Key Points
Summary of Good Practices
Treatment
Design and created by Guideline Central in participation with the American Thoracic Society, Centers for Disease Control and Prevention, European Respiratory Society, and Infectious Diseases Society of America.
Treatment of Drug-Resistant Tuberculosis
American Thoracic Society
Centers for Disease Control and Prevention
European Respiratory Society
Infectious Diseases Society of America
Publication Date: January 28, 2020
Key Points
- In this pocket guide, the guideline committee provides new recommendations for treatment of multiple drug-resistant tuberculosis (MDR-TB) and for treatment of isoniazid-resistant-TB.
- MDR-TB is defined specifically as resistance to at least isoniazid and rifampin, the two most important first-line drugs.
- The guideline is intended for settings in which treatment is individualized and where mycobacterial cultures, molecular (genotypic) and culture-based (phenotypic) drug susceptibility tests (DSTs), and radiographic facilities are available.
- Treatment success was most likely with regimens for MDR-TB containing 5 effective drugs in the intensive phase. Mortality was also significantly reduced for those taking 5 or 6 effective drugs.
Definitions
| MDR-TB | Resistance to at least isoniazid and rifampin |
| pre-XDR-TB | A subset of MDR-TB with additional resistance to one but not both fluoroquinolone and a second-line injectable agent |
| Extensively drug-resistant tuberculosis (XDR-TB) | A subset of MDR-TB with additional resistance to both a fluoroquinolone and a second-line injectable agent |
Summary of Good Practices
For patients being evaluated and treated for any form of drug-resistant TB, the following 6 ungraded good practice statements are emphasized since the writing committee had high confidence in their net benefit:
- Consultation should be requested with a TB expert when there is suspicion of or confirmation of DR-TB. In the United States, TB experts can be found through CDC-supported TB Centers of Excellence for Training, Education, and Medical Consultation (http://www.cdc.gov/tb/education/rtmc/default.htm ), through local health department TB control programs (https://www.cdc.gov/tb/links/tboffices.htm ), and through international MDR-TB expert groups such as the Global TB Network.
- Molecular DSTs should be obtained for rapid detection of mutations associated with resistance. When rifampin resistance is detected, additional DST should be performed immediately for first-line drugs, fluoroquinolones, and aminoglycosides. Resistance to fluoroquinolones should be excluded whenever isoniazid resistance is found.
- Regimens should include only drugs to which the patient’s M. tuberculosis isolate has documented or high likelihood of susceptibility (hereafter defined as effective). Drugs known to be ineffective based on in vitro growth to based or molecular resistance should NOT be used. This recommendation applies to all drugs and treatment regimens discussed in this practice guideline, unless reliable methods of testing susceptibility for a drug have yet to be developed.
- Treatment response should be monitored clinically, radiographically and bacteriologically, with cultures obtained at least monthly for pulmonary TB. When cultures remain positive after three months of treatment, susceptibility tests for drugs should be repeated. Weight and other measures of clinical response should be recorded monthly.
- Patients should be educated and asked about adverse effects at each visit. Adverse effects should be investigated and ameliorated.
- Patient-centered case management helps patients understand their diagnoses, understand and participate in their treatment, and discuss potential barriers to treatment. Patient-centered strategies and interventions should be used to minimize barriers to treatment.
Treatment
For the selection of an effective MDR-TB treatment regimen and duration of MDR-TB treatment:
We suggest using at least five drugs in the intensive phase of treatment and four drugs in the continuation phase of treatment. ( C, VL )
We suggest an intensive-phase duration of treatment of between 5 and 7 months after culture conversion. ( C, VL )
We suggest a total treatment duration of between 15 and 21 months after culture conversion. ( C, VL )
In patients with pre-extensively drug-resistant TB (pre-XDR-TB) and extensively drug-resistant TB) and extensively drug-resistant TB (XDR-TB), which are both subsets of MDR-TB, we suggest a total treatment duration of between 15 and 24 months after culture conversion. ( C, VL )
For the selection of oral drugs for MDR-TB treatment (in order of strength of recommendation):
We recommend including a later-generation fluoroquinolone (levofloxacin or moxifloxacin). ( S, L )
We recommend including bedaquiline. ( S, VL )
We suggest including linezolid. ( C, VL )
We suggest including clofazimine. ( C, VL )
We suggest including cycloserine. ( C, VL )
We suggest including ethambutol only when other more effective drugs cannot be assembled to achieve a total of five drugs in the regimen. ( C, VL )
We suggest including pyrazinamide in a regimen for treatment of patients with MDR-TB or with isoniazid-resistant TB, when the M. tuberculosis isolate has not been found resistant to pyrazinamide. ( C, VL )
The guideline panel was unable to make a clinical recommendation for or against delamanid because of the absence of data in the PS-matched IPDMA conducted for this practice guideline.
