Abstract
Based on the assessment of new evidence, the World Health Organization (WHO) updated its guidelines for the treatment of drug-resistant tuberculosis (TB) in December 2022. The new recommendations and the latest study data made it necessary to update the existing guideline on the treatment of at least rifampicin-resistant TB (RR-TB) for the German-speaking countries, replacing the respective chapters of the treatment guidelines published in 2022. A shortened treatment of proven RR-TB and multidrug-resistant TB for at least 6 months using the fixed and non-modifiable drug combination of bedaquiline, pretomanid, linezolid, and moxifloxacin (BPaLM) is now also recommended for Austria, Germany, and Switzerland under certain conditions considering the existing barriers for the implementation of the new treatment regimen. For the treatment of pre-extensively drug-resistant (pre-XDR-) TB, an individualized treatment for 18 months continues to be the primary recommendation. The non-modifiable drug combination of bedaquiline, pretomanid, and linezolid (BPaL) may be used alternatively in selected pre-XDR-TB cases, provided that all prerequisites are met. The necessary requirements for using BPaLM and BPaL are presented in detail in this amendment to the consensus-based TB treatment guideline for adult patients.
Introduction and Summary
Based on new study data [1‒3], the World Health Organization (WHO) updated their recommendations for the treatment of drug-resistant tuberculosis (TB) in December 2022 [4]. The evaluation of these recommendations and new study data made it necessary to update the respective recommendations of the recently published treatment guideline for the German-speaking countries [5]. Two primary options are now also recommended for the treatment of multidrug-resistant TB (MDR-TB) and other rifampicin-resistant TB (RR-TB) (for definition, see [5, 6]) in Austria, Germany, and Switzerland:
- 1.
MDR-/RR-TB treatment with a shortened duration of at least 6 months with bedaquiline, pretomanid, linezolid, and moxifloxacin (BPaLM) as a fixed and non-modifiable drug combination (Table 1) if certain requirements are met (Box 1)
- 2.
Individualized MDR-/RR-TB treatment for 18 months with drugs from WHO groups A–C (Table 2), if the requirements for BPaLM cannot be met
Dosing of treatment for MDR-/RR-TB with BPaLM and pre-XDR with BPaL (according to WHO [4])
. | BPaL(M) . | WHO abbreviation (Table 2) . | Standard dosing (all oral) . | Alternative dosing (all oral) . |
---|---|---|---|---|
Bedaquiline | B | Bdq | Week 1–2: 400 mg daily | Week 1–8: 200 mg daily |
Week 3–26: 200 mg 3x/week | Week 9–26: 100 mg daily | |||
Pretomanid | Pa | Week 1–26: 200 mg daily | ||
Linezolid | L | Lzd | Week 1–26: 600 mg daily | Reduction to 300 mg daily possible in case of relevant toxicity |
Moxifloxacin | M | Mfx | Week 1–26: 400 mg daily |
. | BPaL(M) . | WHO abbreviation (Table 2) . | Standard dosing (all oral) . | Alternative dosing (all oral) . |
---|---|---|---|---|
Bedaquiline | B | Bdq | Week 1–2: 400 mg daily | Week 1–8: 200 mg daily |
Week 3–26: 200 mg 3x/week | Week 9–26: 100 mg daily | |||
Pretomanid | Pa | Week 1–26: 200 mg daily | ||
Linezolid | L | Lzd | Week 1–26: 600 mg daily | Reduction to 300 mg daily possible in case of relevant toxicity |
Moxifloxacin | M | Mfx | Week 1–26: 400 mg daily |
Requirements for the treatment of multidrug-resistant (MDR)/rifampicin-resistant (RR) tuberculosis with BPaLM and pre-extensively drug-resistant (pre-XDR) tuberculosis with BPaL in Austria, Germany, and Switzerland
Treatment should be started and continuously managed by or in close cooperation with a specialized TB treatment center [5] |
At the time when this guideline amendment was published, pretomanid was not licensed by German authorities and the applicable license of the European Medicines Agency (EMA) only covered the indications for pre-XDR-, XDR-, or MDR-TB complicated by intolerance to or failure of the individualized 18-month treatment. The EMA license does not include first-line MDR-TB treatment for uncomplicated cases as it is recommended by WHO [4] and by this amendment. Under these circumstances, the coverage of costs for the BPaL(M) drug combination must be clarified in advance for the in- and outpatient treatment of each individual case to ensure an uninterrupted course of treatment. If this is not possible, an individualized treatment should be favored |
