Nahid
et al., 2016; Thwaites, 2009). Given the severity of the process,
good quality data supporting corticosteroid use in more severe
forms of the disease, and a paucity of information in patients
with less severe tuberculosis meningitis, corticosteroid treat-
ment – specifically with dexamethasone or prednisolone – is
recommended for all patients (Nahid et al., 2016).
The other major central nervous system form of tubercu-
losis, the tuberculoma, presents a more subtle clinical
274 Tuberculosis Treatment
picture than does tuberculous meningitis. The response to
antituberculosis chemotherapy is good, and corticosteroids
are generally used if there is an increase in intracranial
pressure.
Lymphatic Tuberculosis
Tuberculous lymphadenitis is a common form of extrapulmo-
nary tuberculosis. Cervical adenopathy is most common, but
inguinal, axillary, mesenteric, mediastinal, and intramammary
involvement have also been described (Golden and Vikram,
2005). A 6-month regimen is recommended for treatment of
tuberculous lymphadenitis (Nahid et al., 2016; Campbell,
1990; Campbell and Dyson, 1977; Jawahar et al., 1990).
However, even with effective regimens, the rate of response is
much slower than with pulmonary tuberculosis. Lymph nodes
may enlarge, new nodes may appear, and fistulas may develop
during treatment that ultimately proves effective. This transient
worsening may be a manifestation of the immune reconstitu-
tion syndrome. Overall, true bacteriologic relapse after comple-
tion of therapy is unusual.
Pleural Tuberculosis
Two forms of tuberculous involvement of the pleura are
seen; a hypersensitivity to bacilli present in the pleural space
resulting in pleurisy, and a distinct form that represents true
empyema (Baumann et al., 2007). Treatment of the hyper-
sensitivity variety of tuberculous pleural effusion consists
of standard antituberculosis drug regimens (Nahid et al.,
2016). Repeat thoracenteses is occasionally used to relieve
symptoms, but drainage via tube thoracostomy is rarely
necessary. In general, the amount of residual pleural scarring
from this form is small.
The second variety of tuberculous involvement of the pleura
is a true empyema. This is much less common than tuberculous
pleurisy with effusion and results from a large number of organ-
isms spilling into the pleural space, usually from rupture of
a cavity or an adjacent parenchymal focus by way of a broncho-
pleural fistula. Although standard chemotherapy should be insti-
tuted for tuberculous empyema, it is unlikely to clear the pleural
space infection, probably because penetration of the antituber-
culosis agents into the pleural cavity is limited. For this reason,
surgical drainage is often necessary and may be required for
a prolonged period of time both as treatment for the infection
and because of the frequent association with a bronchopleural
fistula. Drainage may be accomplished with a standard thoracos-
tomy tube. In selected patients, creation of an Eloesser flap, in
which a small portion of rib overlying the empyema space is
resected and the skin is sutured to the pleura, is the procedure
of choice. Corticosteroids have no role in treating this form of
pleural tuberculosis.
Genitourinary Tuberculosis
The principal means of diagnosing genitourinary tuberculosis is
the isolation of M. tuberculosis from urine (Christensen, 1974).
In general, renal tuberculosis is treated with a standard 6-
month regimen (Nahid et al., 2016). Nephrectomy is seldom
indicated, though surgical or endoscopic procedures may be
necessary to correct ureteral strictures and to augment the
capacity of a contracted bladder.
Bone and Joint Tuberculosis
In musculoskeletal tuberculosis, the spine, hip, and knee
are the most common sites of M. tuberculosis infection
(Davidson and Horowitz, 1970; Ludwig and Lazarus,
2007). Spinal tuberculosis (Pott’s disease) involves the
thoracic spine in 50% of cases (Watts and Lifeso, 1996).
Standard chemotherapy of 6–9 months’ duration is highly
successful in skeletal tuberculosis, but surgery is occasion-
ally a necessary adjunct. The role of emergency spinal
cord decompression in such patients is unclear, and if para-
plegia is already present, the benefit of surgical intervention
is even less clear. Longer duration of treatment (12 months)
has been suggested by some experts in the presence of
hardware. Several controlled studies have documented
that chemotherapy conducted largely on an ambulatory
basis is effective in curing spinal tuberculosis without the
need for immobilization. Moreover, there is no well-
defined surgical procedure of choice. Surgery may be indi-
cated in other forms of articular tuberculosis when there is
extensive destruction of the joint or surrounding soft
tissues, in which case synovectomy and joint fusions may
be necessary.
