1369CHAPTER 178 Tuberculosis

meningitis is suspected as well as a replacement test (preferable to

conventional microscopy, culture, and histopathology) for selected

nonrespiratory specimens—those obtained by gastric lavage, fineneedle aspiration, or pleural or other biopsies. Sensitivity varies

according to specimen type being the lowest in pleural fluid (50%

with Xpert MTB/RIF and 71% with Ultra) and the highest in synovial

fluid (97%) and lymph node biopsy (100% with Ultra). “Trace calls” in

specimens from persons with extrapulmonary TB, as well as for HIVinfected patients and children, should be considered true positives,

given the high risk of severe morbidity and premature death, while

among other cases they warrant additional tests to confirm the diagnosis of TB and prevent overtreatment. Among patients with a recent

history of TB, “trace calls” may represent false positivity due to DNA

from dead bacilli under degradation.

Truenat MTB and MTC Plus are two newly introduced rapid

molecular tests with a sensitivity of 83% and 89%, respectively, if

compared to bacteriological culture, and with specificity of 98% and

99%, respectively. Truenat MTB-Rif Dx detects rifampin resistance

with a sensitivity of 93% and a specificity of 95%. These rapid tests,

developed in India by MolBio Diagnostics Pvt Ltd Goa, have accuracy

comparable to that of Xpert MTB/RIF and Ultra. Being portable and

battery-operated, they can be used in the most peripheral care settings.

New high-throughput automated platforms for TB diagnosis and drugresistant variants are becoming available (Abbott RealTime MTB and

RIF/INH, FluoroType MTBDR, BD Max MDR-TB). These platforms

are suitable for centralized laboratories and have the advantage of processing a large number of samples in a reasonable time. Sensitivity is

higher than 91% and specificity ranges from 97 to 100%. Head-to-head

studies with Xpert MTB/RIF have shown comparable performance.

Another available molecular test for detection of M. tuberculosis is

based on the loop-mediated isothermal amplification (LAMP) temperature-independent technology that amplifies DNA, is relatively simple

to use, and is interpreted through a visual display. The TB-LAMP assay

(LoopampTM M. tuberculosis complex detection kit; Eiken Chemical

Company, Japan) requires minimal laboratory infrastructure and has

few biosafety requirements. It may be used as a replacement for sputum-smear microscopy for the diagnosis of adult pulmonary TB and

as a follow-up test to smear microscopy for the further investigation

of smear-negative specimens from adults with suspected pulmonary

TB. The TB-LAMP assay should not replace rapid molecular tests that

detect both TB and rifampin resistance, and its usefulness in HIV-infected people in whom TB is suspected remains unclear.

■ AFB MICROSCOPY

In many low- and middle-income settings, a presumptive diagnosis is

still commonly based on the finding of AFB on microscopic examination of a diagnostic specimen, such as a smear of expectorated

sputum or of tissue (e.g., a lymph node biopsy). Although inexpensive,

AFB microscopy has relatively low sensitivity (40–60%) in cultureconfirmed cases of pulmonary TB. The traditional method—light

microscopy of specimens stained with Ziehl-Neelsen basic fuchsin

dyes—is satisfactory, although time consuming and operator dependent. Most modern laboratories processing large numbers of diagnostic specimens use auramine–rhodamine staining and fluorescence

microscopy; this approach is more sensitive than the Ziehl-Neelsen

method. However, it is expensive because it requires high-cost mercury

vapor light sources and a darkroom. Less expensive light-emitting

diode (LED) fluorescence microscopes are now recommended by the

WHO as the microscopy tool of choice. They are as sensitive as—or

more sensitive than—traditional fluorescence microscopes. As a result,

conventional light and fluorescence microscopes are being replaced

with this more recent technology, especially in developing countries.

