1396 PART 5 Infectious Diseases

are often tested for antibiotic susceptibility, but the value and meaning

of these tests are undetermined.

■ PREVENTION

Prophylaxis of MAC disease in patients infected with HIV is started

when the CD4+ T lymphocyte count falls to <50/μL. Azithromycin

(1200 mg weekly), clarithromycin (1000 mg daily), or rifabutin (300 mg

daily) is effective. Macrolide prophylaxis in immunodeficient patients

who are susceptible to NTM (e.g., those with defects in the IFN-γ/IL-12

axis) has not been prospectively validated but seems prudent.

TREATMENT

Nontuberculous Mycobacteria

NTM cause chronic infections that evolve relatively slowly over a

period of weeks to years. Therefore, it is rarely necessary to initiate

treatment on an emergent basis before the diagnosis is clear and

the infecting species is known. Treatment of NTM is complex,

often poorly tolerated, and potentially toxic. Just as in tuberculosis,

inadequate single-drug therapy is almost always associated with the

emergence of antimicrobial resistance and relapse.

MAC infection often requires multidrug therapy, the foundation

of which is a macrolide (clarithromycin or azithromycin), ethambutol, and a rifamycin (rifampin or rifabutin). For disseminated

nontuberculous mycobacterial disease in HIV-infected patients, the

use of rifamycins poses special problems—i.e., rifamycin interactions with protease inhibitors. For pulmonary MAC disease, thriceweekly administration of a macrolide, a rifamycin, and ethambutol

has been successful. Therapy is prolonged, generally continuing for

12 months after culture conversion; typically, a course lasts for at

least 18 months. Other drugs with activity against MAC organisms

include IV and aerosolized aminoglycosides, fluoroquinolones, and

clofazimine. In elderly patients, rifabutin can exert significant toxicity. However, with only modest efforts, most antimycobacterial

regimens are well tolerated by most patients. Resection of cavitary

lesions or severely bronchiectatic segments has been advocated for

some patients, especially those with macrolide-resistant infections.

The success of therapy for pulmonary MAC infections depends on

whether disease is nodular or cavitary and on whether it is early or

advanced, ranging from 20 to 80%.

M. kansasii lung disease is similar to tuberculosis in many ways

and is also effectively treated with isoniazid (300 mg/d), rifampin

(600 mg/d), and ethambutol (15 mg/kg per day). Other drugs with

very high-level activity against M. kansasii include clarithromycin,

fluoroquinolones, and aminoglycosides. Treatment should continue until cultures have been negative for at least 1 year. In

most instances, M. kansasii infection is easily cured. Bulky, severe,

necrotizing M. kansasii lymphadenopathy, especially in the mediastinum, is strongly associated with GATA2 deficiency.

Rapidly growing mycobacteria pose special therapeutic problems. Extrapulmonary disease in an immunocompetent host is

usually due to inoculation (e.g., via surgery, injections, or trauma)

or to line infection and is often treated successfully with a macrolide

and another drug (with the choice based on in vitro susceptibility),

along with removal of the offending focus. In contrast, pulmonary

disease, especially that caused by M. abscessus, is extremely difficult to cure. Repeated courses of treatment are usually effective in

reducing the infectious burden and symptoms. Therapy generally

includes a macrolide along with an IV-administered agent such as

amikacin, a carbapenem, cefoxitin, or tigecycline. Other oral agents

(used according to in vitro susceptibility testing and tolerance)

include fluoroquinolones, doxycycline, linezolid, and the newer

tetracycline family drugs, omadacycline and eravacycline. Because

nontuberculous mycobacterial infections are chronic, care must be

taken in the long-term use of drugs with neurotoxicities, such as

linezolid and ethambutol. Prophylactic pyridoxine has been suggested in these cases. Durations of therapy for M. abscessus lung disease are difficult to predict because so many cases are chronic and

require intermittent therapy. Expert consultation and management

are strongly recommended.

Once recognized, M. marinum infection is highly responsive

to antimicrobial therapy and is cured relatively easily with any

combination of a macrolide, ethambutol, and a rifamycin. Therapy

should be continued for 1–2 months after clinical resolution of isolated soft-tissue disease; tendon and bone involvement may require

longer courses in light of clinical evolution. Other drugs with

activity against M. marinum include sulfonamides, trimethoprimsulfamethoxazole, doxycycline, and minocycline.

Treatment of the other NTM is less well defined, but macrolides

and aminoglycosides are usually effective, with other agents added

as indicated. Expert consultation is strongly encouraged for difficult

or unusual infections due to NTM.

■ PROGNOSIS

The outcomes of nontuberculous mycobacterial infections are closely

tied to the underlying condition (e.g., IFN-γ/IL-12 pathway defect,

cystic fibrosis) and can range from recovery to death. With no or inadequate treatment, symptoms and signs can be debilitating, including

persistent cough, fever, anorexia, and severe lung destruction. With

treatment, patients typically regain strength and energy. The optimal

duration of therapy when NTM persist in sputum is unknown, but

treatment in this situation can be prolonged. In general, for severe

underlying immunodeficiencies, hematopoietic stem cell transplantation is recommended and may be helpful in the resolution of severe

mycobacterial disease.

■ GLOBAL CONSIDERATIONS

In many countries, pulmonary tuberculosis is diagnosed by smear

alone, which is also the method used for monitoring of response and

relapse. However, examination of mycobacteria from the affected

“relapsed” patients shows that a significant proportion of isolates are

actually NTM. Overall, as rates of tuberculosis decline, the proportion

of positive smears caused by NTM will increase. Advances in speciation will distinguish tuberculosis from nontuberculous mycobacterial

infections and thereby affect rates of assumed relapse and resistance,

leading to more targeted and appropriate therapy.

■ FURTHER READING

Flume PA et al: Advances in bronchiectasis: Endotyping, genetics,

microbiome, and disease heterogeneity. Lancet 392:880, 2018.

Holland SM et al: Case 28-2017. A 13-month-old girl with pneumonia and a 33-year-old woman with hip pain. N Engl J Med 377:1077,

2017.

Hong GH et al: Natural history and evolution of anti-interferon-γ

autoantibody-associated immunodeficiency syndrome in Thailand

and the United States. Clin Infect 71:53, 2020.

Kim RD et al: Pulmonary nontuberculous mycobacterial disease: Prospective study of a distinct preexisting syndrome. Am J Respir Crit

Care Med 178:1066, 2008.

Lovell JP et al: Mediastinal and disseminated Mycobacterium kansasii

disease in GATA2 deficiency. Ann Am Thorac Soc 13:2169, 2016.

Marras TK et al: Relative risk of all-cause mortality in patients with

nontuberculous mycobacterial lung disease in a US managed care

population. Respir Med 145:80, 2018.

Olivier KN et al: Inhaled amikacin for treatment of refractory pulmonary nontuberculous mycobacterial disease. Ann Am Thorac Soc

11:30, 2014.

Spinner MA et al: GATA2 deficiency: A protean disorder of hematopoiesis, lymphatics, and immunity. Blood 123:809, 2014.

Szymanski EP et al: Pulmonary nontuberculous mycobacterial infection. A multisystem, multigenic disease. Am J Respir Crit Care Med

192:618, 2015.

Wu UI et al: Patients with idiopathic pulmonary nontuberculous

mycobacterial disease have normal Th1/Th2 cytokine responses

but diminished Th17 cytokine and enhanced granulocytemacrophage colony-stimulating factor production. Open Forum

Infect Dis 6:ofz484, 2019.

1397CHAPTER 181 Antimycobacterial Agents

Agents used for the treatment of mycobacterial infections, including

tuberculosis (TB), leprosy, and infections due to nontuberculous

mycobacteria (NTM), are administered in multiple-drug regimens

for prolonged courses. Currently, >160 species of mycobacteria have

been identified, the majority of which do not cause disease in humans.

