Provisional CDC Guidance for the Use of Pretomanid as part of a Regimen [Bedaquiline, Pretomanid, and Linezolid (BPaL)] to Treat Drug-Resistant Tuberculosis Disease

Tuberculosis (TB) is caused by bacteria of the Mycobacterium tuberculosis complex, most commonly M. tuberculosis (MTB). TB infection is usually transmitted from one person to another by airborne droplet nuclei containing the bacteria. Multidrug-resistant tuberculosis (MDR TB), caused by MTB that is resistant to at least isoniazid (INH) and rifampin (RIF), has traditionally required longer, more intensive treatment than drug-susceptible disease, including 15–21 months of treatment after culture conversion with 4–7 drugs that are less effective, more toxic, and more costly than a standard first-line regimen.[1]. Rifamycin-monoresistant (RMR) TB, (i.e., in the absence of INH resistance), although rare, has also been notably challenging to treat and associated with poor outcomes [2]. Extensively drug-resistant tuberculosis (XDR TB) and pre-extensively drug-resistant tuberculosis (pre-XDR TB) are subsets of MDR TB with additional resistance to the most effective antituberculosis medications.

In the United States, XDR TB is currently defined as disease caused by MTB resistant to INH, RIF, at least one fluoroquinolone, and at least one injectable medication (i.e., amikacin, capreomycin, or kanamycin) used in the treatment of TB; pre-XDR TB is currently defined as disease caused by MTB resistant to INH, RIF, and at least one of the additional groups (i.e., fluoroquinolones or injectables). Pre-XDR and XDR TB often require 15–24 months treatment after culture conversion with potentially toxic and costly first- and second-line TB drugs.

Drug-resistant TB remains challenging to cure; even as efficacy of drug regimens has improved, side effects and length of treatment have continued to impact patients negatively. [3,4] During 2014–2018, 524 new cases of MDR TB were reported in the United States and U.S.-affiliated areas (territories and freely associated states), including 443 with resistance to isoniazid and rifampin, 72 with additional resistance to a fluoroquinolone or an injectable (assessed as amikacin, kanamycin, capreomycin), and 9 with additional resistance to both a fluoroquinolone and an injectable (CDC, unpublished data, 2021). Of 518 MDR TB patients alive at diagnosis, 63% were reported as completing treatment within 24 months, and 8% died before treatment completion (CDC, unpublished data, 2021).

On August 14, 2019, the Food and Drug Administration (FDA) approved the use of pretomanid, a nitroimidazooxazine, as part of an all-oral combination (with bedaquiline and linezolid (BPaL)) administered by direct observation to adults with a diagnosis of pulmonary extensively drug resistant or treatment intolerant or nonresponsive MDR TB (TI/NR MDR TB), based on limited clinical safety and efficacy data [5]. Pretomanid is a novel bicyclic nitroimidazole with antimycobacterial activity comparable to INH [6]; it was developed by TB Alliance under license from Novartis and is available from Viatris (formerly Mylan). Pretomanid kills actively replicating MTB by inhibiting mycolic acid biosynthesis that is needed for cell wall production and kills nonreplicating MTB by nitric oxide release [7].

Pretomanid use was approved in combination with bedaquiline and linezolid. Bedaquiline is available from Janssen, with a patient assistance program in place (https://www.jjpaf.orgexternal icon) and linezolid is available from multiple manufacturers. In murine models, the 3-drug regimen was found to reduce bacterial counts in the lungs and to be associated with fewer relapses at 2 and 3 months than any 2-drug combination of the respective three drugs.

FDA approves drug products for lawful marketing for specific intended uses based on data that establish safety and efficacy and FDA approves labeling specific to those uses. FDA approved pretomanid under FDA’s Limited Population Pathway for Antibacterial and Antifungal Drugs for development of drugs targeting infections that lack effective therapies [8].

FDA approved pretomanid in the context of BPaL with warnings alerting health-care professionals to an increase in hepatotoxicity, myelosuppression, peripheral and optic neuropathy, prolongation of the QTcF*, reproductive effects, and lactic acidosis observed in studies with the combination regimen. As pretomanid may be in part metabolized by CYP3A4, there is concern that its metabolism may be affected by strong or moderate cytochrome P450 inducers, so co-administration with RIF, efavirenz, or other known CYP3A4 inducers should be avoided. FDA approval of pretomanid was conditional on the completion of additional studies to expand on its pharmacokinetics and safety. In particular, studies will be completed to evaluate potential risk of pretomanid in patients with renal or hepatic impairment, assess carcinogenicity, and understand risk to male fertility.