Abdominal Tuberculosis
A 6-month regimen is effective for patients with peritoneal
or intestinal tuberculosis (Nahid et al., 2016; Demir et al.,
2001; Singh et al., 1969). Surgery may be necessary to estab-
lish a diagnosis and, in addition, is necessary to relieve
intestinal obstruction if it should occur. Corticosteroids
have been advocated in tuberculous peritonitis to reduce
the risk of adhesions causing intestinal obstructions,
however this recommendation is controversial because the
frequency of obstruction is generally low, and in small
studies the use of corticosteroids did not reach statistical
significance in preventing fibrotic complications (Singh
et al., 1969).
Pericardial Tuberculosis
A 6-month regimen is recommended for the treatment of
pericardial tuberculosis. Because of its potentially life-
threatening nature, antituberculosis agents should be insti-
tuted promptly once the diagnosis is made or strongly
suggested. It appears that the likelihood of pericardial
constriction is greater in patients who have had symptoms
longer; thus, early therapy may reduce the incidence of this
complication. Several studies have suggested that corticoste-
roids have a beneficial effect in treating both tuberculous
pericarditis with effusion and constrictive pericarditis

(Mayosi et al., 2002; Strang et al., 1987). However, a meta-a-
nalysis of studies examining the effects of corticosteroids in
tuberculous pericarditis concluded that although steroids
could have an important effect, the studies were too small
to be conclusive (Mayosi et al., 2002). A recent well-
conducted, double-blind, randomized controlled trial
compared prednisolone and Mycobacterium indicus pranii in
a 2-by-2 factorial design in patients with tuberculous pericar-
ditis. Neither prednisolone nor M. indicus pranii had
a significant effect on the composite of death, cardiac tampo-
nade requiring pericardiocentesis, or constrictive pericarditis
(Mayosi et al., 2014). As noted in the accompanying edito-
rial, the results of this trial suggest that routine use of cortico-
steroids for all patients with tuberculous pericarditis cannot
be endorsed. Nonetheless, patients with large effusions, those
with high levels of inflammatory cells or markers in pericar-
dial fluid, or those with early signs of constriction may
benefit and should only be used with expert consultation
(Richard et al., 2014).
If hemodynamic compromise occurs, pericardiectomy
may be necessary. Although pericardiocentesis generally
improves the circulatory status, the improvement is usually
temporary. Pericardial windows with drainage into the left
pleural space also generally provide only temporary relief.
The criteria for selecting patients for pericardiectomy are not
clear, apart from those patients who have severe hemody-
namic compromise.
Disseminated Tuberculosis
Standard antituberculosis chemotherapeutic regimens
should be employed for disseminated tuberculosis unless
meningitis is present in which case the recommended dura-
tion is 9–12 months (Nahid et al., 2016). Some experts use
corticosteroids for severe pulmonary disease with respiratory
failure.
New Drugs for Tuberculosis
The ultimate goal of new antituberculosis drug development
will be to dramatically shorten the duration of treatment for
both drug-susceptible and drug-resistant tuberculosis from
the current 6 months to an ideal of 1–2 months in duration.
In conjunction, the regimens need to be better tolerated and
have minimal drug–drug interactions. More effective and
shorter treatments for latent tuberculosis infection have
been developed (Sterling et al., 2011) and ultra-short
regimens are being evaluated (see Relevant Websites; Identi-
fier: NCT01404312) providing hope for potential gains in
active tuberculosis.
The recent identification of XDRTB and continued escala-
tion of MDRTB further underscores the urgent need for the
development of new drugs. The dramatic increase in knowl-
edge concerning the biochemistry, genomics, transcriptomics,
and proteomics of M. tuberculosis will contribute for identifica-
tion of new drug targets as well as rapid diagnostics
(Zhang, 2005; Zumla et al., 2013).
Tuberculosis Treatment 275
See also: Respiratory Diseases: Overview; Respiratory
Infections, Acute; Tuberculosis Epidemiology; Tuberculosis
Prevention; Tuberculosis: Overview.
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Relevant Websites
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http://www.who.int/tb/publications/2006/istc_report.pdf – Hopewell (last accessed on
11.08.16.).