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Antimycobacterial Agents

Chapter 186 | Part 5: Infectious Diseases · Part 5 – Infectious Diseases: Bacterial

Detailed clinical reference synthesised from Harrison's Principles of Internal Medicine, 22nd Edition

🔑 Key Clinical Points

  1. TB treatment requires multi-drug regimens to prevent resistance; standard intensive phase is 2 months (HRZE) followed by continuation phase (HR).
  2. Latent TB Infection (LTBI) regimens include Isoniazid plus Rifapentine (3 months weekly), Rifampin (4 months daily), or Isoniazid (6-9 months).
  3. MDR-TB is defined by resistance to Isoniazid and Rifampin; new WHO guidelines recommend all-oral bedaquiline-containing regimens (e.g., BPaLM) for 6 months.
  4. Isoniazid toxicity includes hepatotoxicity (discontinue if ALT >5x ULN or >3x ULN with symptoms) and peripheral neuropathy (prevent with pyridoxine).
  5. Rifampin is a potent CYP450 inducer causing drug interactions (e.g., warfarin, protease inhibitors); it turns body fluids orange-red.
  6. HIV co-infection requires careful ART timing (within 2 weeks if CD4 <=50) and monitoring for Immune Reconstitution Inflammatory Syndrome (IRIS).
  7. NTM treatment depends on species (MAC, M. kansasii, M. abscessus, M. marinum) and susceptibility; M. abscessus is difficult to cure and often requires surgical resection.
  8. Drug resistance mechanisms include katG mutations (isoniazid), inhA promoter mutations (isoniazid), pncA mutations (pyrazinamide), and efflux pump upregulation.
  9. Monitoring includes monthly clinical assessment, liver function tests (ALT, bilirubin), and specific toxicity checks (visual acuity for ethambutol, QTc for fluoroquinolones).
  10. Treatment adherence is critical; strategies include Directly Observed Therapy (DOT), mobile health technologies, and monthly dispensing.

📑 Table of Contents

1. DEFINITION & OVERVIEW

  • 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, >180 species of mycobacteria have been identified, the majority of which do not cause disease in humans.
  • While the overall incidence of disease caused by Mycobacterium tuberculosis has been declining, there has been a recent increase in incidence in the context of the COVID-19 pandemic.
  • TB remains a leading cause of morbidity and mortality in low- and middle-income countries—especially in sub-Saharan Africa where TB/HIV co-infection is common.
  • Infections with NTM have gained in clinical prominence in the United States and other developed countries.
  • These NTM organisms often establish infection in immunocompromised patients or in persons with structural lung disease.
  • 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).
  • 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.
  • 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 186-2).

1.1 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 specialization will distinguish tuberculosis from nontuberculous mycobacterial infections and thereby affect rates of assumed relapse and resistance, leading to more targeted and appropriate therapy.

1.2 Nontuberculous Mycobacteria (NTM)

  • NTM infections are largely environmental organisms.
  • They often establish infection in immunocompromised patients or in persons with structural lung disease.
  • 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.

2. EPIDEMIOLOGY

  • The overall incidence of disease caused by Mycobacterium tuberculosis has been declining.
  • There has been a recent increase in incidence in the context of the COVID-19 pandemic.
  • TB remains a leading cause of morbidity and mortality in low- and middle-income countries—especially in sub-Saharan Africa where TB/HIV co-infection is common.
  • 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.
  • Infections with NTM have gained in clinical prominence in the United States and other developed countries.
  • These NTM organisms often establish infection in immunocompromised patients or in persons with structural lung disease.

2.1 TB/HIV Co-infection

  • TB/HIV co-infection is common in sub-Saharan Africa.
  • 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.

2.2 NTM Epidemiology

  • Infections with NTM have gained in clinical prominence in the United States and other developed countries.
  • These NTM organisms often establish infection in immunocompromised patients or in persons with structural lung disease.

3. ETIOLOGY & PATHOPHYSIOLOGY

  • M. tuberculosis is the primary pathogen for TB disease.
  • NTM species include MAC (Mycobacterium avium complex), M. kansasii, M. abscessus, and M. marinum.
  • Resistance mechanisms include:
  • katG mutations (isoniazid resistance).
  • inhA promoter mutations (isoniazid resistance).
  • pncA mutations (pyrazinamide resistance).
  • Efflux pump upregulation (e.g., efpA, mmpL7, mmr, p55, Rv1258c).
  • Loss of NADH dehydrogenase 2 activity.
  • Alterations in kasA (mycolic acid elongation).
  • IRIS (Immune Reconstitution Inflammatory Syndrome) may appear as early as 1 week after initiation of ART and manifests as paradoxical worsening or unmasking of existing TB infection.
  • IRIS is a diagnosis of exclusion.