* The QT interval is a measure of the time between the start of the Q wave and the end of the T wave in the heart’s electrical cycle. A lengthened QT interval is a biomarker for ventricular tachyarrhythmias and a risk factor for sudden death. The QT interval is dependent on the heart rate and may be corrected by calculation to improve the detection of patients at increased risk of ventricular arrhythmia. One correction formula focuses on the QT interval divided by cube-root of RR (QTcF), where RR is the interval from the onset of one QRS complex (the graphical deflections seen on an electrocardiogram [ECG] that correspond to the depolarization of the right and left ventricle with each heartbeat) to the onset of the next QRS complex, measured in milliseconds.

A scientific literature search of peer-reviewed manuscripts and presented abstracts was initially conducted April 2020 (updated October 2021) with support from the CDC library. Due to the limited number of available studies, a formal evidence evaluation framework could not be developed; therefore, this guidance is based on the available evidence and expert opinion.

Data supporting use of BPaL came from the Nix-TB therapeutic trial, a small, single-arm, open-label South African study with specific inclusion and exclusion criteria for a high-mortality condition with limited treatment options that included 62% of patients with XDR TB. The remaining 38% of patients had TI/NR MDR TB [9], i.e., they did not respond to treatment with an available regimen for 6 months or more prior to enrollment or were unable to continue a second-line drug regimen because of drug intolerance. Notably, over 50% of the participants in the Nix-TB study were persons with HIV and the reported 89% favorable outcome was consistent for both HIV-infected and non-HIV-infected participants.

In August 2020, a draft of proposed guidance was provided to seven non-CDC subject matter experts (SMEs) with drug-resistant TB expertise in epidemiology, clinical research, diagnosis, treatment, laboratory testing, and public health programs. Experts provided: 1) individual perspectives on the review; 2) experience with use of various regimens in treating MDR and TI/NR MDR TB; and 3) individual viewpoints on the proposed guidance. The draft guidance was also shared for public comment during the Advisory Council for the Elimination of Tuberculosis meeting on December 11, 2020. Comments were then incorporated into this guidance.

Management decisions in the care of patients with drug-resistant TB may be modified based on what is clinically indicated by unique patient circumstances.

Candidates for the BPaL regimen

General Use

The BPaL regimen was approved for treatment of pulmonary XDR TB and TI/NR MDR TB (including pre-XDR TB). CDC includes patients with pre-XDR TB, defined as TB disease due to infection with MTB resistant to INH, RIF, and either fluoroquinolone or injectable medication, whereas in the Nix-TB trial, this distinction between XDR TB and Pre-XDR TB was not made [9].

In the Nix-TB trial, drug resistance was documented by phenotypic or genotypic tests. In the United States, rapid molecular testing for resistance in patients being evaluated for drug-resistant TB should be obtained with confirmatory sequencing, available at many local or state public health laboratories or through CDC’s Molecular Detection of Drug Resistance (MDDR) service. For more information about MDDR, see CDC’s Laboratory User Guide for U.S. Public Health Laboratories: Molecular Detection of Drug Resistance (MDDR) in Mycobacterium tuberculosis Complex by DNA Sequencing (https://www.cdc.gov/tb/topic/laboratory/mddrusersguide.pdfpdf icon ). To submit a sample for the MDDR service, complete CDC’s MDDR Request Form (https://www.cdc.gov/tb/topic/laboratory/MDDRsubmissionform.pdfpdf icon).

Persons with HIV

The BPaL regimen can be used in patients living with HIV diagnosed with pre-XDR, XDR, or TI/NR MDR TB disease. Although pharmacokinetic data are not available to describe the impact of pretomanid within the BPaL regimen, this drug is metabolized through the CYP3A pathway, suggesting  levels or drug concentrations in blood and tissue may be reduced with use of efavirenz (EFV) [10]. Given known drug interactions with bedaquiline, both efavirenz and cobicistat (COBI) should be avoided in the antiretroviral therapy (ART) regimen for a patient receiving BPaL [11]. Additionally, coadministration with either rifampin or efavirenz significantly decreases pretomanid levels; these agents should not be used together with pretomanid [10, 11]. Therefore, persons with HIV with a CD4+ count >50 cells/μL receiving antiretroviral regimens that do not have known drug-drug interactions with medications in the BPaL regimen are candidates for this regimen.