For patients with signs or symptoms of pulmonary TB, it has been

recommended that one or two sputum specimens, preferably collected

early in the morning, should be submitted to the laboratory for AFB

smear and mycobacterial culture. If tissue is obtained, it is critical

that the portion of the specimen intended for culture not be put in

preservation fluid such as formaldehyde. The use of AFB microscopy

in examining urine or gastric lavage fluid is limited by the low numbers

of organisms, which can cause false-negative results, or the presence of

commensal mycobacteria, which can cause false-positive results.

■ MYCOBACTERIAL CULTURE

Definitive diagnosis depends on the isolation and identification of

M. tuberculosis from a clinical specimen. Commercial liquid-culture

systems such as the Mycobacterial Growth Indicator Tube (MGIT)

system (Becton Dickinson; Franklin Lakes, NJ) are recommended by

the WHO as the reference standard for culture. The MGIT system uses

a fluorescent compound sensitive to the presence of oxygen dissolved

in the liquid medium. The appearance of fluorescence, detected by fluorometric technology, indicates active growth of mycobacteria. MGIT

cultures usually become positive after a period ranging from 10 days to

2–3 weeks; the tubes are read weekly until the eighth week of incubation before the result is declared to be negative. Specimens may also be

inoculated onto egg- or agar-based medium (e.g., Löwenstein-Jensen or

Middlebrook 7H10 or 7H11) and incubated at 37°C (under 5% CO2

 for

Middlebrook medium). Because most species of mycobacteria, including M. tuberculosis, grow slowly, 4–8 weeks may be required before

growth is detected on these conventional culture media. Although M.

tuberculosis may be identified presumptively on the basis of growth

time and colony pigmentation and morphology, a variety of biochemical tests have traditionally been used to speciate mycobacterial isolates.

In modern, well-equipped laboratories, commercial liquid culture for

isolation and species identification by molecular methods or highpressure liquid chromatography of mycolic acids has replaced isolation

on solid media and identification by biochemical tests. A low-cost,

rapid immunochromatographic lateral-flow assay based on detection

of MTP64 antigen may also be used for species identification of the M.

tuberculosis complex in culture isolates. These new methods, which are

increasingly used in limited-resource settings, have decreased the time

required for bacteriologic confirmation of TB to 2–3 weeks.

■ DRUG SUSCEPTIBILITY TESTING

Universal DST is considered by the WHO as the current standard of

care for all TB patients and should consist of DST to at least rifampin

for all initial isolates of M. tuberculosis, as rifampin resistance is an

excellent proxy for MDR-TB diagnosis. Susceptibility testing is particularly important if one or more risk factors for drug resistance are

identified or if the patient either fails to respond to initial therapy or

has a relapse after the completion of treatment (see “Treatment Failure

and Relapse,” below). In addition, expanded and rapid susceptibility

testing for isoniazid and key second-line anti-TB drugs (especially the

fluoroquinolones and the injectable drugs) is mandatory when RR-TB

is found in order to guide selection of the appropriate treatment regimens. Susceptibility testing may be conducted directly by molecular

techniques (with the clinical specimen) or indirectly (with mycobacterial cultures) on solid or liquid medium. Results are obtained rapidly

by direct susceptibility testing on liquid medium, with an average

reporting time of 3 weeks. With indirect testing on solid medium,

results may not be available for ≥8 weeks. Highly reliable genotypic

methods for the rapid identification of genetic mutations in gene

regions known to be associated with resistance to rifampin (such as

those in rpoB) and isoniazid (such as those in katG and inhA) have

been developed and are being widely implemented for screening of

patients at increased risk of drug-resistant TB. Apart from the Xpert

MTB/RIF, Xpert MTB/RIF Ultra, and Truenat MTB-Rif Dx assays,

which, as mentioned above, effectively detect rifampin resistance, the

most widely used tests are molecular line probe assays (LPAs). LPAs

are a family of DNA strip-based tests capable of detecting bacterial

DNA and identifying drug resistance-associated mutations. After

extraction of DNA from M. tuberculosis isolates or from clinical specimens, the resistance gene regions are amplified by polymerase chain

reaction (PCR), and labeled and probe-hybridized PCR products are

detected by colorimetric development. This assay reveals the presence

of M. tuberculosis as well as mutations in target resistance-gene regions.

