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. 2025 May 24;40:100536. doi: 10.1016/j.jctube.2025.100536

Operational considerations of select new treatment recommendations for drug-susceptible and drug-resistant tuberculosis

John W Wilson a,⁎, Zelalem Temesgen a, James T Gaensbauer b
PMCID: PMC12166396  PMID: 40520337

Abstract

A number of management updates recently have been published for both drug-susceptible and drug-resistant tuberculosis (TB), TB in children, and contacts of patients with drug-resistant TB. The operationalization and application of these recommendations, which reflect favorable clinical trial outcomes, may vary significantly for different patient groups and in different settings. Defining the best treatment approach for each patient requires the integration of multiple data points including organism culture growth and corresponding drug susceptibility profiles, specific TB syndrome, concurrent patient co-morbidities and available public health resources. We review several updated TB treatment recommendations and discuss applicable strengths, select limitations and corresponding precautions as they pertain to diverging patient groups, TB syndromes, and public health capacity.

1. Introduction

After decades of relatively slow advancement in the treatment of tuberculosis (TB), many new treatment options and considerations for drug-susceptible and drug-resistant TB in adults and children have become available. Choosing the most appropriate drug combination and corresponding duration of therapy for any patient is predicated on the integration of specific clinical patient and microbiologic data and must align with available local public health resources (Table 1). The U.S. Centers for Disease Control and Prevention (CDC), European Respiratory Society (ERS) and World Health Organization (WHO) endorse a team-based approach to the management of tuberculosis, employing a collaborative engagement among health providers, public health officials and clinical microbiology laboratory personnel to provide the best opportunities for successful outcomes[[1], [2], [3]].

Table 1.

Considerations influencing drug selection and duration of TB treatment.

Microbiology
  • •

    MTB drug susceptibility profile (molecular and phenotypic testing)

  • •

    Time to sputum culture conversion after starting treatment

  • •

    Monomicrobial vs. polymicrobial infection

  • •

    MTB virulence factors
TB syndrome / Patient clinical features
  • •

    Cavitary vs. non-cavitary pulmonary disease

  • •

    Pulmonary vs. extrapulmonary TB disease (including CNS and bone involvement)

  • •

    Localized vs. disseminated (multi-organ) TB disease

  • •

    Patient immunocompetence

  • •

    Patient medical co-morbidities (including hepatic, renal, cardiac disease, etc)

  • •

    Patient’s other medications (polypharmacy, drug interactions)
Public Health resources
  • •

    TB medication access and pharmaceutical budgetary provisions

  • •

    Ability to provide daily directly observed therapy (DOT)

  • •

    Personnel to provide optimized case management.

  • •

    Resources for additional radiology imaging, laboratory testing and patient monitoring (before, during, after treatment)
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MTB = M. tuberculosis.

CNS = Central nervous system.

2. Drug susceptible TB

The recent 2025 updated American Thoracic Society (ATS)/CDC/Infectious Diseases Society of America (IDSA)/ERS guidelines on the treatment of drug-susceptible and drug-resistant tuberculosis highlight a number of changes and new evidence-based treatment recommendations accrued by clinical experts and research teams globally[1]. The new 4-month combination regimen of isoniazid, rifapentine, moxifloxacin and pyrazinamide (HPMZfor the treatment of drug-susceptible pulmonary tuberculosis enables a shorter duration compared to the traditional 6-month program of rifampin, isoniazid (INH), pyrazinamide (PZA), and ethambutol (RIPE). The HPMZ regimen was evaluated in Study 31/A5349, a multicenter open labeled trial enrolling patients with drug-susceptible pulmonary tuberculosis (including patients with HIV and those with cavitary lung disease) that compared the standard six-month RIPE-based treatment regimen with two separate 4 month treatment regimens (one replacing rifampin with rifapentine and the other replacing both rifampin and ethambutol with rifapentine and moxifloxacin)[4]. The 4-month HPMZ regimen (but not rifapentine without moxifloxacin) was noninferior to the RIPE-based regimen regarding TB disease-free survival at 12 months and also demonstrated a shorter time to sputum culture conversion. Identifying management strategies that shorten the duration of TB treatment without compromising patient outcome has been an objective of many clinical TB trials. Shorter regimens may improve both patient compliance and treatment completion rates and also reduce public health expense. As providers and public health programs begin to use this new 4-month HPMZ regimen, however, there are important considerations to note.

