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Management of tuberculosis

The management of tuberculosis (TB), an infectious disease primarily caused by the bacterium Mycobacterium tuberculosis, involves integrated strategies for early , multidrug , prevention of , and patient-centered to achieve cure rates over 85% while minimizing . These efforts are guided by evidence-based recommendations from authoritative bodies like the (WHO) and the Centers for Disease Control and Prevention (CDC), emphasizing rapid detection, adherence support through directly observed therapy (DOT), and tailored interventions for vulnerable populations such as children, people living with , and those with comorbidities. TB remains a major global health challenge, with an estimated 10.7 million incident cases and 1.23 million deaths in 2024 (per the WHO Global Tuberculosis Report 2025), predominantly in low- and middle-income countries like , , , the , , , , and , which account for over two-thirds of the burden. The disease spreads through airborne droplets from individuals with active pulmonary TB, with about one-quarter of the world's population latently infected, though only 5–10% progress to active disease over their lifetime, a risk heightened by factors including co-infection, , , use, and dependency. Effective management is critical not only for individual recovery but also to curb , as incomplete treatment fuels multidrug-resistant TB (MDR-TB) and extensively drug-resistant TB (XDR-TB), which complicate therapy and increase mortality. Diagnosis forms the cornerstone of TB management, relying on symptom screening followed by confirmatory tests such as sputum microscopy, culture, and rapid molecular assays like for detecting M. tuberculosis and rifampicin resistance within hours. WHO guidelines recommend these tools for all individuals with presumptive TB, including extrapulmonary cases, with enhanced algorithms for high-risk groups: concurrent testing of multiple samples for people with regardless of age, and adjusted approaches for children under 10 without known status to improve yield in pediatric cases. or skin tests identify latent TB infection (LTBI), enabling preventive to avert progression, particularly in household contacts, healthcare workers, and immunocompromised individuals. Treatment regimens for drug-susceptible TB have evolved to prioritize shorter, safer options while maintaining efficacy. For adults and adolescents (≥12 years) with pulmonary TB, the CDC and ATS/ERS/IDSA conditionally recommend a novel 4-month regimen of high-dose , isoniazid, pyrazinamide, and (2HPZM/2HP), offering noninferior outcomes to the traditional 6-month course (2HRZE/4HR) with fewer adverse events and higher completion rates. In children with nonsevere TB, a 4-month rifampin-based regimen (2HRZ/2HR, with ethambutol optional) is strongly recommended over longer durations. , including video-assisted variants, is the standard to ensure adherence, with monthly monitoring for clinical response, adverse effects (e.g., from isoniazid or rifamycins), and drug susceptibility. For drug-resistant TB, WHO's 2025 consolidated guidelines advocate individualized regimens of 6–18 months using second-line drugs like , , and , often requiring expert consultation and extended hospitalization for severe cases. Prevention complements curative efforts through vaccination, infection control, and LTBI management. The provides partial protection against severe childhood TB forms, though not against adult pulmonary disease, and is routinely administered in high-burden settings. WHO's module on prevention strongly recommends 1- to 3-month rifamycin-based preventive regimens (e.g., 3HP: isoniazid plus weekly for 12 weeks) for LTBI in high-risk groups, including MDR-TB contacts, reducing progression risk by up to 90% with fewer doses than traditional 6- to 9-month isoniazid monotherapy. Airborne precautions, ventilation, and in healthcare and community settings further mitigate transmission, aligning with CDC infection control guidelines that mandate administrative, environmental, and personal protective measures. Patient support is integral, addressing barriers like , socioeconomic challenges, and comorbidities through nutritional , psychosocial counseling, and digital adherence tools, as outlined in WHO's care recommendations to foster and long-term success. Overall, these strategies have driven a 29% decline in global TB mortality since 2015 (as of 2024), but sustained investment is needed to meet End TB targets by 2030.

Antitubercular Medications

First-Line Drugs

First-line drugs for the treatment of drug-susceptible tuberculosis (TB) form the cornerstone of standard therapy, consisting primarily of isoniazid (INH), rifampicin (RIF), pyrazinamide (PZA), and ethambutol (EMB), often abbreviated as the HRZE regimen. These agents are selected for their potent bactericidal and sterilizing activities against , targeting different aspects of bacterial metabolism and replication to achieve rapid sputum conversion and high cure rates in susceptible cases. Isoniazid (INH) is a prodrug activated by mycobacterial catalase-peroxidase (KatG), exerting bactericidal effects primarily against actively dividing bacilli by inhibiting mycolic acid synthesis, a key component of the cell wall. The standard adult dose is 5 mg/kg orally once daily, not exceeding 300 mg, administered for its high efficacy in the initial phase of treatment. However, INH is associated with hepatotoxicity, necessitating regular liver function monitoring, and peripheral neuropathy, which is mitigated by co-administration of pyridoxine (vitamin B6) at 10-25 mg daily. Rifampicin (RIF), also known as rifampin, is a bactericidal that binds to the β-subunit of bacterial DNA-dependent , inhibiting RNA synthesis and disrupting transcription. It is dosed at 10 mg/kg orally once daily, with a maximum of 600 mg, and is essential for shortening treatment duration due to its activity against both intracellular and extracellular organisms. RIF induces enzymes, leading to significant drug interactions that may reduce the efficacy of concomitant medications like antiretrovirals or oral contraceptives. Pyrazinamide (PZA) serves as a sterilizing agent, particularly effective in the acidic environment of macrophages and , where it is converted to pyrazinoic acid, disrupting membrane energetics and inhibiting fatty acid synthase II. The recommended dose is 25 mg/kg orally once daily, capped at 2 g, though adjusted lower (e.g., 20-25 mg/kg) in some guidelines to minimize toxicity. PZA is hepatotoxic and can cause , potentially leading to or , requiring baseline assessment. Ethambutol (EMB) acts as a by inhibiting arabinosyl , an enzyme involved in cell wall synthesis, thereby preventing mycobacterial growth. It is administered at 15-20 mg/kg orally once daily, with the higher end used in intensive phases for enhanced efficacy. The primary adverse effect is , which is dose- and duration-dependent, necessitating monthly and testing, especially in patients with renal impairment where dose adjustments are required. In combination, the HRZE regimen leverages synergistic interactions: INH and provide rapid killing of actively replicating bacilli, PZA targets persistent forms in acidic niches, and EMB prevents emergent during the early phase. Randomized controlled trials (RCTs) have demonstrated cure rates of 85-95% with this regimen in drug-susceptible pulmonary TB, with sputum culture conversion rates exceeding 80% by the end of the intensive phase, underscoring its role as the global standard before considering second-line options for intolerance or failure.
DrugMechanismStandard Adult DoseKey Adverse Effects
Isoniazid (INH)Inhibits synthesis in actively dividing 5 mg/kg (max 300 mg) daily, (prevented by )
Rifampicin (RIF)Inhibits bacterial RNA polymerase10 mg/kg (max 600 mg) daily, drug interactions via CYP450 induction
Pyrazinamide (PZA)Disrupts membrane energetics in acidic environments25 mg/kg (max 2 g) daily,
Ethambutol (EMB)Inhibits arabinogalactan synthesis15-20 mg/kg daily (monitor vision)

Second-Line Drugs

Second-line drugs for (TB) are utilized primarily in cases of multidrug-resistant TB (MDR-TB) or when patients cannot tolerate first-line agents due to or adverse effects. These medications generally exhibit greater toxicity and require careful monitoring compared to first-line options, but they play a crucial role in salvage therapy to achieve cure rates exceeding 80% in appropriately designed regimens. The selection of these drugs is guided by drug susceptibility testing, patient factors, and international recommendations emphasizing all-oral regimens to minimize injectable-related complications. Fluoroquinolones, such as levofloxacin, are core components of second-line therapy due to their potent bactericidal activity against . They inhibit and topoisomerase IV, enzymes essential for and repair in the bacterium. The typical adult dose is 750–1000 mg daily, administered orally. Key risks include tendonitis and , particularly in older adults or those with renal impairment, as well as QT interval prolongation, necessitating baseline and periodic electrocardiograms. Injectable agents like and capreomycin are traditionally used in the intensive phase of MDR-TB treatment, though WHO now prioritizes all-oral options where possible. These drugs disrupt protein synthesis by binding to ribosomal subunits— targets the subunit, while capreomycin interacts with the 70S initiation complex. The standard adult dose is 15 mg/kg administered intramuscularly or intravenously daily, with a maximum of 1 g to reduce toxicity. , manifesting as , and are primary concerns, requiring regular , serum creatinine monitoring, and avoidance in patients with baseline renal or auditory issues. Ethionamide and its analog prothionamide inhibit synthesis, a critical component of the mycobacterial , by forming a covalent with NAD+ that blocks enoyl-ACP reductase (InhA). The recommended adult dose is 15–20 mg/kg daily, divided into 2–3 administrations to improve tolerability, with a maximum of 1 g. Gastrointestinal intolerance, including and , is common and often managed with antiemetics, while may develop due to interference with thyroid hormone synthesis, warranting baseline and monthly . Cycloserine acts as a by competitively blocking the incorporation of D-alanine into precursors, thereby weakening the bacterial envelope. Adult dosing is 10–15 mg/kg daily, up to a maximum of 1 g, typically split into two doses with supplementation to mitigate . Psychiatric side effects, such as , anxiety, and , occur in up to 30% of patients and require neuropsychiatric evaluation, dose adjustment, or discontinuation if severe. Bedaquiline, introduced in as the first new TB drug class in decades, targets to halt energy production in M. tuberculosis. The loading dose is 400 mg daily for 2 weeks, followed by 200 mg three times weekly for at least 22 weeks, taken with food to enhance absorption. Cardiac QT prolongation is a major risk, especially when combined with other QT-prolonging agents, mandating ECG monitoring at baseline, during treatment, and 2 weeks post-completion. Linezolid inhibits protein synthesis by binding to the 50S ribosomal subunit, preventing formation of the initiation complex. It is dosed at 600 mg daily in adults for TB, often for shorter durations to limit toxicity. Long-term use (>6 months) is associated with myelosuppression (, ) and irreversible , requiring monthly complete blood counts and assessments. The classifies second-line drugs into Groups A, B, and C based on efficacy, safety, and evidence from clinical trials, prioritizing Group A agents (levofloxacin or , , ) for inclusion in all MDR-TB regimens, followed by (clofazimine, cycloserine) and Group C (including , injectables like ). This hierarchical system ensures optimized, individualized while minimizing . These drugs are integrated into MDR-TB regimens to achieve high success rates.