Notes: We make a research recommendation for the conduct of randomized clinical trials and cohort studies evaluating the efficacy, safety, and tolerability of delamanid in combination with other oral agents.
Until additional data are available, the guideline panel concurs with the conditional recommendation of the 2019 WHO Consolidated Guidelines on Drug-Resistant Tuberculosis Treatment that delamanid may be included in the treatment of patients with MDR/rifampin-resistant (RR)-TB aged ≥3 on longer regimens.
For selected oral drugs previously included in regimens for the treatment of MDR-TB:
We recommend NOT including amoxicillin-clavulanate, with the exception of when the patient is receiving a carbapenem wherein the inclusion of clavulanate is necessary. ( S, VL )
We recommend NOT including the macrolides azithromycin and clarithromycin. ( S, VL )
We suggest NOT including ethionamide/prothionamide if more effective drugs are available to construct a regimen with at least 5 effective drugs. ( C, VL )
We suggest NOT including p-aminosalicylic acid in a regimen if more effective drugs are available to construct a regimen with at least 5 effective drugs. ( C, VL )
For the selection of drugs administered through injection when needed to compose an effective treatment regimen for MDR-TB:
We suggest including amikacin or streptomycin when susceptibility to these drugs is confirmed. ( C, VL )
We suggest including a carbapenem (always to be used with amoxicillin-clavulanic acid). ( C, VL )
We suggest NOT including kanamycin or capreomycin. ( C, VL )
For the use of the WHO-recommended standardized shorter-course 9–12 month regimen for MDR-TB:
The shorter-course regimen is standardized with the use of kanamycin (which the committee recommends against using), and includes drugs for which there is documented or high likelihood of resistance (e.g., isoniazid, ethionamide, pyrazinamide).
Notes: Although the STREAM (Standard Treatment Regimen of Anti-Tuberculosis Drugs for Patients with MDR-TB) Stage 1 randomized trial found the shorter-course regimen to be noninferior to longer injectable containing regimens with respect to the primary efficacy outcome, the guideline committee cannot make a recommendation either for or against this standardized shorter-course regimen, compared with longer individualized all-oral regimens that can be composed in accordance with the recommendations in this practice guideline.
The guideline committee makes a research recommendation for the conduct of randomized clinical trials evaluating the efficacy, safety, and tolerability of modified shorter-course regimens that include newer oral agents, exclude injectables, and include drugs for which susceptibility is documented or highly likely.
For the role of surgery in the treatment of MDR-TB:
We suggest elective partial lung resection (e.g., lobectomy or wedge resection), rather than medical therapy alone, for adults with MDR-TB receiving antimicrobial-based therapy. ( C, VL )
The writing committee believes this option would be beneficial for patients for whom clinical judgement, supported by bacteriological and radiographic data, suggest a strong risk of treatment failure or relapse with medical therapy alone.
We suggest medical therapy alone, rather than including elective total lung resection (pneumonectomy), for adults with MDR-TB receiving antimicrobial therapy. ( C, VL )
For the treatment of isoniazid-resistant TB:
We suggest adding a later-generation fluoroquinolone to a 6-month regimen of daily rifampin, ethambutol, and pyrazinamide for patients with isoniazid-resistant TB. ( C, VL )
In patients with isoniazid-resistant TB treated with a daily regimen of a later-generation fluoroquinolone, rifampin, ethambutol, and pyrazinamide, we suggest that the duration of pyrazinamide can be shortened to 2 months in selected situations (i.e., noncavitary and lower burden disease or toxicity from pyrazinamide). ( C, VL )
For the management of contacts to patients with MDR-TB:
We suggest offering treatment for latent TB infection (LTBI) for contacts to patients with MDR-TB versus following with observation alone. ( C, VL )
We suggest 6–12 months of treatment with a later-generation fluoroquinolone alone or with a second drug, on the basis of drug susceptibility of the source-case M. tuberculosis isolate. On the basis of evidence of increased toxicity, adverse events, and discontinuations, pyrazinamide should not be routinely used as the second drug.