While the incidence of disease caused by Mycobacterium tuberculosis

has been declining in the United States, TB remains a leading cause

of morbidity and mortality in low- and middle-income countries—for

example, in sub-Saharan Africa and Asia, where the HIV epidemic

rages. Well-organized infrastructure for early diagnosis, treatment

of TB infection and disease, and development of effective drug regimens and vaccines remain vital to the global strategies for TB control

(Chaps. 472 and 474). Infections with NTM have gained in clinical

prominence in the United States and other developed countries. These

largely environmental organisms often establish infection in immunocompromised patients or in persons with structural lung disease.

TUBERCULOSIS

■ GENERAL PRINCIPLES

The earliest recorded human case of TB dates back 9000 years. Early

treatment modalities, such as bloodletting, were replaced by the sanatorium movement in the late nineteenth century, which focused on fresh

air, nutrition, and bed rest to treat consumptive patients and came with

the benefit of isolating infected individuals. The discovery of streptomycin in 1943 launched the era of antibiotic treatment for TB. Over

subsequent decades, the discovery of additional agents and the use of

multiple-drug regimens allowed progressive shortening of the treatment course from years to as little as 6 months for drug-susceptible TB.

Latent TB infection (LTBI) and active TB disease are diagnosed by history, physical examination, radiographic imaging, tuberculin skin test,

interferon-γ release assays, acid-fast staining, mycobacterial cultures,

and/or new molecular diagnostics. LTBI is treated with isoniazid plus

rifapentine (weekly for 3 months), rifampin (daily for 4 months), isoniazid plus rifampin (daily for 3 months), or isoniazid (optimally daily

or twice weekly for 6−9 months) (Table 181-1). The 3-month, weekly

regimen of isoniazid with rifapentine is currently the regimen of choice

in children >2 years of age and in all adults including HIV-positive individuals. The regimen is not recommended for pregnant women and for

persons with hypersensitivity reactions to isoniazid or rifampin. Shorter

duration rifamycin-based regimens (rifampin alone for 4 months or for

3 months in combination with isoniazid) are currently preferred for the

treatment of LTBI over isoniazid for 6−9 months in adults and children

due to their effectiveness, safety, and tolerability. Caution is advised in

181

HIV-positive individuals due to potential for drug interactions, lack of

definitive data on effectiveness, and the possibility of subclinical TB

disease that could facilitate the development of rifampin resistance.

Completions rates of a self-administered, once-weekly regimen of

isoniazid plus rifapentine for 3 months with monthly monitoring were

found to be noninferior to those seen with directly observed therapy

(DOT) in the United States, and thus, this regimen is considered an

acceptable strategy for treating LTBI in countries with a focus on secondary prevention of TB disease. Recently, a 1-month daily regimen of

rifapentine and isoniazid in HIV-positive individuals was found to be

noninferior to 9 months of isoniazid; this regimen will be included in

the new World Health Organization (WHO) LTBI treatment guidelines.

For active or suspected TB disease, clinical factors, including HIV

co-infection, symptom duration, radiographic appearance, and public

health concerns about TB transmission, drive diagnostic testing and

treatment initiation. Confirmation of active TB relies on detection

of M. tuberculosis via culture or molecular testing. A combination of

drugs is used for the treatment of TB disease (Table 181-2). For drugsusceptible disease, a standardized regimen is used with an intensive

phase consisting of four drugs—isoniazid, rifampin, pyrazinamide, and

ethambutol—given for 2 months, which is followed by a continuation

phase of isoniazid and rifampin for 4 months, for a total treatment

duration of 6 months. U.S. guidelines recommend extension of the

continuation phase to 7 months (for a total treatment duration of

9 months) for patients with cavitary disease; if the 2-month course of

pyrazinamide is not completed; or if sputum cultures remain positive

beyond 2 months of treatment (delayed culture conversion), which also

warrants evaluation for development of drug resistance.

Treatment of TB in patients co-infected with HIV poses significant

challenges, but some progress is being made. To improve survival,

current recommendations include initiation of antiretroviral therapy

(ART) in HIV patients co-infected with M. tuberculosis within 2 weeks

of the initiation of treatment for TB (except TB meningitis) if the CD4+

T-cell count is ≤50/μL and by 8–12 weeks of TB treatment initiation if

the CD4+ T-cell count is ≥50/μL. Interactions of rifampin with protease

inhibitors or nonnucleoside reverse transcriptase inhibitors can be significant and require close monitoring and dose adjustments. Reassuringly, a recent study comparing the safety and efficacy of rifampin for

4 months in patients with LTBI showed that it was as effective as isoniazid for 9 months and was also well tolerated and safe for treatment

in persons living with HIV. Rifabutin is an alternative drug of choice

in HIV patients co-infected with M. tuberculosis, as it is a less potent

cytochrome P3A inhibitor than rifampin. The TB immune reconstitution inflammatory syndrome (IRIS) may appear as early as 1 week after

initiation of ART and manifests as paradoxical worsening or unmasking of existing TB infection. Conservative management consists of continued administration of ART and TB medications. However, severe

or debilitating IRIS has been treated in reported case series with varying doses of glucocorticoids. A randomized, double-blind, placebocontrolled trial showed that a 4-week course of prednisone significantly

reduced need for hospitalization and hastened symptom improvement

and quality of life in TB IRIS. Intermittent antimycobacterial therapy

Antimycobacterial Agents

Divya Reddy, Sebastian G. Kurz,

Max R. O’Donnell

TABLE 181-1 Regimens for the Treatment of Latent Tuberculosis Infection in Adults

REGIMEN SCHEDULE DURATION COMMENTS

Isoniazid plus

rifapentine

900 mg (15 mg/kg) weekly

plus 900 mg (for weight

>50 kg) weekly

3 months Directly observed therapy is recommended for once-weekly treatment in HIV-positive

and -negative individuals. This regimen may be supplemented with pyridoxine

(25–50 mg/d).

Rifampin 600 mg/d (10 mg/kg) 4 months Recommended in HIV-negative individuals and in children. Data on effectiveness in

HIV-positive patients are unavailable.

Isoniazid plus

rifampin

300 mg/d (5 mg/kg) plus

600 mg/d (10 mg/kg)

3 months Risk of hepatotoxicity may be higher with the combination regimen compared to that of the

individual drugs.

Isoniazid 300 mg/d (5 mg/kg)

Alternative: 900 mg twice

weekly (15 mg/kg)

6–9 months (6 months

acceptable)

Supplement with pyridoxine (25–50 mg daily)

6 months’ duration strongly recommended for HIV-negative patients and conditional for

HIV-positive patients. 9 months may be more effective but with higher risk of hepatic

toxicity. Twice-weekly regimens require directly observed therapy.

Source: Sterling TR et al. Guidelines for the treatment of latent tuberculosis infection: Recommendations from the National Tuberculosis Controllers Association and CDC,

2020. MMWR Recomm Rep 69(No. RR-1):1, 2020.

1398 PART 5 Infectious Diseases

in patients infected with HIV and M. tuberculosis has been associated

with low plasma levels of several key TB drugs and with higher rates

of treatment failure or relapse; therefore, intermittent twice-weekly

therapy for TB in HIV-co-infected individuals is not recommended.