Given the rapidity and accuracy of commercially available LPAs, the

WHO recommends that they (rather than phenotypic culture-based

tests) may be used to detect resistance to isoniazid and rifampin when

1370 PART 5 Infectious Diseases

patients have sputum smear–positive specimens or a cultured isolate of

M. tuberculosis. These recommendations do not eliminate the need for

conventional culture-based testing to identify resistance to other drugs

and to monitor emergence of additional drug resistance. A similar

approach has been developed for second-line anti-TB drugs, such as

the fluoroquinolones and the injectable drugs kanamycin, amikacin,

and capreomycin. Therefore, second-line LPAs (instead of phenotypic

culture-based DST) are now recommended by the WHO as the initial

test for rapid detection of resistance to the fluoroquinolones or the

second-line injectable drugs in isolates from patients with confirmed

RR-TB or MDR-TB. As with first-line LPAs, these recommendations do

not eliminate the need for conventional phenotypic, culture-based testing to identify resistance to other drugs and to monitor for the emergence of additional resistance. Detection of pyrazinamide resistance is

important among persons with MDR/RR-TB. The WHO has recently

recommended the use of a LPA with reverse hybridization-based technology in culture isolates rather than phenotypic culture-based DST.

Finally, a few noncommercial, inexpensive culture and susceptibility

testing methods (e.g., microscopically observed drug susceptibility,

nitrate reductase, and colorimetric redox indicator assays) have been

used in resource-limited settings. Their use is restricted to national

reference laboratories with proven proficiency and adequate external

quality control as an interim solution while genotypic or automated

liquid-culture technology is introduced.

Whole genome sequencing (WGS) of M. tuberculosis provides

comprehensive information on mutations conferring resistance and

is a promising alternative to existing phenotypic and molecular DST

methods. Recent studies have confirmed the potential for WGS to

identify genetic polymorphisms that reliably predict drug susceptibility

phenotype within a clinically relevant timeframe and a comparable

cost range. The clinical use of WGS, however, has been hampered by

the requirement for a culture sample before DNA processing. Recently,

amplification and sequencing of relevant genomic targets directly

from sputum samples have been successfully tested and targeted newgeneration sequencing (tNGS) is now a possible option. Evidence is

accumulating supporting the clinical application of NGS-based diagnostic systems for TB to replace traditional diagnostic tests in the future.

■ RADIOGRAPHIC PROCEDURES

CXR is a rapid imaging technique that has historically been used as

a primary tool to detect pulmonary TB. CXR has high sensitivity but

poor specificity. Although TB may often present with typical patterns

strongly suggesting the disease, some abnormalities seen in TB are also

present in several other lung conditions. The initial suspicion of pulmonary TB is often based on abnormal CXR findings in a patient undergoing triage for respiratory symptoms. The presence of lesions suggestive

of TB should prompt bacteriologic investigations in all cases, without

exception. Although the “classic” picture is that of upper-lobe disease

with infiltrates and cavities (Fig. 178-6), virtually any radiographic

pattern—from a normal film or a solitary pulmonary nodule to diffuse

alveolar infiltrates in a patient with adult respiratory distress syndrome—may be seen. In the era of HIV/AIDS, no radiographic pattern

can be considered pathognomonic, but CXR can assist in diagnosing

TB or ruling it out before initiation of any preventive treatment. CXR

is also helpful as a screening test used preceding rapid molecular assays

to improve their predictive value. Digital CXR technology, which allows

display of images in a digital format on a computer screen instead of on

x-ray film, offers several advantages: the procedure time is reduced, the

running costs are lower, the imaging is of superior quality, and telemedicine assistance is available, including computer-aided detection (CAD)

and interpretation of findings using software programs that analyze digital imaging for abnormalities compatible with TB. However, the limited

evidence available suggests that while sensitivity may be high, specificity

is variable. A recent systematic review of CAD studies concluded that

the diagnostic accuracy of this technology is still limited and that generalizability to low-prevalence settings is still uncertain.