Table 1. Summary of Recommendations on Drugs for Use in a Treatment Regimen for Patients with MDR-TB, Including Strength of Recommendation, Certainty in the Evidence and Relative Effects on Death and Treatment Success
| Drug/Drug Class | Recommendation | Certainty in the evidence | Relative (95% CI) Death | Relative (95% CI) Successa | |
|---|---|---|---|---|---|
| FOR | AGAINST | ||||
| Bedaquiline | Strong | Very Low | aOR 0.4 (0.3–0.5) | aOR 2.0 (1.4–2.9) | |
| Fluoroquinolone: Moxifloxacin | Strong | Very Low | aOR 0.5 (0.4–0.6) | aOR 3.8 (2.8–5.2) | |
| Fluoroquinolone: Levofloxacin | Strong | Very Low | aOR 0.6 (0.5–0.7) | aOR 4.2 (3.3–5.4) | |
| Linezolid | Conditional | Very Low | aOR 0.3 (0.2–0.3) | aOR 3.4 (2.6–4.5) | |
| Clofazimine | Conditional | Very Low | aOR 0.8 (0.6–1.0) | aOR 1.5 (1.1–2.1) | |
| Cycloserine | Conditional | Very Low | aOR 0.6 (0.5–0.6) | aOR 1.5 (1.4–1.7) | |
| Injectables: Amikacin | Conditional | Very Low | aOR 1.0 (0.8–1.2) | aOR 2.0 (1.5–2.6) | |
| Injectables: Streptomycin | Conditional | Very Low | aOR 0.8 (0.6–1.1) | aOR 1.5 (1.1–2.1) | |
| Ethambutol | Conditional | Very Low | aOR 1.0 (0.9–1.2) | aOR 0.9 (0.7–1.1) | |
| Pyrazinamide | Conditional | Very Low | aOR 0.7 (0.6–0.8) | aOR 0.7 (0.5–0.9) | |
| Carbapenems w/ clavulanic acid | Conditional | Very Low | aOR 1.0 (0.5–1.7) | aOR 4.0 (1.7–9.1) | |
| Delamanid | Concur with WHO conditional recommendation | ||||
| Ethionamide Prothionamide | Conditional | Very Low | aOR 0.9 (0.8–1.0) | aOR 0.8 (0.7–0.9) | |
| Injectables: Kanamycin | Conditional | Very Low | aOR 1.1 (0.9–1.2) | aOR 0.5 (0.4–0.6) | |
| P-Aminosalicylic Acid | Conditional | Very Low | aOR 1.2 (1.1–1.4) | aOR 0.8 (0.7–1.0) | |
| Injectables: Capreomycin | Conditional | Very Low | aOR 1.4 (1.1–1.7) | aOR 0.8 (0.6–1.1) | |
| Macrolides: Azithromycin Clarithromycin | Strong | Very Low | aOR 1.6 (1.2–2.0) | aOR 0.6 (0.5–0.8) | |
| Amoxicillin-clavulanate | Strong | Very Low | aOR 1.7 (1.3–2.1) | aOR 0.6 (0.5–0.8) | |
a Success defined as end of treatment cure or treatment completion
Table 2a. Clinical Strategy to Build an Individualized Treatment Regimen for MDR-TB
| |
|---|---|
| STEP 1 Choose one later-generation fluoroquinolone |
|
| STEP 2 Choose both of these prioritized drugs |
|
| STEP 3 Choose both of these prioritized drugs |
|
| STEP 4 If a regimen cannot be assembled with five effective oral drugs, and the isolate is susceptible, use one of these injectable agentsa |
|
| STEP 5 If needed or if oral agents preferred over injectable agents in STEP 4, use the following drugsb |
|
| STEP 6 If limited options and cannot assemble a regimen of five effective drugs, consider use of the following drugs |
|
| The following drugs are no longer recommended for inclusion in MDR-TB regimens: |
|
a Amikacin and streptomycin should be used only when the patient's isolate is susceptible to these drugs. Because of their toxicity, these drugs should be reserved for when more effective or less toxic therapies cannot be assembled to achieve a total of five effective drugs.