Treatment with BPaL(M) can be started immediately after molecular resistance prediction testing for fluoroquinolones. However, susceptibility to the other substances in the BPaL(M) drug combination should be tested as soon as possible. Molecular resistance prediction tests for bedaquiline and linezolid should be carried out in specialized laboratories. Phenotypic drug susceptibility testing (DST) for pretomanid is currently being evaluated and can be carried out in specialized laboratories. Cooperation with a specialized laboratory that provides complete molecular resistance prediction and DST is another prerequisite for the use of BPaL(M) |
In the TB-PRACTECAL trial, the significantly lower number of treatment discontinuations mainly due to adverse drug reactions (ADRs) was of critical importance for the superiority of BPaL(M) over the previous WHO standard regimens [3]. Active monitoring for frequent ADRs must always be carried out when using BPaL(M) [5, 9]. Serious adverse events (SAEs) must be reported to the responsible national authorities to improve knowledge about treatment safety. Follow-up for 24 months as recommended in the German-speaking countries for patients with MDR-TB [5] should be intensified by means of shorter follow-up intervals to detect relapses at an early stage, if additional risk factors for unfavorable outcomes are present (e.g., initially high sputum smear grade, presence of lung cavities [10]) |
Close monitoring and support of the participants were important parts of the TB-PRACTECAL trial, including (video-) observed and supported treatment [3]. This intensified support may have contributed to the very good treatment results. Intense psychosocial support and monitoring to help patients adhere to the full treatment course using adequate, individually tailored measures are an indispensable prerequisite for the treatment of any drug-resistant TB |
In case of moxifloxacin low-level resistance, data supporting the use of moxifloxacin high-dose treatment within the BPaL(M) drug combination are lacking. This also applies to the replacement of moxifloxacin with levofloxacin. If moxifloxacin cannot be used, treatment for pre-XDR-TB should be used (see recommendation 4) |
Exclusion criteria for the use of BPaL(M) according to WHO [4] |
Children and adolescents under 14 years of age |
Pregnancy or breastfeeding |
TB with involvement of the central nervous system, bones or joints, and disseminated TB |
Use with caution after outweighing benefits and harms and if the treating physician judges BPaL(M) to be the best option despite these contraindications, according to WHO [4] |
People living with HIV infection (PLWH) with CD4+ cell count below 100 cells/mm3 |
Increased liver function tests threefold above normal values |
Corrected QT interval using Fridericia’s formula (QTcF) above 500 ms, or a history of heart disease, syncope, significant arrhythmias, congenital QT prolongation, torsade de pointes, or cardiomyopathy |
Peripheral neuropathy grade 3–4 |
Moribund patients |
Very low BMI (<17) |
Treatment should be started and continuously managed by or in close cooperation with a specialized TB treatment center [5] |
At the time when this guideline amendment was published, pretomanid was not licensed by German authorities and the applicable license of the European Medicines Agency (EMA) only covered the indications for pre-XDR-, XDR-, or MDR-TB complicated by intolerance to or failure of the individualized 18-month treatment. The EMA license does not include first-line MDR-TB treatment for uncomplicated cases as it is recommended by WHO [4] and by this amendment. Under these circumstances, the coverage of costs for the BPaL(M) drug combination must be clarified in advance for the in- and outpatient treatment of each individual case to ensure an uninterrupted course of treatment. If this is not possible, an individualized treatment should be favored |