Adherence to medications is critical in achieving a cure with antimycobacterial therapy. In addition to DOT by trained staff, either in the

clinic or at home, case management interventions such as patient

education/counseling, field/home visits, and patient reminders are also

recommended to improve treatment adherence. Use of mobile health

technologies, including video DOT, text messaging, and next-generation

electronic pillboxes, shows promise in promoting TB adherence. In

drug-susceptible TB, monthly dispensing of TB medications is also

advised for all patients to allow essential clinical monitoring for hepatotoxicity due to these medications. Clinical monitoring includes at

least monthly assessment for symptoms (nausea, vomiting, abdominal

discomfort, and unexplained fatigue) and signs (jaundice, dark urine,

light stools, diffuse pruritus) of hepatotoxicity, although the latter represent comparatively late manifestations (Table 181-3). The presence

TABLE 181-2 Simplified Approach to Treatment of Active Tuberculosis (TB) in Adults

CULTURE RESULTS INTENSIVE PHASE CONTINUATION PHASE EXTENSION OF TOTAL TREATMENT

Culture-positive,

drug-susceptible

HRZE for 2 months, dailya

 or

3 times per week (with dose

adjustment)

HR for 4 months, daily or 5 days per week

or

HR for 4 months, 3 times per weekb

 (with

dose adjustment)

Continuation phase extended to 7 months if 2 months of Z is not

completed, if the patient is infected with HIV and is not receiving

antiretroviral therapy, or if culture conversion is prolonged and/or

cavitation is evident on chest radiography (U.S. guidelines)c

Culture-negative HRZE for 2 months HR for 2 months, daily or 2 or 3 times

per weekd

Continuation phase extended to 4 months if the patient is infected

with HIV

Extrapulmonary,

drug-susceptible

HRZE for 2 months HR for 4–7 months, daily or 5 days per

weeke

Continuation phase extended to 10 months in TB meningitis;

7 months recommended by some authorities for bone/joint TB

a

Daily treatment is preferred; however, thrice-weekly therapy in the intensive phase (with or without an initial 2 weeks of daily therapy) may be considered in patients who

are not infected with HIV and are at low risk of relapse (i.e., in pulmonary tuberculosis caused by drug-susceptible organisms that, at the start of treatment, is noncavitary

and/or smear negative). b

Use regimen with caution in HIV patients and/or those with cavitary disease, as missed doses can lead to treatment failure, relapse, and acquired

drug resistance. c

Culture conversion is prolonged if it occurs beyond 2 months. d

Twice-weekly treatment regimens are not recommended in patients infected with HIV and

those with cavitary pulmonary disease suspected to be TB. e

Standard daily 6-month TB treatment regimen is considered to be adequate for most forms of extrapulmonary

TB, including miliary TB. For TB meningitis, the addition of glucocorticoids is recommended.

Abbreviations: E, ethambutol; H, isoniazid; R, rifampin; Z, pyrazinamide.

Sources: Official American Thoracic Society/Centers for Disease Control and Prevention/Infectious Diseases Society of America: Clinical practice guidelines: Treatment of

drug-susceptible tuberculosis. Clin Infect Dis 63:e147, 2016.

TABLE 181-3 Monitoring and Clinical Management of Tuberculosis (TB) Treatment in Adultsa

DRUG ASSESSMENT MANAGEMENT

LTBI Treatment

With hepatic risk factorsb

, check ALT and bilirubin at baseline. If ALT is ≥3 × ULN or total bilirubin is >2 × ULN, defer treatment and reevaluate.

Isoniazid Determine whether hepatic risk factors

are present. If so, obtain baseline and

periodic ALT and bilirubin values

If ALT is 5 × ULN (or 3 × ULN with symptoms)c

 or if bilirubin reaches jaundice levels

(usually >2 × ULN), interrupt treatment. With normalization, consider an alternative agent.

Rifampin Same as above Same as above

TB Treatment

Check ALT, bilirubin, platelets, creatinine, and hepatitis panel for all patients at baseline. If hepatic risk factors are present, check ALT and bilirubin monthly.

Isoniazid If ALT is >5 × ULN (or >3 × ULN with

hepatitis symptoms)c

Obtain history of alcohol consumption and concomitant drug use.

In most instances, discontinue H, Z, R, and other hepatotoxic drugs. Consider alternative agents.

Obtain viral hepatitis serologies.

Rechallenge: With normalization of liver enzymes, R and H may be sequentially reintroduced.

With no recurrence of hepatotoxicity, Z is not resumed in many cases. Alternative rechallenge

protocols have been used.

Rifampin If primary elevation is in bilirubin and

alkaline phosphatase, most likely due to

rifampin

Discontinue R if total bilirubin reaches jaundice levels (usually >2 × ULN).

May try to reintroduce; if not tolerated, may substitute Q.

Ethambutol Decrease in visual acuity or color vision

on monthly screening

Discontinue ethambutol and repeat ocular examination. Peripheral neuropathy may be a

precursor of ocular toxicity; if it occurs, consider repeat ocular examination.

Pyrazinamide If ALT is >5 × ULN (or >3 × ULN with

symptoms)c

Same as for H.

Fluoroquinolone,

bedaquiline, delamanid

QTc prolongation is a concern and should

be monitored, especially if drugs are used

in combination

Asymptomatic QTc prolongation should prompt consideration of stopping known QT-prolonging

drugs and/or close monitoring, depending on the clinical situation and degree of prolongation.

Symptomatic QTc prolongation (e.g., palpitations or arrhythmias) should prompt discontinuation

of drugs.

Linezolid Visual impairment; monitor for

peripheral neuropathy and bone

marrow suppression including anemia,

thrombocytopenia, and leukopenia

Discontinue linezolid if visual toxicity develops. Rechallenge after complete resolution, especially

with a lower dose, is an option. Stop if peripheral neuropathy or bone marrow suppression

develops.

a

All regimens require monthly clinical monitoring. b

Hepatic risk factors: chronic alcohol use, viral hepatitis, preexisting liver disease, pregnancy or ≤3 months postpartum,

hepatotoxic medications. c

Relevant manifestations include nausea, vomiting, abdominal pain, jaundice, or unexplained fatigue.

Abbreviations: ALT, alanine aminotransferase; H, isoniazid; LTBI, latent tuberculosis infection; Q, fluoroquinolone; QTc, corrected QT interval; R, rifampin; ULN, upper limit of

normal; Z, pyrazinamide.

Sources: JJ Saukkonen et al: An official ATS statement: Hepatotoxicity of antituberculosis therapy. Am J Respir Crit Care Med 174:935, 2006; American Thoracic Society/

Centers for Disease Control and Prevention/Infectious Diseases Society of America: Treatment of tuberculosis. Am J Respir Crit Care Med 167:603, 2003; WHO consolidated

guidelines on drug-resistant tuberculosis treatment. Geneva: World Health Organization; 2019. License: CC BY-NC-SA 3.0 IGO.

1399CHAPTER 181 Antimycobacterial Agents

of such symptoms and signs mandates provisional discontinuation of

potentially hepatotoxic agents; discontinuation at the onset of hepatitis

symptoms reduces the risk of progression to fatal hepatitis. Although

biochemical monitoring is not routinely recommended, baseline

assessment of liver function is recommended in adults including testing of at least serum alanine aminotransferase (ALT) and total bilirubin

levels (Table 181-3). (See Chap. 178 for further details.) For patients

with active TB, monthly mycobacterial cultures of sputum are recommended until it is certain that the organisms have been cleared and

the patient has responded to therapy or until no sputum is available

for culture.

If significant clinical improvement does not occur or the patient’s

condition deteriorates over the course of therapy, possibilities include

treatment failure due to nonadherence, poor medication absorption,

or the development of resistance. For patients co-infected with HIV

and M. tuberculosis, IRIS, which is a diagnosis of exclusion, should

also be a consideration. Drug susceptibility testing should be repeated

at this point. If resistance is documented or strongly suspected, at

least two efficacious drugs to which the isolate is susceptible or which

the patient has not already taken should be added to the therapeutic

regimen.

Multidrug-resistant tuberculosis (MDR-TB) is defined as disease

caused by a strain of M. tuberculosis that is resistant to both isoniazid

and rifampin—the most efficacious of the first-line TB drugs. The risk

of MDR-TB is elevated in patients presenting from geographic areas in

which ≥5% of incident cases are MDR-TB and in patients previously

treated for TB. Treatment regimens for MDR-TB are rapidly evolving, and in 2019, the WHO issued a new classification of second-line

agents to treat drug-resistant disease (See Table 178-4). Current WHO

recommendations are emphasizing an all-oral bedaquiline-containing

regimen with the goal to limit treatment duration to 9−11 months

compared to conventional durations of 18−20 months (Table 181-4).