Pregnant Persons and Children

Pretomanid 200mg within the BPaL regimen does not have an approved indication for use in pregnant persons or children. Both of these patient populations were excluded from enrollment in the Nix-TB study [9]. Providers experienced in treating patients with XDR, pre-XDR, or TI/NR MDR TB need to weigh the risk and benefit of treating pregnant patients and children with BPaL when a safe and effective treatment regimen cannot otherwise be provided.

Other Populations

The following TB patients were excluded from the Nix-TB trial:

• those with baseline peripheral neuropathy of grade 3 or 4
• patients who had already received over 2 weeks of linezolid or bedaquiline
• patients with QTcF >500 ms
• patients with baseline liver function tests over 5 times the upper limit of normal
• patients with serum hemoglobin less than 8
• patients with serum potassium below the limits of normal.

There are insufficient data to make a recommendation on whether these patients are candidates for the BPaL regimen at this time. Patients who have had prior linezolid or bedaquiline are still eligible for the BPaL regimen if their MTB isolate is found to be susceptible to these agents with molecular-based resistance testing conducted prior to BPaL use.

Additional studies are currently underway utilizing pretomanid in short course regimens for treatment of patients with all forms of MDR TB; in particular, results of the TB PRACTECAL trial show preliminary favorable results with the treatment of MDR TB with pretomanid, bedaquiline, lower-dose linezolid, and moxifloxacin for 6 months (52^nd Union World Conference on Lung Health of the International Union Against Tuberculosis and Other Lung Diseases (IUATLD) Abstract Book TB PRACTECAL: trial results and next steps. S31 SP-34. https://conf2021.theunion.org/pdfs/UNION2021_Abstracts_High.pdfpdf iconexternal icon; TB PRACTECAL Clinical Trial: https://clinicaltrials.gov/ct2/show/NCT02589782external icon).

Initiating the BPaL Regimen

Any patient who is under consideration for or initiated on the BPaL regimen should be reported in a timely manner to the local and state TB public health authorities (http://www.tbcontrollers.org/community/statecityterritory/external icon). A physician with expertise in drug-resistant TB treatment should be involved in the patient’s treatment plan. Physicians with this expertise may be available through the local or state public health TB control program; CDC funds TB programs and TB Centers of Excellence (TB COEs) to facilitate timely medical consultations at no charge for patients with complex or drug-resistant TB disease (https://www.cdc.gov/tb/education/tb_coe) [12].

Providers should ensure the ability to complete safety and adherence monitoring prior to initiation of the BPaL regimen (see Precautions and Adverse Event Monitoring). Before administering each dose of BPaL, the patient should be clinically assessed for signs or symptoms of central or peripheral neuropathies, hepatotoxicity, and hypersensitivity, among other concerns. Pharmacovigilance should include the ability to perform appropriate laboratory testing, QTcF interval monitoring, sputum collection, adverse event (AE) monitoring, and monitoring of clinical response (e.g., chest radiograph, symptoms, weight). Therapeutic drug monitoring (TDM) for linezolid with dose adjustment may be helpful [1, 13]. TB control programs should train providers in the process of monitoring and managing adverse events given the limited data available for pretomanid and minimal data on adverse events with use of BPaL.

Patient-centered care is a critical component of the treatment plan for patients receiving the BPaL regimen. When patients are educated about their diagnosis and given the ability to understand and participate in their treatment, potential barriers to treatment can be addressed and outcomes can be optimized.

Dosing

FDA-approved doses in the BPaL regimen in adults are as follows:

• Pretomanid 200 mg administered orally once daily for 26 weeks.
• Bedaquiline 400 mg administered orally once daily for 2 weeks, followed by 200 mg administered orally 3 times weekly, with at least 48 hours between doses, for 24 weeks for a total treatment duration of 26 weeks.
• Linezolid starting at 1200mg orally per day for 26 weeks, with dose adjustments to 600 mg daily and further reduction to 300 mg daily or interruption of dosing as necessary for known linezolid adverse reactions of myelosuppression, peripheral neuropathy, and optic neuropathy.

In the Nix-TB trial, high rates of neuropathy and myelosuppression occurred during treatment with the linezolid 1200mg dose (81% and 48%, respectively); of the 109 patients treated with BPaL, only 16 (15%) completed treatment using the initial linezolid dose of 1200mg [9]. Nix-TB providers were allowed to modify treatment by decreasing the dose, temporarily interrupting its use, or discontinuing it after completion of the first month. Of note, in the Nix-TB trial, TDM was not available at any point for linezolid dose adjustments to minimize serum troughs. In other treatment regimens for MDR TB in the United States, the recommended initiation dose of linezolid for MDR treatment regimens is 600 mg daily and TDM is suggested to minimize toxicity [1]. In the early period after FDA approval, 16 of 17 U.S. patients who received BPaL received an off-label initial linezolid dose lower than the approved 1200 mg dose and achieved good outcomes. (https://academic.oup.com/ofid/article/8/Supplement_1/S784/6451138external icon)

