1373CHAPTER 178 Tuberculosis

organisms that, at the start of treatment, is noncavitary and/or sputum smear–negative). The same guidelines suggest that a 4-month

regimen consisting of isoniazid, rifampin, pyrazinamide, and ethambutol may be adequate for treatment of HIV-negative adults with

sputum smear–negative and culture-negative pulmonary TB (i.e.,

paucibacillary TB).

A continuation phase of once-weekly rifapentine and isoniazid

is effective in HIV-seronegative patients without cavitation on

CXR. In general, however, this regimen should be used with great

caution. Patients with cavitary pulmonary TB and delayed sputumculture conversion (i.e., those who remain culture-positive at

2 months) should be retested immediately for drug-resistant TB,

and a change of regimen should be considered. A full course of

6 months with four-drug therapy should be performed not including

interruptions of >4 weeks. In some developing countries where the

ability to ensure adherence to treatment is limited, a continuationphase regimen of daily isoniazid and ethambutol for 6 months

has been used in the past. This regimen is clearly associated with

a higher rate of relapse, treatment failure, and death, especially

among HIV-infected patients, and is no longer recommended by

the WHO. Several studies attempting to reduce treatment duration

to 4 months by using fluoroquinolones (with moxifloxacin replacing ethambutol or isoniazid, or gatifloxacin replacing ethambutol)

were conducted over the last decade. The main finding was that

shorter (4-month) fluoroquinolone-containing regimens are associated with significantly higher rates of relapse at 18 months than

the standard 6-month rifampin-containing regimen. In addition,

the studies showed no reduction in adverse events with the fluoroquinolone-containing regimen and no difference in all-cause and

TB-related mortality rates. Therefore, shortening of the treatment

duration to 4 months through the use of fluoroquinolones has

not been recommended. However, the recent Tuberculosis Trials

Consortium Study 31/AIDS Clinical Trials Group A5349 (Study

31/A5349) showed that a 4-month daily regimen that included

isoniazid, pyrazinamide, rifapentine at a daily dose of 1200 mg

and moxifloxacin at a daily dose of 400 mg was noninferior to

the standard 6-month regimen and had a similar adverse event

profile. In early 2021, this option was therefore considered by the

WHO as a possible alternative to the old standard provided that

rigorous antibacterial stewardship is ensured especially to prevent

fluoroquinolone resistance and that rifapentine becomes more

widely available. Alternative regimens for patients who exhibit drug

intolerance or adverse reactions are listed in Table 178-3. However,

severe side effects prompting discontinuation of any of the first-line

drugs and use of these alternative regimens are uncommon. To prevent isoniazid-related neuropathy, pyridoxine (10–25 mg/d) should

be added to the regimen given to persons at high risk of vitamin B6

deficiency (e.g., alcoholics; malnourished persons; pregnant and

lactating women; and patients with conditions such as chronic renal

failure, diabetes, and HIV infection, which are also associated with

neuropathy). Finally, to facilitate absorption of rifampin, the drug

should be taken on an empty stomach and without meals.

PATIENT CARE AND SUPPORT

Poor adherence to treatment is one of the most important impediments to cure. Moreover, the tubercle bacilli harbored by patients

who do not fully adhere to the prescribed regimen are likely to

become resistant to the drugs to which they are irregularly exposed.

Both patient- and provider-related factors may affect adherence.

Patient-related factors include a lack of belief that the illness is worth

the cost of adherence; the existence of concomitant medical conditions (notably alcohol or substance abuse); lack of social support; fear

of the stigma and discrimination associated with TB; and poverty,

with attendant joblessness and homelessness. Provider-related factors

that may prevent adherence include lack of support, education, and

encouragement of patients and inconvenient clinical services.

A variety of interventions to increase the chances of completion

of the months-long treatment course are available. First, a package of

social support interventions that are complementary and not mutually exclusive, consisting of educational, psychological, and material

goods and services, may enable people with TB to address hurdles

to treatment adherence. Health education and counseling on the disease’s seriousness and solutions and on the importance of treatment

adherence until cure should be provided to all patients at the start

of and throughout the course of TB therapy. Psychological support

(i.e., counseling sessions or peer-group support) can be particularly relevant in the context of the stigma and discrimination often

affecting people with TB and their families. Material support (e.g.,

food or financial support in forms such as meals, food baskets, food

supplements, food vouchers, transport subsidies, living allowances,

housing incentives, or financial bonuses) reduces indirect costs

incurred by patients or their attendants in accessing health services

and mitigates the consequences of income loss related to the disease.

Second, it is paramount that health services be arranged to meet

the needs and reasonable expectations of patients. Components of

optimal health services include a suitable geographic location, a

schedule responsive to patients’ needs, functional channels of communication between patients and their health care providers (e.g.,

TABLE 178-3 Recommended Antituberculosis Treatment Regimens

INITIAL PHASE CONTINUATION PHASE

INDICATION DURATION, MONTHS DRUGS DURATION, MONTHS DRUGS

New smear- or culture-positive cases 2 HRZEa,b 4 HRa,c

New culture-negative cases 2 HRZEa 4 HRa,d

Pregnancy 2 HREe 7 HR

Relapses and treatment defaultf Tailored according to rapid drug susceptibility testing