Results from several recent large clinical trials have formed the

basis of these recommendations. The “Bangladesh regimen” was

the first short-course MDR-TB regimen systematically studied in

the STREAM-1 trial and was able to reduce treatment duration to

9−12 months with favorable outcomes in up to 90% of patients. It consists of a seven-drug intensive phase (kanamycin, prothionamide, isoniazid, fluoroquinolone, ethambutol, pyrazinamide, and clofazimine)

and a four-drug continuation phase (fluoroquinolone, ethambutol,

pyrazinamide, and clofazimine). In 2018, a large meta-analysis, which

pooled individual data from >12,000 patients enrolled in 50 trials,

assessed the role of individual drugs to treat MDR-TB. This analysis

showed an association of significantly better treatment outcomes with

TABLE 181-4 Simplified Approach to Treatment of Drug-Resistant Tuberculosis (TB) in Adultsa

CULTURE RESULTS INTENSIVE PHASE CONTINUATION PHASE EXTENSION OF TOTAL TREATMENT

Resistant to H Lfx RZEb

 for 6 months … Prolonged culture conversion and/or

evidence of cavitation on chest radiography

Resistant to HR (MDR)c

WHO short course regimend

WHO extended regimene

Bdq, Lfx or Mfx, Eto, E, Z, Hh, Cfz for

4–6 months

At least five effective second-line agents,

including all group A and at least one

group B, add group C if intolerant to A or B

drugs for 5–7 months

Lfx or Mfx, Cfz, Z, E for 5 months

4 drugs for a total of 18–20 months or for

15–17 months after culture conversion

Prolonged culture conversion, delayed

response, and/or evidence of cavitation on

chest radiography

Prolonged culture conversion, delayed

response, and/or evidence of cavitation on

chest radiography

a

Drug-resistant TB treatment regimens should be constructed and care provided in close consultation with experienced drug-resistant TB clinicians. Surgical management

should also be considered in appropriate cases. b

Prolonged pyrazinamide duration may be associated with increased risk of liver toxicity. c

Monoresistance to R is rare

and should be treated as MDR. d

The WHO short-course regimen is for patients with no prior exposure to second-line drugs and documented fluoroquinolone susceptibility

only. Patients with treatment intolerance to antimycobacterial agents, disseminated TB, or pregnancy should be excluded from short-course regimens. It is currently not

endorsed by U.S. societies. e

Patients who do not qualify for WHO short-course regimens should be treated using extended MDR-TB treatment regimens. The construction

of extended regimens is guided by the requirement for selection of effective antimycobacterial agents, the need to combine sufficient medicines to maximize relapse-free

survival, and the need to minimize toxicity.

Abbreviations: Bdq, bedaquiline; Cfz, clofazimine; E, ethambutol; Eto, ethionamide; H, isoniazid; Hh, high-dose isoniazid; Lfx, levofloxacin; MDR, multidrug resistant; Mfx,

moxifloxacin; Pa, pretomanid; Q, fluoroquinolone; R, rifampin; WHO, World Health Organization; Z, pyrazinamide.

Sources: Official American Thoracic Society/Centers for Disease Control and Prevention/Infectious Diseases Society of America: Clinical practice guidelines: Treatment

of drug-resistant tuberculosis. Am J Respir Crit Care Med 200:e93, 2019; World Health Organization consolidated guidelines on drug-resistant tuberculosis treatment. WHO

2019; Rapid Communication: Key changes to the treatment of drug-resistant tuberculosis, WHO December 2019.

the use of linezolid, bedaquiline, clofazimine, carbapenems, and later

generation fluoroquinolones and worse outcomes with kanamycin and

capreomycin in these patients. As a result of this analysis, oral drug

combinations are now prioritized, while several traditional second-line

drugs, including kanamycin and capreomycin, are no longer recommended. A further step toward a shortened all-oral regimen was the

Nix-TB study, which showed that a 6-month regimen of bedaquiline,

pretomanid, and linezolid (BPaL regimen) for treatment of highly

drug-resistant TB was associated with favorable outcomes (absence of

clinical or bacteriologic treatment failure or relapse within 6 months of

treatment completion) in 89% of patients. While a major breakthrough,

caution has been raised regarding higher rate of side effects mostly due

to linezolid and lack of a control arm. The BPaL regimen is currently

recommended under operational research conditions only.

The shift toward all-oral regimens of shortened duration has been

made possible by the introduction of novel drugs, most prominently

bedaquiline and pretomanid, as well as the repurposing of existing

agents for MDR-TB treatment (e.g., linezolid, clofazimine). High cost

and limited access to these new drugs are barriers that need to be

addressed to facilitate global adaptation of these new regimens.

■ FIRST-LINE ANTITUBERCULOSIS DRUGS

The following discussion of individual anti-TB agents focuses on treatment of TB in adults, unless otherwise noted. Several agents are being

actively investigated during the current remarkable period of drug

development for TB treatment.

Isoniazid Isoniazid is a critical drug for treatment of both TB disease and LTBI. Isoniazid has excellent bactericidal activity against both

intracellular and extracellular, actively dividing M. tuberculosis. This

drug is bacteriostatic against slowly dividing organisms. In treatment

of LTBI, isoniazid is generally well tolerated, has well-established efficacy, and is inexpensive. In this setting, the drug is taken daily, which

is the preferred dosing schedule, or intermittently (i.e., twice weekly)

using DOT for 6 months, which has been found to be equivalent to the

traditional 9 months in most settings. A weekly isoniazid and rifapentine regimen, administered over 3 months under DOT, has been

shown to be noninferior to daily isoniazid given for 9 months and

had a higher treatment completion rate than the single-drug regimen.

More recent evidence also suggests that completion rates of a selfadministered 3-month regimen of weekly isoniazid and rifapentine are

noninferior to those seen with DOT in the United States. It is expected

that a 1-month daily regimen in combination with rifapentine will be

added to new WHO guidelines.

1400 PART 5 Infectious Diseases

For treatment of TB disease, isoniazid is used in combination with

other agents to ensure killing of both actively dividing M. tuberculosis

and slowly growing “persister” mycobacteria. Unless the organism is

resistant, the standard regimen includes isoniazid, rifampin, ethambutol, and pyrazinamide (Table 181-2). Isoniazid is often given together

with 25–50 mg of pyridoxine daily to prevent drug-related peripheral

neuropathy.

MECHANISM OF ACTION Isoniazid is a prodrug activated by the mycobacterial KatG catalase-peroxidase; isoniazid is coupled with reduced

nicotinamide adenine dinucleotide (NADH). The resulting isonicotinic acyl–NADH complex blocks the mycobacterial ketoenoylreductase known as InhA through binding to its substrate and inhibiting

fatty acid synthase and ultimately mycolic acid synthesis. Mycolic acids

are essential components of the mycobacterial cell wall. KatG activation of isoniazid also results in the release of free radicals that have

antimycobacterial activity, including nitric oxide.

The minimal inhibitory concentrations (MICs) of isoniazid for wildtype (untreated) susceptible strains are <0.1 μg/mL for M. tuberculosis

and 0.5–2 μg/mL for M. kansasii.

PHARMACOLOGY Isoniazid is the hydrazide of isonicotinic acid, a

small, water-soluble molecule. The usual adult oral daily dose of 300 mg

results in peak serum levels of 3–5 μg/mL within 30 min to 2 h after

ingestion—well in excess of the MICs for most susceptible strains of

M. tuberculosis. Both oral and IM preparations of isoniazid reach effective levels in the body, although antacids and high-carbohydrate meals

may interfere with oral absorption. Isoniazid diffuses well throughout

the body, reaching therapeutic concentrations in body cavities and

fluids, with concentrations in cerebrospinal fluid (CSF) comparable to

those in serum.