Third-Line Drugs

Newer anti-TB drugs, including and delamanid, are approved agents used in second-line regimens for drug-resistant TB (DR-TB), particularly multidrug-resistant (MDR-TB) and extensively drug-resistant (XDR-TB), often as part of shorter all-oral combinations as recommended in the 2025 WHO guidelines. These drugs target unique aspects of mycobacterial and are incorporated into individualized regimens under expert guidance, with access supported through global programs despite costs and regulatory hurdles. Clinical trials support their use in regimens achieving high culture conversion and success rates. Pretomanid, a nitroimidazole derivative, exerts bactericidal activity against non-replicating, anaerobic M. tuberculosis by generating reactive nitrogen species that disrupt cellular respiration. It is administered at a dose of 200 mg once daily for 6 months as part of the BPaL regimen (bedaquiline, pretomanid, and linezolid), which has demonstrated superior sputum culture conversion rates compared to longer traditional regimens in patients with fluoroquinolone-resistant pulmonary TB. The 2025 WHO guidelines recommend BPaLM (BPaL plus moxifloxacin) for fluoroquinolone-resistant MDR/RR-TB. A key adverse effect is peripheral neuropathy, occurring in up to 20% of recipients, necessitating regular neurological monitoring. Delamanid, a nitro-dihydro-imidazooxazole compound, shares mechanistic similarities with by inhibiting synthesis under hypoxic conditions, enhancing efficacy against dormant . The standard adult dose is 100 mg twice daily for up to 6 months, integrated into optimized background regimens for MDR-TB, where it has improved 6-month culture conversion rates to approximately 45% in phase III trials versus . The 2025 updates include delamanid in the novel 6-month BDLLfxC regimen (, delamanid, , levofloxacin, ) for fluoroquinolone-susceptible DR-TB. Notable risks include prolongation, requiring electrocardiographic surveillance, while pediatric dispersible tablets facilitate use in children under 5 years, addressing a critical gap in younger populations. Among novel investigational agents, sutezolid, an oxazolidinone antibiotic, inhibits protein synthesis at the bacterial with minimum inhibitory concentrations (MICs) as low as 0.25 μg/mL against M. tuberculosis, showing promising early bactericidal activity in phase IIa trials for shortening DR-TB regimens. Similarly, BTZ-043, a benzothiazinone targeting decaprenyl-phosphoryl-β-D-ribose-2'-epimerase (DprE1) for cell wall arabinan , achieves MICs below 0.01 mg/L and demonstrated dose-dependent lung lesion reductions in phase 1b studies, advancing to phase 2b evaluations for all-oral combinations. These agents highlight a shift toward shorter, less toxic therapies but remain in clinical development without widespread approval. Access to these drugs in low-resource settings is facilitated through compassionate use programs, such as those for delamanid via manufacturer-sponsored , which have enabled for over 1,000 patients globally with high culture negativity rates when combined with active companions, though logistical barriers like cold-chain requirements persist. As of 2025, WHO guidelines emphasize integration of these agents into all-oral, 6-month regimens like BPaLM or BDLLfxC for fluoroquinolone-susceptible DR-TB, prioritizing them over injectable-containing options to enhance tolerability and completion rates. These drugs are briefly referenced in XDR-TB combinations to salvage outcomes in ultimate-resistance scenarios.

Standard Regimens for Drug-Susceptible TB

Intensive Phase

The intensive phase of treatment for drug-susceptible (TB) typically involves a 2-month regimen of daily of first-line drugs, though specifics vary by guideline and group. For adults and adolescents (≥12 years) with pulmonary TB, the 2025 ATS/CDC/ERS/IDSA guidelines conditionally recommend a novel 4-month regimen starting with 2 months of high-dose , isoniazid, pyrazinamide, and (HPZM) to rapidly reduce the bacterial load, prevent , and achieve sputum smear conversion in 80–90% of cases. The traditional 6-month regimen, per WHO guidelines, uses isoniazid, rifampicin, pyrazinamide, and ethambutol (HRZE) for this phase. Dosages are determined by patient weight bands to ensure efficacy and minimize toxicity, with fixed-dose combinations recommended for adults; for the traditional HRZE regimen, individuals weighing 50–69 kg receive approximately 300 mg isoniazid, 600 mg rifampicin, 2,000 mg pyrazinamide, and 1,200 mg ethambutol daily. The incorporation of pyrazinamide, based on British Medical Research Council trials from the 1970s, was pivotal in shortening overall therapy from 9 to 6 months by enhancing early bactericidal and sterilizing effects against persistent . Response to treatment is monitored via sputum smear microscopy, typically performed monthly during this phase to evaluate conversion and detect any delays that may indicate resistance or non-adherence. Successful completion of the intensive phase, marked by negative smears in most patients, leads to transition to the continuation phase for further consolidation.

Continuation Phase

The continuation phase for drug-susceptible pulmonary TB involves 2–4 months of therapy following the 2-month intensive phase, for a total duration of 4–6 months depending on the regimen and patient group. For adults and adolescents (≥12 years), the recommended 4-month regimen per 2025 ATS/CDC/ERS/IDSA guidelines uses 2 months of , , and (HPM) to eradicate semi-dormant . The WHO standard 6-month regimen uses and (HR) for 4 months. This phase focuses on consolidating therapeutic gains by targeting intracellular persister that survive initial bactericidal activity. Rifapentine's (or rifampicin's) key contribution during this period is its sterilizing activity against low-metabolic-state populations within host cells, helping prevent . Historical clinical trials, including those by the British Medical Research Council in the 1970s and 1980s across , , and other low-burden settings, demonstrated the non-inferiority of the 6-month regimen compared to 9-month alternatives, with relapse rates of 1-5% in both arms under supervised therapy. Adjustments to duration apply based on 2025 guidelines: the 4-month HPZM/HPM regimen is conditionally recommended for adults/adolescents ≥12 years with nonsevere pulmonary DS-TB (e.g., no , no ); for children <12 years with nonsevere TB (e.g., non-cavitary pulmonary, lymph node, pleural), a 4-month rifampin-based regimen (2HRZ(E)/2HR, ethambutol optional) is strongly recommended. In resource-limited settings, intermittent dosing options such as thrice-weekly during the continuation phase are feasible for the 6-month regimen when daily directly observed therapy is infeasible, provided no doses are missed, as this approach has shown comparable outcomes to daily regimens in high-burden areas. Throughout this phase, ongoing monitoring for adverse effects, such as hepatotoxicity from or , remains essential to ensure treatment completion.

Rationale and Evidence

The recommended regimens for drug-susceptible TB, including the 4-month isoniazid, rifapentine, pyrazinamide, and moxifloxacin (HPZM/HPM) per 2025 ATS/CDC/ERS/IDSA guidelines and the 6-month HRZE/HR per WHO, are grounded in pharmacokinetic-pharmacodynamic (PK-PD) principles that optimize bactericidal and sterilizing effects against Mycobacterium tuberculosis. In vitro and in vivo studies demonstrate synergistic activity, with time-kill curves revealing a biphasic reduction in colony-forming units (CFU): an initial rapid phase targeting actively replicating bacilli, achieving early bactericidal activity (EBA) of approximately 0.11 log CFU/day over the first 14 days, followed by slower sterilization of persistent, semi-dormant populations. Modeling across virtual granulomas indicates that these regimens eliminate over 80% of CFU within the first two months in most cases, with drug penetration into lung tissue and caseous lesions (e.g., high for isoniazid and pyrazinamide) enhancing overall efficacy. Landmark clinical trials by the British Medical Research Council (MRC), spanning the 1950s to 1980s, provided the foundational evidence for the 6-month regimen, shortening treatment from 18-24 months while preserving outcomes. Early 1950s trials established multi-drug therapy's superiority over monotherapy, reducing resistance emergence. By the 1970s, regimens incorporating shortened durations to 9 months with cure rates exceeding 90%. The pivotal 1980s Singapore Tuberculosis Service/BMRC trial demonstrated that adding pyrazinamide to and for 6 months yielded relapse-free success rates of 85-95% at 24 months, noninferior to 9-month courses and superior to regimens without pyrazinamide, thus defining the traditional intensive and continuation phases. Subsequent meta-analyses have reinforced these findings, confirming the regimen's reliability in adherent patients. Cochrane reviews from the 2010s, synthesizing data from over 50 trials, report pooled treatment success rates (cure plus completion) of 88-90% for daily or intermittent 6-month variants in pulmonary , with failures primarily linked to nonadherence rather than regimen inadequacy. Relapse risk modeling from large cohorts shows 2-5% recurrence after full completion (e.g., in patients without cavitation or positive 2-month cultures), versus 20-30% with interruptions, underscoring adherence's role in preventing resistance and reinfection. As of 2025, updated guidelines incorporate evidence from phase 3 trials supporting shorter alternatives as preferred options in eligible cases. The 4-month regimen of isoniazid, rifapentine, pyrazinamide, and moxifloxacin (2HPZM/2HPM) demonstrates noninferiority to the 6-month standard, with 84.6% favorable outcomes versus 85.4% in non-severe, drug-susceptible pulmonary TB among adults and adolescents ≥12 years without contraindications (e.g., no extensive cavitation, no HIV), and similar efficacy in children aged 3 months to 16 years with nonsevere forms such as peripheral or non-obstructive intrathoracic lymphadenopathy using 2HRZ(E)/2HR. This option, conditionally recommended for adults (moderate-certainty evidence) and strongly for children, reduces pill burden and duration while maintaining safety profiles comparable to HRZE.

Monitoring and Adherence Strategies

Directly Observed Therapy (DOTS)

Directly Observed Therapy, Short-course (DOTS) is a comprehensive strategy endorsed by the World Health Organization (WHO) for tuberculosis (TB) control, particularly in resource-limited settings, emphasizing supervised treatment to ensure adherence and cure. Introduced in 1994, DOTS integrates five core components: political commitment with sustained financing to support national TB programs; case detection through quality-assured sputum smear microscopy for symptomatic individuals presenting at health facilities; provision of standardized short-course chemotherapy regimens under proper case-management conditions; a reliable supply of high-quality, uninterrupted anti-TB drugs; and a standardized recording and reporting system for monitoring treatment outcomes and program impact. Implementation of DOTS typically involves community health workers or trained supervisors who directly observe patients ingesting their medications, often at home or community sites, to minimize interruptions and foster trust. This approach has been shown to reduce treatment default rates by approximately 49% compared to self-administered therapy, as evidenced by systematic reviews and meta-analyses of global programs. By addressing barriers such as stigma, distance to clinics, and forgetfulness, DOTS promotes completion of the full regimen, typically 6-8 months, thereby preventing relapse and transmission. Evidence from WHO-led initiatives in the 1990s, building on earlier trials in high-burden countries, demonstrated that significantly improved treatment success rates, achieving over 80% cure rates among smear-positive cases by the late 1990s and reaching a global average of 85% by the mid-2000s, surpassing the WHO target of 85%. These outcomes were pivotal in treating over 17 million patients between 1994 and 2003, averting millions of deaths and reducing TB incidence in implementing areas. As an evolution of , digital adherence tools such as have emerged, allowing remote supervision via smartphones, with randomized trials showing comparable adherence and completion rates to traditional in-person observation while enhancing patient convenience. DOTS is highly cost-effective in high-burden countries, with health system costs typically ranging from US$10 to US$100 per patient in low-income settings. This strategy has been extended briefly to for managing drug-resistant TB by incorporating additional diagnostics and second-line drugs under similar supervised frameworks.