Failuresf Tailored according to rapid drug susceptibility testing

Resistance (or intolerance) to H Throughout (6) RZEQ

Resistance (or intolerance) to R Same as for MDR-TB; see below

MDR-TB (resistance to at least H + R) See Tables 178-4 and 178-5

XDR-TB See Table 178-4

Intolerance to Z 2 HRE 7 HR

a

All drugs should be given daily. b

A 4-month regimen of 8 weeks of once-daily rifapentine, isoniazid, pyrazinamide and moxifloxacin followed by 9 weeks of once-daily

rifapentine, isoniazid, and moxifloxacin is a possible alternative. c

A clinical trial showed that HIV-negative patients with noncavitary pulmonary tuberculosis who have

negative sputum AFB smears after the initial phase of treatment can be given once-weekly rifapentine/isoniazid in the continuation phase. However, this regimen is rarely

used. d

The American Thoracic Society, the Centers for Disease Control and Prevention, and the Infectious Diseases Society of America suggest that a 2-month continuation

phase could be used in HIV-seronegative patients with sputum smear–negative and culture-negative TB. e

The 6-month regimen with pyrazinamide can probably be used

safely during pregnancy and is recommended by the WHO and the International Union Against Tuberculosis and Lung Disease. If pyrazinamide is not included in the initial

treatment regimen, the minimal duration of therapy is 9 months. f

The availability of rapid molecular methods to identify drug resistance allows initiation of a proper regimen

at the start of treatment.

Abbreviations: E, ethambutol; H, isoniazid; MDR-TB, multidrug-resistant tuberculosis; Q, a quinolone antibiotic; R, rifampin; WHO, World Health Organization; XDR-TB,

extensively drug-resistant tuberculosis; Z, pyrazinamide.

1374 PART 5 Infectious Diseases

a telephone short-messaging system, audio/video call capability,

home or workplace visits), and a staff willing and competent to care

for people with TB, to address their concerns, and to base the care

they provide on sound ethical standards.

Third, it is crucial to offer the patient a suitable option for treatment administration that minimizes the chance of nonadherence.

Such options traditionally include unsupervised, self-administered

therapy; in-person directly observed therapy (DOT); and nondaily

DOT (e.g., supervision not for every dose but weekly or a few

times per week) at a location mutually agreed on by patient and

health care provider, with supervisory responsibility delegated to

a qualified person. Direct supervision of adherence is crucial in

view of the lack of tools to accurately predict adherence to selfadministered treatment and of the public health importance of TB.

The WHO, along with the ATS, the CDC, and the IDSA, states that

ideally all patients should have their therapy directly supervised,

especially during the initial phase, with proper social support

based on a patient-centered approach as described above. In several countries, personnel to supervise therapy are usually available

through TB control programs of local public health departments,

often involving members of the community who are accepted by the

patient and who have been properly trained and educated by health

workers to undertake the supervisory role. Direct supervision with

social support has been shown to significantly increase the proportion of patients completing treatment in all settings and to lessen

the chances of treatment failure, relapse, and default. In general,

community- or home-based DOT is recommended over health

facility–based DOT or unsupervised treatment; DOT administered

by trained lay providers or health care workers is recommended

over DOT administered by family members. Recently, comparison

of video-observed therapy (VOT) with in-person DOT has shown

similar outcomes. In a multicenter, analyst-blinded, randomized

controlled superiority trial of VOT through daily remote observation using a smartphone app versus DOT done 3−5 times weekly at

home, community, or clinic settings, VOT was superior to DOT in

ensuring scheduled observation of drug intake. Therefore, VOT can

replace DOT when Internet access is good and video communication technology (e.g., smartphones, tablets, computers) is available.

The system can be appropriately organized and operated by health

care providers and patients. Other digital health tools can facilitate

the monitoring of adherence, including digital medication monitors; these monitors can register when the pillbox is opened, with

options to emit audio signals or a short message to remind patients

to take medicines. These tools are customized to the needs and

preferences of the individual patient and the provider.

In addition to the above measures promoting adherence, provision of fixed-dose combination products that reduce the number of

tablets the patient needs to swallow is recommended over separate

drug formulations. Various fixed-dose combination products are

available (e.g., isoniazid/rifampin, isoniazid/rifampin/pyrazinamide,

and isoniazid/rifampin/pyrazinamide/ethambutol). Fixed-dose

combinations increase patient satisfaction and minimize the likelihood of prescription error or of development of drug resistance

resulting from monotherapy if a drug is out of stock or the patient

prefers one drug over others. In addition, these combinations facilitate programmatic management of procurement and supply. In the

past, the bioavailability of rifampin was found to be substandard in

some formulations of fixed-dose combinations. Medical regulatory

authorities should ensure that combination products are of good

quality; however, top standards for drug quality assurance are not

always operative, especially in limited-resource countries. Prescribers should be aware of this potential problem.

MONITORING TREATMENT RESPONSE AND DRUG TOXICITY

Bacteriologic evaluation through commercial liquid-culture systems

(or—when liquid-culture capacity is not yet available—through

smear microscopy) is essential in monitoring the response to TB

treatment. In addition, the patient’s weight should be monitored

regularly and the drug dosage adjusted with any significant weight

change. Patients with pulmonary disease should have their sputum

examined monthly until cultures become negative to allow early

detection of treatment failure. With the recommended 6-month

standard first-line regimen, >80% of drug-susceptible TB patients

will have negative sputum cultures at the end of the second month

of treatment. By the end of the third month, the sputum of virtually

all patients should be culture negative. In some patients, especially

those with extensive cavitary disease and large numbers of organisms, AFB smear conversion may lag behind culture conversion as

a result of the expectoration and microscopic visualization of dead

bacilli. Therefore, as capacity is built, smear microscopy should be

progressively abandoned as a monitoring tool in favor of liquid culture. As noted above, patients with cavitary disease in whom sputum

culture conversion does not occur by 2 months require immediate

testing or retesting for drug resistance. When a patient’s sputum

cultures or smears remain positive at ≥3 months despite good adherence, treatment failure caused by drug resistance is likely. The pattern of drug resistance should guide the choice of the best treatment

option (see below). A sputum specimen should be collected at the

end of treatment to document cure. In settings where mycobacterial

cultures are not yet available, monitoring by AFB smear examination should be undertaken at 2, 5, and 6 months. Bacteriologic

monitoring of patients with extrapulmonary TB is more difficult

and often is not feasible. In these cases, the response to treatment

must be assessed clinically with the help of medical imaging.