Treatment with BPaL(M) can be started immediately after molecular resistance prediction testing for fluoroquinolones. However, susceptibility to the other substances in the BPaL(M) drug combination should be tested as soon as possible. Molecular resistance prediction tests for bedaquiline and linezolid should be carried out in specialized laboratories. Phenotypic drug susceptibility testing (DST) for pretomanid is currently being evaluated and can be carried out in specialized laboratories. Cooperation with a specialized laboratory that provides complete molecular resistance prediction and DST is another prerequisite for the use of BPaL(M) |
In the TB-PRACTECAL trial, the significantly lower number of treatment discontinuations mainly due to adverse drug reactions (ADRs) was of critical importance for the superiority of BPaL(M) over the previous WHO standard regimens [3]. Active monitoring for frequent ADRs must always be carried out when using BPaL(M) [5, 9]. Serious adverse events (SAEs) must be reported to the responsible national authorities to improve knowledge about treatment safety. Follow-up for 24 months as recommended in the German-speaking countries for patients with MDR-TB [5] should be intensified by means of shorter follow-up intervals to detect relapses at an early stage, if additional risk factors for unfavorable outcomes are present (e.g., initially high sputum smear grade, presence of lung cavities [10]) |
Close monitoring and support of the participants were important parts of the TB-PRACTECAL trial, including (video-) observed and supported treatment [3]. This intensified support may have contributed to the very good treatment results. Intense psychosocial support and monitoring to help patients adhere to the full treatment course using adequate, individually tailored measures are an indispensable prerequisite for the treatment of any drug-resistant TB |
In case of moxifloxacin low-level resistance, data supporting the use of moxifloxacin high-dose treatment within the BPaL(M) drug combination are lacking. This also applies to the replacement of moxifloxacin with levofloxacin. If moxifloxacin cannot be used, treatment for pre-XDR-TB should be used (see recommendation 4) |
Exclusion criteria for the use of BPaL(M) according to WHO [4] |
Children and adolescents under 14 years of age |
Pregnancy or breastfeeding |
TB with involvement of the central nervous system, bones or joints, and disseminated TB |
Use with caution after outweighing benefits and harms and if the treating physician judges BPaL(M) to be the best option despite these contraindications, according to WHO [4] |
People living with HIV infection (PLWH) with CD4+ cell count below 100 cells/mm3 |
Increased liver function tests threefold above normal values |
Corrected QT interval using Fridericia’s formula (QTcF) above 500 ms, or a history of heart disease, syncope, significant arrhythmias, congenital QT prolongation, torsade de pointes, or cardiomyopathy |
Peripheral neuropathy grade 3–4 |
Moribund patients |
Very low BMI (<17) |
WHO classification of drugs for the individualized treatment of drug-resistant TB [14‒16], adapted to the drug availability in German-speaking countries
WHO groups (and recommendations) . | Drug (WHO abbreviation), in alphabetical order . |
---|---|
Group A (include all 3 drugs) | Bedaquiline (Bdq) |
Levofloxacin (Lfx) or Moxifloxacin (Mfx) | |
Linezolid (Lzd) | |
Group B (add one or both drugs) | Clofazimine (Cfz) |
Terizidone (Trd)1 | |
Group C (add to complete the regimen if drugs from group A and B cannot be used) | Amikacin2,3 (Am) |
Delamanid (Dlm) | |
Ethambutol (E) | |
Imipenem-Cilastin (Ipm-Cln) or Meropenem (Mpm) both in combination with Amoxicillin/Clavulanic acid4 | |
Para-Aminosalicylic Acid (PAS) | |
Protionamide (Pto)5 | |
Pyrazinamide (Z) |
WHO groups (and recommendations) . | Drug (WHO abbreviation), in alphabetical order . |
---|---|
Group A (include all 3 drugs) | Bedaquiline (Bdq) |
Levofloxacin (Lfx) or Moxifloxacin (Mfx) | |
Linezolid (Lzd) | |
Group B (add one or both drugs) | Clofazimine (Cfz) |
Terizidone (Trd)1 | |
Group C (add to complete the regimen if drugs from group A and B cannot be used) | Amikacin2,3 (Am) |
Delamanid (Dlm) | |
Ethambutol (E) | |
Imipenem-Cilastin (Ipm-Cln) or Meropenem (Mpm) both in combination with Amoxicillin/Clavulanic acid4 | |
Para-Aminosalicylic Acid (PAS) | |
Protionamide (Pto)5 | |
Pyrazinamide (Z) |
1Terizidone is used instead of cycloserine in the German-speaking countries.