DOTS-Plus for Drug Resistance

DOTS-Plus represents an extension of the Directly Observed Treatment, Short-course (DOTS) strategy specifically adapted for the management of multidrug-resistant tuberculosis (MDR-TB) and rifampicin-resistant TB (RR-TB), emphasizing the incorporation of drug susceptibility testing (DST) to guide the initiation of second-line treatments. This framework builds on the foundational DOTS approach by requiring culture-based or rapid molecular DST, such as Xpert MTB/RIF, to confirm resistance patterns before prescribing second-line drugs, thereby enabling individualized regimens tailored to the patient's specific resistance profile. The integration of DST ensures that ineffective first-line drugs are avoided and appropriate second-line options are selected promptly, reducing the risk of treatment failure and resistance amplification. Prior to the 2010s, access to second-line drugs under DOTS-Plus was overseen by the World Health Organization's Green Light Committee (GLC), established in 2000 by the Stop TB Partnership to facilitate affordable, quality-assured supplies while promoting rational use through pilot projects and national program approvals. The GLC reviewed proposals for DOTS-Plus implementation, ensuring adherence to standardized protocols and monitoring to prevent misuse of scarce resources. Treatment outcomes under early DOTS-Plus initiatives demonstrated cure rates of 60-70% for MDR-TB, significantly higher than the approximately 30% success rates observed in unmanaged or inappropriately treated cases without systematic DST and supervised therapy. As of 2025, DOTS-Plus has evolved under WHO guidelines to incorporate universal DST as a standard for all TB patients, alongside the adoption of shorter all-oral regimens lasting 6-9 months for eligible MDR/RR-TB cases, replacing longer conventional approaches and expanding access through national programs. These updates, including regimens like BPaLM, aim to improve global treatment success rates, which reached 68% for MDR-TB in 2021 (latest available data as of the 2024 WHO report), while addressing barriers in low-resource settings. However, traditional DOTS-Plus regimens often extended 18-24 months, contributing to higher default rates due to prolonged duration, patient fatigue, and socioeconomic challenges, underscoring the need for ongoing adherence support.

Interventions to Enhance Compliance

Patient education plays a crucial role in enhancing compliance with (TB) treatment by addressing knowledge gaps, misconceptions, and stigma associated with the disease. Counseling sessions that emphasize the benefits of completing therapy, such as preventing transmission to family members and achieving cure, have been shown in randomized controlled trials (RCTs) to improve treatment completion rates, with relative risks (RR) of 1.71 (95% CI 1.32–2.22) for adherence and 2.15 (95% CI 1.58–2.92) for cure compared to standard care. These interventions often incorporate models like the to reduce stigma and foster motivation, leading to higher adherence in diverse settings. Incentives, such as food vouchers or transport reimbursements, provide material support to overcome socioeconomic barriers to adherence, particularly in low-resource areas. An RCT in Timor-Leste found no significant difference in treatment completion rates between food incentives and nutritional advice (76% vs 78%), though incentives improved weight gain. Similarly, monthly vouchers in other trials have boosted successful outcomes by reducing loss to follow-up (RR 0.74, 95% CI 0.60–0.90). These enablers are especially effective in high-burden regions where economic constraints contribute to defaulting. Digital tools, including SMS reminders and mobile apps for self-reporting, have emerged as scalable adjuncts to traditional strategies like Directly Observed Therapy (DOTS). Meta-analyses indicate that these interventions, such as drug box reminders combined with text messaging, significantly reduce missed doses (mean ratio 0.49, 95% CI 0.27–0.88). For instance, daily or weekly SMS combined with education reduced missed doses (mean ratio 0.58, 95% CI 0.42–0.79) and enhanced clinic attendance in active . Apps facilitating video-observed therapy or self-monitoring have similarly achieved high adherence rates up to 96% in pilot studies. As of 2025, WHO endorses expanded use of and AI-driven digital tools in the End TB Strategy to further improve compliance in high-burden settings. Family involvement strengthens compliance by providing emotional and practical support, such as reminding patients of doses or accompanying them to clinics. Studies in high-burden settings reveal that robust family support is associated with improved adherence among newly diagnosed patients, where overall good adherence was 45.7%, and correlates with lower odds of poor adherence (OR 0.34 for supervision, 95% CI 0.16–0.70). Training programs like Tuberculosis Family Support Training (TB FaST) have increased family members' intentions to encourage treatment, leading to higher completion rates. Economic enablers extended to families in resource-limited areas further mitigate barriers like nutritional deficits. Addressing barriers such as depression through mental health integration is essential, as comorbid mental illness affects up to 44% of TB patients and doubles default risk. Integrating screening and support within TB services, including counseling for anxiety and depression, has improved treatment completion (RR 1.47, 95% CI 1.08–2.00) by alleviating psychological hurdles. Interventions targeting stigma-related depression, such as patient-centered care groups, reduce loss to follow-up and enhance overall outcomes in vulnerable populations.

Adverse Effects and Toxicity Management

Drug-Induced Hepatitis

Drug-induced hepatitis represents one of the most serious adverse effects associated with first-line antituberculosis medications, particularly , , and , which are core components of the standard . This hepatotoxicity can range from asymptomatic elevations in liver enzymes to severe acute liver failure, necessitating prompt recognition and intervention to prevent morbidity and ensure treatment continuation. The incidence of hepatotoxicity in patients receiving the HRZE regimen varies widely across studies, typically ranging from 5% to 28%, with clinical hepatitis (symptomatic or severe) occurring in approximately 2% to 11% of cases. Asymptomatic transaminase elevations are more common, affecting up to 20% of patients on INH monotherapy and higher proportions in combination therapy. Risk factors significantly elevate this incidence; for instance, chronic hepatitis B virus (HBV) carriers experience rates up to 16%, compared to 4.7% in uninfected individuals, while alcoholics and those with heavy alcohol intake face a markedly increased risk due to compounded liver stress. Advanced age also contributes, with patients over 60 years showing a 3.5-fold higher likelihood, and those over 35 years exhibiting incidence rates of 33% versus 17% in younger adults. Pathophysiologically, the hepatotoxicity is primarily idiosyncratic rather than dose-dependent, involving the formation of toxic metabolites from INH, RIF, and PZA during hepatic metabolism. INH is acetylated by N-acetyltransferase 2 (NAT2) and further oxidized by cytochrome P450 2E1 (CYP2E1) to reactive species like hydrazine, which generate free radicals, induce oxidative stress, and trigger immune-mediated hepatocyte injury. RIF exacerbates this by inducing CYP3A4, thereby increasing INH metabolite production, and inhibiting the bile salt export pump (BSEP), leading to cholestasis and hyperbilirubinemia. PZA contributes through dose-related mechanisms, including disruption of nicotinamide adenine dinucleotide (NAD) levels and free radical-mediated damage, often resulting in granulomatous hepatitis. These processes predominantly affect the centrilobular regions of the liver, with slow acetylator status (common in certain populations) heightening susceptibility to INH-related injury. Monitoring protocols are essential to detect hepatotoxicity early, beginning with baseline liver function tests (LFTs), including alanine aminotransferase (), aspartate aminotransferase (), bilirubin, and alkaline phosphatase, for all patients, with heightened scrutiny for those with risk factors such as HBV, alcohol use, or advanced age. During treatment, monthly LFT checks are recommended for at-risk individuals, while symptomatic patients (e.g., nausea, jaundice, fatigue) warrant immediate testing regardless of schedule. Discontinuation of hepatotoxic drugs is advised if ALT exceeds 3 times the upper limit of normal () in the presence of symptoms or jaundice, or 5 times ULN in asymptomatic cases, to avert progression to fulminant failure. Management involves immediate temporary suspension of all potentially hepatotoxic agents (INH, RIF, PZA), with supportive care including hydration, avoidance of other hepatotoxins, and exclusion of alternative causes like viral hepatitis or alcohol via serology and history. Once LFTs normalize (typically ALT <2x ULN), rechallenge proceeds sequentially under close monitoring: rifampin is often reintroduced first (due to lower hepatotoxicity risk), followed by ethambutol, pyrazinamide, and isoniazid last, with LFTs checked weekly initially and doses held if elevations recur. In severe cases, alternative regimens excluding PZA (e.g., extended HRZE without PZA) may be used, and consultation with hepatology experts is recommended for persistent injury. Most patients tolerate rechallenge without recurrence, though 10-20% may require permanent omission of one drug. Preventive strategies emphasize risk mitigation through patient education on symptoms and alcohol abstinence, as even moderate consumption amplifies metabolite toxicity and enzyme elevations. For elderly patients, while standard dosing applies, enhanced baseline screening and more frequent monitoring (e.g., biweekly initially) are advised due to age-related hepatic reserve decline. Pre-treatment HBV and hepatitis C screening allows for antiviral co-management if needed, and slow acetylators may benefit from pharmacogenetic testing in high-prevalence settings, though routine use is not universally recommended. No specific hepatoprotective agents are endorsed, but avoiding concurrent hepatotoxins remains paramount.

Other Common Adverse Effects

Rifampicin commonly causes harmless orange discoloration of body fluids, such as urine, sweat, and tears, which patients should be informed about to avoid unnecessary concern. With intermittent dosing regimens, rifampicin can induce a flu-like syndrome characterized by fever, chills, myalgia, and malaise, occurring in up to 20% of cases due to immune-mediated reactions involving rifampicin-dependent antibodies. Initial management involves switching to daily dosing if feasible, with symptoms typically resolving upon regimen adjustment. Isoniazid is associated with peripheral neuropathy, manifesting as tingling, numbness, or pain in the extremities, with an incidence of approximately 5-10% in tuberculosis patients, particularly those with malnutrition, diabetes, or slow acetylator status. This effect arises from isoniazid-induced vitamin B6 (pyridoxine) deficiency, which interferes with nerve function. Prevention and treatment involve daily supplementation with 25-50 mg of pyridoxine, which effectively reduces the risk without impacting treatment efficacy. Pyrazinamide frequently leads to hyperuricemia, affecting 40–100% of patients through inhibition of uric acid excretion, potentially precipitating acute gout attacks with symptoms of joint pain and swelling, especially in those with preexisting renal impairment or gout history. Management includes monitoring serum uric acid levels and, if gout flares occur, temporary discontinuation or addition of urate-lowering agents like allopurinol under specialist guidance. Ethambutol carries a risk of optic neuritis, occurring in 0.2–2% of patients on standard doses (15 mg/kg daily), with risk increasing at higher doses, presenting with blurred vision, reduced visual acuity, or color vision deficits, particularly red-green discrimination. Early detection relies on baseline and monthly color vision testing using or automated perimetry to identify subclinical changes. Upon suspicion, ethambutol should be promptly discontinued, with ophthalmologic consultation to assess reversibility, as vision loss can persist if untreated. Among second-line agents, amikacin, an injectable aminoglycoside, poses a risk of ototoxicity, including hearing loss and vestibular dysfunction, with significant incidence when cumulative doses exceed 10 g, often after 3-6 months of therapy in multidrug-resistant tuberculosis cases. Risk escalates with higher daily doses (>15 mg/kg) or prolonged exposure, necessitating baseline and serial monitoring. Fluoroquinolones, such as levofloxacin or , are linked to tendonitis and rupture, particularly of the , with elevated risk in older adults or those on corticosteroids, though incidence in tuberculosis treatment remains low but requires on pain or swelling. Discontinuation and supportive care, including rest, are initial steps if symptoms arise. The standard HRZE regimen (isoniazid, rifampicin, pyrazinamide, ethambutol) disrupts the gut , leading to that manifests as and other gastrointestinal disturbances in a substantial proportion of patients. This alteration persists for months post-treatment, potentially exacerbating . Evidence on for mitigating these effects is mixed, with some studies showing reduced incidence but no consistent impact on overall resolution. While drug-induced hepatitis remains the most severe toxicity requiring vigilant monitoring, these other effects are generally manageable with prompt intervention to maintain treatment adherence.