b Patient preferences in terms of the harms and benefits associated with injectables (the use of which is no longer obligatory), the capacity to appropriately monitor for significant adverse effects, consideration of drug-drug interactions and patient comor-bidities should be considered in selecting Step 5 agents over injectables. Ethambutol and pyrazinamide had mixed/marginal performance on outcomes assessed in our PS-matched IPDMA. However, some experts may prefer these drugs over injectable agents to build regimen of at least 5 effective oral drugs. Use pyrazinamide and ethambutol only when the isolate is documented as susceptible.
c Data on dosing and safety of delamanid are available in children ≥3 years of age.
d Mutations in the inhA region of the M. tuberculosis genome can confer resistance to ethionamide/ prothionamide as well as to INH. In this situation, ethionamide/prothionamide may not be a good choice unless the isolate is shown to be susceptible with in vitro testing.
e Divided daily intravenous dosing limits feasibility. Optimal duration of use not defined.
f Fair/poor tolerability and low performance. Adverse effects reported to be less common in children.
g Data not reviewed in our PS-matched IPDMA, but high-dose isoniazid can be considered despite low-level isoniazid resistance but not with high level INH resistance.
b Patient preferences in terms of the harms and benefits associated with injectables (the use of which is no longer obligatory), the capacity to appropriately monitor for significant adverse effects, consideration of drug-drug interactions and patient comor-bidities should be considered in selecting Step 5 agents over injectables. Ethambutol and pyrazinamide had mixed/marginal performance on outcomes assessed in our PS-matched IPDMA. However, some experts may prefer these drugs over injectable agents to build regimen of at least 5 effective oral drugs. Use pyrazinamide and ethambutol only when the isolate is documented as susceptible.
c Data on dosing and safety of delamanid are available in children ≥3 years of age.
d Mutations in the inhA region of the M. tuberculosis genome can confer resistance to ethionamide/ prothionamide as well as to INH. In this situation, ethionamide/prothionamide may not be a good choice unless the isolate is shown to be susceptible with in vitro testing.
e Divided daily intravenous dosing limits feasibility. Optimal duration of use not defined.
f Fair/poor tolerability and low performance. Adverse effects reported to be less common in children.
g Data not reviewed in our PS-matched IPDMA, but high-dose isoniazid can be considered despite low-level isoniazid resistance but not with high level INH resistance.
Table 2b. Doses of Drugs for Treatment of Adults and Children with MDR-TB
| STEP | Drug | Route of Administration | Adults |
|---|---|---|---|
| 1 | Levofloxacin | PO / IV | 750–1000 mg dailyb |
| Moxifloxacin | PO / IV | 400–(600–800 mg) dailyc | |
| 2 | Bedaquiline | PO | 400 mg daily × 14 days then 200 mg 3×/week |
| Linezolid | PO / IV | 600 mg daily | |
| 3 | Clofazimine | PO | 100 mg daily |
| Cycloserine/terizidone | PO | 250–750 mg dailyd to achieve serum 20–35 mg/L in plasmae | |
| 4 | Amikacin | IV / IM | 15 mg/kg daily |
| Streptomycin | IV / IM | 15 mg/kg daily. Some clinicians prefer 25 mg/kg 3 × weekly. | |
| 5 | Delamanid | PO | 100 mg twice daily |
| Ethambutol | PO / IV | Low dose (companion drug): 15 mg/kg daily High dose (bacteriostatic drug): 25–30 mg/kg daily | |
| Pyrazinamide | PO | 25–40 mg/kg daily | |
| 6 | Ethionamide | PO | 15–20 mg/kg total (usually 250–500 mg once or twice daily)g |
| Prothionamide | PO | 15–20 mg/kg total (usually 250–500 mg once or twice daily) | |
| Imipenem-cilastatin | IV | 1000 mg 3–4× a day | |