Monitoring of the response to chemotherapy by nucleic acid

amplification technology, such as the Xpert MTB/RIF assay, is not

suitable because these tests can produce positive results due to

nonviable bacilli. Likewise, serial chest radiographs are not recommended because radiographic changes may lag behind bacteriologic

response and are not highly sensitive. After the completion of treatment, neither sputum examination nor CXR is recommended for

routine follow-up purposes. However, a chest radiograph obtained

at the end of treatment may be useful for comparative purposes

should the patient develop symptoms of recurrent TB months or

years later. Patients should be instructed to report promptly for

medical assessment if they develop any such symptoms.

During treatment, patients should also be monitored for drug

toxicity. The most common adverse reaction of significance among

people treated for drug-susceptible TB is hepatitis. Patients should

be carefully educated about the signs and symptoms of drug-induced

hepatitis (e.g., dark urine, loss of appetite, nausea) and should be

instructed to discontinue treatment promptly and see their health

care provider if these manifestations occur. Although biochemical

monitoring is not routinely recommended, all adult patients should

undergo baseline assessment of liver function (e.g., measurement

of serum levels of hepatic aminotransferases and bilirubin). Older

patients, those with concomitant diseases, those with a history of

hepatic disease (especially hepatitis C), and those using alcohol

daily should be monitored especially closely (i.e., monthly), with

repeated measurements of aminotransferases, during the initial phase

of treatment. Up to 20% of patients have small increases (up to

three times the upper limit of normal) in serum levels of aspartate

aminotransferase that are not accompanied by symptoms and are of

no consequence. Suspension of treatment should be considered for

patients with symptomatic hepatitis, especially when accompanied by

at least a three-fold increase in serum levels of AST and/or ALT, and

for patients without symptoms of hepatic injury who have marked

(at  least five-fold) elevations in serum levels of AST and/or ALT.

Drugs should be reintroduced one at a time after liver function has

returned to normal. Hypersensitivity reactions usually require the

discontinuation of all drugs and rechallenge to determine which agent

is the culprit. Because of the variety of regimens available, it usually

is not necessary—although it is possible—to desensitize patients.

Hyperuricemia and arthralgia caused by pyrazinamide can usually be

managed by the administration of acetylsalicylic acid; however, pyrazinamide treatment should be stopped if the patient develops gouty

arthritis. Individuals who develop autoimmune thrombocytopenia

secondary to rifampin therapy should not receive the drug thereafter.

Similarly, the occurrence of optic neuritis with ethambutol is an indication for permanent discontinuation of this drug. Other common

1375CHAPTER 178 Tuberculosis

manifestations of drug intolerance, such as pruritus and gastrointestinal upset, can generally be managed without the interruption of

therapy. Treatment with second-line agents for drug-resistant TB is

associated with a variety of adverse drug reactions that are more frequent and severe than in patients receiving first-line TB regimens (see

below). The likelihood of drug–drug interactions is also higher when

second-line regimens are used.

TREATMENT FAILURE AND RELAPSE

As stated above, treatment failure should be suspected when a

patient’s cultures (or sputum smears, when cultures are not available) remain positive after 3 months of treatment. In the management of such patients, it is imperative that the current isolate be

urgently retested (or tested for the first time if, for some reason,

rapid molecular susceptibility testing was not performed at the start

of treatment) for susceptibility to first-line agents and, if resistance

to rifampin is detected, to second-line agents as well. The treatment

approach should start with molecular testing for—at the least—

resistance to rifampin and isoniazid. Because results are expected

to become available within a few days, changes in the regimen

can be postponed until that time. However, if the patient’s clinical

condition is deteriorating rapidly, an earlier change in regimen may

be indicated. A cardinal rule in the latter situation is always to add

more than one drug, preferably two or three, at a time to a failing

regimen; in practice, starting an empirical regimen for MDR-TB

(see “Drug-Resistant TB,” below) is warranted. The patient may

continue to take isoniazid and rifampin along with these new agents

pending the results of susceptibility tests.

Patients who experience a recurrence after apparently successful

treatment (i.e., a relapse) are less likely to harbor drug-resistant

strains than are patients in whom treatment has failed. Acquired

resistance is uncommon among strains from patients in whom

relapse follows the proper completion of a standard 6-month regimen. The treatment decision depends on a general assessment of

the risk of drug resistance, the severity of the case, and the results

of rapid susceptibility testing. Patients whose treatment has been

interrupted and who have a high likelihood of MDR-TB should

receive an empirical MDR-TB regimen that includes second-line

agents (Table 178-3). Once drug susceptibility results are available,

the regimen can be adjusted accordingly.

DRUG-RESISTANT TB

Strains of M. tuberculosis resistant to individual drugs arise by

spontaneous point mutations in the mycobacterial genome

that occur at low but predictable rates (10–7–10–10 for the key

drugs). Resistance to rifampin is associated with mutations in the

rpoB gene in 95% of cases, that to isoniazid with mutations mainly

in the katG gene (50–95% of cases) and the inhA gene promoter

region (up to 45%), that to pyrazinamide in the pncA gene (up to

98%), that to ethambutol in the embB gene (50–65%), that to the

fluoroquinolones in the gyrA–gyrB genes (75–95%), and that to the

aminoglycosides mainly in the rrs gene (up to 80%); the C-12T

mutation is the most common mutation in the eis promoter region

associated with aminoglycoside resistance, especially in Eastern

European countries. Because there is no cross-resistance among the

commonly used classes of drugs, the probability that a strain will be

resistant to two drug classes is the product of the probabilities of

resistance to each drug class and thus is low. The development of

drug-resistant TB almost invariably follows monotherapy—i.e., the

failure of the health care provider to prescribe at least two drugs to

which tubercle bacilli are susceptible; of the patient to absorb or

take properly prescribed therapy; or of the bioavailability of

poor-quality drugs or preparations (e.g., due to crushing of tablets).