Isoniazid is metabolized in the liver via acetylation by N-acetyltransferase 2 (NAT2) and hydrolysis. Both fast- and slow-acetylation phenotypes occur; patients who are “fast acetylators” may have lower serum

levels of isoniazid, whereas “slow acetylators” may have higher levels

and experience more toxicity. Satisfactory isoniazid levels are attained

in the majority of homozygous fast NAT2 acetylators given a dose of

6 mg/kg and in the majority of homozygous slow acetylators given

only 3 mg/kg. Genotyping is increasingly being used to characterize

isoniazid-related pharmacogenomic responses.

Isoniazid’s interactions with other drugs are due primarily to its

inhibition of the cytochrome P450 system. Among the drugs with

significant isoniazid interactions are warfarin, carbamazepine, benzodiazepines, acetaminophen, clopidogrel, maraviroc, dronedarone,

salmeterol, tamoxifen, eplerenone, and phenytoin.

DOSING The recommended daily dose of isoniazid for the treatment of

TB is 5 mg/kg for adults and 10 mg/kg for children (U.S. guidelines recommend 10−15 mg), with a maximal daily dose of 300 mg for both. For

intermittent therapy in adults (usually twice per week), the dose is 15 mg/

kg, with a maximal daily dose of 900 mg. Isoniazid does not require dosage adjustment in patients with renal disease. When the 12-dose, 3-month

weekly LTBI regimen is used, the dose of isoniazid is 15 mg/kg, with a

maximal dose of 900 mg, and the drug is co-administered with rifapentine. The novel 1-month regimen uses isoniazid 300 mg in conjunction

with rifapentine for people aged >13 years without weight adjustment.

RESISTANCE Although isoniazid, along with rifampin, is the mainstay

of TB treatment regimens, ~7% of clinical M. tuberculosis isolates in

the United States are resistant. Rates of primary isoniazid resistance

among untreated patients are significantly higher in many populations

born outside the United States. Five separate pathways for isoniazid

resistance have been elucidated. Most strains have amino acid changes

in either the catalase-peroxidase gene (katG) or the mycobacterial

ketoenoylreductase gene (inhA). Less frequently, alterations in kasA,

the gene for an enzyme involved in mycolic acid elongation, and

loss of NADH dehydrogenase 2 activity confer isoniazid resistance.

In 20–30% of isoniazid-resistant M. tuberculosis isolates, increased

expression of efflux pump genes, such as efpA, mmpL7, mmr, p55,

and the Tap-like gene Rv1258c, has been implicated as the underlying

mechanism of resistance.

ADVERSE EFFECTS Although isoniazid is generally well tolerated,

drug-induced liver injury and peripheral neuropathy are significant

adverse effects associated with this agent. Isoniazid may cause asymptomatic transient elevation of aminotransferase levels (often termed

hepatic adaptation) in up to 20% of recipients. Other adverse reactions include rash (2%), fever (1.2%), anemia, acne, arthritic symptoms, a systemic lupus erythematosus–like syndrome, optic atrophy,

seizures, and psychiatric symptoms. Symptomatic hepatitis occurs in

<0.1% of persons treated with isoniazid alone for LTBI, and fulminant

hepatitis with hepatic failure occurs in <0.01%. Isoniazid-associated

hepatitis is idiosyncratic, but its incidence increases with age, with

daily alcohol consumption, and in women who are within 3 months

postpartum.

In patients who have liver disorders or HIV infection, who are pregnant or in the 3-month postpartum period, who have a history of liver

disease (e.g., hepatitis B or C, alcoholic hepatitis, or cirrhosis), who

use alcohol regularly, who have multiple medical problems, or who

have other risk factors for chronic liver disease, the risks and benefits

of isoniazid treatment for LTBI should be weighed. If treatment is

undertaken, these patients should have serum concentrations of ALT

determined at baseline. Routine baseline hepatic ALT testing based

solely on an age of >35 years is optional and depends on individual

concerns. Monthly biochemical monitoring during isoniazid treatment is indicated for patients whose baseline liver function tests yield

abnormal results and for persons at risk for hepatic disease, including

the groups just mentioned. Guidelines recommend that isoniazid be

discontinued in the presence of hepatitis symptoms or jaundice and

an ALT or AST level three times the upper limit of normal or in the

absence of symptoms with an ALT or AST level five times the upper

limit of normal (Table 181-3).

Peripheral neuropathy associated with isoniazid occurs in up to 2%

of patients given 5 mg/kg. Isoniazid appears to interfere with pyridoxine (vitamin B6

) metabolism. The risk of isoniazid-related neurotoxicity is greatest for patients with preexisting disorders that also pose

a risk of neuropathy, such as HIV infection; for those with diabetes

mellitus, alcohol abuse, or malnutrition; and for those simultaneously

receiving other potentially neuropathic medications, such as stavudine.

These patients should be given prophylactic pyridoxine (25–50 mg/d).

Rifampin Rifampin is a semisynthetic derivative of Amycolatopsis

rifamycinica (formerly known as Streptomyces mediterranei). The most

active antimycobacterial agent available, rifampin is the keystone of

first-line treatment for TB. Introduced in 1968, this drug eventually

permitted dramatic shortening of the TB treatment course. Rifampin

has both sterilizing and bactericidal activity against dividing and

nondividing M. tuberculosis. The drug is also active against an array

of other organisms, including some gram-positive and gram-negative

bacteria, Legionella, M. kansasii, and Mycobacterium marinum.

MECHANISM OF ACTION Rifampin exerts both intracellular and extracellular bactericidal activities. Like other rifamycins, rifampin specifically

binds to and inhibits mycobacterial DNA-dependent RNA polymerase,

blocking RNA synthesis. Susceptible strains of M. tuberculosis as well as

M. kansasii and M. marinum are inhibited by rifampin concentrations

of 1 μg/mL.

PHARMACOLOGY Rifampin is a fat-soluble, complex macrocyclic

molecule readily absorbed after oral administration. Serum levels

of 10–20 μg/mL are achieved 2.5 h after the usual adult oral dose of

10 mg/kg (given without food). Rifampin has a half-life of 1.5–5 h. The

drug distributes well throughout most body tissues, including CSF.

Rifampin turns body fluids such as urine, saliva, sputum, and tears a

reddish-orange color—an effect that offers a simple means of assessing

patients’ adherence to this medication. Rifampin is excreted primarily

through the bile and enters the enterohepatic circulation; <30% of a

dose is renally excreted.

As a potent inducer of the hepatic cytochrome P450 system, rifampin can decrease the half-life of some drugs, such as digoxin, warfarin,

phenytoin, prednisone, cyclosporine, methadone, oral contraceptives, clarithromycin, azole antifungal agents, quinidine, antiretroviral

1401CHAPTER 181 Antimycobacterial Agents

protease inhibitors, and nonnucleoside reverse transcriptase inhibitors.

The Centers for Disease Control and Prevention (CDC) has issued

guidelines for the management of drug interactions during treatment

of HIV and M. tuberculosis co-infection (www.cdc.gov/tb/).

DOSING The daily dosage of rifampin is 10 mg/kg for adults and

10–20 mg/kg for children, with a maximum of 600 mg/d for both.

The drug is given once daily, twice weekly, or three times weekly. No

adjustments of dose or frequency are necessary in patients with renal

insufficiency.

RESISTANCE Resistance to rifampin in M. tuberculosis, M. leprae, and

other organisms is the consequence of spontaneous, mostly missense

point mutations in a core region of the bacterial gene coding for the β

subunit of RNA polymerase (rpoB). RNA polymerase altered in this

manner is no longer subject to inhibition by rifampin. Most rapidly and

slowly growing NTM harbor intrinsic resistance to rifampin, for which

the mechanism has yet to be determined.