| Meropenem | IV | 1000 mg 3× a dayh | |
| Clavulanate (component of amoxicillin- clavulanate) for co-administration with carbapenems (imipenem-cilastatin and meropenem) | PO / IV | 250 mg 3× a day | |
| p-aminosalicylic acid | PO / IV | 4 g 2–3× a dayi | |
| High-dose isoniazidk | PO / IV | 15 mg/kg daily |
| STEP | Children | Reduced Renal Functiona |
|---|---|---|
| 1 | 15–20 mg/kg/day once dailyb | 3×/wk |
| 10–15 mg/kg/day once daily | No change needed | |
| 2 | ≥12 years and ≥30 kg: adult dose Studies ongoing in lower age groups and weights. Based on expert opinion, for children >6 years and weight 15–30 kg half the adult dose can be used (200/day × 2 weeks then 100 mg M/W/F for 22–24 weeks) | No change needed |
| ≥12 years: 10 mg/kg once daily (300 or 600 mg) <12 years: Based on modelled pharmacokinetic data for lower weight bands: 5–9 kg: 15 mg/kg once daily 10–23 kg: 12 mg/kg once daily >23 kg: 10 mg/kg once daily | No change needed | |
| 3 | 2–5 mg/kg/day | No change needed |
| 15–20 mg/kg/day | Start with 250 mg daily and verify with TDM in setting of renal disease | |
| 4 | 15–20 mg/kg/day | Patients with decreased renal function may require the 15 mg/kg dose to be given only 2–3 times weekly to allow for drug clearance. |
| 15–20 mg/kg daily or 25–30 mg/kg twice-weeklyf | Patients with decreased renal function may require the 15 mg/kg dose to be given only 2–3 times weekly to allow for drug clearance. | |
| 5 | ≥ 35 kg: adult dose ≥ 6 years and 20–34 kg: 50 mg 2× a day >3–5 years and 10–20 kg: 25 mg 2× a day Lower age/weight: studies ongoing | Mild-moderate renal insufficiency – no change. Severe insufficiency – limited data, use with caution |
| 20–25 mg/kg/day | 3×/wk | |
| 30–40 mg/kg/day | 3×/wk | |
| 6 | 15–20 mg/kg total (divided 1–2 times daily) | No change needed |
| 15–20 mg/kg total (divided 1–2 times daily) | No change needed | |
| (imipenem component) 15–25 mg/kg/dose 4× a day | May reduce frequency | |
| 20–40 mg/kg/dose 3× a day | May reduce frequency | |
| 25 mg/kg/dose of amoxicillin component 3 ×/day | May reduce frequency to match carbapenem | |
| 200–300 mg/kg/day in two divided dosesj | No change needed | |
| 15–20 mg/kg/day | No change needed |
a Dosages may not apply to patients with severely decreased kidney function, including in the setting of dialysis, for which consultation with a nephrologist is advised.
b Levofloxacin doses of up to 1,250 mg have been used safely when needed to achieve therapeutic concentrations. A recent population pharmacokinetic study in South African children found that higher levofloxacin doses from 18 mg/kg/d for younger children, up to 40 mg/kg/d for older children, may be required to achieve adult-equivalent exposures.
c Higher moxifloxacin doses have been used safely when the isolate is resistant to ofloxacin and the minimum inhibitory concentration for levofloxacin or moxifloxacin suggests higher doses may overcome resistance. Higher doses also are used in cases of malabsorption.
d Cycloserine doses can be divided if needed (typically twice daily). Doses >750 mg are difficult for many patients to tolerate.
e Cycloserine dose may be lowered if serum concentrations exceed 35 mg/ml, even if patient is not experiencing toxicity, to prevent central nervous system toxicity.
f Modified from adult intermittent dose of 25 mg/kg, and accounting for larger total body water content and faster clearance of injectable drugs in most children. Dosing can be guided by serum concentrations.
g Ethionamide can be given at bedtime or with a meal to reduce nausea. Experienced clinicians suggest starting with 250 mg once daily and gradually increasing the dose over 1 week. Serum concentrations may be useful in determining the appropriate dose. Few patients tolerate 500 mg twice daily.