Preventive Measures and Monitoring

Preventive strategies for minimizing toxicities in tuberculosis treatment begin with comprehensive baseline assessments conducted prior to initiating therapy. These include (LFTs) to evaluate hepatic status, renal function tests such as serum creatinine and (eGFR), and testing due to the risk of from ethambutol, and screening to guide concurrent management and heightened monitoring needs. Such evaluations help identify pre-existing conditions that could exacerbate drug-related adverse effects, allowing for tailored regimens from the outset. Ongoing monitoring protocols are essential to detect early signs of . For standard drug-susceptible TB regimens, clinical assessments and tests—including LFTs, renal , and —should occur monthly throughout treatment, with increased frequency to weekly during the first two months for high-risk patients, such as those with abnormalities, older age, or comorbidities like . In cases involving injectable agents like or for drug-resistant TB, audiometry followed by monthly testing is recommended to monitor for . Dose adjustments are critical in renal impairment; for ethambutol, patients with creatinine clearance (CrCl) less than 30 mL/min require a reduced frequency of 15-25 mg/kg administered three times weekly rather than daily to prevent accumulation and . The 2025 WHO consolidated guidelines provide updated recommendations on monitoring, including standardized protocols for reporting and management in resource-limited settings. Patient education plays a pivotal role in proactive toxicity prevention by empowering individuals to recognize and report warning signs promptly. Clinicians should instruct patients on symptoms indicative of potential adverse effects, such as or dark urine for hepatotoxicity and or color desaturation for optic issues, emphasizing immediate contact with healthcare providers if these occur. Emerging pharmacogenomic research on N-acetyltransferase 2 (NAT2) polymorphisms suggests higher risks of isoniazid-induced in slow acetylators, potentially enabling personalized dosing or intensified monitoring in the future.

Treatment in Special Populations

Extrapulmonary and CNS Tuberculosis

Extrapulmonary tuberculosis (EPTB) refers to TB infection outside the lungs, commonly affecting lymph nodes, pleura, and bones or joints. For adults, management typically follows the standard drug-susceptible regimen of an intensive phase with isoniazid (INH), rifampicin (RIF), pyrazinamide (PZA), and ethambutol (EMB) for 2 months, followed by a continuation phase of INH and RIF for 4 months, totaling 6 months for most sites like peripheral lymph nodes and pleural effusions. In children and adolescents (3 months–16 years) with nonsevere EPTB (e.g., peripheral lymph nodes, uncomplicated pleural effusions), 2025 ATS/CDC/ERS/IDSA guidelines recommend a shortened 4-month regimen (2HRZ(E)/2HR). For skeletal TB involving bones or joints, treatment duration is typically 6-9 months, extended to 12 months if slow response or severe involvement, based on expert consensus and observational data showing higher failure rates with shorter courses. Central nervous system (CNS) TB, manifesting as or tuberculomas, demands specialized adaptations due to limited drug penetration across the blood-brain barrier. The regimen mirrors the standard intensive phase but extends the total duration to 12 months for in children per WHO guidelines, or 9-12 months in adults; standard dosing is used (INH 10 mg/kg for children, up to 300 mg/day), with high-dose INH (15 mg/kg, up to 20 mg/kg in select protocols) optional to achieve therapeutic levels, while maintaining standard doses for RIF, PZA, and EMB initially. Adjunctive corticosteroids, such as dexamethasone at 0.3-0.4 mg/kg/day tapered over 6-8 weeks, are recommended to mitigate and improve survival in meningitis. and therapeutic monitoring rely on for CSF analysis, including , culture, and molecular tests, with serial LPs to assess response in complicated cases. Shortened regimens are not recommended for severe CNS TB. Outcomes for CNS TB remain challenging, with mortality rates of 50-70% in cases of delayed and due to rapid progression and neurological complications. Observational studies indicate that shorter regimens (e.g., 6 months) are inferior for EPTB sites like CNS and skeletal involvement, yielding higher relapse and failure rates compared to extended therapy.

TB in Pregnancy and Pediatrics

The management of tuberculosis (TB) in prioritizes both maternal treatment and fetal safety, with first-line drugs isoniazid (INH), , and ethambutol (EMB) considered safe throughout ; pyrazinamide (PZA) inclusion (as HRZE) is accepted by WHO but not routinely recommended in guidelines due to limited safety data, often leading to a 9-month regimen (2HRE/7HR). is avoided due to its association with in the . Per CDC 2025, if PZA is excluded, the regimen is INH, , and EMB for 2 months followed by INH and for 7 months for drug-susceptible pulmonary TB. INH is continued throughout due to its efficacy and low risk profile, but close monitoring for drug-induced is essential, as may increase susceptibility to from these agents. Evidence from cohort studies indicates no increased risk of teratogenicity with first-line HR(E) therapy, with adverse fetal outcomes primarily linked to untreated maternal TB rather than the drugs themselves. is compatible with HR(E) treatment, as these drugs transfer into at low concentrations insufficient to cause toxicity in infants, and the benefits of outweigh potential risks. In , TB treatment regimens are adapted for children under 18 years, emphasizing weight-based dosing to ensure efficacy while minimizing toxicity, with child-friendly formulations such as dispersible tablets or oral solutions preferred for better adherence. For drug-susceptible TB, the standard regimen is 2 months of ZE followed by 4 months of , dosed as follows: INH at 10 mg/kg (range 7-15 mg/kg, max 300 mg/day), at 15 mg/kg (10-20 mg/kg, max 600 mg/day), PZA at 35 mg/kg (30-40 mg/kg, max 2000 mg/day), and EMB at 20 mg/kg (15-25 mg/kg, max 1000-2500 mg/day depending on and ). Recent 2025 updates from the Infectious Diseases Society of America (IDSA), American Thoracic Society (ATS), Centers for Disease Control and Prevention (CDC), and European Respiratory Society (ERS) endorse a shortened 4-month rifampin-based regimen (2HRZ(E)/2HR) for nonsevere TB in children 3 months–16 years; for adolescents ≥12 years, a 4-month regimen with high-dose , moxifloxacin, pyrazinamide, and isoniazid (2HRZMx/2HRMx) is conditionally recommended for nonsevere pulmonary TB. Extrapulmonary TB in children, such as lymphadenitis, follows similar principles but may require extended durations based on site. For neonates exposed to active TB in the , particularly from maternal , prophylaxis with INH at 10 mg/kg daily is recommended for 6 months, alongside separation from the infectious source until the mother is non-infectious. BCG vaccination is administered at birth or upon completion of prophylaxis in high-burden settings, providing protection against severe disseminated TB forms. Emerging 2025 data support the cautious use of in the second for drug-resistant cases when first-line options fail, showing no significant increase in congenital anomalies in limited observational studies.

TB with Comorbidities (HIV, Liver, Kidney, Epilepsy)

In patients with tuberculosis (TB) and human immunodeficiency virus (HIV) coinfection, antiretroviral therapy (ART) should be initiated as soon as possible, ideally within 2 weeks of starting TB treatment, regardless of CD4 cell count, to reduce mortality risk. For those with very low CD4 counts (below 50 cells/μL), initiation within 8 weeks may be considered to balance immune recovery against immune reconstitution inflammatory syndrome (IRIS) risk, though early start is prioritized. Drug interactions between rifamycins and antiretrovirals necessitate regimen adjustments; rifabutin is preferred over rifampin when using non-nucleoside reverse transcriptase inhibitors (NNRTIs) or protease inhibitors (PIs), with dosing reduced to 150 mg daily to minimize toxicity while maintaining efficacy. TB-associated IRIS, occurring in up to 20% of coinfected patients post-ART initiation, manifests as worsening TB symptoms due to immune recovery and is managed with corticosteroids such as prednisone (1-2 mg/kg/day, tapered over 4-6 weeks) alongside continued TB and ART therapy. Per 2025 guidelines, shortened regimens for drug-susceptible TB apply regardless of HIV status. For TB patients with , pyrazinamide (PZA) should be omitted from the regimen due to its high risk, particularly in those with moderate to severe impairment (e.g., >3 mg/dL or transaminases >5 times upper limit of normal). An alternative regimen of isoniazid (H) and rifampin (R) for 9 months, with or without ethambutol (E) initially, provides effective treatment while minimizing liver stress; (LFTs) must be monitored monthly, with immediate drug interruption if abnormalities exceed three times the upper limit. This approach aligns with guidelines emphasizing single or dual hepatotoxic drug use in to prevent acute . In individuals with TB and kidney impairment, dosing adjustments are required for ethambutol and aminoglycosides (e.g., streptomycin or amikacin) based on estimated glomerular filtration rate (eGFR) to avoid accumulation and toxicity such as optic neuritis or ototoxicity. For eGFR 30-60 mL/min, ethambutol is administered at 15-25 mg/kg three times weekly rather than daily; below 30 mL/min, hemodialysis patients receive it post-dialysis with supplemental doses. Aminoglycosides follow extended-interval dosing (e.g., 15 mg/kg once weekly for amikacin if eGFR <30 mL/min), with therapeutic drug monitoring to ensure peak levels of 20-35 μg/mL and trough <1 μg/mL. TB management in patients with requires caution with neurotoxic drugs; should be avoided due to its dose-dependent risk, mediated by antagonism and inhibition. Isoniazid (INH) can lower the , particularly in those with low levels, so all such patients receive supplementation at 25-50 mg daily to prevent and seizures. Alternative second-line agents like may be considered if is contraindicated, with close neurological monitoring.