CT (Fig. 178-7) may be useful in interpreting questionable findings

on plain CXR and in diagnosing some forms of extrapulmonary TB

(e.g., intrabdominal disease, Pott’s disease; Fig. 178-10). A recent study

has shown the potential of positron emission tomography combined

with CT for detection of subclinical disease that may be progressing

toward full-blown TB in HIV-infected people. MRI is useful in the

diagnosis of bone lesions and intracranial TB.

■ ADDITIONAL DIAGNOSTIC PROCEDURES

Other diagnostic tests may be used when pulmonary TB is suspected.

Sputum induction by ultrasonic nebulization of hypertonic saline

may be useful for patients who cannot produce a sputum specimen

spontaneously. Frequently, patients with radiographic abnormalities

that are consistent with other diagnoses (e.g., bronchogenic carcinoma) undergo fiberoptic bronchoscopy with bronchial brushings

and endobronchial or transbronchial biopsy of the lesion. Bronchoalveolar lavage of a lung segment containing an abnormality may also

be performed. In all cases, it is essential that specimens be submitted

for molecular testing with the Xpert MTB/RIF assay, mycobacterial

culture, and AFB smear. For the diagnosis of primary pulmonary TB

in children, who often do not expectorate sputum, induced sputum

specimens and specimens from early-morning gastric lavage may yield

positive results in the Xpert MTB/RIF assay or on culture.

Invasive diagnostic procedures are indicated for patients with suspected

extrapulmonary TB. In addition to testing of specimens from involved sites

(e.g., CSF for tuberculous meningitis, pleural fluid and biopsy samples

for pleural disease), biopsy and culture of bone marrow and liver tissue

have a good diagnostic yield in disseminated (miliary) TB, particularly in

HIV-infected patients, who also have a high frequency of positive blood

cultures. Xpert MTB/RIF should always be the initial diagnostic test in

patients where TB meningitis is suspected; any positive results should

prompt immediate treatment initiation, while negative results should be

followed up by additional testing. In some cases, the results of culture or

Xpert MTB/RIF are negative but a clinical diagnosis of TB is supported

by consistent epidemiologic evidence (e.g., a history of close contact with

an infectious patient) and a compatible clinical and radiographic response

to treatment. In the United States and other industrialized countries with

low rates of TB, some patients with limited abnormalities on CXR and

sputum positive for AFB are infected with nontuberculous mycobacteria, most commonly organisms of the M. avium complex or M. kansasii

(Chap. 180). Factors favoring the diagnosis of nontuberculous mycobacterial disease over TB include an absence of risk factors for TB and the

presence of underlying chronic pulmonary disease.

Patients with HIV-associated TB pose several diagnostic problems

(see “HIV-Associated TB,” above). HIV-infected patients with sputum culture–positive, AFB-positive TB may present with a normal

chest radiograph. The Xpert MTB/RIF assay is the preferred rapid

diagnostic test in this population of patients because of its simplicity

and increased sensitivity (~60–70% among AFB-negative, culturepositive cases and 97–98% among AFB-positive cases). With the advent

of ART, the occurrence of disseminated M. avium complex disease that

can be confused with TB has become much less common. A test based

on the detection of mycobacterial lipoarabinomannan antigen in urine

has emerged as a potentially useful point-of-care test for TB in HIVinfected persons with low CD4+ T-cell counts. The lateral-flow urine

lipoarabinomannan assay can be performed manually and read by

eye. After a systematic review of the evidence, the WHO recommends

that this assay be used to assist in the diagnosis of TB in HIV-positive

adults who have signs and symptoms of TB and a CD4+ T-cell count

of ≤100 cells/μL or in HIV-positive patients who are seriously ill

regardless of CD4+ T-cell count or with an unknown CD4+ count. The

WHO recommends that this test not be used, pending information on

recent promising technological test advances, for TB diagnosis or as a

screening test for TB in any other patient categories. One limitation of

the available lipoarabinomannan point-of-care test, AlereLAM (Alere

Determine TB LAM Ag), is the low sensitivity (45%). A novel assay,

FujiLAM (SILVAMP TB LAM) has recently shown a sensitivity of 70%.