Compared to the traditional RIPE-based therapy for drug susceptible TB, HPMZ requires a higher pill-burden for the patient. Rifapentine is dispensed in 150 mg tablets and thus the 1,200 mg dosing recommendation requires 8 pills daily. When combined with INH (with vitamin B6), PZA, and moxifloxacin, the entire regimen totals 13–15 pills daily during the first two months, followed by 11 pills daily (after discontinuing PZA) for the subsequent two months of treatment[5]. This contrasts to the RIPE regimen that contains 7–11 pills in the intensive phase and 3–4 pills in continuation phase of treatment; even fewer pills are needed where combination formulations (e.g. Rifamate, Rifater) are utilized. This increased volume of pills in the HPMZ regimen may adversely impact patient preference, tolerance and compliance; therefore, patients should be aware of the pill burden before starting treatment. Indeed, comparatively high rates of patient intolerance to HPMZ have already been reported[6]. The utilization of directly observed therapy (DOT) by local public health programs should apply to all patients with active TB, and especially when using HPMZ to help mitigate these concerns.

Daily treatment with rifapentine may place additional pressure on drug supply sustainability for some TB treatment programs, and it will be imperative to ensure that patients started on HPMZ have sustainable rifapentine availability to complete treatment. In the U.S. there have been both national and regional rifapentine shortages, and the drug remains listed by FDA in short supply[7]. Supply-chain pressures and shortages also impact public health programs utilizing the 12-week INH-rifapentine (3HP) for treatment of latent TB infection (LTBI)[8], and may require health departments to decide whether to prioritize the use of rifapentine for either the treatment of patients with LTBI (72 tablets per course), especially those at higher risk of progression to active disease, or active TB disease with HPMZ (952 tablets per course). The HPMZ regimen may also be more expensive for public health departments than standard RIPE treatment, and the consequential impacts on limited pharmaceutical budgets and necessity to ensure treatment availability for all patients with active TB will need to be reassessed.

The inclusion of moxifloxacin requires up-front confirmation of fluoroquinolone (FQ) drug activity against the M. tuberculosis isolate. Many mycobacterial laboratories, however, do not routinely perform FQ drug susceptibility testing (DST) as part of their 1st-line drug panel for M. tuberculosis. The laboratory may need to be contacted to add moxifloxacin DST, and some labs may need to develop further capacity for FQ testing or identify protocols for forwarding samples to referral laboratories for FQ DST in a time-sensitive fashion.

Despite these considerations, the shortened 4-month treatment program including rifapentine and moxifloxacin can be an attractive treatment option for patients unable or unwilling to complete a 6-month RIPE treatment program. Examples of patients for whom the shorter regimen may be particularly useful include visitors or other patients departing the jurisdiction or country within 6 months from time of TB diagnosis, those incarcerated with a short duration remaining on their sentence, and patients waiting for select medical treatments (elective surgery, select immunosuppressive therapies) that favor completion of TB therapy as quickly as possible. Increasing the options to treat tuberculosis with different medications within shortened time periods can further improve favorable patient outcomes through individualized patient care.

Changes to the treatment of pediatric pulmonary TB have recently been made. Pediatric patients with pulmonary TB commonly present with AFB smear negative, non-cavitary, primary disease with a lower TB bacillary burden[9] yet historically received similar treatment durations as adults with TB. Shortening the treatment duration from 6 to 4 months in adults with culture-negative TB and those with select cases of drug susceptible, low-TB burden pulmonary disease have been shown to be successful[2,10,11] but were not typically applied to children. The SHINE trial was a multicenter international randomized controlled trial compared 4 vs 6 months of standard TB drug therapy in children under 16 years ago with non-severe, drug susceptible TB (e.g., AFB smear-negative, non-cavitary, and single lobe pulmonary disease and without complex pleural effusion, airway obstruction, dissemination, or peripheral lymph node involvement)[12]. The 4-month duration of therapy was found to be as effective as six months in this cohort of children and has now become the accepted international standard of care in pediatric cases of drug susceptible, non-severe pulmonary TB. Efficacy of the 4-month duration has also been demonstrated among children living with HIV[13].

3. Drug-resistant TB

Since 2020, a number of new combination treatment options for multidrug-resistant (MDR) and rifamycin-resistant (RR) TB have been introduced through the Nix-TB, ZeNix TB, TB-PRACTECAL, BEAT-Tuberculosis, endTB, SimpliciTB trials, utilizing drugs with increased potency to achieve shortened treatment durations with higher clinical outcome success rates and better patient tolerance[4,12,[14], [15], [16], [17], [18], [19], [20]]. Most of these MDR/RR TB treatment regimens contain bedaquiline, linezolid and a newer FQ and represent more simplified treatment options compared to those listed in prior published guidelines[21]. The use of combination bedaquiline, pretomanid, linezolid (BPaL) without or with moxifloxacin (BPaLM) currently is the preferred treatment approach for most adult patients with pulmonary MDR/RR TB disease and is endorsed by the CDC and WHO[1,22]. Globally, these regimens are being used more frequently and with improved patient tolerance using reduced linezolid dosing and therapeutic drug monitoring (TDM)[23,24]. Updated laboratory monitoring and recommended post-treatment patient assessments can be accessed in the 2025 ATS/CDC/ERS/IDSA Clinical Practice Guideline[1]. BPaL and BPaLM currently are not endorsed for most children under 14 years of age, primarily due to a paucity of dosing and safety data for pretomanid; however, a phase I clinical trial is currently underway to evaluate pretomanid use in children[25].