ADVERSE EFFECTS Adverse events associated with rifampin are

infrequent and generally mild. Hepatotoxicity due to rifampin alone is

uncommon in the absence of preexisting liver disease and often consists of isolated hyperbilirubinemia rather than aminotransferase elevation. Other adverse reactions include rash, pruritus, gastrointestinal

symptoms, and pancytopenia. Rarely, a hypersensitivity reaction may

occur with intermittent therapy, manifesting as fever, chills, malaise,

rash, and—in some instances—renal and hepatic failure.

Pyrazinamide A nicotinamide analog, pyrazinamide is an important bactericidal drug used in the initial phase of TB treatment. Its

administration for the first 2 months of therapy with rifampin and

isoniazid allows treatment duration to be shortened from 9 to 6 months

and decreases rates of relapse.

MECHANISM OF ACTION Pyrazinamide’s antimycobacterial activity is

essentially limited to M. tuberculosis. The drug is more active against

slowly replicating organisms than against actively replicating organisms. Pyrazinamide is a prodrug that is converted by the mycobacterial

pyrimidase to the active form, pyrazinoic acid (POA). This agent is

active only in acidic environments (pH <6.0), as are found within

phagocytes or granulomas. The exact mechanism of action of POA

is unclear, but fatty acid synthetase I may be the primary target in M.

tuberculosis. Susceptible strains of M. tuberculosis are inhibited by pyrazinamide concentrations of 16–50 μg/mL at pH 5.5.

PHARMACOLOGY AND DOSING Pyrazinamide is well absorbed after

oral administration, with peak serum concentrations of 20–60 μg/mL

at 1–2 h after ingestion of the recommended adult daily dose of 15–30

mg/kg (maximum, 2 g/d). It distributes well to various body compartments, including CSF, and is an important component of treatment for

tuberculous meningitis. The serum half-life of the drug is 9–11 h with

normal renal and hepatic function. Pyrazinamide is metabolized in the

liver to POA, 5-hydroxypyrazinamide, and 5-hydroxy-POA. A high

proportion of pyrazinamide and its metabolites (~70%) is excreted in

the urine. The dosage must be adjusted according to the level of renal

function in patients with reduced creatinine clearance.

ADVERSE EFFECTS At the higher dosages used previously, hepatotoxicity was seen in as many as 15% of patients treated with pyrazinamide.

However, at the currently recommended dosages, hepatotoxicity now

occurs less commonly when this drug is administered with isoniazid

and rifampin during the treatment of TB. Older age, active liver disease, HIV infection, and low albumin levels may increase the risk of

hepatotoxicity. The use of pyrazinamide with rifampin for the treatment of LTBI is no longer recommended because of unacceptable rates

of hepatotoxicity and death in this setting. Hyperuricemia is a common

adverse effect of pyrazinamide therapy that usually can be managed

conservatively. Clinical gout is rare.

Although pyrazinamide is recommended by international TB organizations for routine use in pregnancy, it is not recommended in the

United States because of inadequate teratogenicity data.

RESISTANCE The basis of pyrazinamide resistance in M. tuberculosis

is a mutation in the pncA gene coding for pyrazinamidase, the enzyme

that converts the prodrug to active POA. Resistance to pyrazinamide

is associated with loss of pyrazinamidase activity, which prevents

conversion of pyrazinamide to POA. Of pyrazinamide-resistant M.

tuberculosis isolates, 72–98% have mutations in pncA. Conventional

methods of testing for susceptibility to pyrazinamide may produce

both false-negative and false-positive results because the high-acidity

environment required for the drug’s activation also inhibits the growth

of M. tuberculosis. There is some controversy as to the clinical significance of in vitro pyrazinamide resistance.

Ethambutol Ethambutol is a bacteriostatic antimycobacterial agent

first synthesized in 1961. A component of the standard first-line regimen,

ethambutol provides synergy with the other drugs in the regimen and

is generally well tolerated. Susceptible species include M. tuberculosis,

M. marinum, M. kansasii, and organisms of the Mycobacterium avium

complex (MAC); however, among first-line drugs, ethambutol is the

least potent against M. tuberculosis. This agent is also used in combination with other agents in the continuation phase of treatment when

patients cannot tolerate isoniazid or rifampin or are infected with

organisms resistant to either of the latter drugs.

MECHANISM OF ACTION Ethambutol is bacteriostatic against M.

tuberculosis. Its primary mechanism of action is the inhibition of the

arabinosyltransferases involved in cell wall synthesis, which probably

inhibits the formation of arabinogalactan and lipoarabinomannan.

The MIC of ethambutol for susceptible strains of M. tuberculosis is

0.5–2 μg/mL.

PHARMACOLOGY AND DOSING From a single dose of ethambutol,

75–80% is absorbed within 2–4 h of administration. Serum levels peak

at 2–4 μg/mL after the standard adult daily dose of 15 mg/kg. Ethambutol is well distributed throughout the body except in the CSF; a dosage

of 25 mg/kg is necessary for attainment of a CSF level half of that in

serum. For intermittent therapy, the dosage is 25–35 mg/kg thrice

weekly. To prevent toxicity, the dosage must be lowered and the frequency of administration reduced for patients with renal insufficiency.

ADVERSE EFFECTS Ethambutol is usually well tolerated and has no

significant interactions with other drugs. Optic neuritis, the most serious adverse effect reported, typically presents as reduced visual acuity,

central scotoma, and loss of the ability to see green (or, less commonly,

red). The cause of this neuritis is unknown, but it may be due to an effect

of ethambutol on the amacrine and bipolar cells of the retina. Symptoms typically develop several months after initiation of therapy, but

ocular toxicity soon after initiation of ethambutol has been described.

The risk of ocular toxicity is dose dependent, with occurrence in 1–5%

of patients, and can be increased by renal insufficiency. The routine use

of ethambutol in younger children is not recommended because monitoring for visual complications can be difficult. If drug-resistant TB is

suspected, ethambutol can be used for treatment of children.

All patients starting therapy with ethambutol should have a baseline

test for visual acuity, visual fields, and color vision and should undergo

an examination of the optic fundus. Visual acuity and color vision

should be monitored monthly or less often as needed. Cessation of

ethambutol in response to early symptoms of ocular toxicity usually

results in reversal of the deficit within several months. Recovery of all

visual function may take up to 1 year. In the elderly and in patients

whose symptoms are not recognized early, deficits may be permanent.

Some experts think that supplementation with hydroxycobalamin

(vitamin B12) is beneficial for patients with ethambutol-related ocular

toxicity. Other adverse effects of ethambutol are rare. Peripheral sensory neuropathy occurs in rare instances.

RESISTANCE Ethambutol resistance in M. tuberculosis and NTM is

associated primarily with missense mutations in the embB gene that

encodes for arabinosyltransferase. Mutations have been found in resistant strains at codon 306 in 50–70% of cases. Mutations at embB306

can cause significantly increased MICs of ethambutol, resulting in

clinical resistance.

1402 PART 5 Infectious Diseases

■ OTHER RIFAMYCIN DRUGS

Rifabutin Rifabutin, a semisynthetic derivative of rifamycin S,

inhibits mycobacterial DNA-dependent RNA polymerase. Rifabutin

is recommended in place of rifampin for the treatment of TB in HIVco-infected individuals who are taking protease inhibitors or nonnucleoside reverse transcriptase inhibitors, particularly nevirapine. A study

in India showed better TB treatment outcomes in HIV-co-infected

patients given daily rifabutin plus atazanavir/ritonavir than in those

given thrice-weekly rifabutin plus atazanavir/ritonavir. Rifabutin’s

effect on hepatic enzyme induction is less pronounced than that of

rifampin. Protease inhibitors may cause significant increases in rifabutin levels through inhibition of hepatic metabolism. Rifabutin is more

active in vitro than rifampin against MAC organisms and other NTM,

but its clinical superiority has not been established.