3.1 Resistance Mechanisms

  • Isoniazid resistance:
  • 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.
  • Pyrazinamide 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.
  • Rifampin resistance:
  • Monoresistance to R is rare and should be treated as MDR.

3.2 IRIS Pathophysiology

  • IRIS may appear as early as 1 week after initiation of ART.
  • It manifests as paradoxical worsening or unmasking of existing TB infection.
  • Conservative management consists of continued administration of ART and TB medications.
  • Severe or debilitating IRIS has been treated in reported case series with varying doses of glucocorticoids.
  • A randomized, double-blind, placebo-controlled trial showed that a 4-week course of prednisone significantly reduced the need for hospitalization and hastened symptom improvement and quality of life in TB IRIS.

4. CLINICAL FEATURES

  • TB symptoms include persistent cough, fever, anorexia, and severe lung destruction.
  • With no or inadequate treatment, symptoms and signs can be debilitating.
  • With treatment, patients typically regain strength and energy.
  • NTM symptoms include 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.
  • IRIS manifests as paradoxical worsening or unmasking of existing TB infection.
  • Drug toxicity symptoms include nausea, vomiting, abdominal discomfort, unexplained fatigue, jaundice, dark urine, light stools, diffuse pruritus.

4.1 TB Clinical Features

  • Persistent cough.
  • Fever.
  • Anorexia.
  • Severe lung destruction.
  • Symptoms and signs can be debilitating with no or inadequate treatment.
  • Patients typically regain strength and energy with treatment.

4.2 NTM Clinical Features

  • Persistent cough.
  • Fever.
  • Anorexia.
  • Severe lung destruction.
  • Symptoms and signs can be debilitating with no or inadequate treatment.
  • Patients typically regain strength and energy with treatment.
  • The optimal duration of therapy when NTM persist in sputum is unknown, but treatment in this situation can be prolonged.

4.3 Drug Toxicity

  • Hepatotoxicity: Nausea, vomiting, abdominal discomfort, unexplained fatigue, jaundice, dark urine, light stools, diffuse pruritus.
  • Peripheral neuropathy: Numbness, tingling, pain.
  • Optic neuritis: Decrease in visual acuity or color vision.
  • QTc prolongation: Palpitations or arrhythmias.
  • Bone marrow suppression: Anemia, thrombocytopenia, leukopenia.

5. DIFFERENTIAL DIAGNOSIS

  • TB vs NTM: Advances in specialization will distinguish tuberculosis from nontuberculous mycobacterial infections.
  • Drug-resistant TB: 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.
  • IRIS: Diagnosis of exclusion.
  • Mimics: NTM infections often establish infection in immunocompromised patients or in persons with structural lung disease.

5.1 MDR-TB Definition

  • 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.

5.2 IRIS Diagnosis

  • IRIS is a diagnosis of exclusion.
  • It should also be a consideration for patients co-infected with HIV and M. tuberculosis.

6. INVESTIGATIONS & DIAGNOSIS

  • LTBI is diagnosed by history, physical examination, radiographic imaging, tuberculin skin test, interferon-γ release assays, acid-fast staining, mycobacterial cultures, and/or new molecular diagnostics.
  • Active TB diagnosis relies on detection of M. tuberculosis via culture or molecular testing.
  • Drug susceptibility testing should be repeated if treatment failure is suspected.
  • Monitoring includes monthly clinical assessment, liver function tests (ALT, bilirubin), and specific toxicity checks (visual acuity for ethambutol, QTc for fluoroquinolones).

Table 1 — Table 186-1 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) 9 months may be more effective but with higher risk of hepatic toxicity. Twice-weekly regimens require directly observed therapy.

Table 2 — Table 186-2 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, daily 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 week (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)
Culture-negative HRZE for 2 months HR for 2 months, daily or 2 or 3 times per week 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 week Continuation phase extended to 10 months in TB meningitis; 7 months recommended by some authorities for bone/joint TB

Table 3 — Table 186-3 Monitoring and Clinical Management of Tuberculosis (TB) Treatment in Adults

Drug Assessment Management
LTBI Treatment With hepatic risk factors, check ALT and bilirubin at baseline. If ALT is ≥3× ULN or total bilirubin is >2× ULN, defer treatment and reevaluate. Same as above
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) 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. Same as for H.
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 ocular toxicity 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) Same as for H.
Fluoroquinolone, bedaquiline 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.