h Studies are ongoing evaluating meropenem at higher doses (ClinicalTrials.gov identifiers: NCT03174184 and NCT02349841).
i Some experts prescribe p-aminosalicylic acid at 6 g, and up to12 g, administered once daily.
j For children, some experts prescribe p-aminosalicylic acid at 200 mg/kg administered once daily.
k Isoniazid is tested at two concentrations. Some experts use these results (or resistance conferred through mutations in inhA) to select a higher dose when it tests resistant at the lower concentration and susceptible at the higher concentration. The higher dose may achieve in vivo concentrations sufficiently high to overcome low-level resistance.
b Levofloxacin doses of up to 1,250 mg have been used safely when needed to achieve therapeutic concentrations. A recent population pharmacokinetic study in South African children found that higher levofloxacin doses from 18 mg/kg/d for younger children, up to 40 mg/kg/d for older children, may be required to achieve adult-equivalent exposures.
c Higher moxifloxacin doses have been used safely when the isolate is resistant to ofloxacin and the minimum inhibitory concentration for levofloxacin or moxifloxacin suggests higher doses may overcome resistance. Higher doses also are used in cases of malabsorption.
d Cycloserine doses can be divided if needed (typically twice daily). Doses >750 mg are difficult for many patients to tolerate.
e Cycloserine dose may be lowered if serum concentrations exceed 35 mg/ml, even if patient is not experiencing toxicity, to prevent central nervous system toxicity.
f Modified from adult intermittent dose of 25 mg/kg, and accounting for larger total body water content and faster clearance of injectable drugs in most children. Dosing can be guided by serum concentrations.
g Ethionamide can be given at bedtime or with a meal to reduce nausea. Experienced clinicians suggest starting with 250 mg once daily and gradually increasing the dose over 1 week. Serum concentrations may be useful in determining the appropriate dose. Few patients tolerate 500 mg twice daily.
h Studies are ongoing evaluating meropenem at higher doses (ClinicalTrials.gov identifiers: NCT03174184 and NCT02349841).
i Some experts prescribe p-aminosalicylic acid at 6 g, and up to12 g, administered once daily.
j For children, some experts prescribe p-aminosalicylic acid at 200 mg/kg administered once daily.
k Isoniazid is tested at two concentrations. Some experts use these results (or resistance conferred through mutations in inhA) to select a higher dose when it tests resistant at the lower concentration and susceptible at the higher concentration. The higher dose may achieve in vivo concentrations sufficiently high to overcome low-level resistance.
Table 3. Select Antiretroviral and Non–rifamycin-based Anti-tuberculosis Drug Overlapping Toxicities and Potential Adverse Drug-drug Interactions
| Potential overlapping toxicities and drug-drug interactions | Antiretroviral drugs | Non-Rifamycin TB drugs |
|---|---|---|
| Arrhythmias, QT-interval prolongation | Lopinavir/ritonavir, efavirenz Note PR interval prolongationa with atazanavir, lopinavir/ritonavir | Fluoroquinolones,b bedaquiline, delamanid, clofazimine |
| Hepatic cytochrome P450 enzyme system metabolism | Induce CYP P450 metabolism: efavirenz, etravirine and nevirapine Impede CYP P450 metabolism: Protease inhibitors, cobicistat | Bedaquiline, delamanid |
| Nephrotoxicity | Tenofovirc, atazanavir Isolated creatinine elevation:d cobicistat, dolutegravir | Aminoglycosides, capreomycin |
| Mental health changes (depression, psychosis, dizziness, etc.) | Efavirenz, rilpivirine; dolutegravir, elvitegravir, raltegravir | Cycloserine, isoniazid, ethionamide, fluoroquinolonesb |
| Peripheral neuropathy | Stavudine, zidovudine | Aminoglycosides, capreomycin, linezolid, isoniazid, ethionamide, cycloserine, fluoroquinolonesb |
| Hepatoxicity | Lactic acidosis with hepatic steatosis higher risk with stavudine, zidovudine; protease inhibitors; nevirapine (higher risk in patients with elevated CD4 cell counts); less common with efavirenz, etravirine and rilpivirine; maraviroc Indirect hyperbilirubinemia:e atazanavir | Isoniazid, pyrazinamide, ethionamide, p-aminosalicylic acid, clofazimine |
| Skin rash | Nevirapine (higher risk in patients with elevated CD4 cell counts), efavirenz, etravirine, rilpivirine; Any protease inhibitor (esp. those containing sulfonamide moiety: e.g., darunavir); abacavir (hypersensitive reaction a risk in patient who are HLA-B5701 positive); raltegravir | All TB drugs Note skin pigmentation with clofazimine use Thioacetazone should be avoided in people with HIV, because of an elevated risk of a severe adverse skin reaction. |
| Dysglycemia | Lopinavir/ritonavir, ritonavir, stavudine, zidovudine | Ethionamide, p-aminosalicylic acid, fluoroquinolones, linezolid |
| Myelosuppression/ cytopenias | Zidovudine | Linezolid |
| Lactic acidosis | Stavudine, zidovudine |
Note: Saquinavir, indinavir, fosamprenavir, tipranavir, and didanosine are older antiretroviral drugs that are rarely used in the United States. They do have many of the adverse interactions listed above with select TB drugs, and clinicians considering the use of these agents should therefore consult with an expert.