Other less well-known six-month treatment regimens for patients with pulmonary MDR/RR TB have been demonstrated in the SimpliciTB and BEAT-Tuberculosis trials. The SimpliciTB clinical trial enrolled adult patients in eight countries with pulmonary drug-susceptible as well as MDR TB[18]. Patients with MDR TB received combination bedaquiline, pretomanid, moxifloxacin and pyrazinamide (BPaMZ) for a 6-month duration, and 86 % of patients enrolled experienced sputum culture conversion within 8 weeks of therapy and with favorable clinical outcomes reported at week 104. These response rates were similar to those reported with the six-month BPaL and BPaLM regimens. Approximately 14 % of patients receiving BPaMZ did experience significant elevation of liver enzymes; but the regimen remains an option in setting of either linezolid-resistance or patient intolerance to linezolid. The same BPaMZ combination in this same trial was also studied as a 4-month regimen for the treatment of drug susceptible pulmonary TB and actually performed better that RIPE in achieving a shorter time to sputum culture conversion, but BPaMZ did not meet the non-inferiority criteria in the intention to treat population due to higher withdrawal rates from hepatoxicity.

In the BEAT-Tuberculosis clinical trials in South Africa and India, patients with MDR- and XDR-TB, including patients living with HIV, received 6-months of bedaquiline, delamanid, linezolid and either levofloxacin or clofazimine (based on FQ susceptibility results; and included both levofloxacin and clofazimine when FQ susceptibility was unknown) and demonstrated favorable outcomes comparable to those reported for BPaL and BPaLM[19,20]. The clinical trial data is currently under further analysis, but these regimens provide additional options in setting of FQ-resistant MDR TB in settings where pretomanid is either not available or not advised (e.g. children, pregnant women).

There have been a number of updated 9-month treatment options for MDR/RR pulmonary TB. The endTB trial was a randomized control trial done in multiple countries comparing five different 9-month treatment regimens for the treatment of MDR-or RR-pulmonary tuberculosis[17]. Three regimens had comparatively favorable outcomes (bedaquiline, linezolid, moxifloxacin, pyrazinamide {BLMZ}; bedaquiline, clofazimine, linezolid, levofloxacin, pyrazinamide {BLLfxCZ}; and bedaquiline, delamanid, linezolid, levofloxacin, pyrazinamide {BDLLfxZ}) compared to longer combination drug regimens (≥18 months) for patients who did not demonstrate FQ resistance. Outcome results from these 3 endTB drug regimens were similar compared to published BPaLM outcomes. The other two regimens did not contain bedaquiline nor perform as well (clofazimine, delamanid, linezolid, levofloxacin, pyrazinamide; and clofazimine, delamanid, moxifloxacin, pyrazinamide). The 3 bedaquiline containing endTB regimens were recently endorsed by WHO and with the added emphasis for special patient groups including children, adolescent, and pregnant women with FQ susceptible, RR tuberculosis[22]. Among these regimens, WHO favors the use of BLMZ over BLLfxCZ, and BLLfxCZ over BDLLfxZ when feasible and with added requirement of baseline FQ susceptibility testing.

Among adult patients with MDR pulmonary TB in South Korea enrolled into the randomized controlled MDR END trial with pulmonary MDR-, FQ-susceptible pulmonary TB, patients received either 9 months of delamanid, linezolid, levofloxacin and pyrazinamide (DLLfxZ) or a 20–24-month combination therapy based on prior published 2014 WHO guidelines[26]. The 9 month DLLfxZ regimen was found overall to be non-inferior but with higher success in the modified intention to treat analysis regarding the primary endpoint (treatment success after 24 months). A potential consideration for this regimen can be for patients with FQ-susceptible, MDR TB that is also resistant to bedaquiline and/or clofazimine. Although excluded in the study, the absence of pretomanid in this regimen could provide an additional therapeutic option for children under 14 years of age and pregnant women.