In the ZeNix trial, patients were treated for 6 months with bedaquiline, pretomanid, and were equally randomized, dose-blinded, to daily linezolid starting at 1200 mg for 6 months (1200L6M), 1200 mg for 2 months (1200L2M), 600 mg for 6 months (600L6M), or 600 mg for 2 months (600L2M). 181 participants were enrolled, including 20% who were HIV positive. A high success rate at the primary endpoint, similar to Nix-TB, was observed: 93% in 1200L6M, 89% in 1200L2M, 91% in 600L6M and 84% in 600L2M, with notably fewer adverse events in the 600L6M and 600L2M, also with fewer treatment interruptions or discontinuations (International AIDS Society 2021 Abstract Book. Conradie F, Everitt D, Olugbosi M, Wills G, Fabiane S, Timm J, Spigelman M, for the ZeNix Study Team. High rate of successful outcomes treating highly resistant TB in the ZeNix study of pretomanid, bedaquiline and alternative doses and durations of linezolid. OALB01LB02. July 21, 2021. IAS2021_Abstracts_web.pdfpdf iconexternal icon). Initiating BPaL with a reduced dose of linezolid of 600 mg daily might therefore be considered by some expert clinicians.

Treatment can be extended beyond 26 weeks up to 9 months (39 weeks) based on delayed treatment response within the first 8 weeks as assessed by time to culture conversion, persistent culture positivity, clinical response to treatment, and other underlying clinical factors, or modified based on adverse events.

Administration

BPaL is taken with food. Pretomanid is available in 200 mg tablets and is swallowed whole with water (https://www.drugs.com/pro/pretomanid-tablets.htmlexternal icon). Providers should carefully review all medications the patient is taking to evaluate for any drug-drug interactions with components of BPaL.

Pretomanid should not be used as a single drug unless or until further evidence is available. Regarding its use with other antituberculosis medications, it is currently only approved for use in combination with bedaquiline and linezolid in the treatment of TB [14]; additional data from clinical studies examining pretomanid-based regimens are forthcoming. The BPaL regimen should be administered only by directly observed therapy and with case management strategies. Such strategies could include the use of incentives and enablers (e.g., food certificates, bus passes, cash, housing) to ensure adherence to the treatment regimen. Patients should be advised that nonadherence to a treatment regimen could result in treatment failure, relapse, or acquired resistance. An evaluation for the development of resistance to the BPaL regimen, including repeat drug susceptibility testing, is recommended for patients with treatment failure or relapse (see Microbiologic Monitoring).

Clinicians are encouraged to contact their state or local drug-resistant TB experts, CDC’s TB program, or their designated TB Center of Excellence for technical assistance, including advice for safety monitoring or referral for TDM of linezolid.

For linezolid, some experts use serum drug levels to adjust the linezolid dose or dosing interval to minimize the trough level below 2 μg/mL, which has been associated with lower risk of known toxicities (e.g., myelosuppression, peripheral neuropathy, and optic neuritis), and to achieve a peak serum linezolid level of 12–26 μg/mL [15-17]. Some experts also adjust linezolid dose to ensure the patient’s peak serum linezolid concentration is at least 4–16 times over the MTB organism’s Minimum Inhibitory Concentration (MIC) (or Critical Concentration) [18, 19]. Similar to other second-line TB medications, linezolid should be provided to patients with close clinical and laboratory monitoring, and in the setting of severe toxicity, discontinuation should be considered.   

Persons receiving the BPaL regimen should be monitored weekly for nausea, headache, hemoptysis, chest pain, arthralgia, rash, liver toxicity, signs of optic and peripheral neuropathy; treatment should be modified as clinically indicated. Complete blood count, comprehensive metabolic panel (to include potassium, bicarbonate, creatinine, serum aminotransferases, bilirubin, amylase, lipase, calcium, magnesium), and thyroid studies to rule out hypothyroidism (thyroid stimulating hormone level) should be conducted at baseline. A complete blood count and listed components of the comprehensive metabolic panel should be repeated monthly. Patients should also be monitored for other suspected adverse reactions tailored to side effects specific to other drugs in the regimen and the potential for drug interactions with bedaquiline and pretomanid; specific examples of adverse reactions observed in the Nix-TB clinical trial using pretomanid, bedaquiline, and linezolid are detailed below [9].