Modifications to Standard Regimens

Omitting Specific Drugs

In the management of drug-susceptible tuberculosis (TB), standard first-line regimens incorporate isoniazid (INH), rifampicin (RIF), pyrazinamide (PZA), and ethambutol (EMB) to achieve high cure rates with minimal duration. However, individual drugs may need to be omitted due to contraindications such as severe adverse reactions, confirmed monoresistance, or pharmacological intolerance, necessitating regimen adjustments to preserve bactericidal activity and prevent treatment failure. These modifications prioritize retaining the most potent agents while extending duration or substituting with compatible alternatives, though they often result in prolonged therapy and require vigilant monitoring for efficacy and . When INH is omitted, typically in scenarios of confirmed INH monoresistance or INH-induced unresponsive to supplementation, the recommends a 6-month regimen of , EMB, PZA, and levofloxacin (or another fluoroquinolone). This approach, evaluated in observational cohorts and randomized trials, yields treatment success rates of 85-90% at 24 months post-treatment, comparable to standard regimens for susceptible TB, though with a slightly elevated of acquired if fluoroquinolone susceptibility is not confirmed. Omitting , often necessitated by severe , , or significant drug interactions (e.g., with certain antiretrovirals), substantially compromises regimen potency and requires extended therapy to mitigate high rates. Guidelines suggest 12-18 months of INH, EMB, PZA, and (or another injectable if needed), administered daily during the intensive phase and thrice-weekly thereafter if adherence is ensured. Historical cohort studies report success rates of 70-85% with this regimen, but occurs in up to 20% of cases, underscoring the critical role of in preventing recurrence; modern alternatives may incorporate newer agents for shorter durations in select patients, but traditional non-rifamycin approaches remain standard where resources limit advanced options. PZA omission is primarily indicated in patients with preexisting or acute , as it carries a high risk of exacerbating hepatic injury. In such cases, the regimen extends to 9 months of daily INH, , and EMB (HRE), with the initial 2 months emphasizing intensive monitoring of liver enzymes. Clinical data from prospective studies indicate that this modification achieves cure rates exceeding 90% in non-cavitary pulmonary TB, similar to the standard 6-month regimen, though the longer duration increases the potential for non-adherence and requires baseline assessment of renal function due to EMB accumulation. EMB is rarely omitted but may be excluded in patients with history or baseline , where it poses a risk of irreversible damage. If INH is verified via drug susceptibility testing and initial is normal, a 6-month course of INH, RIF, and PZA (HRZ) suffices, with monthly ophthalmologic evaluations to detect early changes. Evidence from analyses shows rates of 85-95% with this regimen in low-resistance settings, maintaining bacteriological rates akin to full HRZE therapy, provided is absent and adherence is optimized through directly observed treatment. Across these adjusted regimens, overall remains around 80-90% in controlled settings, as supported by meta-analyses of historical and contemporary data, but longer durations elevate and dropout risks by 10-15% compared to standard 6-month therapy, emphasizing the need for individualized testing and assessment prior to modification.

Shortened or Alternative Regimens

In response to challenges with adherence to longer treatment durations, shortened regimens have been developed and recommended for specific subsets of patients with drug-susceptible pulmonary (TB). The (WHO) and other authoritative bodies endorse a 4-month regimen consisting of an initial 2-month intensive phase of daily isoniazid (H), (P), pyrazinamide (Z), and (M), followed by a 2-month continuation phase of daily H, P, and M (2HPZM/2HPM), for adults and adolescents aged 12 years and older with non-severe, microbiologically confirmed pulmonary TB. This regimen replaces ethambutol with to enhance efficacy while reducing overall duration compared to the standard 6-month course. Evidence from a phase 3 demonstrated that the 4-month HPZM regimen achieved non-inferior treatment success rates compared to the standard 6-month regimen (HRZE/4HR), with unfavorable outcomes of 15.5% versus 14.6% in the microbiologically eligible population (adjusted difference 1.0%, 95% -2.6 to 4.5). The trial included patients aged 12 years and older with pulmonary TB, encompassing those with and coinfection, though real-world applicability may vary. WHO guidelines conditionally recommend this approach for non-severe cases, excluding children under 12 years and extrapulmonary TB manifestations. For patients with more extensive disease, such as cavitary lesions or persistent smear-positive after the initial 2 months of , guidelines recommend extending the standard regimen to a total of 9 months by prolonging the continuation phase to 7 months of isoniazid and rifampicin (2HRZE/7HR). This adjustment aims to ensure complete bacteriological conversion and reduce risk, based on observational data showing improved outcomes with prolonged rifampicin exposure in delayed responders. Alternative dosing schedules, such as intermittent thrice-weekly administration throughout (2HRZE/4HR), offer logistical advantages in resource-limited settings under directly observed and have demonstrated equivalent efficacy to daily regimens in randomized controlled trials and meta-analyses. These regimens maintain high success rates (approximately 85-90% in adherent populations) while reducing clinic visits, though they are not suitable for all patients due to risks of acquired if doses are missed. In some contexts, alternatives may involve omitting certain drugs like pyrazinamide for intolerance, provided the core rifampicin-isoniazid backbone is preserved.

Drug-Resistant Tuberculosis

Definitions and Epidemiology

Drug-resistant tuberculosis (TB) refers to forms of TB caused by strains of Mycobacterium tuberculosis that are resistant to one or more anti-TB drugs. Multidrug-resistant TB (MDR-TB) is defined as TB caused by strains resistant to at least isoniazid and rifampicin, the two most effective first-line drugs used in standard TB treatment regimens. Extensively drug-resistant TB (XDR-TB) builds on this definition and is characterized by MDR-TB strains that are additionally resistant to any fluoroquinolone (such as levofloxacin or ) and at least one of the following injectable second-line drugs: capreomycin, kanamycin, or . These definitions, updated by the (WHO) in 2021, aim to standardize surveillance and guide treatment decisions based on phenotypic and genotypic testing. Globally, drug-resistant TB remains a major public health challenge, with an estimated 400,000 new cases of MDR or rifampicin-resistant (MDR/RR) TB occurring in 2023, representing about 3.7% of the total 10.8 million incident TB cases that year. Among new TB cases, 3.2% (95% uncertainty interval [UI]: 2.5–3.8%) were MDR/RR-TB, while the proportion was higher at 16% (95% UI: 9.0–24%) among previously treated cases, reflecting the impact of inadequate prior therapy. High-burden countries account for the majority of cases, with India, the Russian Federation, Indonesia, China, and the Philippines together accounting for more than half of global MDR/RR-TB incidence; for instance, the Philippines contributed 7.2% of worldwide cases in 2023 despite its smaller population share. Key risk factors include prior TB treatment, which amplifies resistance acquisition due to incomplete adherence or poor drug quality, and HIV coinfection, which increases susceptibility to active disease from resistant strains by up to 18-fold compared to HIV-uninfected individuals. Regional hotspots, particularly in Asia, show elevated rates; national surveys in the Philippines have reported MDR-TB in up to 21% of retreatment cases. Transmission of drug-resistant TB occurs primarily through airborne routes, similar to drug-susceptible TB, but can be amplified in healthcare settings (nosocomial ) or community environments with close contacts. Nosocomial spread is a concern in under-resourced facilities where is limited, while community drives ongoing epidemics in high-prevalence areas. Genomic surveillance using whole-genome sequencing technology (WGST) has become essential for tracking transmission clusters, identifying outbreak strains, and informing responses by distinguishing recent transmission from reactivation of latent . As of 2025, epidemiological trends indicate a slow global decline in MDR/RR-TB incidence since 2015, but progress is uneven; has seen consistent reductions through strengthened and access, while experiences rising challenges linked to high prevalence, which exacerbates TB incidence and resistance development. These patterns underscore the need for integrated HIV-TB strategies to curb further spread. Treatment implications include the requirement for longer, more complex regimens for MDR- and XDR-TB, often lasting 6–20 months with second- and third-line drugs.

Treatment of Multidrug-Resistant TB (MDR-TB)

The management of (MDR-TB), defined as resistance to at least isoniazid and rifampicin, relies on WHO-recommended regimens tailored to drug susceptibility testing results, patient factors, and resource availability. These regimens prioritize all-oral options to improve tolerability and adherence, phasing out injectable agents like kanamycin or capreomycin. For eligible patients without resistance to key drugs, a shorter all-oral regimen of 9-11 months is recommended, consisting of , levofloxacin (or another fluoroquinolone), , , pyrazinamide (PZA), and (or terizidone). This regimen involves an intensive phase of 4-6 months followed by a continuation phase, with adjustments if fluoroquinolone resistance is present. In 2025, WHO expanded shorter options to include novel 6-month all-oral regimens, such as BDLLfxC (, delamanid, , levofloxacin, ), for rifampicin-resistant TB without additional fluoroquinolone resistance, aiming to reduce treatment burden and enhance outcomes. When shorter regimens are unsuitable—due to resistance patterns, intolerance, or intolerance to components—a longer individualized all-oral regimen of 18 months or more is used, incorporating 5-6 drugs selected from WHO priority groups. drugs (, , and levofloxacin or another fluoroquinolone) form the core, supplemented by (, /terizidone) and (other agents like ethambutol or PZA) based on . Regimen design requires at least four likely effective drugs in the intensive phase (6-8 months) and three in continuation, with durations extended if response is slow. Monitoring involves monthly clinical assessments, smear , and cultures to track bacteriological response, with adjustments if conversion is not achieved by month 6. Electrocardiograms (ECGs) are recommended at baseline and periodically (e.g., monthly initially) to monitor for prolongation, particularly with and fluoroquinolones. For localized disease, surgical resection may be considered adjunctively under specialist guidance. Global treatment success rates for MDR-TB cohorts are approximately 60%, reflecting challenges like loss to follow-up and , though all-oral shorter regimens achieve higher rates of 80-90% in trials and real-world settings. In 2025, WHO guidelines emphasize universal access to as a cornerstone of MDR-TB therapy, supported by expanded global procurement and reduced costs, enabling its inclusion in nearly all eligible regimens worldwide.

Treatment of Extensively Drug-Resistant TB (XDR-TB)

Treatment of (XDR-TB), defined by resistance to rifampicin, isoniazid, fluoroquinolones, and at least one injectable second-line drug, requires intensified regimens that build on those for multidrug-resistant TB (MDR-TB) by incorporating novel agents such as and delamanid to overcome additional resistances. Traditional XDR-TB regimens often extend to 18-24 months and may include a backbone of , , and or , supplemented with or delamanid for enhanced efficacy against highly resistant strains. These all-oral combinations aim to minimize injectables and reduce treatment duration while targeting persistent mycobacteria. A major advancement is the BPaLM regimen, consisting of , , , and , administered for 6 months in eligible patients with XDR-TB or treatment-intolerant MDR-TB. This shorter, all-oral demonstrated approximately 90% treatment success in clinical s, with favorable outcomes including culture conversion and survival at 6 months post-. The regimen's stems from synergistic activity against resistant , though dosing is adjusted (e.g., 600 mg daily) to balance and . The landmark Nix-TB trial, conducted from 2018 to 2019, established the efficacy of the precursor BPaL regimen (, , without ), achieving 89% favorable outcomes at 6 months in patients with XDR-TB across and . This open-label study supported regulatory approvals and informed WHO recommendations for shorter regimens in fluoroquinolone-resistant cases. Despite these advances, XDR-TB treatment faces significant challenges, with historical cure rates ranging from 30% to 40% due to limited effective drugs and high toxicity profiles, including from and QT prolongation from . For treatment failures, compassionate use programs provide access to investigational agents like delamanid under expanded protocols, though adverse events necessitate close and regimen adjustments. As of 2025, emerging therapies include trials targeting mycobacterial infections in refractory cases, with preclinical data showing promise in lysing drug-resistant strains, and host-directed therapies that modulate immune responses to enhance efficacy and reduce . These adjunctive approaches are in early-phase clinical evaluation, aiming to improve outcomes beyond conventional regimens.