Drug-resistant TB may be either primary or acquired. In primary

drug resistance, the patient is infected from the start by a drugresistant strain. Acquired resistance develops in the infecting strain

during treatment. In North America, Western Europe, most of

Latin America, and the Persian Gulf states, rates of primary resistance are generally low and isoniazid resistance is most common. In

the United States, although rates of primary isoniazid resistance

have been stable at ~7–8%, the rate of primary MDR-TB has

declined from 2.5% in 1993 to <1% since 2000. As described above,

MDR-TB is an increasingly serious problem in some regions, especially in the countries of the former Soviet Union and some countries of Asia (Fig. 178-12). Even more serious is the occurrence of

MDR strains that are also resistant to additional second-line agents

used in treatment, such as the fluoroquinolones. Creation of

Percentage

of cases

0–2.9

3–5.9

6–11

12–17

18–24

≥25

No data

Not applicable

FIGURE 178-12 Percentage of new cases of multidrug-resistant/rifampin-resistant tuberculosis (TB) in all countries surveyed by the World Health Organization (WHO) Global

Drug Resistance Surveillance Project during 1994–2018. Figures are based on the most recent year for which data have been reported, which varies among countries. Data reported

before the year 2002 are not shown. (See disclaimer in Fig. 178-2. Reproduced with permission from Global Tuberculosis Report 2019. Geneva, World Health Organization; 2019.)

1376 PART 5 Infectious Diseases

drug-resistant TB can be prevented by adherence to the principles of

sound treatment: inclusion of at least two quality-assured, bactericidal drugs to which the organism is susceptible; use of effective

combination regimens; supervision of treatment with patient support; and verification that patients complete the prescribed course.

The use of fixed-dose combination products may prevent selective

drug intake and therefore possibly protect against the creation of

drug resistance. Transmission of drug-resistant strains can be prevented by the implementation of respiratory infection-control measures (see below) and by early detection of people with active TB

followed by immediate initiation of treatment with an effective

regimen.

Isoniazid-Resistant TB For the treatment of patients with

isoniazid-resistant disease, a combination of rifampin, ethambutol,

pyrazinamide, and levofloxacin for 6 months is recommended.

This fluoroquinolone-containing regimen should not be used until

rifampin resistance has been excluded by a reliable diagnostic test

to avoid inadvertent treatment of MDR-TB with an inadequate regimen. Ideally, a laboratory test for susceptibility should also be done

for the fluoroquinolones and pyrazinamide. If the fluoroquinolone

is contraindicated because of intolerance or resistance, the patient

can be given a 6-month regimen of rifampin, ethambutol, and pyrazinamide. Isoniazid probably does not contribute to a successful

outcome in these regimens but may be retained (also to facilitate

treatment with the four-drug fixed-dose formulation). Other drugs,

such as the injectable aminoglycosides, are unlikely to play a role in

the treatment of most isoniazid-resistant TB cases. However, they

may be considered in the presence of additional resistance (e.g., to

pyrazinamide or ethambutol) or of drug intolerance.

RR-, MDR-TB MDR-TB, in which bacilli are resistant to (at least)

isoniazid and rifampin, is more difficult to manage than is disease

caused by drug-susceptible organisms because these two bactericidal drugs are the most potent first-line agents available and

because associated resistance to other first-line drugs as well (e.g.,

ethambutol) is not uncommon. Treatment for RR-TB and MDR-TB

has traditionally been a topic of much debate, given its complexity, long duration, toxicity, and limited efficacy; the cost of most

second-line drugs; and the lack of randomized controlled clinical

trials to support combinations. Until recently, recommendations

were therefore based largely on low-quality evidence from observational studies and on best-practice consensus among experts.

Recent developments include the accrual of individual datasets

for patients treated worldwide, the release of findings from two

randomized controlled phase 3 clinical trials (the STREAM Stage 1

trial comparing a 9-month, shorter MDR-TB regimen with the previous optimized WHO background regimen; and Otsuka’s phase 3

trial 213 comparing the addition of the new drug delamanid to the

previous optimized WHO background regimen with the addition

of placebo), the publication of results of an open-label, single group

study enrolling highly drug-resistant cases on a regimen composed

of three oral drugs (bedaquiline, pretomanid, and linezolid), and

the assessment of programmatic data from South Africa on the

large-scale use of a shorter all-oral bedaquiline-containing regimen.

The assessment of this information resulted in an update of WHO

guidance for the treatment of MDR-TB and all other RR-TB cases

in which isoniazid resistance is absent or unknown.

As a result, two main approaches are now recommended by the

WHO to treat MDR/RR-TB: (1) an individualized longer regimen

of 18–20 months’ duration (or 15-17 months after culture conversion) consisting of an optimal combination of oral drugs chosen

according to a rational approach and using the WHO priority

grouping of medicines (Table 178-4); and (2) a shorter, all-oral,

bedaquiline-containing regimen of 9–12 months’ duration. While

these recommendations may change when new data indicate the

need, all-oral regimens are now the preferred options and the use

of either a shorter or a longer regimen depends on the assessment

of the severity of disease, knowledge of drug resistance pattern, and

history of previous treatment.