Clinically significant safety risks associated with the BPaL regimen in the Nix-TBexternal icon trial were peripheral neuropathy, optic neuritis, myelosuppression, hepatotoxicity, and pancreatitis [9]. Most adverse events were managed by treatment interruptions, dose reductions, or discontinuations of linezolid alone. In 6 participants, adverse events led to death (gastrointestinal hemorrhage, pancreatitis with hemorrhage, sepsis). As per study design, pretomanid and bedaquiline doses were not adjusted during the trial. Below, both the safety risks and adverse event data from previous studies are described.

Hepatotoxicity

Persons receiving BPaL should be advised to avoid alcohol and other hepatotoxic drugs or supplements and should be monitored closely as noted below.

• BPaL can be administered to patients with mild to moderate hepatic impairment (Child-Pugh A or Bexternal icon) but should be avoided in patients with severe hepatic impairment (Child-Pugh C).
• Aspartate aminotransferase (AST), alanine aminotransferase (ALT), bilirubin, and alkaline phosphatase should be monitored at baseline, at 2 weeks, monthly, and, if symptomatic, more frequent monitoring should be considered, especially if administered with other hepatotoxic medications or supplements or in those with underlying liver disease.
• An increase of serum aminotransferases to >3 times the upper limit of normal (ULN) should be followed by repeat testing within 48 hours. National guidelines for management of hepatotoxicity should be followed [21]. Testing for HIV and viral hepatitis should be performed, and other hepatotoxic medications discontinued.
• Evidence of new or worsening liver dysfunction (including clinically significant elevation of aminotransferases or bilirubin or the appearance of symptoms such as fatigue, anorexia, nausea, jaundice, dark urine, liver tenderness, or hepatomegaly) should prompt additional evaluation by the medical provider.
• Discontinuation of BPaL should be considered if the following laboratory abnormalities are present:

• • serum aminotransferase elevations accompanied by total bilirubin elevation >2 times ULN,
  • serum aminotransferase elevations >8 times ULN, and
  • serum aminotransferase elevations that persist beyond 2 weeks.

Summary of hepatotoxicity-related data

• Hepatotoxicity was associated with BPaL treatment in the Nix-TB trial and was managed by temporary discontinuation of the regimen [9]. Serious liver injury was not noted. Specifically, one patient met the Hy’s Law cautionary levels of ALT >3 times ULN, total bilirubin >2 times ULN, and alkaline phosphatase <2 times ULN [9]. One patient had ALT >3 times ULN, total bilirubin >2 times ULN, but alkaline phosphatase >2 times ULN. Both had interruption in the treatment, and the regimen was successfully restarted and completed. Hepatotoxicity is included in the warnings and precautions section of the bedaquiline packet insert. Hepatic transaminases were increased, and drug-induced liver injury was reported in phase III trials of pretomanid administered with other antimycobacterial drugs. Studies NC-005 and NC-006 treatment regimens included pretomanid: in NC-005, bedaquiline, pretomanid, and pyrazinamide, with or without moxifloxacin (BPaMZ and BPaZ) [22]; in NC-006, also known as the “STAND” trial, moxifloxacin, pretomanid, and pyrazinamide (MPaZ) [23]. In study NC-006, three patients died around week 4 of treatment due to acute liver failure; these 3 deaths were considered related to the MPaZ regimen.
• In the Nix-TB trial, persons with HIV experienced more elevations in hepatic transaminases and hemopoietic cytopenia (i.e., anemia, neutropenia, and thrombocytopenia) than did HIV-negative subjects, which would be expected because of higher likelihood of underlying comorbidity and concomitant treatment with antiretrovirals and other medications.

Renal impairment

Pretomanid is minimally excreted by the kidneys, does not require dosage adjustment in patients with mild to moderate renal impairment (not requiring dialysis), and should be administered with caution in patients with severe renal impairment requiring dialysis.

Summary of Renal Impairment and Creatinine level data:

Patients with creatinine >2 times ULN were excluded from the Nix-TB trial per protocol, and a safety signal for renal toxicity was not evident in the post baseline creatinine levels. Five patients had creatinine elevations > ULN and ≤2 times ULN at baseline. Based on these limited data and clinical trial exclusions, safety of the BPaL regimen or pretomanid in patients with renal impairment has not been assessed.