PHARMACOLOGY Like rifampin, rifabutin is lipophilic and is absorbed

rapidly after oral administration, reaching peak serum levels 2–4 h

after ingestion. Rifabutin distributes best to tissues, reaching levels

5–10 times higher than those in plasma. Unlike rifampin, rifabutin and

its metabolites are partially cleared by the hepatic microsomal system.

Rifabutin’s slow clearance results in a mean serum half-life of 45 h—

much longer than the 3- to 5-h half-life of rifampin. Clarithromycin

(but not azithromycin) and fluconazole appear to increase rifabutin

levels by inhibiting hepatic metabolism.

ADVERSE EFFECTS The most common adverse effects of rifabutin

treatment are gastrointestinal; other reactions include rash, headache,

asthenia, chest pain, myalgia, and insomnia. Less common adverse

reactions include fever, chills, a flulike syndrome, anterior uveitis,

hepatitis, Clostridium difficile–associated diarrhea, a diffuse polymyalgia syndrome, and yellow skin discoloration (“pseudo-jaundice”).

Laboratory abnormalities include neutropenia, leukopenia, thrombocytopenia, and increased levels of liver enzymes. Rifabutin appears

to be better tolerated by the majority (72%) of adult TB patients who

have developed rifampin-related adverse effects. Female patients, those

co-infected with hepatitis B or hepatitis C, and those with rifampinrelated arthralgias, dermatologic reactions, and cholestasis are more

likely to develop mild to severe rifabutin-related adverse effects.

RESISTANCE Similar to rifampin resistance, rifabutin resistance is

mediated by mutations in rpoB.

Rifapentine Rifapentine is a semisynthetic cyclopentyl rifamycin,

sharing a mechanism of action with rifampin. Rifapentine is lipophilic and has a prolonged half-life that permits weekly or twice-weekly

dosing. Therefore, rifapentine is the subject of intensive clinical

investigation aimed at determining optimal dosing and frequency of

administration. Currently, it is an alternative to rifampin in the continuation phase of treatment for noncavitary drug-susceptible pulmonary

TB in HIV-seronegative patients who have negative sputum smears at

completion of the initial phase of treatment. When administered in

these specific circumstances, rifapentine (10 mg/kg, up to 600 mg) is

given once weekly with isoniazid. Because of higher rates of relapse,

this regimen is not recommended for patients with TB disease and HIV

co-infection; moreover, it has not been approved for children <12 years

of age. In a phase 2 study, substituting daily rifapentine for rifampin

yielded higher rates of sputum sterilization after 2 months of intensive

treatment. Higher doses of rifapentine (20 mg/kg vs 10 mg/kg) had

better results and were safe and well tolerated. Regimens containing

high doses of rifapentine are being evaluated to see whether they can

shorten the TB treatment course to <6 months.

PHARMACOLOGY Rifapentine’s absorption is improved when the

drug is taken with food. After oral administration, rifapentine reaches

peak serum concentrations in 5–6 h and achieves a steady state in

10 days. The half-life of rifapentine and its active metabolite,

25-desacetyl rifapentine, is ~13 h. The administered dose is excreted

via the liver (70%).

ADVERSE EFFECTS The adverse effects profile of rifapentine is similar

to that of other rifamycins. Rifapentine is teratogenic in animal models

and is relatively contraindicated in pregnancy.

RESISTANCE Rifapentine resistance is mediated by mutations in rpoB.

Mutations that cause resistance to rifampin also cause resistance to

rifapentine.

■ SECOND-LINE ANTITUBERCULOSIS DRUGS

Second-line anti-TB agents are indicated for treatment of drug-resistant

TB, for patients who are intolerant or allergic to first-line agents, and

when first-line supplemental agents are unavailable. According to their

usability, they are divided into three WHO groups.

Group A •  FLUOROQUINOLONES Fluoroquinolones inhibit

mycobacterial DNA gyrase and topoisomerase IV, preventing cell replication and protein synthesis, and are bactericidal. Given their excellent activity, they have been investigated for their potential to shorten

the course of treatment for drug-susceptible TB from 6 to 4 months. In

contrast to prior trials, a recent large, open-label randomized controlled

trial (TBTC Study 31) yielded promising results for shortening of TB

treatment. Patients with drug susceptible TB disease were randomized

to receive either standard six-month TB regimen or 4-month regimen

containing rifapentine (8 weeks of once-daily rifapentine, isoniazid,

pyrazinamide, and ethambutol followed by 9 weeks of once-daily rifapentine and isoniazid) or 4-month regimen containing rifapentine and

moxifloxacin (8 weeks of once-daily rifapentine, isoniazid, pyrazinamide, and moxifloxacin followed by 9 weeks of once-daily rifapentine,

isoniazid, and moxifloxacin). The trial demonstrated that a four-month

regimen using daily rifapentine and moxifloxacin (but not the rifapentine only regimen) was non-inferior to the standard six-month TB

treatment regimen using an end point of TB-free survival 12 months

after randomization. Combining once daily rifapentine with moxifloxacin allows for synergistic action on sputum conversion in a compliance-friendly once-daily option. Current recommendations continue

to be for a standard six-month regimen though it is anticipated that

these results will inform future guidelines. Gatifloxacin has fallen out of

favor because of significant dysglycemia. Ciprofloxacin and ofloxacin

are no longer recommended for the treatment of TB because of poor

efficacy. Despite documented resistance to early-generation fluoroquinolones (e.g., ofloxacin and ciprofloxacin), use of a later-generation

fluoroquinolone in patients with drug-resistant TB has been associated

with favorable outcomes. Fluoroquinolones are also considered safe

alternatives for patients who develop treatment-limiting adverse effects

from first-line agents. Levofloxacin and moxifloxacin have both been

used effectively in the treatment of MDR-TB. The optimal dose of

levofloxacin for this indication is being actively studied, but doses of at

least 750 mg are commonly used. High-dose moxifloxacin (800 mg) is

recommended for standardized shorter MDR-TB regimens.

The fluoroquinolones are well absorbed orally, reach high serum

levels, and distribute well into body tissues and fluids. Their absorption is decreased by co-ingestion with products containing multivalent

cations, such as antacids. Adverse effects are relatively infrequent

(0.5–10% of patients) and include gastrointestinal intolerance, rashes,

dizziness, and headache. Most studies of fluoroquinolone side effects

have been based on relatively short-term administration for bacterial

infections, but trials have now shown the relative safety and tolerability

of fluoroquinolones administered for months during TB treatment in

adults. Although the potential to prolong the QTc interval, leading to

cardiac arrhythmias, has been a source of concern with fluoroquinolones, cessation of treatment due to this adverse effect is rare. Because

the benefits may outweigh the risks in treatment of drug-resistant TB,

there is increasing interest in the use of fluoroquinolones in children,

which has traditionally been avoided because of the risks of tendon

rupture and cartilage damage.

Multiple courses of empirical fluoroquinolone therapy for presumed

community-acquired pneumonia are associated with delayed diagnosis

of active pulmonary TB and increased fluoroquinolone resistance in M.

tuberculosis. Mutations in the genes encoding for DNA gyrase (gyrA

and gyrB) are implicated in the majority of cases—but not all cases—of

clinical resistance to fluoroquinolones.

DIARYLQUINOLINES Bedaquiline (TMC207 or R207910) is a diarylquinoline with a novel mechanism of action: inhibition of the

1403CHAPTER 181 Antimycobacterial Agents

mycobacterial ATP synthetase proton pump. Bedaquiline is bactericidal for M. tuberculosis. Resistance has been reported due to point

mutations in the atpE gene encoding for subunit c of ATP synthetase.