a Fluoroquinolones include ciprofloxacin, ofloxacin, levofloxacin, gatifloxacin and moxifloxacin
b Use with caution in patients with underlying cardiac dysrhythmia
c Tenofovir alafenamide (TAF) – a prodrug of tenofovir and FDA-approved in 2015. It is associated with decreased incidence of osteoporosis and nephrotoxicity compared to tenofovir disoproxil fumarate (TDF) through achieving higher intra-cellular drug concentrations with a lower dose administered
d Increases in serum creatinine via decrease renal tubular creatinine excretion are commonly seen with cobicistat and dolute-gravir usage. This is not a toxicity.
e Indirect hyperbilirubinemia is expected with atazanavir and indinavir. This is not a toxicity.
Grading of Recommendations, Assessment, Development, and Evaluation (GRADE)-Based Recommendations
| Implications for: | Strong Recommendation (S) | Conditional Recommendation (C) |
|---|---|---|
| Patients | Most individuals in this situation would want the recommended course of action, and only a small proportion would not. | The majority of individuals in this situation would want the suggested course of action, but many would not. |
| Clinicians | Most individuals should receive the intervention. Adherence to this recommendation according to the guideline could be used as a quality criterion or performance indicator. Formal decision aids are not likely to be needed to help individuals make decisions consistent with their values and preferences. | Recognize that different choices will be appropriate for individual patients and that you must help each patient arrive at a management decision consistent with his or her values and preferences. Decision aids may be useful in helping individuals to make decisions consistent with their values and preferences. |
| Policy | The recommendation can be adopted as policy in most situations. | Policymaking will require substantial debate and involvement of various stakeholders. |
| Certainty in the Evidence | |||
|---|---|---|---|
| High | H | Low | L |
| Moderate | M | Very Low | VL |
Source: Grading of Recommendations Assessment, Development and Evaluation Working Group (Schunemann HJ et al. Am J Respir Crit Care Med. 2006;174:605-14. Guyatt GH et al. BMJ 2008;336:924-6).
Abbreviations
- ATS
- American Thoracic Society
- CDC
- Centers for Disease Control and Prevention
- DR-TB
- Drug-resistant TB
- DST
- drug susceptibility test
- ERS
- European Respiratory Society
- IDSA
- Infectious Diseases Society of America
- IM
- intramuscular
- IPDMA
- Individual Patient/Participant Data Meta-Analysis
- IV
- intravenous
- MDR-TB
- multi-drug resistant tuberculosis
- PO
- oral
- pre-XDR-TB
- pre-extensively drug-resistant TB
- TB
- tuberculosis
- TDM
- therapeutic drug monitoring
- WHO
- World Health Organization
- XDR-TB
- extensively drug-resistant TB
Source Citation
Treatment of Drug-Resistant Tuberculosis. An Official ATS/CDC/ERS/IDSA Clinical Practice Guideline. Am J Respir Crit Care Med 2019;200:e93–e142
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