2Amikacin (ideally as a once-daily application via a port system) should only be part of the drug combination if adverse drug reactions can be monitored closely.
3Streptomycin is listed by the WHO as an alternative but is not available in the German-speaking countries at the time of publishing this guideline amendment.
4Meropenem should be administered intravenously 2–3 times a day together with clavulanic acid (commercially available only as amoxicillin-clavulanic acid), ideally via a port system.
5Protionamide is used instead of ethionamide in the German-speaking countries.
Another WHO-recommended fixed-dose MDR-TB treatment regimen for 9–12 months (Box 2) can only be considered in individual cases that are relatively rare in the German-speaking countries.
For the treatment of pre-extensively drug-resistant TB (pre-XDR-TB) (for definition, see [5, 6]), two options are now also recommended in the German-speaking countries:
Composition of and contraindications for a 9–12-month fixed-dose drug combination for the treatment of multidrug-resistant tuberculosis in adults according to WHO [4]
Composition |
4–6 months: bedaquiline (used for 6 months), levofloxacin or moxifloxacin, protionamide (can be replaced by 2 months of linezolid 600 mg/d), ethambutol, pyrazinamide, high-dose isoniazid and clofazimine (extension from 4 to 6 months if sputum microscopy is still positive at the end of the 4th month of treatment) followed by 5 months: levofloxacin or moxifloxacin, ethambutol, pyrazinamide, and clofazimine |
Contraindications* |
Resistance to or suspected ineffectiveness of one of the drugs (in case of proven low-level isoniazid resistance, the fixed-dose drug combination can be given with high-dose isoniazid; in case of a proven katG mutation, high-dose isoniazid treatment should not be used) |
Pretreated MDR-/RR-TB |
Severe, extensive, or extrapulmonary TB |
*The WHO also lists pregnancy as a contraindication. According to the guideline group, MDR-/RR-TB treatment during pregnancy should always be carried out by a specialized TB treatment center and the 9–12-month fixed-dose drug combination can be a treatment option |
Composition |
4–6 months: bedaquiline (used for 6 months), levofloxacin or moxifloxacin, protionamide (can be replaced by 2 months of linezolid 600 mg/d), ethambutol, pyrazinamide, high-dose isoniazid and clofazimine (extension from 4 to 6 months if sputum microscopy is still positive at the end of the 4th month of treatment) followed by 5 months: levofloxacin or moxifloxacin, ethambutol, pyrazinamide, and clofazimine |
Contraindications* |
Resistance to or suspected ineffectiveness of one of the drugs (in case of proven low-level isoniazid resistance, the fixed-dose drug combination can be given with high-dose isoniazid; in case of a proven katG mutation, high-dose isoniazid treatment should not be used) |
Pretreated MDR-/RR-TB |
Severe, extensive, or extrapulmonary TB |
*The WHO also lists pregnancy as a contraindication. According to the guideline group, MDR-/RR-TB treatment during pregnancy should always be carried out by a specialized TB treatment center and the 9–12-month fixed-dose drug combination can be a treatment option |
Scientific evidence and international recommendations for the diagnosis and treatment of TB are rapidly changing. It is therefore to be expected that the recommendations of this amendment will also need to be updated soon. If further updates are required before the expiry date of the current guideline and amendment, the DZK as the coordinating organization will publish them separately on their Website and newsletter.