4. Complex extrapulmonary TB

For cases of extrapulmonary MDR TB including central nervous system (CNS) and bone/joint involvement, there is a paucity of clinical trial data to recommend the use of BPaL/BPaLM or other bedaquiline-based regimens. Current U.S. treatment guidelines for MDR or RR tuberculosis do not provide clear guidance in cases of extrapulmonary TB. Rodent models with TB meningitis provide mixed outcome results with pretomanid use[27] and more favorable results including bedaquiline[28,29]. Levofloxacin, moxifloxacin and linezolid, however, have collectively demonstrated favorable cerebrospinal fluid (CSF) drug concentrations and clinical outcomes when used in combination therapy among patients with TB meningitis, including MDR TB[30,31]. When compared to many antimicrobials used to treat MDR TB in prior published guidelines[21] that demonstrate inherently poor CNS/CSF penetration (including amikacin, clofazimine, and PAS), the pharmacokinetic profiles regarding brain parenchyma and CSF penetration of linezolid, FQs, pretomanid, and bedaquiline-based combinations are more promising and support their inclusion[32,33].

Nevertheless, concerns remain regarding the adequacy of these newer regimens in treatment of CNS disease, especially achieving adequate CSF concentrations in cases of TB meningitis. Using PET imaging among animal models with radio-labeled drugs, pretomanid and bedaquiline were found correspondingly to have higher brain parenchymal tissue concentrations compared to the CSF, while linezolid demonstrated higher CSF concentrations[27]. These discordances in CSF to parenchymal tissue drug levels may raise concern regarding the adequacy of BPaL sterilizing capacity within the CSF in cases of meningitis. For cases of drug-resistant TB meningitis, the WHO recommends including agents with high CSF penetration capacity (i.e., levofloxacin, moxifloxacin, linezolid, cycloserine, PZA, or ethionamide) and for possibly longer durations when possible[3]. The use of BPaLM in the treatment of MDR and RR extrapulmonary TB, including CNS and bone/joint disease, should be explored further. Whether to supplement BPaL and BPaLM with 1–2 additional drugs with favorable CSF and parenchymal pharmacodynamics in patients with CNS TB remains a question for further study.

For extrapulmonary drug-resistant TB not involving the CNS, treatment outcomes appear favorable despite the continued paucity of supporting published data. A cohort of 68 patients treated with BPaL within the U.S. included 17 with various forms of extrapulmonary tuberculosis (2 of whom had spine involvement). All of these patients completed treatment successfully without relapse, though 8 patients required longer duration of treatment for bone disease (n=5) or delayed culture conversion (n=3)[23]. Current U.S. guidelines for treatment of drug-resistant tuberculosis do not provide specific recommendations in cases of extrapulmonary disease. Optimized drug selection, dosing and durations of therapy have not been clearly determined for patients with various forms of extrapulmonary disease. Given the limited treatment options available, the WHO endorses the use of BPaL/BPaLM in most “noncomplex” forms of extrapulmonary disease; however, CNS, osteoarticular and disseminated (miliary) forms of TB remain excluded given the current paucity of published outcome clinical data.

5. Detection of resistance to new TB drugs

Corresponding with the increased use of BPaL, BPaLM and other bedaquiline-containing combination regimens, is the emergence of bedaquiline resistance (and corresponding clofazimine cross-resistance) via mutations in the atpE, rv0678 and pepQ genes. The occurrence of bedaquiline resistance developing during treatment though the emergence of these mutations is over 15 %[34,35]. Bedaquiline can produce a delayed bactericidal response which, coupled with its long half-life, may elevate the risk of drug resistance development early during therapy and reinforces the necessity of including other active TB drugs in combination therapy[36]. In a systematic review of bedaquiline resistance in patients treated for MDR-TB, baseline pretreatment molecular detection of bedaquiline resistance was detected in 4.4 % of cases[37]. Coupled with a rising rate a FQ and linezolid resistance among patients with MDR TB (24 % and 10–15 % respectively in select patient groups), it cannot be assumed that newer bedaquiline containing regimens to treat MDR TB will be uniformly or durably active[[38], [39], [40]]. Caution must be applied in the interpretation of identified rv0678 nad pepQ gene mutations, as many variants have been identified with corresponding phenotypic bedaquiline resistance and occasionally in drug susceptible M. tuberculosis (MTB) strains[41]. It therefore remains important that confirmed or suspected MDR TB isolates be tested by both molecular and phenotypic DST to these newer agents in qualified reference laboratories (e.g. the CDC Division of TB Elimination, Laboratory branch; the New York Wadsworth State Mycobacteriology Laboratory; the Johns Hopkins Mycobacteriology Research Laboratory; the Florida State Mycobacteria Laboratory).