Cardiac toxicity

Persons receiving the BPaL regimen should be closely monitored for signs of cardiac toxicity with repeated ECG and other measures as follows:

• Baseline ECG should be obtained and repeated at least 2, 12, and 24 weeks after starting treatment [24].
• Serum potassium, calcium, magnesium, and thyroid function tests should be obtained at baseline and monthly whenever clinically indicated, especially if QTcF prolongation is detected. Any abnormalities that are detected should be addressed, and electrolytes should be monitored until fully corrected.
• The concurrent use of other drugs known also to cause QTcF prolongation could be associated with increased risk of cardiotoxicity when patients are receiving bedaquiline. Persons who receive BPaL should be monitored weekly with an ECG if they:
  • receive other QTcF prolonging drugs;
  • have a history of torsade de pointes, congenital long QT syndrome, hypothyroidism and bradyarrhythmias, or uncompensated heart failure; or
  • have serum calcium, magnesium, or potassium levels below the lower limits of normal.

Discontinuation of bedaquiline and all other QTcF-prolonging drugs should be considered if the patient develops:

• clinically significant ventricular arrhythmia, or
• a QTcF of >500 ms (confirmed by repeat ECG).

If pretomanid is discontinued for cardiotoxicity, ECGs should be monitored frequently to confirm that QTcF has returned to baseline. If syncope occurs, an ECG should be obtained to evaluate for QTcF prolongation.

Summary of data regarding QT prolongation:

Mild QT prolongation was reported in Nix-TB trial [8]. QT prolongation is associated with bedaquiline. Pretomanid had no clinically significant effect on the QT interval in a Thorough QT (TQT) study [25]. Minimal QT prolongation was observed at 15 times human exposure in monkeys [23], but was attributed to ketamine anesthetic used to collect ECG measurements.

Optic Neuritis/Neuropathy/Myelosuppression/Lactic Acidosis/Acute Pancreatitis

Optic Neuritis: Visual acuity and color vision assessment with Ishihara testing should be monitored in all patients receiving linezolid as part of the BPaL regimen (https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/021130s032,021131s026,021132s031lbl.pdfpdf iconexternal icon). If symptoms of visual impairment are identified, interrupt linezolid dosing and obtain prompt ophthalmologic evaluation (https://www.tballiance.org/sites/default/files/assets/Pretomanid_Full-Prescribing-Information.pdf).

Neuropathy: While receiving linezolid as part of the BPaL regimen, patients should be monitored for symptoms (e.g., tingling, pain, or numbness of hands or feet) and signs of peripheral neuropathy. Clinical evaluation of peripheral neuropathy should include questions regarding tingling, burning, freezing, numbness, stinging, or itching of the hands and feet, as well as a physical examination including a monofilament test. For more information about the monofilament test please visit: https://www.annfammed.org/content/7/6/555.longexternal icon

Myelosuppression: Complete blood counts should be monitored regularly, such as weekly, during the first 6–8 weeks, then monthly as needed based on symptoms. Interrupting linezolid or adjusting the dose or dosing interval, aiming for serum drug level <2 μg/mL, should be done in patients who develop or have worsening myelosuppression. Importantly, other etiologies for myelosuppression should also be investigated while making any treatment adjustments.

Lactic Acidosis and Acute Pancreatitis: Patients who develop recurrent nausea, vomiting, or abdominal pain should receive immediate medical evaluation, including evaluation of bicarbonate and lactic acid levels, transaminases, lipase/amylase levels, and the interruption/dose adjustment of linezolid or interruption of BPaL.

Summaries of clinical trial data on Optic Neuritis/Peripheral Neuropathy/Myelosuppression/Lactic Acidosis/Acute Pancreatitis

Optic Neuritis: Known adverse reaction associated with linezolid, was fully reversible when linezolid was discontinued [9]. Ophthalmological examinations and Age-Related Eye Disease Study 2 (AREDS2) scores showed no evidence that pretomanid induces cataract formation in humans [5, 23].

Peripheral Neuropathy: Peripheral neuropathy associated with linezolid was the most common AE, reported in 87 (80%) of patients in the Nix-TB trial, in which participants initiated BPaL with a linezolid dose of 1200 mg daily for at least 4 weeks [9]. Over 50% of the cases of AEs were moderate to severe, including some that were not reversible by end of study. Peripheral neuropathy increased with the duration of BPaL treatment. Prior studies have documented irreversibility of some linezolid-associated neuropathies [26, 27].

Myelosuppression: In the Nix-TB study in which all participants initiated BPaL with a linezolid dose of 1200 mg daily, myelosuppression associated with linezolid was reversible except for 3 patients who had ongoing events at the time of data cutoff. [9]. Myelosuppression increased with the duration of BPaL treatment.