Methods
The aim of this amendment about the treatment of drug-resistant TB was to reflect the current state of knowledge. It is aimed at physicians and other medical professionals in Austria, Germany, and Switzerland who treat adult patients with RR-/MDR- or pre-XDR-TB. The amendment was developed using a structured consensus finding process according to the system and rules of the Association of the Scientific Medical Societies in Germany (AWMF). With few exceptions, the members of the recent guideline group from 2022 also drafted the current amendment [5]. All potential conflicts of interest were assessed by the guideline group and published on the AWMF Website [7]. The current WHO recommendations [4] and evidence from treatment studies relevant for this guideline were reviewed, but no systematic literature review or formal assessment had to be carried out for this consensus-based AWMF guideline. Further information on methodology and conflicts of interest can be found on the AWMF Website [8].
Results
MDR-TB Treatment with Bedaquiline, Pretomanid, Linezolid, and Moxifloxacin for at Least 6 Months
Recommendation 1: if the conditions listed in Box 1 are met, patients with MDR-TB should be offered treatment for at least 6 months with the fixed and non-modifiable drug combination BPaLM (Table 1). Otherwise, individualized MDR-TB treatment should be administered for usually at least 18 months (see recommendation 2).
Based on the available evidence, the WHO recommends the drug combination BPaLM primarily for the treatment of MDR- and RR-TB [4]. The guideline group agrees with this WHO recommendation. However, it should be noted that in the German-speaking countries, the requirements listed in Box 1 must be met. If this is not the case, individualized MDR-TB treatment should be administered for usually at least 18 months.
After clinical assessment, it may be necessary to extend treatment to 9 months of BPaLM or to switch to 18 months of individualized treatment. An indicator for the necessity of treatment extension is the lack of conversion or a reversion of sputum cultures between month 4 and 6 of treatment [4]. If treatment is interrupted for more than 14 consecutive days or for more than 1 month cumulatively, a restart of BPaLM or change to an individualized treatment must be discussed with a specialized TB treatment center. In the event of complications or side effects leading to the permanent discontinuation of BPaLM, treatment should be changed to an individually composed MDR-TB regimen for 18 months.
Individualized MDR-/RR-TB Treatment for at Least 18 Months
Recommendation 2A: an individualized MDR-/RR-TB treatment should consist of all 3 drugs of WHO group A (bedaquiline + levofloxacin or moxifloxacin + linezolid) and at least 1 drug of WHO group B (clofazimine, terizidone) (Table 2). However, it must be adapted to the results of drug susceptibility testing (DST).
Recommendation 2B: if group A or group B substances cannot be used due to drug resistance or intolerance, WHO group C drugs (Table 2) should be added until an MDR-/RR-TB treatment regimen of at least 4 substances with proven efficacy is composed.
Recommendation 2C: generally, the duration of the individualized MDR-/RR-TB treatment should be at least 18 months. A shorter duration of treatment should only be considered after consulting a specialized TB treatment center.
Individualized MDR-/RR-TB treatment should be started based on the results of molecular resistance prediction tests. If resistance-associated mutations are present, the corresponding substance should not be used, or dose adjustment should be considered for specific drugs after consulting a specialized TB treatment center. As results can differ in some cases, molecular resistance prediction must be compared with the results of phenotypic DST later in treatment [5].
Bedaquiline, levofloxacin or moxifloxacin, and linezolid (WHO group A) are the most effective drugs in MDR-TB therapy according to a retrospective analysis of individual data from more than 12,000 patients [11]. There is also a significant treatment benefit for the use of clofazimine and cycloserine (WHO group B) [11]. If there is no indication suggesting the ineffectiveness or intolerance of a drug for MDR-/RR-TB treatment, the initial treatment regimen should consist of all three WHO group A drugs bedaquiline, levofloxacin or moxifloxacin, linezolid and at least one of the two WHO group B drugs clofazimine and/or terizidone until further information is obtained from genotypic or phenotypic resistance testing (Table 2) [12]. If the MDR-/RR-TB treatment regimen cannot be composed of WHO groups A and B, WHO group C drugs should be added according to the results of DST. The treatment regimen should always consist of at least 4 effective substances (Table 2).