The management of patients with extensively drug-resistant (XDR) TB, defined as MTB resistant to levofloxacin or moxifloxacin and to either bedaquiline or linezolid remains ill-defined. Whether to retain these drugs within a combination treatment regimen often depends upon the specific molecular resistance identified and phenotypic minimum inhibitory concentration (MIC) values through DST. Additional or alternative ‘active’ drugs defined by DST results may need to be included but with a few caveats. The combination of pretomanid and PZA may be associated with higher rates of hepatoxicity. The STAND trial found the combination of pretomanid, PZA and moxifloxacin produced more hepatoxicity and less clinical efficacy compared to standard RIPE in patients with drug susceptible pulmonary TB[42]. Elevated rates of hepatotoxicity were also reported in the SimpliciTB trial using pretomanid and PZA along with bedaquiline and moxifloxacin (BPaMZ)[18]. Bedaquiline-resistant TB may be cross-resistant to clofazimine, and combining bedaquiline and clofazimine together may increase the risk of QTc prolongation, especially if a FQ is included as well. Thus, patient safety and drug activity must be considered together when composing secondary salvage treatment regimens.

6. TB prevention among contacts

The management of infected contacts of patients with pulmonary MDR TB has been a historical challenge given the paucity of available agents with published clinical outcome data. FQ monotherapy for contacts of patients with active pulmonary MDR/FQ-susceptible TB has been shown to reduce rates of progression to active TB in both adults and children[43,44] and was strongly recommended in a 2024 WHO Rapid Communication[45]. When FQs cannot be utilized, combination therapy with 2 identified active drugs by susceptibility testing from the index case has also been considered, although pyrazinamide containing regimens have been shown to be generally less well tolerated and thus, less favored[46]. Other novel approaches for preventative therapy for FQ-resistant MDR-TB include monotherapy with linezolid or delamanid[47,48]. Larger active clinical trials are underway evaluating treatment of contacts with MDR-TB include the PHOENIx trial (comparing 6 months of delamanid to INH) and the BREACH-TB trial (comparing one month of bedaquiline to current WHO endorsed treatment options)[49,50]. In the absence of available treatment options, close observation without treatment for immunocompetent contacts along with serial clinical and radiologic monitoring over a 2-year period is an alternate strategy. Thus, the treatment of infected contacts to a known case of pulmonary MDR TB needs to be individualized and predicated on the MTB DST profile, the likelihood of infection acquisition from the index case, and factors pertaining to the contact patient including age, immunologic status, medical co-morbidities, other concurrent medications, and willingness to take medications.

For contacts of patients with drug susceptible pulmonary TB and those incidentally diagnosed with latent TB infection (LTBI) without risk factors for drug resistance, currently supported treatment options include once weekly high-dose INH and rifapentine for 12 weeks (3HP), daily INH plus rifampin (3HR) for 3 months, daily oral rifampin for 4 months (4R) and daily oral INH for 6–9 months[51]. An additional LTBI treatment consideration is daily oral INH plus rifapentine (1HP) for 4 weeks and was demonstrated through the BRIEF-TB trial to be non-inferior compared to 9 months of oral daily INH[52]. However, concerns regarding wide-spread implementation of the 1HP regimen exist and include the low number of enrolled patients in the clinical trial with a documented reactive tuberculosis skin test (TST) or positive interferon gamma release assay (IGRA), the low number of study participants who subsequently developed active TB in either treatment arm, the self-reporting platform of treatment completion, and preponderance of enrolled patients with HIV who potentially may have be more accustomed or conditioned to take daily medications. Nevertheless, 1HP remains an attractive LTBI treatment option and may be appropriate for some patients.

Additional resources and support for providers in the U.S. treating patients with active TB or contacts can be accessed through their regional CDC-supported TB Centers of Excellence (COE) (https://www.cdc.gov/tb-programs/php/about/tb-coe.html).

7. Conclusion

The recent addition of new drugs and effective combination regimens mark a new era in the fight against TB, as health providers now have more favorable treatment options to choose from. Despite this notable progress, TB continues to be a diverse and challenging disease to manage. The application of new guidelines necessitates an individualized patient care approach for optimizing treatment outcomes and involves a collaborative approach between the patient, the provider, the laboratory, and the local public health department.

CRediT authorship contribution statement

John W. Wilson: Writing – review & editing, Writing – original draft, Methodology, Formal analysis, Conceptualization. Zelalem Temesgen: Writing – review & editing, Formal analysis. James T. Gaensbauer: Writing – review & editing, Conceptualization.

Declaration of competing interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

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