Adjunctive and Supportive Therapies

Surgical Interventions

Surgical interventions play a crucial role in the management of (TB) when medical alone fails to control the disease, particularly in cases of drug-resistant pulmonary TB with localized complications. These procedures aim to remove infected or destroyed , eliminate persistent foci of , and restore function, serving as an adjunct to prolonged antituberculous . Historically, surgical approaches evolved significantly post-1950s, shifting from collapse therapies—such as artificial and thoracoplasty, which aimed to immobilize diseased segments—to modern resectional techniques enabled by effective drugs like and improved , reducing operative risks and improving long-term outcomes. Indications for surgery in refractory TB include persistent cavitary lesions in multidrug-resistant (MDR) or extensively drug-resistant (XDR) cases despite optimal , extensive destruction of parenchyma leading to chronic respiratory compromise, and complicated unresponsive to drainage and antibiotics. These interventions are typically reserved for patients with localized disease, adequate cardiopulmonary reserve, and a high of treatment failure or , as determined by radiographic evidence and persistence. In drug-resistant contexts, addresses scenarios where extensive resistance limits medical efficacy, such as massive from eroded vessels or trapped from . Common procedures encompass resectional surgeries like (removal of a single lobe), (removal of an entire ), and segmentectomy (removal of a lung segment), which target isolated infectious foci while preserving as much functional tissue as possible. For , involves peeling away the restrictive pleural peel to allow re-expansion, often performed via video-assisted thoracic surgery (VATS) for its minimally invasive benefits, including smaller incisions, reduced postoperative pain, shorter hospital stays (approximately 8 days versus 12 days for open approaches), and fewer complications compared to traditional . VATS has demonstrated equivalent sputum conversion rates to open but with lower blood loss and faster recovery in TB patients. All procedures are conducted under general with double-lumen endotracheal to facilitate single- . Timing of surgery is critical and generally occurs after 3-6 months of antituberculous to allow partial response and assess drug susceptibility, though it may be delayed longer in XDR-TB due to slower sputum conversion; preoperative treatment averages around 11 months in some cohorts. In cohorts from earlier studies (pre-2020), 20-30% of MDR-TB cases required surgical when medical failure was evident; however, with newer shorter regimens achieving 85-90% success rates, this proportion may be lower as of 2025. Postoperative continues for 12-24 months or until sustained negative cultures are achieved. Outcomes of surgical interventions are generally favorable, with culture conversion rates reaching 80-90% immediately post-resection in persistent cases, and overall treatment success of 82% in MDR/XDR cohorts (90% for MDR, 67% for XDR), attributed to the removal of resistant bacterial reservoirs. Operative mortality remains low at under 5%, though complications such as bronchopleural occur in 5-12% of cases, particularly in advanced disease; VATS approaches further mitigate these risks by reducing infection and pain. Long-term success is enhanced when is combined with individualized regimens, underscoring its role in achieving cure rates otherwise unattainable with alone.

Nutritional and Vitamin Supplementation

Malnutrition is a significant risk factor for poor outcomes in (TB) patients, with low () independently predicting elevated mortality risk. Patients who are ( <18.5 kg/m²) face approximately double the mortality risk compared to those with normal , as evidenced by hazard ratios around 2.35 in studies. Therapeutic feeding interventions, such as daily provision of energy- and protein-enriched rations, promote , with median increases of 4.6 kg observed over six months in programmatic settings, correlating with reduced mortality hazard (adjusted HR 0.39 for ≥5% in the first two months). As per WHO's October 2025 guidelines on and undernutrition, nutritional care should be integrated into TB programs, including routine screening for undernutrition, provision of energy-protein supplements (e.g., food baskets), and addressing deficiencies to improve treatment adherence, , and overall outcomes, particularly in low-resource settings. is prevalent in 50-70% of TB patients, contributing to impaired immune responses against . Supplementation at doses of 4000 daily supports antimicrobial immunity by enhancing function and cathelicidin production, but randomized controlled trials (RCTs) show mixed results on accelerating conversion, with no overall effect (adjusted 1.06) in individual participant data meta-analyses, though benefits appear in multidrug-resistant TB subgroups. A 2025 meta-analysis confirmed no significant acceleration in conversion (RR 0.96 at 4-8 weeks) but noted symptom improvement. Zinc and supplementation aid immune modulation in TB by boosting serum levels of these micronutrients and improving markers like and smear conversion rates (RR 1.16 at two months for combined ), yet they do not significantly enhance overall treatment success rates. In HIV-TB co-infection, protein-energy supplements provide modest benefits, such as increased handgrip strength in patients with low counts (2.3 kg gain at five months), but yield no consistent overall improvements in weight or . Meta-analyses of nutritional support interventions, including food baskets and micronutrient-enriched rations, indicate a 10-15% improvement in treatment adherence in several low- and middle-income country settings, with adherence rates rising from 75-88% in controls to 95-97% in intervention groups. As of 2025, emerging evidence highlights gut induced by the standard HRZE regimen (isoniazid, rifampin, pyrazinamide, ethambutol), which persists for months post-treatment and may impair recovery; prebiotics show promise in restoring microbial diversity and mitigating antibiotic-associated imbalances, as supported by preclinical and early clinical data on microbiota-based therapies.

Corticosteroid Use

are used as adjunctive therapy in the management of to mitigate severe inflammatory responses in specific manifestations, particularly where inflammation contributes significantly to morbidity and mortality. Their role is limited to cases where benefits outweigh risks, and they are always administered alongside standard antituberculous therapy. Key indications include (TBM), tuberculous pericarditis, and severe pulmonary tuberculosis with significant inflammation. In TBM, corticosteroids reduce and , improving outcomes in advanced disease. For pericarditis, they help prevent complications such as and by decreasing and inflammation. In severe pulmonary cases, they may be considered to alleviate acute respiratory distress, though evidence is less robust compared to extrapulmonary forms. Standard regimens typically involve prednisolone at 1-2 mg/kg/day (maximum 60 mg/day) for 4 weeks, followed by a gradual taper over 2-4 additional weeks to minimize rebound . For TBM specifically, dexamethasone is often preferred at 0.3–0.4 mg/kg/day (maximum 12 mg/day for adults) intravenously initially, then orally, tapered over 6-8 weeks, due to its superior penetration compared to prednisolone. In pericarditis, prednisolone dosing is similar, starting at 1.5 mg/kg/day for 4 weeks with tapering. A 2025 clinical practice guideline, building on prior meta-analyses (e.g., 2016 Cochrane RR 0.75 overall for mortality reduction at 2 months to 2 years), supports adjunctive corticosteroids for TBM, reducing mortality in HIV-uninfected patients (moderate evidence) and disability in HIV-infected, though no clear mortality benefit in the latter. Similar benefits have been observed in , with reduced rates of pericardial constriction. As of 2025, updated WHO guidelines continue to endorse corticosteroids for TBM in all patients, including those with , with dexamethasone increasingly favored in high-resource settings for optimized CNS penetration. Potential risks include secondary bacterial or fungal infections due to , delayed if inflammatory signs are masked, and exacerbation of disease progression if antituberculous therapy is ineffective. Corticosteroids are contraindicated in (MDR-TB), as they may promote without adequate bacterial control; drug susceptibility testing is essential prior to initiation. Close monitoring for adverse effects, such as and gastrointestinal complications, is required during therapy.

Management of Latent Tuberculosis Infection

Indications for Treatment

Treatment of latent tuberculosis infection (LTBI) is indicated for individuals who test positive for Mycobacterium tuberculosis infection but show no evidence of active disease, aiming to prevent progression to active tuberculosis (TB). High-priority candidates include recent skin test converters, defined as those whose tuberculin skin test (TST) or interferon-gamma release assay (IGRA) result has recently become positive, typically within the past two years. Other key high-risk groups encompass people living with HIV, close contacts of individuals with active TB cases, and immigrants or refugees from high TB-burden countries, as these populations face elevated risks of reactivation. Additional vulnerable groups include children under five years, those with immunosuppressive conditions such as diabetes mellitus or silicosis, and residents or staff in congregate settings like prisons or homeless shelters. Diagnosis relies on a positive —induration of ≥5 mm in high-risk individuals—or a positive IGRA result, confirmed by the absence of active TB symptoms, normal , and negative evaluation if indicated. Risk stratification guides decision-making: untreated LTBI carries a 5–10% lifetime risk of progression to active TB, with approximately half of cases occurring within the first two years post-infection. In low-risk individuals without additional factors, the annual progression risk is about 0.1%, underscoring the need to prioritize treatment in those with compounded vulnerabilities, such as co-infection, where annual risk can reach 5–10%. Contraindications to LTBI treatment include confirmed active TB , which must first be excluded through clinical and radiographic , and significant or to first-line agents. Severe hepatic or active may also preclude certain regimens due to hepatotoxicity risks.

Regimens for Latent TB

The management of latent tuberculosis infection (LTBI) involves preventive regimens aimed at reducing the risk of progression to active , with options selected based on patient factors such as age, comorbidities, and . Preferred regimens include shorter courses that balance , , and completion rates, while alternatives are used when preferred options are unsuitable.
RegimenDescription and DosageDuration and DosesTarget PopulationEfficacy and Key Evidence
3HP (Isoniazid + Rifapentine)Once-weekly oral isoniazid (15 mg/kg, max 900 mg for adults/≥12 years; 25 mg/kg, max 900 mg for children 2–11 years) plus rifapentine (weight-based, max 900 mg), administered via directly observed or self-administered therapy.3 months (12 doses).Adults and children ≥2 years, including HIV-infected individuals on compatible antiretroviral therapy; not recommended for pregnant persons or those <2 years.Comparable efficacy to 9 months of isoniazid in preventing active TB, with superior treatment completion rates (e.g., 82% vs. 69% in trials); the PREVENT TB study (2011, updated recommendations 2018) demonstrated noninferiority to 9H with fewer discontinuations due to adverse events. Completion rates often exceed 90% in programmatic settings with optimized delivery.
4R (Rifampin)Daily oral rifampin (10 mg/kg, max 600 mg for adults; 15–20 mg/kg, max 600 mg for children).4 months (120 doses).All ages, particularly for isoniazid-intolerant patients or HIV-negative individuals; use caution with certain HIV regimens due to interactions.Noninferior to 9 months of isoniazid in preventing active TB (incidence rates ~0.1% per 100 person-years in both arms), with higher completion (79% vs. 63%). Supported by a 2018 randomized trial showing similar protective effects and better tolerability.
6H (Isoniazid)Daily oral isoniazid (5 mg/kg, max 300 mg for adults; 10–20 mg/kg, max 300 mg for children), or twice-weekly under direct observation (15–40 mg/kg, max 900 mg).6 months (180 daily doses or 52 twice-weekly doses).All ages, including HIV-infected; alternative when shorter regimens are unavailable.60–90% reduction in progression to active TB compared to no treatment, based on historical controlled trials, though completion rates are lower (~50–70%) due to hepatotoxicity risks.
3HR (Isoniazid + Rifampin)Daily oral isoniazid (5 mg/kg, max 300 mg for adults; 10–20 mg/kg, max 300 mg for children) plus rifampin (10 mg/kg, max 600 mg for adults; 15–20 mg/kg, max 600 mg for children).3 months (90 doses).Children of all ages as an alternative; adults when other options are contraindicated.Effective in reducing TB incidence (odds ratio 0.40 vs. no treatment), with good tolerability in pediatric populations; conditionally recommended by guidelines for shorter duration in young patients.
For pediatric patients, the 3HR regimen is particularly suitable as a shorter alternative to monotherapy, offering comparable protection with fewer doses and lower risk than longer isoniazid courses. The choice of regimen should consider indications such as recent exposure or , prioritizing shorter options like 3HP or 4R for improved adherence. Monitoring for all regimens focuses on adverse effects, particularly , with monthly clinical assessments for symptoms like , , or . Baseline (AST, ALT, ) are recommended for high-risk groups (e.g., those with , , or alcohol use), and treatment should be paused if transaminases exceed 3–5 times the upper limit of normal. This approach is less intensive than for active TB but essential to ensure safety and completion.