Clinical bedaquiline resistance has also been reported due to nontarget mutations in Rv0678 (a negative repressor of the MmpL5 efflux

pump) and PepQ (a cytoplasmic peptidase), both of which may cause

cross-resistance to clofazimine. Bedaquiline is metabolized by the

hepatic cytochrome CYP3A4. Rifampin lowers bedaquiline levels by

50%, and protease inhibitors also interact significantly with this drug.

Because efavirenz induces CYP3A4, there is concern about lower

bedaquiline levels with co-administration. In a study of co-treatment

with bedaquiline and efavirenz in healthy volunteers, bedaquiline levels were reduced by only 20%; however, in a study modeling chronic

co-administration of these two drugs, the reduction in bedaquiline

levels was estimated to be 50%, leading many national TB programs to

avoid efavirenz co-administration with bedaquiline.

The oral bioavailability of bedaquiline appears to be excellent. The

dosage is 400 mg/d for the first 2 weeks and then 200 mg thrice weekly

typically for 6 months total. The elimination half-life is long (>14 days).

A single dose of this drug can inhibit the growth of M. tuberculosis for

up to 1 week through a combination of long plasma half-life, high-level

tissue penetration, and long tissue half-life. Bedaquiline added to a background regimen improved the 2-month sputum culture–conversion rate

in multicenter, randomized placebo-controlled trials, and these results

led to approval by the U.S. Food and Drug Administration (FDA).

However, the death rate in one trial was higher in the bedaquiline

arm than in the control arm (11.4% vs 2.5%); the result was a “black

box” warning from the FDA, which also included QT prolongation.

Subsequent studies have not found an association with significant

mortality. The CDC has made a provisional recommendation for the

use of bedaquiline for 24 weeks in adults with laboratory-confirmed

pulmonary MDR-TB when no other effective treatment regimen can

be provided. Bedaquiline is an integral part of all shorter course, oral

MDR treatment regimens endorsed by the WHO.

OXAZOLIDINONES Linezolid is an oxazolidinone used primarily for

the treatment of drug-resistant gram-positive bacterial infections.

However, this drug is active in vitro against M. tuberculosis and NTM.

Several case series have suggested that linezolid may help clear mycobacteria relatively rapidly when included in a regimen for the treatment of

complex cases of drug-resistant TB. Linezolid’s mechanism of action is

disruption of protein synthesis by binding to the 50S bacterial ribosome.

Linezolid has nearly 100% oral bioavailability, with good penetration

into tissues and fluids, including CSF. Clinical resistance to linezolid

has been reported and is typically associated with mutations in the 23S

rRNA and in two ribosomal proteins, L3 (rplC) and L4 (rplD). Adverse

effects may include optic and peripheral neuropathy, pancytopenia, and

lactic acidosis and are usually associated with higher doses. Linezolid

is a weak monoamine oxidase inhibitor and can be associated with

the serotonin syndrome when given concomitantly with serotonergic

drugs (primarily antidepressants such as selective serotonin reuptake

inhibitors). It has been shown that ~80% of patients with MDR-TB can

be successfully treated with linezolid-containing, individualized anti-TB

regimens based on drug sensitivity testing. Replacement of ethambutol

with linezolid for 2–4 weeks during the intensive phase of treatment

of drug-susceptible TB is currently being evaluated for possible faster

sputum conversion and a shorter treatment regimen. For MDR-TB

treatment, linezolid is usually administered at a dose of 600 mg (or less

in some cases) once daily, which appears to be effective. A single daily

dose is associated with fewer adverse events than twice-a-day dosing.

Sutezolid, a modified version of oxazolidinones and protein synthesis inhibitor, is found to have higher early bactericidal activity

compared to linezolid and is currently undergoing phase 2A trials. It

is currently FDA approved for complex skin infections and appears to

have less frequent side effects compared to linezolid; the adverse effects

profile of long-term exposure compared with that of linezolid needs

further investigation.

Group B •  CLOFAZIMINE Clofazimine is a fat-soluble riminophenazine dye used primarily in the treatment of leprosy worldwide.

It is currently gaining popularity in the management of drug-resistant

TB because of its low cost and its intracellular and extracellular activity.

By increasing reactive oxidant species and causing membrane destabilization, clofazimine may promote killing of antibiotic-tolerant M.

tuberculosis “persister” organisms. In addition to antimicrobial activity,

the drug has other pharmacologic activities, such as anti-inflammatory,

pro-oxidative, and immunopharmacologic properties. Clofazimine has

a half-life of ~70 days in humans, and average steady-state concentrations are achieved at ~1 month. Intake with fatty meals can improve its

low and variable rates of absorption (45–62%). Common side effects

include gastrointestinal intolerance, and reversible orange to brownish

discoloration of skin, bodily fluids, and secretions. Dose adjustment

may be necessary in patients with severe hepatic impairment. Clofazimine was studied as part of a regimen developed in Bangladesh

for potential shortening of the MDR-TB treatment course. A metaanalysis suggested that inclusion of clofazimine in a multidrug regimen

for treatment of MDR-TB was associated with a favorable outcome.

Newer analogues with improved pharmacokinetics and alternative

formulations of clofazimine (liposomal, nanosuspension, inhalational)

are being studied.

CYCLOSERINE Cycloserine is an analog of the amino acid d-alanine

and prevents bacterial cell-wall synthesis. It inhibits the action of

enzymes, including alanine racemase, that are involved in the production of peptidoglycans. Cycloserine is active against a range of bacteria,

including M. tuberculosis. Mechanisms of mycobacterial resistance

are not well understood, but overexpression of alanine racemase can

confer resistance in Mycobacterium smegmatis. Cycloserine is well

absorbed after oral administration and is widely distributed throughout body fluids, including CSF. The usual adult dosage is 250 mg two or

three times per day. Serious potential side effects include seizures and

psychosis (with suicide in some cases), peripheral neuropathy, headache, somnolence, and allergic reactions. Drug levels are monitored

to achieve optimal dosing and to reduce the risk of adverse effects,

especially in patients with renal failure. Cycloserine should be administered as DOT only with caution and with support from experienced TB

physicians to patients with epilepsy, active alcohol abuse, severe renal

insufficiency, or a history of depression or psychosis.

Group C •  NITROIMIDAZOLES The prodrugs delamanid

(OPC-67683) and pretomanid (PA 824) are novel nitro-dihydroimidazooxazole derivatives that are activated by M. tuberculosis–

specific flavin-dependent nitroreductases and whose antimycobacterial

activity is attributable to inhibition of mycolic acid biosynthesis. Delamanid was shown in a randomized, placebo-controlled, multinational

clinical trial to significantly improve the culture conversion rate at

2 months. QT prolongation occurred significantly more often in delamanid-treated patients, but no clinically relevant events were reported.

In a subsequent randomized phase 3 trial, there was no significant

difference in 6 months sputum conversion between delamanid and

placebo among patients with an optimized background regimen. Currently, it is part of several ongoing clinical trials including combination

with bedaquiline. It is recommended for the use in children younger

than 6 years with rifampicin-resistant TB. Usual adult dose is 100 mg

twice daily.

Pretomanid, the second novel agent from this class, has shown

promising results in the treatment of drug-resistant TB in combination

with bedaquiline. A combination of pretomanid with moxifloxacin and

pyrazinamide for treatment of drug-susceptible TB was found to have

higher culture conversation rates at 8 weeks compared to HRZE; however, a subsequent phase 3 study raised concern for higher frequency of

potentially fatal hepatotoxicity. It is currently being evaluated in several

phase 3 clinical trials in various combinations, including with fluoroquinolones and pyrazinamide. Based on the previously mentioned

results with the BPaL regimen (Nix-TB study), the FDA has granted

approval for specific highly resistant TB cases. Adult treatment dose is

200 mg administered daily.

AMOXICILLIN-CLAVULANATE AND CARBAPENEMS β-Lactam agents

are largely ineffective for the treatment of M. tuberculosis because of