Longer MDR-TB Regimen In MDR/RR-TB patients where infecting strains have or are presumed to have additional resistance

(e.g., resistance to the fluoroquinolones), in those who have severe

pulmonary or extrapulmonary disease, or those who have been

treated previously with second-line drugs, a longer regimen is recommended. Table 178-4 shows the priority grouping of drugs recommended by the WHO and the approach to the design of a longer

regimen for both adults and children. As much as possible, the

regimen is composed of all group A agents and at least one group

B agent. The use of bedaquiline and linezolid is promoted, together

with a fluoroquinolone (levofloxacin or moxifloxacin), whenever

possible, in all patients. Clofazimine and cycloserine (group B) are

the two preferred options to be added to group A drugs. Group C

drugs can replace group A and B agents that cannot be used, and

the choice should be based on drug susceptibility testing, drug

resistance levels in the population, the patient’s history of previous

use of these drugs, and potential intolerance or toxicity. The injectable agents (e.g., amikacin, streptomycin, and the carbapenems)

are assigned a lower priority because of inconvenience of use and

the toxicity of aminoglycosides. A fully oral regimen is thus also

the first choice and most desirable option even for the most severe

cases who are ineligible for a shorter regimen. Nevertheless, when

injectables are necessary and DST supports their use, amikacin has

been found to be the most effective drug in this class, followed by

streptomycin, while kanamycin and capreomycin seem less effective, both having been associated with higher risks of failure and

relapse when compared with longer regimens in which other agents

were used instead. A treatment course of at least 18–20 months is

recommended, but duration may depend on the patient’s response.

Important considerations when treating MDR-TB patients include

the safety and effectiveness of bedaquiline use beyond 6 months.

Likewise, the ideal duration of use of linezolid, which is known to

be highly effective but also very frequently produces toxicity (e.g.,

peripheral and optic neuropathy, and bone marrow suppression), is

unclear. Additional considerations concern the use of pyrazinamide

and of the aminoglycosides amikacin and streptomycin, which is

now restricted to cases with proven susceptibility to those agents.

The role of delamanid in the treatment of MDR-TB remains to be

assessed, although, as stated earlier, data from the phase 3 clinical

trial of this agent as an addition to the longer regimen previously

recommended by the WHO did not demonstrate a higher rate of

treatment success than was obtained with the background regimen

plus placebo. Furthermore, evidence on the safety and effectiveness

of delamanid given for >6 months is presently incomplete.

Shorter MDR-TB Regimen In MDR/RR-TB patients with no extensive pulmonary disease or severe extrapulmonary disease, without

history of previous treatment with second-line drugs, and whose

TABLE 178-4 Groups of Drugs Recommended for Use in Longer

MDR-TB Regimens and Approach to the Design of a Longer Regimen

for Adults and Children

GROUP DRUG

Group A: Drugs to be prioritized and

included in all regimens, unless they

cannot be used

Levofloxacin or moxifloxacin

Bedaquiline

Linezolid

Group B: Drugs to be added in all

regimens, unless they cannot be used 

Clofazimine

Cycloserine or terizidone

Group C: Drugs to be used to complete

the regimen and when drugs from

groups A and B cannot be used 

Ethambutol

Delamanid

Pyrazinamide

Imipenem-cilastatin or meropenem

Amikacin or streptomycin

Ethionamide or prothionamide

p-Aminosalicylic acid

Source: Adapted from the World Health Organization, 2018.

1377CHAPTER 178 Tuberculosis

infecting strains are not resistant to the fluoroquinolones, a shorter,

all-oral, bedaquiline-containing regimen is recommended. Recent

observational programmatic data from South Africa, assessed by

WHO in 2019, showed that a fully oral regimen starting with

6  months of bedaquiline accompanied by 4−6 months of levofloxacin or moxifloxacin, ethionamide, ethambutol, pyrazinamide,

high-dose isoniazid (10–15 mg/kg per day), and clofazimine, and

followed by 5 months of levofloxacin (or moxifloxacin), clofazimine,

pyrazinamide and ethambutol, was associated with low toxicity and

better outcomes than the older, standardized, injectable-containing

regimen when used in patients, including the HIV-infected, with no

extensive pulmonary disease or severe extrapulmonary disease, fluoroquinolone resistance, or previous history of second-line drug use.

The WHO therefore now recommends the adoption of this regimen

and the progressive phasing-out of the previously recommended

injectable-containing shorter regimen. The WHO also recommends

that any modifications of a shorter regimen, where injectables are

replaced by drugs other than bedaquiline, should be tested under

operational research conditions and not adopted on a large programmatic scale until evidence shows their safety, tolerability, and efficacy.

The criteria used to define eligible patients are listed in

Table 178-5. Adults and children eligible for the shorter regimen

may still be offered the option of a new longer regimen if their completion of the full duration is adequately supported; with the longer

regimen, the likelihood of relapse-free cure could be increased, and

its administration is fully oral. As with any anti-TB regimen, the risk

of creating additional resistance is high if the regimen is used incorrectly (e.g., in someone with preexisting fluoroquinolone resistance).

As in past recommendations, informed consent should be sought

from patients treated with all MDR-TB regimens, and active TB drug

safety monitoring is recommended. Patients taking QT interval–

prolonging drugs (bedaquiline, delamanid, clofazimine, and fluoroquinolones) should be closely monitored, with electrocardiography

performed at the start of treatment and repeated during treatment;

patients with a QTc interval >500 ms or a history of ventricular

arrhythmias should not be given these drugs. Patients taking

amikacin should undergo serial audiometry to detect any hearing

loss early on. Incentives and other forms of support can encourage

patients not to interrupt treatment.