Public Health and Policy Approaches

National and International Guidelines

The (WHO) provides comprehensive consolidated guidelines on (TB) management, with the 2025 edition of Module 4 focusing on treatment and care for both drug-susceptible and drug-resistant TB. These guidelines emphasize shorter regimens for multidrug-resistant TB (MDR-TB), such as 6-month all-oral options incorporating , , and , alongside universal drug susceptibility testing (DST) to guide therapy initiation. They also integrate patient support measures, including adherence counseling and comorbidity management, to improve outcomes. The WHO's Global TB Report 2025 highlights progress with 8.3 million people newly diagnosed and accessing treatment in 2024, but notes stagnant funding at $5.9 billion against a $22 billion annual need to meet End TB Strategy targets. In the United States, the Centers for Disease Control and Prevention (CDC) and American Thoracic Society (ATS), in collaboration with the European Respiratory Society (ERS) and Infectious Diseases Society of America (IDSA), updated their clinical practice guidelines in 2025 to prioritize latent TB infection (LTBI) screening among high-risk groups, such as people living with . These recommendations advocate for annual LTBI testing in HIV patients using interferon-gamma release assays (IGRAs) or tuberculin skin tests, followed by shorter rifamycin-based regimens like 3 months of once-weekly isoniazid and to prevent progression to active disease, with integrated HIV-TB care to address immune suppression. Nationally, India's National TB Elimination Programme (NTEP) mandates daily fixed-dose combinations of isoniazid (), rifampicin (), pyrazinamide (), and ethambutol ()—known as HRZE—for the 2-month intensive phase of drug-susceptible TB in adults, followed by 4 months of daily , aiming to enhance adherence and reduce in a high-burden setting. The 2025 WHO guidelines, which China aligns with in its national TB control program, prioritize early detection and management of drug-resistant strains through expanded molecular DST, recommending individualized regimens for rifampicin-resistant TB that include fluoroquinolones and injectables only when necessary, reflecting the country's high prevalence of resistance. The WHO's End TB Strategy sets global targets for 2035, including a 90% reduction in TB incidence and a 95% reduction in TB deaths compared to levels, guiding national policies toward universal access to diagnostics, treatments, and preventive therapy. Harmonization efforts reveal variations, such as differences in pediatric dosing—where WHO uses weight-banded regimens while some national guidelines adjust for local —and in use, with WHO strongly endorsing adjunctive steroids for TB to reduce mortality, though implementation thresholds differ by country. Regional adaptations, like those in high-burden areas of and , tailor these guidelines to local without altering core regimens.

Strategies in High-Burden Regions

In high-burden regions of , tuberculosis management strategies are tailored to address dense populations, limited healthcare infrastructure, and high rates of , emphasizing decentralized care, rapid diagnostics, and community involvement to mitigate transmission and improve treatment adherence. These adaptations build on core (DOTS) frameworks while incorporating local epidemiological data and resource constraints to enhance case detection and outcomes. India, accounting for approximately 26% of the global TB burden, has prioritized programmatic management of drug-resistant tuberculosis (PMDT) to handle its estimated 130,000 annual multidrug-resistant TB (MDR-TB) cases, with services expanding rapidly to include shorter regimens and universal drug susceptibility testing. Private sector engagement is a key component, as it notifies about 30% of cases under the National TB Elimination Programme, supported by incentives and regulatory measures to align private providers with national protocols for standardized care. In the , where MDR-TB constitutes a significant challenge with an estimated 18% prevalence among previously treated cases, strategies focus on expanding community-based DOTS to MDR-TB patients through a hub-and-spoke model that decentralizes treatment delivery and improves adherence in resource-limited settings. Across , including , the rollout of has accelerated MDR-TB detection, enabling same-day rifampicin resistance testing and reducing diagnostic delays in high-incidence areas. Cross-border control initiatives, such as collaborative surveillance and information sharing among countries like and , address migratory flows that exacerbate transmission along porous borders. Vietnam has achieved near-universal DOTS coverage, integrating nutritional into TB programs to address malnutrition's role in poor outcomes, with facilities providing meals and supplements to enhance success rates that reached 89% in 2024. By 2025, tools for , inspired by post-COVID innovations, are being scaled in these regions to identify latent TB exposures more efficiently, using apps and AI-driven platforms to preventive initiation amid ongoing recovery. Non-governmental organizations provide supplementary in implementing these and strategies.

Role of Non-Governmental Organizations

Non-governmental organizations (NGOs) play a pivotal role in (TB) management by implementing community-based interventions, advancing , and enhancing case detection and adherence, particularly in high-burden regions like . These efforts complement national programs by addressing gaps in access, stigma reduction, and patient support, often in resource-limited settings. In , where TB incidence remains among the highest globally, NGOs have pioneered models that integrate care into local communities, improving outcomes for vulnerable populations. The Global Fund supports many of these NGO initiatives, allocating $800 million for TB in 2024, though facing an 11% cut in the 2025 grant cycle. Partners In Health (PIH) has developed influential community-based models for TB , initially in and adaptable to Asian contexts through partnerships. In , PIH's approach emphasizes peer counseling and supporters—non-clinical members who provide at-home adherence support—resulting in over 90% adherence rates for multidrug-resistant TB (MDR-TB) . This model, implemented via alliances like Socios En Salud, involves multidisciplinary teams that deliver second-line drugs directly to patients' homes, reducing default rates and fostering social support networks. PIH's innovations, such as mobile TB clinics in urban , have screened thousands and improved early detection, with similar accompaniment strategies applied in collaborative efforts across to bolster adherence in diverse settings. The TB Alliance, a global NGO focused on drug development, has accelerated progress toward shorter, more effective TB regimens through clinical trials conducted in high-burden Asian countries like and . The organization's SimpliciTB trial evaluated the BPaMZ regimen (, , , and pyrazinamide), demonstrating high bactericidal activity and potential to shorten treatment for both drug-sensitive and drug-resistant TB to four to six months. Building on this, the PAN-TB collaboration, involving TB Alliance and partners, advances pan-TB regimens tested in Phase 2 trials across , aiming to simplify and improve completion rates by reducing pill burden and duration. These efforts have informed WHO recommendations for shorter regimens, enhancing accessibility in 's dense populations. In , specialized NGOs like REACH in and BRAC in exemplify targeted interventions. REACH India, through its TB Call to Action project, focuses on pediatric TB management by engaging private providers and advocating for child-friendly diagnostics and s, scaling up access for under-five children in high-burden states. This includes training on pediatric-specific protocols and integrating TB care into child services, addressing diagnostic delays that affect nearly 45% of India's pediatric cases. Meanwhile, BRAC in has pioneered the (DOTS) strategy since 1984, operating urban and rural centers that diagnose and treat over 100,000 cases annually with 95% success rates. BRAC's model trains workers to supervise and conduct active case finding, contributing to national coverage of 79% in 2023. NGO-led initiatives have boosted TB case detection by 20-30% in supported areas, primarily through and involvement. For instance, TB REACH-funded projects, often implemented by NGOs in , increased notifications by up to 33% via innovative outreach, while international NGOs in contributed to 36% of new detections in targeted townships. These gains stem from active case-finding in underserved communities, reducing the undiagnosed burden estimated at 30% globally. In 2025, NGOs have intensified advocacy for sustained TB funding amid post-pandemic recovery challenges, including disruptions from that reversed detection gains. Organizations like the Stop TB Partnership and TB Alliance have lobbied for increased Global Fund commitments, highlighting how USAID funding—$406 million in 2024—faced cuts and freezes in 2025 that threaten Asian programs, and calling for resilient domestic financing to prevent a resurgence in cases. This advocacy emphasizes integrating TB services into broader health systems in high-burden Asian countries to ensure equitable recovery.

Treatment Outcomes and Challenges

Treatment Failure

Treatment failure in tuberculosis (TB) is defined as the persistence of positive sputum cultures after at least five months of effective therapy, or clinical or radiological worsening despite adherence to the regimen. According to (WHO) guidelines, it also encompasses scenarios where the treatment regimen must be terminated or permanently altered due to lack of bacteriological conversion, adverse drug reactions, or confirmed . This contrasts with , which involves recurrence after initial cure. The primary causes of treatment failure include non-adherence to therapy, , and of medications. Non-adherence accounts for a significant proportion of cases, often cited as the leading factor in up to 50% of failures due to interrupted dosing leading to inadequate drug levels. , particularly to rifampicin or isoniazid, contributes substantially, especially in regions with high multidrug-resistant TB (MDR-TB) prevalence. , though rarer, can occur in patients with comorbidities like or gastrointestinal disorders, resulting in subtherapeutic drug concentrations. Management of treatment failure begins with a comprehensive evaluation, including repeat drug susceptibility testing (DST) to identify resistance patterns. If MDR-TB is confirmed, the regimen is switched to second-line drugs such as fluoroquinolones, , or , guided by WHO recommendations for individualized therapy. Adherence is reinforced through directly observed therapy () and to address behavioral barriers. Outcomes for treatment failure are poor, particularly if MDR-TB is involved, with mortality rates ranging from 20% to 40% depending on access to second-line treatments and patient factors like co-infection. Early intervention can improve , but delays often lead to prolonged and higher transmission risk. Prevention focuses on rigorous early monitoring under the DOTS strategy, which includes regular sputum examinations at key intervals (e.g., months 2 and 5) and DOT to ensure compliance from the outset.