Lactic Acidosis: Lactic acidosis occurred in 7.3% patients in the Nix-TB trial, in which all participants initiated BPaL with a linezolid dose of 1200 mg daily and was mostly associated with linezolid [8]. Lactic acidosis is listed in warnings in the linezolid US package insert (https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/021130s032,021131s026,021132s031lbl.pdfpdf iconexternal icon). Lactic acidosis was not reported in other trials of pretomanid-containing regimens [22, 28, 29]. 

Acute pancreatitis: Acute pancreatitis was reported in 3 patients in the Nix-TB trial [8]. It is not clear whether these were associated with the study drugs or with potential risk factors for pancreatitis (e.g., alcohol use, HIV, and antiretroviral therapy such as lopinavir/ ritonavir). Pancreatitis was reported in animal studies of bedaquiline [28, 30].

• Neurotoxicity: Convulsions and ataxia were noted in cynomolgus monkeys receiving 5 times the maximum recommended human dose (450 mg/kg)[14]. Neither ataxia, convulsions, nor other CNS-related clinical signs were seen in monkeys dosed for 39 weeks at exposures (based on area under the curve over 24 hours) similar to the predicted exposures in patients at the maximum recommended human dose. Two participants in Nix-TB had convulsions but had reported a medical history of convulsions [9].
• Lens Disorders/Cataract: Cataracts were seen in rat studies with 2 times the human exposure at maximum recommended human dose over 26 weeks [14]. Cataracts did not develop in monkeys given daily doses of pretomanid 100 mg/kg for 39 weeks. This dose produced an average area under the curve over 24 hours (AUC_0-24) value of more than twice the exposure patients would experience at the maximum recommended human dose of pretomanid. No cataracts were observed in the following human studies of pretomanid: NC-002, NC-005, NC-006, and Nix-TB [8, 22, 29].
• Testicular Toxicity: In animal toxicology studies of pretomanid, testicular toxicity resulting in infertility was noted in male rats[13]. Reduced fertility was observed in male rats given daily oral pretomanid for 13 weeks at 30 mg/kg. Spermatocyte degeneration was noted in rats at 1.5 times the human exposure. The no observed adverse effect level for testicular toxicity was 50 mg/kg, which was associated with an AUC of 70 μg*h/m. This is 1.2 times the maximum recommended human dose. At 100 mg/kg (3.5 times the clinical dose), pretomanid was associated with reduced body weight, complete irreversible infertility, testicular atrophy, lower sperm counts, reduced sperm motility, lower serum inhibin B concentration, and higher serum FSH concentration (Rat Study 1408-002external icon). These effects were irreversible at 100 mg/kg. Reduced fertility appears to be a result of the effects on spermatogenesis in males. However, male hormones were normal in the following human phase 2 and 3 studies: NC-002, NC-005, NC-006. Preliminary data presented in October 2021 support lack of adverse effects on male reproductive hormones with pretomanid-containing regimens (52^nd Union World Conference on Lung Health of the IUATLD Abstract Book; Boekelheide, M. Olugbosi, D. Everitt, J. Nedelman, E. Sun, M. Spigelman. No adverse effects on male reproductive hormones in patients treated with pretomanid-containing regimens. EP-14-228; https://conf2021.theunion.org/pdfs/UNION2021_Abstracts_High.pdfpdf iconexternal icon).
• Female Reproductive and Maternal Toxicity: Female rats dosed daily with oral pretomanid for 2 weeks showed body weight loss, reduced feed consumption, reduced number of estrous stages per 14 days, and a greater incidence of prolonged diestrus at 100 mg/kg/day [13]. The number of live fetuses and fetal body weight were lower, and skeletal development was slowed. Rat pups from dams that experienced maternal toxicity showed a slight delay in the age at which the air-drop righting reflex developed and an increase in basic and fine movement as well as total distance travelled. Reproductive and developmental toxicity have not been evaluated in human studies.

Additional serious adverse events observed in Phase III and Phase III human studies

• In study NC-002 (https://clinicaltrials.gov/ct2/show/NCT01498419external icon), serious adverse events in patients treated with pretomanid, moxifloxacin, and pyrazinamide included agranulocytosis, elevated hepatic transaminases, pneumothorax, atrioventricular block, seizure, and dyspnea.[22]

BPaL use in the treatment of adults with pulmonary XDR TB, pre-XDR TB, or TI/NR MDR TB should be accompanied by microbiologic monitoring. At least one sputum specimen should be submitted for culture monthly throughout and at end of treatment, even after conversion to negative cultures. This is consistent with the United States and World Health Organization guidance for care of patients with drug-resistant TB [1]. Laboratory results indicating XDR, pre-XDR, or MDR, including those from phenotypic drug susceptibility testing (DST), rapid molecular testing, or a combination of both should be obtained to document drug-resistant TB status. Ideally, molecular DST would be performed to evaluate the presence of mutations known to be associated with first- and second line antituberculosis drug resistance as well as with newer drugs like bedaquiline [32]. These results, in combination with phenotypic results, are preferrable for informing clinical decision making.