Depending on the severity of disease, the spectrum of antibiotic resistance, and concomitant diseases, an MDR-/RR-TB treatment duration shorter than the generally recommended 18 months can be successful in individual cases. Biomarkers for an individualized duration of treatment are currently being clinically tested. However, they have not yet been sufficiently validated for a general recommendation [13]. Treatment should only be shortened after discussing the individual case with a specialized TB treatment center.
Fixed-Dose MDR-TB Treatment for 9–12 Months according to WHO
Recommendation 3: after excluding contraindications, individual patients with MDR-TB can be offered treatment for 9–12 months with the oral, non-modifiable drug combination of bedaquiline, levofloxacin or moxifloxacin, protionamide (can be replaced by linezolid 600 mg/d), ethambutol, pyrazinamide, high-dose isoniazid and clofazimine [4, 17] (Box 2).
In Europe, the WHO-recommended fixed-dose MDR-TB treatment regimen for 9–12 months is only suitable for a small number of patients as a high proportion of MDR-TB cases have additional drug resistance [18‒21]. In the German-speaking countries, this WHO treatment can be started in rare, individual cases after excluding all contraindications (Box 2). In the event of complications that make a change in treatment necessary, the patient should be switched to an individualized MDR-/RR-TB treatment.
Treatment for Drug Resistance or Intolerance to Rifampicin with Proven Susceptibility to Isoniazid and Moxifloxacin
In case of rifampicin resistance or intolerance with proven susceptibility to isoniazid and moxifloxacin, the guideline group recommends treatment with BPaLM for at least 6 months in line with the MDR-TB treatment recommended in this amendment (recommendation 1), adhering to the requirements listed in Box 1.
Treatment for Pre-XDR-TB or Drug Intolerance to at Least Rifampicin and Levofloxacin or Moxifloxacin
Recommendation 4A: pre-XDR-TB treatment should be individualized based on the results of DST and should consist of at least 4 drugs with proven susceptibility given for at least 18 months.
Recommendation 4B: if the requirements listed in Box 1 are met, a shortened treatment for 6 months with the fixed and non-modifiable drug combination BPaL can be offered to patients with pre-XDR-TB (Table 1).
Individualized pre-XDR-TB treatment should be started based on the results of molecular resistance prediction tests. The molecular resistance prediction must be compared with the results of phenotypic DST later in treatment. The same principles described in this amendment for the individualized treatment of MDR-/RR-TB apply here (see recommendation 2). At least 4 drugs from WHO groups A–C (Table 2) with proven susceptibility should be used for at least 18 months.
The drug combination BPaL is recommended by the WHO as the first option for treatment of pre-XDR-TB [4]. Based on the available data on efficacy, pre-XDR-TB treatment with only 3 drugs is possible with this drug combination [1‒3]. The guideline group controversially discussed whether a regimen with 3 drugs given for 6–9 months can be considered sufficient for pre-XDR-TB, especially in patients with extensive or severe disease (e.g., with initially high sputum smear grade or presence of lung cavities [10]). Most authors preferred individualized treatment for at least 18 months for pre-XDR-TB cases. Nevertheless, a shortened treatment with BPaL for 6 months can be used in Germany, Switzerland, and Austria if managed by or in close cooperation with a specialized TB treatment center as well as in accordance with the other requirements listed in Box 1.
When using BPaL, it may be necessary to extend treatment to 9 months or to switch to 18 months of individualized treatment after clinical assessment. An indicator for a necessary treatment extension is the lack of conversion or a reversion of sputum cultures between month 4 and 6 of treatment [4]. If treatment is interrupted for more than 14 consecutive days or for more than 1 month cumulatively, a restart of BPaL or change to an individualized treatment must be discussed with a specialized TB treatment center. In the event of complications or side effects leading to the permanent discontinuation of BPaL, treatment should be changed to an individually composed regimen for 18 months.