Table 4 — Table 186-4 Simplified Approach to Treatment of Drug-Resistant Tuberculosis (TB) in Adults

Culture Results Intensive Phase Continuation Phase Extension of Total Treatment
Resistant to H Lfx RZE for 6 months Prolonged culture conversion and/or evidence of cavitation on chest radiography. Bdq, Pa, Lz, Mfx for 6 months (may drop Mfx if documented Q resistance)
Resistant to HR (MDR) Bdq plus Lfx or Mfx, Eto, E, Z, Hh, Cfz for 4-6 months Lfx or Mfx, Cfz, Z, E for 5 months At least four effective second-line agents, including all three group A and at least one group B; add group C if intolerant to A or B drugs for 5-7 months
WHO short-course regimen Bdq plus Lfx or Mfx, Eto, E, Z, Hh, Cfz for 4-6 months Lfx or Mfx, Cfz, Z, E for 5 months At least 4 drugs for a total of 18-20 months or for 15-17 months after culture conversion

6.1 LTBI Diagnosis

  • History.
  • Physical examination.
  • Radiographic imaging.
  • Tuberculin skin test.
  • Interferon-γ release assays.
  • Acid-fast staining.
  • Mycobacterial cultures.
  • New molecular diagnostics.

6.2 Active TB Diagnosis

  • Detection of M. tuberculosis via culture or molecular testing.
  • Clinical factors, including HIV co-infection, symptom duration, radiographic appearance, and public health concerns about TB transmission, drive diagnostic testing and treatment initiation.

6.3 Monitoring

  • Monthly clinical assessment for symptoms (nausea, vomiting, abdominal discomfort, and unexplained fatigue) and signs (jaundice, dark urine, light stools, diffuse pruritus) of hepatotoxicity.
  • Baseline assessment of liver function is recommended in adults including testing of at least serum alanine aminotransferase (ALT) and total bilirubin levels.
  • 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.
  • Visual acuity screening for ethambutol.
  • QTc monitoring for fluoroquinolones and bedaquiline.

7. MANAGEMENT & TREATMENT

  • 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 186-2).
  • For drug-susceptible disease, a standardized regimen is used with an intensive phase consisting of four drugs—isoniazid (H), rifampin (R), pyrazinamide (Z), and ethambutol (E)—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), for which also warrants evaluation for development of drug resistance.
  • In 2020, a large multinational randomized trial showed that a 4-month regimen composed of daily rifapentine, isoniazid, pyrazinamide, and moxifloxacin for 8 weeks, followed by rifapentine, isoniazid, and moxifloxacin for 9 weeks, was noninferior to the traditional 6-month HRZE regimen.
  • Patients with HIV and a CD4 count >100 were included. This regimen now has conditional recommendation by the WHO and U.S. guidelines.
  • Remaining concerns are higher daily pill burden, potential side effects from prolonged use of moxifloxacin, and need for fluoroquinolone resistance testing in areas where resistance is prevalent.
  • 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.
  • The presence 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.
  • 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 incomplete adherence, 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 (Table 183-4).
  • New 2022 WHO recommendations emphasize an all-oral bedaquiline-containing regimen with the goal to limit treatment duration to 6 months compared to conventional durations of 9 months or longer (Table 186-4).
  • 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 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.
  • 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).
  • 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 the higher rate of side effects, mostly due to linezolid, and lack of a control arm.
  • The TB PRACTECAL trial was an open-label, multicenter, randomized, controlled, noninferiority trial that evaluated the safety and efficacy of a 24-week regimen of bedaquiline, pretomanid, linezolid, and moxifloxacin (BPaLM) compared to a 9- to 20-month standard-care regimen for the treatment of rifampicin-resistant TB.
  • In this study, the 6-month BPaLM regimen was found to be noninferior in both the intention-to-treat and per-protocol analyses, with a lower percentage of serious adverse events compared to the standard-care regimen.
  • High cost, limited access to these new drugs, and the threat of baseline and emergent resistance, especially to bedaquiline, are barriers that need to be addressed to facilitate global adaptation of these new regimens.
  • 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.
  • Intermittent antimycobacterial therapy 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.

7.1 LTBI Treatment

  • Isoniazid plus rifapentine (weekly for 3 months).
  • Rifampin (daily for 4 months).
  • Isoniazid plus rifampin (daily for 3 months).
  • Isoniazid (optimally daily or twice weekly for 6-9 months).
  • 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 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 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.