• With use of the BPaL regimen, isolates of MTB grown from the initial and any subsequent monthly specimen, including those taken before BPaL treatment initiation, should be evaluated for resistance or changes in susceptibility to regimen drugs through use of phenotypic methods, and when available, molecular methods. Among bedaquiline, pretomanid, and linezolid, the Clinical and Laboratory Standards Institute (CLSI) has defined a critical concentration for susceptibility testing using the fluorescence-based, commercial, shorter-incubation liquid media system (i.e., BD BACTEC Mycobacteria Growth Indicator Tube System or MGIT) for linezolid only [33]. CLSI has not yet defined a critical concentration or breakpoint for testing of bedaquiline but has published a minimum inhibitory concentration (MIC) quality control range for broth microdilution testing of MTB H37Rv for a custom MIC plate that includes both linezolid and bedaquiline [33, 34]. Additionally, WHO has recommended critical concentrations for testing of linezolid, in 7H10 Middlebrook, 7H11 Middlebrook, and MGIT, and bedaquiline in 7H11 Middlebrook and MGIT [35]. There are currently no recommended critical concentrations for testing of pretomanid, and the drug is not widely available for laboratory testing. In the Nix-TB study, phenotypic susceptibility testing for pretomanid was performed by evaluation of MIC using MGIT for baseline and interim evaluation. In Nix-TB, all baseline isolates had pretomanid MIC values of ≤1 μg/ml in MGIT [9]. Phenotypic DST for BPaL is likely to be limited to larger reference laboratories (see below for further information on accessing DST). Minimum inhibitory testing by the broth microdilution method may be appropriate for monitoring changes in susceptibility. CDC can assist in identifying a laboratory that can perform susceptibility testing for this purpose [36].
• Regarding molecular testing, mutations in Rv0678, atpE, and pepQ have been reported as associated with resistance to bedaquiline as have mutations in rplC and rrl for linezolid [37-43]. Pretomanid resistance is thought to be associated with mutations in the deazaflavin (cofactor F420) dependent nitroreductase known as Ddn or mutations in the genes fgd1, fbiA, fbiB, and fbiC involved in cofactor 420 synthesis needed for conversion of the prodrug into its active form [44]. There are existing knowledge gaps regarding which mutations reliably predict resistance for all three drugs of the BPaL regimen. However, even with these limitations, evaluation of isolates by both phenotypic and molecular methods from patients treated with this regimen is critical for resistance monitoring and detection of changes in susceptibility over time. This is particularly important for bedaquiline given that in the Nix-TB study, one of three patients experiencing relapse was reported to have an increased bedaquiline MIC that was associated with a mutation detected in Rv0678 [8]. Some reports indicate detection of resistance to bedaquiline even in the absence of previous exposure to the drug [45, 46]. CDC’s laboratory is working toward implementation of molecular and growth-based testing for bedaquiline and linezolid. In addition, CDC is conducting surveillance of pretomanid resistance by MIC testing as part of a global post-marketing surveillance study. Susceptibility testing for drugs in this regimen may also be available in other laboratories. CDC can assist in identifying a source for this purpose.

Patients treated with the BPaL regimen should be followed for 2 years after treatment completion to evaluate for any evidence of recurrence. This recommendation is not based on clinical trials but rather on reasonable expert opinion in treatment of patients with bedaquiline-containing regimens outside of clinical trials [31].

Any patient with drug-resistant TB must be reported in a timely manner to the local and state TB public health authorities (http://www.tbcontrollers.org/community/statecityterritory/). CDC is collecting post-marketing surveillance data on U.S. TB patients receiving any pretomanid-based regimen, and TB programs are requested to contact BAMproject@cdc.gov when notified about patients initiating any TB regimen containing pretomanid.

Serious drug side effects, product quality problems, and therapeutic failures should be reported to FDA’s MedWatch program at https://www.accessdata.fda.gov/scripts/medwatch/index.cfm?action=reporting.homeexternal icon or by calling 1-800-FDA-1088. Any BPaL-treatment-associated adverse event leading to hospital admission or death should also be reported by clinicians to local or state health departments.