MDR-TB patients with additional resistance to fluoroquinolones

and other second-line medicines have fewer treatment options

and a poorer prognosis. However, the new longer regimen offers

more options for a reasonably effective and tolerable regimen. The

design of regimens for complex patterns of MDR-TB follows the

same principles outlined in Table 178-4 through the selection of

agents likely to be effective and tolerated. Observational studies

have shown that aggressive management in such patients, with early

drug susceptibility testing, use of a rational combination of at least

five effective drugs, strict adherence to directly observed therapy,

monthly bacteriologic monitoring, and intensive patient support,

may—besides interrupting transmission—increase the chances of

cure and avert death. For patients with localized disease and sufficient pulmonary reserve, lobectomy or wedge resection may be

considered as part of treatment. A novel regimen composed of

bedaquiline, the new nitroimidazole compound pretomanid, and

linezolid (BPaL) administered orally for 6 months has been tested by

the Global Alliance for TB Drug Development in South Africa in an

open-label, single-group study enrolling 109 patients with MDR-TB

caused by a strain with additional resistance to a fluoroquinolone

or a second-line injectable drug, or were intolerant of therapy, or in

whom treatment had failed. The cure rate was 90% after a 6-month

course of treatment; the main toxicity, due to linezolid, consisted of

peripheral neuropathy (81%) and myelosuppression (48%), which

were manageable with dose reduction or interruption of the drug.

Based on these findings, in August 2019 the FDA approved the

new drug pretomanid under the Limited Population Pathway for

Antibacterial and Antifungal Drugs (LPAD pathway) as part of a

three-drug, 6-month, all-oral regimen for the treatment of a population of patients with MDR-TB caused by a strain with additional

resistance to a fluoroquinolone or a second-line injectable drug, or

who were intolerant of therapy, or in whom treatment had failed.

Although approved by the FDA and proven as highly efficacious in

the only trial available, in late 2019 the WHO suggested that this

new 6−9 month regimen be used either under operational research

conditions until more information is available on safety and efficacy

or as a last resort in difficult-to-treat individual patients. A new,

dose-blinded study reported in 2021 suggested that BPaL regimens

where linezolid was used at reduced daily dose (from 1200 mg to

600 mg) and/or for a shorter period of time (from 6 to 2 months)

were safer. Another regimen being tested by the Global Alliance is

composed of bedaquiline, pretomanid, moxifloxacin, and pyrazinamide (BPaMZ). In a phase 2B trial, MDR-TB patients became

culture-negative within 8 weeks of treatment three times faster than

drug-sensitive TB patients treated with the standard regimen. The

BPaMZ regimen is now being tested for both MDR-TB and drugsusceptible TB, with the aim of reducing treatment duration to 6

months and 4 months, respectively. Results are expected in late 2021.

Because the management of MDR-TB is complicated by both

social and medical factors, care of seriously ill patients is ideally

provided in specialized centers or, in their absence, in the context

of programs with adequate resources and capacity, including community support. When patients are in stable condition, treatment

and care on an ambulatory basis at a decentralized health care facility should be prioritized as this approach may increase treatment

success and reduce loss to follow-up. This approach should not,

however, preclude hospitalization when it is necessary. Respiratory

infection-control measures should be observed throughout. As

part of a patient-centered approach, palliative and end-of-life care

should be provided as a priority when all recommended treatment

options have been exhausted.

HIV-ASSOCIATED TB

Several observational studies and randomized controlled trials have

shown that treatment of HIV-associated TB with anti-TB drugs and

simultaneous use of ART is associated with significant reductions in

mortality risk and AIDS-related events. Evidence from randomized

controlled trials shows that early initiation of ART during anti-TB

treatment is associated with a 34–68% reduction in mortality rates,

with especially good results in patients with CD4+ T-cell counts of

<50/μL. Therefore, the main aim in the management of HIV-associated TB is to initiate anti-TB treatment and to immediately consider

initiating or continuing ART. All HIV-infected TB patients, regardless of CD4+ T-cell count, are candidates for ART, which optimally

is initiated as soon as possible after the diagnosis of TB and with the

strong recommendation to start within the first 8 weeks of anti-TB

therapy; ART should be started within the first 2 weeks of TB treatment for profoundly immunosuppressed patients with CD4+ T-cell

counts of <50/μL. In general, the standard 6-month daily regimen

is equally efficacious in HIV-negative and HIV-positive patients

with drug-susceptible TB. However, in the uncommon situation

TABLE 178-5 Criteria for Offering a Shorter All-Oral Regimen

(9−11 Months) to Patients with Confirmed Multidrug- or

Rifampin-Resistant (MDR/RR) Tuberculosis (TB)

• Confirmed absence of resistance to or lack of suspicion of the ineffectiveness

of a drug in the shorter MDR-TB regimen (except for isoniazid resistance)

• No history of exposure to one or more second-line drugs used in the shorter

MDR-TB regimen (including bedaquiline) for >1 month

• Confirmed fluoroquinolone-susceptible disease

• No intolerance to drugs used in the shorter MDR-TB regimen or risk of toxicity

(e.g., drug–drug interactions)

• No pregnancy

• No extensive pulmonary disease

• No disseminated, meningeal, or central nervous system TB

• Availability of all drugs in the shorter MDR-TB regimen

Source: Adapted from the World Health Organization, 2019.