■ SEROLOGIC AND OTHER DIAGNOSTIC TESTS FOR

ACTIVE TB

Several serologic tests based on detection of antibodies to a variety

of mycobacterial antigens have been carefully assessed by the WHO

1371CHAPTER 178 Tuberculosis

and found not to be useful as diagnostic aids because of their low

sensitivity and specificity and their poor reproducibility. In 2011, after

a rigorous evaluation of these tests, the WHO issued a “negative” recommendation in order to prevent their abuse in the private sector of

many resource-limited countries. Various methods aimed at detection

of mycobacterial antigens in diagnostic specimens are being investigated but are limited at present by low sensitivity. Determinations of

adenosine deaminase and IFN-γ levels in pleural fluid may be useful

adjunctive tests in the diagnosis of pleural TB; their utility in the diagnosis of other forms of extrapulmonary TB (e.g., pericardial, peritoneal, and meningeal) is less clear.

■ BIOMARKERS

In view of the limitations of current diagnostics, research on TB

biomarkers and multiple marker biosignatures that could be used

as a point-of-care test for disease or triage is a high priority and has

been crystallized in well-defined target product profiles by the WHO.

Recent systematic reviews revealed that promising host biomarkers

under study, such as antibodies, cytokines, chemokines, and RNA

signatures, by far exceed pathogen biomarkers that can be obtained

from urine or blood. However, currently, candidate biomarkers require

additional studies to fully assess their performance.

■ DIAGNOSIS OF M. TUBERCULOSIS INFECTION

Two tests currently exist for identification of individuals with TB infection: the TST and IGRA, both of which measure host immunological

response to TB antigens. These tests have limitations, especially in

settings or populations with high TB and/or HIV prevalence.

Tuberculin Skin Testing In 1891, Robert Koch discovered that

components of M. tuberculosis in a concentrated liquid-culture medium,

subsequently named “old tuberculin,” were capable of eliciting a skin

reaction when injected subcutaneously into patients with TB. In 1932,

Seibert and Munday purified this product by ammonium sulfate precipitation to produce an active protein fraction known as tuberculin purified protein derivative (PPD). In 1941, PPD-S, developed by Seibert and

Glenn, was chosen as the international standard. Later, the WHO and

UNICEF sponsored large-scale production of a master batch of PPD

(RT23) and made it available for general use. The greatest limitation of

PPD is its lack of mycobacterial species specificity, a property due to the

large number of proteins in this product that are highly conserved in the

various species. In addition, subjectivity of the skin-reaction interpretation that is dependent on the operator, deterioration of the product, and

batch-to-batch variations limit the usefulness of PPD.

The skin test with tuberculin PPD (TST) is most widely used in

screening for TB infection. It probably measures the response to

antigenic stimulation by T cells that reside in the skin rather than

the response of recirculating memory T cells. The test is of limited

value in the diagnosis of active TB because of its relatively low sensitivity and specificity and its inability to discriminate between TB

infection and active disease. False-negative reactions are common

in immunosuppressed patients and in those with overwhelming TB.

False-positive reactions may be caused by infections with nontuberculous mycobacteria (Chap. 180) and by BCG vaccination. A repeated

TST can produce larger reaction sizes due to either boosting or true

conversion. The “boosting phenomenon” is a spurious TST conversion

resulting from boosting of reactivity on a subsequent TST 1–5 weeks

after the initial test. Distinguishing boosting from true conversion is

difficult yet important and can be based on clinical and epidemiologic

considerations. For instance, true conversions are likely after BCG

vaccination in a previously TST-negative person or in a close contact

of an infectious patient.