Treatment for XDR-TB or Drug Intolerance to at Least Rifampicin and Levofloxacin or Moxifloxacin and Bedaquiline and/or Linezolid
Due to the widespread use of bedaquiline worldwide without sufficient availability of DST [22], increasing resistance to this important drug is to be expected. If drug resistance or intolerance to bedaquiline or linezolid becomes apparent, treatment should be managed in a specialized TB treatment center and the regimen should be tailored individually based on all available resistance data.
Discussion
Important new treatment options have been recommended by the WHO [4] and their implementation in Austria, Germany, and Switzerland is now supported by this guideline amendment. BPaLM and BPaL offer a shortened 6–9-month treatment for MDR-/RR- and pre-XDR-TB, respectively, with better treatment results and tolerability compared to the MDR-TB regimens recommended before. However, DSTs for all recommended drugs of this combination are not available in most European countries [22]. In Austria, Germany, and Switzerland, only specialized laboratories can offer DSTs and should be consulted as a prerequisite for using BPaLM.
The high costs of bedaquiline and pretomanid and other barriers jeopardize availability and implementation of the BPALM regimen even in high-income countries [23, 24]. Most MDR-/RR-TB patients in Germany have a migratory background and live under circumstances that complicate treatment initiation in an outpatient setting [5]. Consequently, treatment is started in hospitals in most cases. In the German health care system, drug costs in hospitals are included in a flat rate per case paid by the health insurances according to the diagnosis-related groups-reimbursement system. MDR-TB drug costs alone exceed these flat rates, especially during the first 2 weeks of a BPaLM regimen, when a loading dose of bedaquiline is necessary for most patients. However, patient education and intensive psychosocial support are essential at the start of MDR-/RR-TB treatment and need additional resources [5]. Under these conditions, high drug costs represent a barrier to the implementation of the BPaLM regimen in the inpatient setting.
Pretomanid is not licensed in Germany and needs to be imported. The applicable EMA license for pretomanid is based on the outdated trial results, limiting its indications to complicated MDR-TB cases [25]. The indications for BPaLM recommended by WHO [4] and by this guideline amendment are not included in the EMA license. For outpatient treatment in Germany, it will depend on the responsible health insurance company, if they cover the costs for a treatment indication outside the EMA license. Additionally, an important number of MDR-/RR-TB patients do not have a health insurance coverage and communities have to take over the treatment costs.
Conclusion
The latest WHO recommendations on the use of BPaLM and BPaL for MDR-/RR- and pre-XDR-TB, respectively, were adopted to the health care systems of Austria, Germany, and Switzerland with a consensus-based amendment to the recent TB treatment guidelines [5]. Country-specific barriers for the implementation of BPaLM, including the availability of DSTs as well as the availability and costs of MDR-TB drugs, were addressed in this amendment, resulting in a set of requirements (Box 1) that have to be met when choosing the BPaLM or BPaL regimen.
Acknowledgment
Thanks to Vanessa Igbokwe for her important work on the medical translation and submission of the manuscript.
Statement of Ethics
No individual patient data were analyzed for this amendment which therefore did not require the approval of an Ethic’s Comittee.
Conflict of Interest Statement
All potential conflicts of interest (COIs) were assessed by the guideline group and published on the AWMF Website [7].
Funding Sources
This amendment was not supported by any sponsor or funder.
Author Contributions
R.O.-K. drafted the manuscript with support from all authors. B.H. and R.O.-K. organized the guideline development process. All authors reviewed the existing evidence relevant for this guideline and discussed the results and they took part in the development of the manuscript. All authors except J.H. and F.M. (experts without voting rights) took part in the consensus-finding process according to the rules of AWMF. T.S. and T.B. supervised the guideline development process, consensus finding, and manuscript writing.
Additional Information
Amendment to the 2022 consensus-based guideline: Tuberculosis in adulthood by the German Central Committee against Tuberculosis (DZK) on behalf of the German Respiratory Society (DGP) dated September 19, 2023.
Data Availability Statement
Data sharing is not applicable to this article as no new data were created or analyzed for this amendment.