7.2 Active TB Treatment

  • Standard regimen includes isoniazid, rifampin, ethambutol, and pyrazinamide (HRZE) 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), for which also warrants evaluation for development of drug resistance.
  • In 2020, a large multinational randomized trial showed that a 4-month regimen composed of daily rifapentine, isoniazid, pyrazinamide, and moxifloxacin for 8 weeks, followed by rifapentine, isoniazid, and moxifloxacin for 9 weeks, was noninferior to the traditional 6-month HRZE regimen.
  • Patients with HIV and a CD4 count >100 were included. This regimen now has conditional recommendation by the WHO and U.S. guidelines.
  • Remaining concerns are higher daily pill burden, potential side effects from prolonged use of moxifloxacin, and need for fluoroquinolone resistance testing in areas where resistance is prevalent.

7.3 MDR-TB Treatment

  • 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.
  • New 2022 WHO recommendations emphasize an all-oral bedaquiline-containing regimen with the goal to limit treatment duration to 6 months compared to conventional durations of 9 months or longer (Table 186-4).
  • 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 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.
  • 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).
  • 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 the higher rate of side effects, mostly due to linezolid, and lack of a control arm.
  • The TB PRACTECAL trial was an open-label, multicenter, randomized, controlled, noninferiority trial that evaluated the safety and efficacy of a 24-week regimen of bedaquiline, pretomanid, linezolid, and moxifloxacin (BPaLM) compared to a 9- to 20-month standard-care regimen for the treatment of rifampicin-resistant TB.
  • In this study, the 6-month BPaLM regimen was found to be noninferior in both the intention-to-treat and per-protocol analyses, with a lower percentage of serious adverse events compared to the standard-care regimen.
  • High cost, limited access to these new drugs, and the threat of baseline and emergent resistance, especially to bedaquiline, are barriers that need to be addressed to facilitate global adaptation of these new regimens.

7.4 HIV Co-infection Management

  • 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.
  • Intermittent antimycobacterial therapy 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.

7.5 Adherence Strategies

  • 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.
  • The presence 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.

8. PROGNOSIS & COMPLICATIONS

  • 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.
  • Treatment failure due to incomplete adherence, 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.

8.1 NTM Prognosis

  • Outcomes are closely tied to the underlying condition (e.g., IFN-γ/IL-12 pathway defect, cystic fibrosis).
  • 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.

8.2 Treatment Failure

  • Treatment failure due to incomplete adherence.
  • Poor medication absorption.
  • 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.

9. SPECIAL CONSIDERATIONS

  • The regimen is not recommended for pregnant women and for persons with hypersensitivity reactions to isoniazid or rifampin.
  • Caution is advised in 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.
  • 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 186-3).

9.1 Pregnancy

  • The regimen is not recommended for pregnant women.
  • Risks and benefits of isoniazid treatment for LTBI should be weighed in pregnant women or in the 3-month postpartum period.

9.2 Liver Disease

  • 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 186-3).

9.3 HIV Co-infection

  • Caution is advised in 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.
  • 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.
  • Intermittent antimycobacterial therapy 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.

10. KEY PEARLS & CLINICAL TRAPS

  • TB treatment requires multi-drug regimens to prevent resistance; standard intensive phase is 2 months (HRZE) followed by continuation phase (HR).
  • LTBI regimens include Isoniazid plus Rifapentine (3 months weekly), Rifampin (4 months daily), or Isoniazid (6-9 months).
  • MDR-TB is defined by resistance to Isoniazid and Rifampin; new WHO guidelines recommend all-oral bedaquiline-containing regimens (e.g., BPaLM) for 6 months.
  • Isoniazid toxicity includes hepatotoxicity (discontinue if ALT >5x ULN or >3x ULN with symptoms) and peripheral neuropathy (prevent with pyridoxine).
  • Rifampin is a potent CYP450 inducer causing drug interactions (e.g., warfarin, protease inhibitors); it turns body fluids orange-red.
  • HIV co-infection requires careful ART timing (within 2 weeks if CD4 <=50) and monitoring for Immune Reconstitution Inflammatory Syndrome (IRIS).
  • NTM treatment depends on species (MAC, M. kansasii, M. abscessus, M. marinum) and susceptibility; M. abscessus is difficult to cure and often requires surgical resection.
  • Monitoring includes monthly clinical assessment, liver function tests (ALT, bilirubin), and specific toxicity checks (visual acuity for ethambutol, QTc for fluoroquinolones).
  • Treatment adherence is critical; strategies include Directly Observed Therapy (DOT), mobile health technologies, and monthly dispensing.
  • IRIS is a diagnosis of exclusion.

Generated from Harrison's Principles of Internal Medicine, 22nd Edition.