IFN-γ Release Assays Two in vitro assays that measure T-cell

release of IFN-γ in response to stimulation with the highly TB-specific

RD1-encoded antigens ESAT-6 and CFP-10 were introduced in the early

2000s and are commercially available. The T-SPOT.TB test (Oxford

Immunotec; Oxford, United Kingdom) is an enzyme-linked immunospot assay, and the QuantiFERON-TB Gold test (Qiagen GmbH;

Hilden, Germany) is a whole-blood enzyme-linked immunosorbent

assay for measurement of IFN-γ. The QuantiFERON-TB Gold In-Tube

(QFT-GIT) assay, which facilitates blood collection and initial incubation, also contains another specific antigen, TB7.7. These tests

mainly measure the response of recirculating memory CD4+ T cells—

normally part of a reservoir in the spleen, bone marrow, and lymph

nodes—to persisting bacilli-producing antigenic signals. However,

CD8+ cells can also release IFN-γ in vitro in response to stimulation

with TB antigens, and they seem to do so especially in the early phase

of infection and in the phase of reactivation. Therefore, a new version

of the QFT-GIT assay, called QuantiFERON-TB Gold Plus (QFTPlus), has been developed that operates through two antigen tubes:

TB1, containing long peptides from ESAT-6 and CFP-10 and inducing

a CD4+ T-cell response, and TB2 that also contains shorter peptides

stimulating CD8+ cells. The QFT-Plus may have an increased sensitivity, compared to QFT-GID, but this conclusion needs confirmation.

In settings or population groups with low TB and HIV burdens,

IGRAs have previously been reported to be more specific than the

TST as a result of less cross-reactivity with BCG vaccination and sensitization by nontuberculous mycobacteria; i.e., RD1 antigens are not

encoded in the genome of either BCG strains or most nontuberculous

mycobacteria. Recent studies suggest that IGRAs may not perform

well in serial testing (e.g., among health care workers) and that interpretation of results depends on cutoff values used to define positivity.

Potential advantages of IGRAs include logistical convenience, the need

for fewer patient visits to complete testing, and the avoidance of somewhat subjective measurements (e.g., skin induration). However, IGRAs

require that blood be drawn and then delivered to the laboratory in a

timely fashion. IGRAs also require that testing be performed by specially trained technicians in a laboratory setting. These requirements

pose challenges similar to those faced with the TST, including coldchain requirements and batch-to-batch variations. Because of higher

specificity and greater availability of resources, IGRAs have usually

replaced the TST for TB infection diagnosis in low-incidence, highincome settings. However, in high-incidence TB and HIV settings and

population groups, evidence about the performance and usefulness

of IGRAs is still limited, and cost considerations may currently limit

wider use.

A number of national guidelines on the use of IGRAs for TB

infection testing have been issued. In the United States, an IGRA is

preferred to the TST for most persons over the age of 5 years who are

being screened for TB infection. However, for individuals at high risk

of progression to active TB (e.g., HIV-infected persons), either test—

or, to optimize sensitivity, both tests—may be used. Because of the

paucity of data on the use of IGRAs in children, the TST is preferred

for TB infection testing of children aged <5 years. In Canada and some

European countries, a two-step approach for those with positive

TSTs—i.e., an initial TST followed by an IGRA—is often recommended. However, a TST may boost an IGRA response if the interval

between the two tests exceeds 3 days.

In conclusion, both the TST and IGRA, although useful as diagnostic aids, are imperfect tests for TB infection: while they can identify

infected persons, they have low predictive value in identifying individuals with the highest risk of progression toward disease, cannot

differentiate between active TB and TB infection, cannot distinguish

new infections from reinfections, and display reduced sensitivity in

immunocompromised patients.