Relapse and Retreatment

Relapse in (TB) is defined as a new episode of microbiologically confirmed active disease occurring after the completion of a full course of treatment and apparent cure, typically identified more than 12 months after the previous episode to distinguish it from treatment failure. This contrasts with reinfection, where a acquires a new strain of Mycobacterium tuberculosis from external sources, whereas often involves reactivation of persistent endogenous . The risk of among patients with drug-susceptible TB who complete standard first-line therapy is generally low, estimated at 2-5% over follow-up periods of several years. However, this risk increases significantly in the presence of comorbidities such as infection, where recurrence rates can exceed 10-15% due to impaired immune control, and in cases of multidrug-resistant (MDR) TB, where approaches 20% or higher owing to incomplete eradication and acquired . Other contributing factors include underweight status, cavitary lung disease, and non-adherence during prior , though can serve as a precursor increasing susceptibility to . Management of relapsed TB begins with immediate retesting for drug susceptibility using phenotypic or molecular methods, such as Xpert MTB/RIF or line probe assays, to confirm ongoing susceptibility or detect emerging resistance. For patients with confirmed drug-susceptible relapse, the recommended retreatment regimen mirrors the initial first-line : a 2-month intensive phase of isoniazid (H), rifampin (R), pyrazinamide (Z), and ethambutol (E) (HRZE), followed by a 4-month continuation phase of HR, potentially extended to 7 months if extensive disease is present. In cases of detected rifampicin resistance or MDR-TB, an individualized regimen is prescribed per WHO guidelines, typically incorporating , fluoroquinolones, and other second-line agents for 9-18 months, with close monitoring for adverse effects and adherence via directly observed . Evidence from cohort studies indicates that retreatment achieves high success rates of approximately 80% in drug-susceptible relapse cases, defined as cure or treatment completion, when susceptibility is confirmed and adherence is ensured, though outcomes are poorer in MDR scenarios with success below 60%. As of 2025, whole-genome sequencing of M. tuberculosis isolates from initial and relapsed episodes has become a key tool to differentiate relapse (genetic similarity within 5-10 single nucleotide polymorphisms) from reinfection (greater divergence), informing targeted prevention strategies like contact tracing in high-transmission settings.

Trial of Anti-TB Therapy

The trial of anti-TB therapy involves initiating empirical treatment with antituberculosis drugs in patients with a high clinical suspicion of (TB) but inconclusive or negative diagnostic tests, particularly in resource-limited, high-burden settings. This approach is indicated for individuals in areas with high TB prevalence where smear microscopy is negative, yet severe illness—such as disseminated disease, miliary TB, or critical conditions like —warrants urgent intervention to prevent poor outcomes. In such scenarios, delaying treatment while awaiting confirmatory tests like or advanced imaging can lead to high mortality, especially among immunocompromised patients or those with extrapulmonary involvement. The standard protocol entails starting the four-drug intensive-phase regimen of isoniazid, rifampicin, pyrazinamide, and ethambutol (HRZE), administered daily under direct observation where possible. is monitored closely for clinical response, typically assessed at 2 weeks through improvements in symptoms (e.g., reduced fever, , and ) and signs (e.g., decreased or resolution of infiltrates on chest ). If response is observed, therapy continues toward completion; lack of improvement prompts reevaluation for alternative diagnoses or . Adherence is emphasized during this period to ensure reliable assessment of efficacy. Evidence from clinical studies in high-burden regions shows that 70-80% of patients with true drug-susceptible TB exhibit significant clinical improvement within this 2-week window, helping to guide definitive therapy and avoid unnecessary prolonged exposure in non-TB cases. This response rate underscores the diagnostic value of , particularly when integrated with ongoing diagnostic efforts.70360-8/fulltext) However, empirical initiation carries risks, including the potential to mask underlying by providing partial or delayed response that obscures the need for specialized regimens, thereby promoting transmission of resistant strains. Additionally, without confirmed diagnosis, patients face unnecessary drug toxicities, such as (reported in up to 11.5% of cases in high-burden settings) and other adverse effects like from ethambutol. As of 2025, advancements in rapid molecular diagnostics, such as GeneXpert MTB/RIF Ultra, are increasingly combined with trial to shorten the empirical , allowing quicker confirmation or exclusion of TB and , thus minimizing risks in high-suspicion cases.70360-8/fulltext)

Research and Historical Developments

Current Research Directions

Current in (TB) management emphasizes developing shorter, more effective regimens to improve adherence and outcomes, particularly for drug-resistant forms. The TB-PRACTECAL trial, a III study evaluating 24-week all-oral regimens for rifampin-resistant TB, demonstrated superior compared to standard care, with unfavorable outcomes of 11% to 23% of participants across experimental arms versus 48% in the control group (modified intention-to-treat analysis), highlighting the potential of combinations like , , and to shorten duration. Similarly, the SHINE trial supported a 4-month regimen for drug-susceptible pulmonary TB, achieving a 97.1% success rate with isoniazid, rifampin, pyrazinamide (optionally ethambutol), paving the way for guideline updates to reduce from 6 months. These efforts aim to address the burden of prolonged , which contributes to poor completion rates in high-incidence settings. Host-directed therapies (HDTs) represent a promising adjunctive approach by modulating the to enhance bacterial clearance and mitigate pathology, rather than solely targeting the . Anti-inflammatory agents, such as those suppressing excessive storms, have shown potential in preclinical models to reduce lung damage and improve efficacy during TB infection. Immunotherapies, including modulation and chimeric antigen receptor T-cell (CAR-T) therapies, are under investigation to boost protective immunity, with recent studies indicating they could shorten treatment by enhancing killing of . For instance, 7-oxo-DHEA has demonstrated enhanced immune control and reduced tissue damage in animal models when combined with standard drugs. Vaccine development continues to evolve, with the M72/AS01E advancing as a potential tool for both prevention and adjunctive treatment. Phase IIb results (published in 2019) reported 49.7% (90% CI: 12.1-71.2) in preventing active pulmonary TB among latently infected adults over three years, driven by robust + T-cell and humoral responses. A Phase III trial, initiated in March 2024 and fully recruited by April 2025 with over 20,000 participants across multiple high-burden countries, is assessing prophylactic and safety, with exploratory endpoints on its role in accelerating treatment response when used alongside antibiotics. This , targeting the M72 with AS01E , could complement existing regimens by reducing relapse risk in treated individuals. Biomarkers for response are a key focus to enable personalized and shortened , minimizing unnecessary drug exposure. Immune-based markers, such as Mtb-specific + T-cell responses and cytokines like IP-10 and TNF-α, correlate with bacterial burden and have been validated in clinical studies to predict outcomes early in . Noninvasive options, including frequency via tools, show promise for real-time assessment during the first two weeks of , potentially reducing duration from months to days. Multi-omics panels integrating hematological and inflammatory markers, like CRP and IL-6, are being refined for point-of-care use to identify responders and adjust regimens promptly. Looking to 2025 priorities, (AI) integration in drug susceptibility testing (DST) is accelerating diagnostics for resistant strains, with models improving accuracy and speed in identifying patterns from genomic . , using mycobacteriophages to selectively lyse M. tuberculosis in extensively drug-resistant (XDR-TB) cases, is gaining traction in preclinical and early clinical stages, offering a targeted alternative to broad-spectrum antibiotics with minimal impact on host . These innovations align with agendas, such as the NIAID Strategic Plan, emphasizing rapid DST and novel antimicrobials to meet 2025 TB reduction targets.

Historical Evolution of TB Management

Before the discovery of effective antimicrobial agents, the management of tuberculosis (TB) relied primarily on non-pharmacological approaches aimed at rest and isolation. In 1854, Hermann Brehmer introduced the sanatorium cure in , emphasizing fresh air, good nutrition, and graduated physical activity to promote healing of pulmonary lesions through the body's natural defenses. This model spread globally, with the first U.S. sanatorium opening in 1875 in , and by the early , thousands of such facilities operated worldwide, housing patients for months or years. Sanatoria treatment was supplemented in the late 1880s by collapse therapy, including artificial —inducing collapse via air injection to rest the diseased tissue—which became a standard intervention in the and , particularly in and , though it carried risks like and . Surgical variants, such as thoracoplasty, were also employed to permanently collapse segments but were largely abandoned after antibiotics emerged. The mid-20th century marked a revolutionary shift with the advent of . , the first effective anti-TB drug, was isolated in 1943 by and colleagues from griseus and demonstrated antituberculous activity in clinical trials by 1945, dramatically improving outcomes in advanced cases but revealing rapid bacterial resistance when used alone. (INH), a highly potent oral agent, was synthesized in 1952 and quickly became a cornerstone of therapy due to its bactericidal effects against . These discoveries prompted the first randomized controlled trials (RCTs) in ; the 1946–1948 Medical Research Council (MRC) streptomycin trial, involving 107 patients, established the superiority of combined streptomycin and over alone, setting a precedent for evidence-based TB and highlighting the need for to prevent resistance. By the 1970s, advances in drug combinations shortened treatment durations significantly. The introduction of rifampicin in 1968 enabled bactericidal activity against both intracellular and extracellular , allowing regimens to reduce from 18–24 months to 9 months initially. Landmark trials in the mid-1970s, including a 1976 study in and , demonstrated that a 6-month regimen of rifampicin and isoniazid—administered daily for 2 months followed by twice-weekly dosing—achieved relapse rates below 5% in smear-positive pulmonary TB, comparable to longer courses. These findings, corroborated by U.S. Service studies in 1974, established the 6-month regimen as the global standard for drug-susceptible TB, balancing efficacy, adherence, and cost. The 1990s addressed rising treatment interruptions and resistance through standardized strategies. In 1994, the (WHO) launched the (DOTS) strategy, emphasizing supervised drug intake, standardized regimens, case detection via sputum microscopy, and outcome monitoring to achieve cure rates over 85% in high-burden settings. Concurrently, multidrug-resistant TB (MDR-TB)—defined as resistance to at least isoniazid and rifampicin—was increasingly recognized following outbreaks in the U.S. and in the late 1980s and early 1990s, prompting WHO's 1996 guidelines on its laboratory confirmation and management with second-line drugs. DOTS-Plus, introduced in 1999, integrated MDR-TB care into DOTS frameworks, marking a pivotal policy response to resistance. From the 2010s onward, innovations targeted MDR-TB with novel agents and regimens. , a diarylquinoline inhibiting mycobacterial , received accelerated U.S. (FDA) approval in December 2012 for use in MDR-TB as part of , offering a new mechanism after 40 years without anti-TB drug approvals. WHO endorsed its inclusion in MDR-TB regimens by 2013, and by 2019, recommended it as a core drug for all drug-resistant cases. This facilitated a shift to all-oral regimens; in 2020, WHO prioritized 9–11-month bedaquiline-containing protocols over injectable-based ones, reducing and improving tolerability, with studies showing success rates exceeding 80% in eligible patients. By 2022, shorter all-oral bedaquiline regimens were adopted globally, transforming MDR-TB management amid ongoing efforts to address extensively drug-resistant strains.