1378 PART 5 Infectious Diseases

where an HIV-infected patient cannot receive ART, prolongation

of the continuation phase of TB treatment by 3 months can be considered. As in any other TB patient, intermittent regimens should

not be used in HIV-infected people. As for any other adult living

with HIV (Chap. 202), first-line ART for TB patients consists of

two nucleoside reverse transcriptase inhibitors plus a nonnucleoside

reverse transcriptase inhibitor or an integrase or protease inhibitor. Recent guidelines have also considered a two-drug treatment

consisting of one nucleoside reverse transcriptase inhibitor plus an

integrase inhibitor. Although TB treatment modalities are similar

to those in HIV-negative patients, adverse drug reactions may be

more pronounced in HIV-infected patients. In this regard, three

important considerations are relevant: an increased frequency of

paradoxical reactions, interactions between ART components and

rifamycins, and development of rifampin monoresistance with intermittent treatment. IRIS—i.e., the exacerbation of symptoms and

signs of TB—has been described above. Rifampin, a potent inducer

of enzymes of the cytochrome P450 system, lowers serum levels

of many HIV protease inhibitors and some nonnucleoside reverse

transcriptase inhibitors—essential drugs used in ART. In such cases,

rifabutin, which has much less enzyme-inducing activity, has been

used in place of rifampin. However, dosage adjustments for rifabutin

and protease or integrase inhibitors are still being assessed. Several

clinical trials have found that patients with HIV/TB co-infection

whose degree of immunosuppression is advanced (e.g., CD4+ T-cell

counts of <100/μL) are prone to treatment failure and relapse with

rifampin-resistant organisms when treated with “highly intermittent” (i.e., once- or twice-weekly) rifamycin-containing regimens.

Consequently, it is now recommended that all TB patients who

are infected with HIV, like all other TB patients with rifampin-susceptible disease, receive a rifampin-containing regimen on a daily

basis. Because recommendations are frequently updated, consultation of the following websites is advised: www.who.int/hiv, www.who

.int/tb, www.cdc.gov/hiv, and www.cdc.gov/tb.

SPECIAL CLINICAL SITUATIONS

Although comparative clinical trials of treatment for extrapulmonary TB are limited, the available evidence indicates that most

forms of disease should be treated with a 6-month regimen recommended for patients with pulmonary disease. For TB meningitis,

the ATS, the CDC, and the IDSA recommend extension of the

continuation phase for 7–10 months. The WHO and the American Academy of Pediatrics recommend that children with bone

and joint TB, tuberculous meningitis, or miliary TB receive up to

12 months of treatment (2-month induction treatment followed

by 10-month consolidation treatment). Treatment for TB may be

complicated by underlying medical problems that require special

consideration. As a rule, patients with chronic renal failure should

not receive aminoglycosides and should receive ethambutol only if

serum drug levels can be monitored. Isoniazid, rifampin, and pyrazinamide may be given in the usual doses in cases of mild to moderate renal failure, but the dosages of isoniazid and pyrazinamide

should be reduced for all patients with severe renal failure except

those undergoing hemodialysis. Patients with hepatic disease pose

a special problem because of the hepatotoxicity of isoniazid, rifampin, and pyrazinamide. Patients with severe hepatic disease may be

treated with ethambutol, streptomycin, and possibly another drug

(e.g., a fluoroquinolone); if required, isoniazid and rifampin may

be administered under close supervision. The use of pyrazinamide

by patients with liver failure should be avoided. Silicotuberculosis

necessitates the extension of therapy by at least 2 months.

The regimen of choice for pregnant women (Table 178-3) is

9 months of treatment with isoniazid and rifampin supplemented

by ethambutol for the first 2 months. Although the WHO has

recommended routine use of pyrazinamide for pregnant women in

combination with isoniazid and rifampin, this drug has not been

recommended for pregnant women in the United States because of

insufficient data documenting its safety in pregnancy. Streptomycin

is contraindicated because it is known to cause eighth-cranial-nerve

damage in the fetus. The thioamides, bedaquiline, and delamanid

should also be avoided in the treatment of pregnant women with

MDR-TB. Treatment for TB is not a contraindication to breastfeeding; most of the drugs administered will be present in small

quantities in breast milk, albeit at concentrations far too low to provide any therapeutic or prophylactic benefit to the child.

Medical consultation on difficult-to-manage cases is provided by

the US CDC Regional Training and Medical Consultation Centers

(www.cdc.gov/tb/education/rtmc/).

PREVENTION

The primary way to prevent TB is to diagnose and isolate infectious

cases rapidly and to administer appropriate treatment until patients

are rendered noninfectious (usually 2–4 weeks after the start of proper

treatment) and the disease is cured. Additional strategies include BCG

vaccination and preventive treatment of persons with TB infection who

are at high risk of developing active disease.

■ BCG VACCINATION

Historically one of the most used vaccines in the history of medicine,

BCG was derived from an attenuated strain of M. bovis and was first

administered to humans in 1921. Many BCG vaccines are available

worldwide; all are derived from the original strain, but the vaccines vary

in efficacy, ranging from 80% to nil in randomized, placebo-controlled

trials. A similar range of efficacy was found in observational studies

(case-control, historic cohort, and cross-sectional) in areas where infants

are vaccinated at birth. These studies and a meta-analysis also found

higher rates of efficacy in the protection of infants and young children

from serious disseminated forms of childhood TB, such as tuberculous meningitis and miliary TB. BCG vaccine is safe and rarely causes

serious complications. The local tissue response begins 2–3 weeks after

vaccination, with scar formation and healing within 3 months. Side

effects—most commonly, ulceration at the vaccination site and regional

lymphadenitis—occur in 1–10% of vaccinated persons. Some vaccine

strains have caused osteomyelitis in ~1 case per million doses administered. Disseminated BCG infection (“BCGitis”) and death have occurred

in 1–10 cases per 10 million doses administered, although this problem

is restricted almost exclusively to persons with impaired immunity, such

as children with severe combined immunodeficiency syndrome or adults

with HIV infection. BCG vaccination induces TST reactivity, which

tends to wane with time. The presence or size of TST reactions after

vaccination does not predict the degree of protection afforded.