TREATMENT

Tuberculosis

The two main aims of TB treatment are (1) to prevent morbidity and

death by curing TB while preventing recurrences and emergence of

drug resistance, and (2) to interrupt transmission by rendering

patients noninfectious to others. Chemotherapy for TB became possible with the discovery of streptomycin in 1943. Randomized clinical trials clearly indicated that the administration of streptomycin

to patients with chronic TB reduced mortality rates and led to cure

in the majority of cases. However, monotherapy with streptomycin

1372 PART 5 Infectious Diseases

was soon associated with the development of resistance to this drug

and the resulting failure of treatment. With the introduction into

clinical practice of para-aminosalicylic acid (PAS) and isoniazid,

it became axiomatic in the early 1950s that cure of TB required

the concomitant administration of at least two agents to which the

organism was susceptible. Furthermore, early clinical trials demonstrated that a long period of treatment—i.e., 12–24 months—was

required to prevent recurrence. The introduction of rifampin in the

early 1970s heralded the era of effective short-course chemotherapy,

with a treatment duration of <12 months. The discovery that pyrazinamide, which was first used in the 1950s, augmented the potency

of isoniazid/rifampin regimens led to the use of a 6-month course

of this triple-drug regimen as standard therapy. Streptomycin was

added as the fourth drug mainly to prevent the emergence of drug

resistance. These four drugs (with streptomycin replaced by ethambutol) still form the basis of the optimal treatment regimen for

rifampin-susceptible TB. The emergence of drug-resistant TB in the

1990s prompted attempts to standardize the approach to treatment

of this condition mainly on the basis of expert opinion. This event

has also stimulated research on and development of new anti-TB

agents in the past 15 years. In 2013 and 2014, respectively, bedaquiline and delamanid—the first two drugs specifically developed for

TB during nearly half a century—received conditional approval

by the US Food and Drug Administration (FDA) and other drugregulatory authorities; approval was based on the results of phase 2b

clinical trials in which the drugs were added to the 18- to 24-month

WHO-recommended regimen for MDR-TB. Bedaquiline and delamanid are now being used increasingly for treatment of MDR-TB

under specific conditions. In 2019, another new drug, pretomanid,

was approved by the FDA as part of a new combination regimen

with bedaquiline and linezolid for 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.

DRUGS

Four major drugs are considered first-line agents for the treatment of TB: isoniazid, rifampin, pyrazinamide, and ethambutol.

Table 178-2 presents currently recommended dosages in adults and

children. Some studies have suggested increased effectiveness when

isoniazid, rifampin, and pyrazinamide are given at higher dosage;

thus if these findings are confirmed, dosages may be revised in the

future. These drugs are well absorbed after oral administration,

with peak serum levels at 2–4 h and nearly complete elimination

within 24 h. Isoniazid and rifampin, two key anti-TB drugs, are

recommended on the basis of their bactericidal activity (i.e., their

ability to rapidly reduce the number of viable organisms and render

patients noninfectious). All four agents are recommended in light

of their sterilizing activity (i.e., their ability to sterilize the affected

tissues, measured in terms of the ability to prevent relapses) and the

lowered risk that drug-resistant mutant bacilli will be selected when

the drugs are used in combination. Two additional rifamycins,

rifapentine and rifabutin, are also available; however, their level of

cross-resistance with rifampin is high. For a detailed discussion of

the drugs used for the treatment of TB, see Chap. 181.

Because of a lower degree of effectiveness and tolerability, several classes of second-line drugs are generally used only for the

treatment of patients with drug-resistant TB. These agents have

previously been classified in various manners to facilitate a standardized approach to their use. In the latest WHO guidance on the

treatment of MDR-TB, they are now grouped in three ranked categories for the purpose of designing more individualized regimens of

18–20 months’ duration. Group A drugs include three classes

of oral agents: the fluoroquinolones levofloxacin and moxifloxacin; the oxazolidinone linezolid; and the recently introduced diarylquinoline bedaquiline, which was granted accelerated approval

by the FDA in late 2012. Group B drugs include two other oral

agents: clofazimine and cycloserine (or its analogue terizidone).