BCG vaccine is recommended for routine use at birth in countries

or among populations with high TB prevalence (Fig. 178-13). However, because of the low risk of transmission of TB in the United States

and other high-income countries, the variability in protection afforded

by BCG, and its impact on the TST, the vaccine is not recommended

for general use. HIV-infected adults and children should not receive

BCG vaccine. Moreover, infants whose HIV status is unknown but who

have signs and symptoms consistent with HIV infection or who are

born to HIV-infected mothers should not receive BCG.

Over the past decade, renewed research and development efforts

have been made toward a new TB vaccine, and several candidates have

been developed and tested. The MVA-85A was the first new TB vaccine

to be tested in a phase 2B proof-of-concept trial in infants in South

Africa. Results published in 2013 showed that MVA-85A was well tolerated and modestly immunogenic but did not confer significant protection against clinical TB or M. tuberculosis infection. A second, more

promising candidate vaccine, M72/AS01E

, a subunit vaccine pairing two

M. tuberculosis antigens (32A and 39A) with the adjuvant M72/AS01E

,

was recently tested in a randomized trial among 3575 patients with

M. tuberculosis infection to prevent development of active disease. TB

developed in 13 participants among those receiving the vaccine and in

26 among those receiving placebo with an estimated efficacy of 49.7%

at 36 months. Adverse events were not different in the two groups. This

vaccine is now being considered for further development.

As of the end of 2020, 14 candidate vaccines were in various stages

of clinical trials. They included whole-cell or mycobacterial whole-cell

1379CHAPTER 178 Tuberculosis

or lysates, viral vector vaccines, and adjuvant recombinant protein vaccines. Several challenges must be faced in the development of a TB vaccine. For instance, the lack of predictive animal models and protection

correlates renders trials long and expensive. Furthermore, the decision

about whether a candidate vaccine should be developed for prevention

of infection (preexposure) or prevention of reactivation (postexposure)

without an exact understanding of its precise mechanism of action is

complex. Therefore, introduction of a new vaccine on a large scale is

not likely in the near future. This step will require an intensified and

much larger investment in research and development.

■ TB PREVENTIVE TREATMENT (TPT)

It is estimated that 1.7 billion people—more than one-quarter of the

human population—have been infected with M. tuberculosis. Although

only a small fraction of these infections will progress toward active

disease in a lifetime, new active cases will continue to emerge from

this pool of infected individuals. Therefore, TPT (also called chemoprophylaxis or preventive chemotherapy, and previously referred to as

treatment of latent TB infection) is a fundamental intervention in TB

control and elimination strategies.

Infection can be tested using TST or IGRA, although these tests

just measure host immune response to TB antigens. Unfortunately, at

present, there is no gold-standard diagnostic test that can confirm true

infection (as opposed to immunologic memory of previous exposure)

or predict which infected individuals will develop active TB. As a

result, decisions to treat infection should include consideration of the

risk of progression in an individual. For skin testing, five tuberculin

units of polysorbate-stabilized PPD should be injected intradermally

into the volar surface of the forearm (i.e., the Mantoux method). Multipuncture tests are not recommended. Reactions are read at 48–72 h as

the transverse diameter (in millimeters) of induration; the diameter of

erythema is not considered. In some persons, TST reactivity wanes

with time but can be recalled by a second skin test administered

≥1 week after the first (i.e., two-step testing). For persons periodically

undergoing the TST, such as health care workers and individuals

admitted to long-term-care institutions, initial two-step testing may

preclude subsequent misclassification of those who have boosted

reactions as TST converters. The cutoff for a positive TST (and thus

for TPT) is related both to the probability that the reaction represents

true infection and to the likelihood that the individual, if truly infected,

will develop TB. Table 178-6 suggests possible conventional cutoff by

risk group. Thus, positive reactions for persons with HIV infection,

recent close contacts of infectious cases, organ transplant recipients,

Percentage

0–4.9

50–89

90–100

No data

Not applicable

FIGURE 178-13 Coverage of BCG vaccination in 2018. The target population of BCG coverage varies depending on national policies but is typically for the number of live

births in the year of reporting. (See disclaimer in Fig. 178-2. Reproduced with permission from Global Tuberculosis Report 2019. Geneva, World Health Organization; 2019.)

TABLE 178-6 Tuberculin Reaction Size and Cutoff for Tuberculosis

(TB) Preventive Treatment

RISK GROUP

TUBERCULIN REACTION

SIZE, mm

HIV-infected persons ≥5

Recent contacts of a patient with TB ≥5a

Organ transplant recipients ≥5

Persons with fibrotic lesions consistent with old TB

on chest radiography

≥5

Persons who are immunosuppressed—e.g., due to

the use of glucocorticoids or tumor necrosis factor

α inhibitors

≥5

Persons with high-risk medical conditionsb ≥5

Recent immigrants (≤5 years) from high-prevalence

countries

≥10

Injection drug users ≥10

Mycobacteriology laboratory personnel; residents

and employees of high-risk congregate settingsc

≥10

Children <5 years of age; children and adolescents

exposed to adults in high-risk categories

≥10

Low-risk personsd ≥15

a

Tuberculin-negative contacts, especially children, should receive prophylaxis for

2–3 months after contact ends and should then undergo repeat tuberculin skin

testing (TST). Those whose results remain negative should discontinue prophylaxis.

HIV-infected contacts should receive a full course of treatment regardless of TST

results. b

These conditions include silicosis and end-stage renal disease managed

by hemodialysis. c

These settings include correctional facilities, nursing homes,

homeless shelters, and hospitals and other health care facilities. d

Except for

employment purposes where longitudinal TST screening is anticipated, TST is

not indicated for these low-risk persons. A decision to treat should be based on

individual risk/benefit considerations.

Source: Adapted from Centers for Disease Control and Prevention: TB elimination—

treatment options for latent tuberculosis infection (2011). Available at http://www

.cdc.gov/tb/publications/factsheets/testing/skintestresults.pdf.