Group C drugs include the nitroimidazole delamanid; imipenemcilastatin or meropenem; the injectable aminoglycosides amikacin

and streptomycin (the latter formerly a first-line agent, now rarely

used for drug-resistant TB because resistance levels worldwide are

high and it is more toxic than the other drugs in the same class);

ethionamide or prothionamide; and PAS. In addition, the firstline anti-TB drugs ethambutol and pyrazinamide (both included in

Group C) as well as high-dose isoniazid (only for the shorter regimen; see below) are used for MDR-TB treatment. Information about

drugs used in the treatment of drug-resistant TB (including dosages)

can be found in the following WHO Handbook: http://apps.who.int/

iris/bitstream/10665/130918/1/9789241548809_eng.pdf. Recent information from the phase 3 clinical trial of delamanid (a drug granted

accelerated approval by the European Medicines Agency [EMA] in

late 2013) added to an optimized longer WHO background regimen

shows that treatment success is not different from that obtained with

the addition of placebo. The future role of delamanid as a replacement

drug in MDR-TB treatment remains to be assessed. The new classification scheme excludes the second-line injectable aminoglycoside

kanamycin and the polypeptide capreomycin. Amithiozone, which

has been associated with severe and at times fatal skin reactions—

including Stevens-Johnson syndrome—among HIV-infected patients,

is no longer recommended. Finally, amoxicillin–clavulanic acid is recommended only as an adjunct to carbapenems.

REGIMENS

Standard regimens are divided into an intensive (bactericidal) phase

and a continuation (sterilizing) phase. During the intensive phase,

the majority of tubercle bacilli are killed, symptoms resolve, and

usually the patient becomes noninfectious. The continuation phase

is required to eliminate persisting mycobacteria and prevent relapse.

The treatment regimen of choice for virtually all forms of drugsusceptible TB in adults consists of a 2-month initial (intensive)

phase of isoniazid, rifampin, pyrazinamide, and ethambutol followed by a 4-month continuation phase of isoniazid and rifampin

(Table 178-3). This regimen can cure TB in >90% of patients. In

children, most forms of TB in the absence of HIV infection or suspected isoniazid resistance can be safely treated without ethambutol

in the intensive phase. Treatment should be given daily throughout

the course. Systematic reviews have demonstrated that the use of

an intermittent thrice-weekly regimen in the intensive phase is

associated with increased risk of treatment failure, relapse, and

acquisition of drug resistance. Furthermore, a thrice-weekly regimen in the continuation phase only has also been associated with

increased rates of failure and relapse, while a twice-weekly regimen

in the continuation phase increased the risk of acquisition of drug

resistance as well as rates of failure and relapse. Therefore, the

WHO now recommends that TB treatment in all cases be administered daily. The 2016 guidelines by the ATS, the CDC, and the

IDSA, while recommending daily administration of drugs, include

a provision for use of intermittent thrice-weekly supervised regimens among patients who are not infected with HIV and are at low

risk of relapse (i.e., have pulmonary TB caused by drug-susceptible

TABLE 178-2 Recommended Dosagea

 for Initial Treatment of

Tuberculosis in Adults and Children

DAILY DOSE

DRUG ADULT PEDIATRIC

Isoniazid 5 mg/kg, max 300 mg 10 (7–15) mg/kg, max 300 mg

Rifampin 10 mg/kg, max 600 mg 15 (10–20) mg/kg, max 600 mg

Pyrazinamide 25 mg/kg, max 2 g 35 (30–40) mg/kg

Ethambutolb 15 mg/kg 20 (15–25) mg/kg

a

The duration of treatment with individual drugs varies by regimen, as detailed in

Table 178-3. b

In certain settings, streptomycin (15 mg/kg daily, with a maximal dose

of 1 g; or 25–30 mg/kg thrice weekly, with a maximal dose of 1.5 g) can replace

ethambutol in the initial phase of treatment. However, streptomycin generally is no

longer considered a first-line drug.

Source: Based on recommendations of the American Thoracic Society/Infectious

Diseases Society of America/Centers for Disease Control and Prevention and the

World Health Organization.