Multi-drug Resistant Tuberculosis

The Critical Challenge of Drug Resistance

Anyone can be infected with tuberculosis (TB), but the overall proportion of infected individuals who progress to active disease is approximately 10%.1,10 Although efficacious anti-TB drugs have been available for decades, drug resistance in Mycobacterium tuberculosis has also been a challenge.

TB bacteria can acquire resistance to antibiotics during drug treatment if a patient with TB:

  • does not complete the full course of treatment
  • receives only intermittent doses
  • is otherwise inadequately treated (eg, caregiver errors occur in prescribing or administration, or a poor-quality formulation is supplied)

This type of drug resistance, called acquired drug resistance, occurs in TB because a patient’s bacterial population survives for several months during treatment.3,13

  • An incomplete course of TB therapy is considered an important risk factor in the development of TB drug resistance. Patient adherence to therapy can be problematic, particularly in cases where access to proper medical care is lacking to support patients in completing therapy.4,12
  • Prior treatment with anti-TB drugs is considered a strong determinant of contracting a drug-resistant strain.11

Primary drug resistance, on the other hand, occurs when a person contracts an infecting strain of TB that is already resistant to one or more anti-TB drugs.13

Strains of TB resistant to treatment with at least isoniazid and rifampin are known as multi-drug resistant tuberculosis (MDR-TB). MDR-TB is a critical issue to address because it impacts various regions.9

The total number of MDR-TB cases in the US is comprised of MDR-TB among US-born and foreign-born TB cases. The percentage of MDR-TB in both populations show opposite trends. Of the total number of reported primary MDR-TB cases, the proportion occurring in foreign-born persons increased from 25.3% (103 of 407) in 1993 to 82.7% (81 of 98) in 2011.4 The number of MDR-TB cases in US-born persons decreased from 73.9% (301 of 407) in 1993 to 17.3% (17 of 98) in 2011.

The World Health Organization estimated there were 110 new pulmonary MDR-TB cases in the US during 2011.14

Levels of Drug Resistance

Strains of TB may exhibit various ranges of drug resistance, including MDR-TB. These levels of resistance can be classified according to the chart below.

  • Drug-sensitive TB (DS-TB): Sensitive to first-line agents
  • MDR-TB: Strains of TB resistant to treatment with at least isoniazid and rifampin

Classification of TB and Clinical Definition of MDR-TB9

Classification of TB

INDICATIONS AND USAGE

SIRTURO® (bedaquiline) is a diarylquinoline antimycobacterial drug indicated as part of combination therapy in the treatment of adults (≥18 years) with pulmonary multi drug resistant tuberculosis (MDR TB). Reserve SIRTURO® for use when an effective treatment regimen cannot otherwise be provided. Administer SIRTURO® by directly observed therapy (DOT).

This indication is approved under accelerated approval based on time to sputum culture conversion. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.

Limitations of Use

Do not use SIRTURO® for the treatment of:

  • Latent infection due to Mycobacterium tuberculosis
  • Drug-sensitive tuberculosis
  • Extrapulmonary tuberculosis
  • Infections caused by non-tuberculous mycobacteria

The safety and efficacy of SIRTURO® in the treatment of HIV-infected patients with MDR-TB have not been established as clinical data are limited.

IMPORTANT SAFETY INFORMATION

WARNINGS: INCREASED MORTALITY; QT PROLONGATION

    Increased Mortality
  • An increased risk of death was seen in the SIRTURO® treatment group (9/79, 11.4%) compared to the placebo treatment group (2/81, 2.5%) in one placebo-controlled trial. Only use SIRTURO® when an effective treatment regimen cannot otherwise be provided.
    QT Prolongation
  • QT prolongation can occur with SIRTURO®. Use with drugs that prolong the QT interval may cause additive QT prolongation. Monitor ECGs. Discontinue SIRTURO® if significant ventricular arrhythmia or if QTcF interval prolongation of greater than 500 ms develops.

Warnings and Precautions

Increased Mortality

An increased risk of death was seen in the SIRTURO® treatment group. The imbalance in deaths is unexplained. No discernible pattern between death and sputum culture conversion, relapse, sensitivity to other drugs used to treat tuberculosis, HIV status, or severity of disease could be observed. Only use SIRTURO® when an effective treatment regimen cannot otherwise be provided.

QT Prolongation

SIRTURO® prolongs the QT interval. Obtain an ECG before initiation of treatment, and at least 2, 12, and 24 weeks after starting treatment with SIRTURO®. Obtain serum potassium, calcium, and magnesium at baseline and correct if abnormal. Monitor electrolytes if QT prolongation is detected.

SIRTURO® has not been studied in patients with ventricular arrhythmias or recent myocardial infarction.

The following may increase the risk for QT prolongation when patients are receiving SIRTURO®: use with other QT prolonging drugs including fluoroquinolones and macrolide antibacterial drugs and the antimycobacterial drug, clofazimine; a history of Torsade de Pointes; a history of congenital long QT syndrome; a history of or ongoing hypothyroidism; a history of or ongoing bradyarrhythmias; a history of uncompensated heart failure; serum calcium, magnesium, or potassium levels below the lower limits of normal

If necessary, bedaquiline treatment initiation could be considered in these patients after a favorable benefit risk assessment and with frequent ECG monitoring.

Discontinue SIRTURO® and all other QT prolonging drugs if the patient develops clinically significant ventricular arrhythmia or a QTcF interval of greater than 500 ms (confirmed by repeat ECG).

If syncope occurs, obtain an ECG to detect QT prolongation.

Hepatotoxicity

More hepatic-related adverse drug reactions were reported with the use of SIRTURO® plus other drugs to treat tuberculosis compared to other drugs used to treat tuberculosis without the addition of SIRTURO®. Alcohol and other hepatotoxic drugs should be avoided while on SIRTURO®, especially in patients with impaired hepatic function.

Monitor symptoms (such as fatigue, anorexia, nausea, jaundice, dark urine, liver tenderness, and hepatomegaly) and laboratory tests (ALT, AST, alkaline phosphatase, and bilirubin) at baseline, monthly while on treatment, and as needed. Test for viral hepatitis and discontinue other hepatotoxic medications if evidence of new or worsening liver dysfunction occurs. Discontinue SIRTURO® if:

  • aminotransferase elevations are accompanied by total bilirubin elevation greater than two times the upper limit of normal
  • aminotransferase elevations are greater than eight times the upper limit of normal
  • aminotransferase elevations are greater than five times the upper limit of normal and persist beyond two weeks

Drug Interactions

CYP3A4 Inducers/Inhibitors: Bedaquiline is metabolized by CYP3A4 and its systemic exposure and therapeutic effect may therefore be reduced during co-administration with inducers of CYP3A4. Avoid coadministration of strong CYP3A4 inducers such as rifamycins (i.e., rifampin, rifapentine, and rifabutin) or moderate CYP3A4 inducers such as efavirenz. Co-administration of SIRTURO® with strong CYP3A4 inhibitors may increase the systemic exposure to bedaquiline, which could potentially increase the risk of adverse reactions. Therefore, avoid the use of strong CYP3A4 inhibitors used for more than 14 consecutive days while on SIRTURO®, unless the benefit of treatment with the drug combination outweighs the risk. Appropriate clinical monitoring for SIRTURO®-related adverse reactions is recommended.

Adverse Reactions

Adverse reactions that occurred more frequently than placebo during treatment with SIRTURO® included: nausea (38% vs. 32%), arthralgia (33% vs. 22%), headache (28% vs. 12%), hemoptysis (18% vs. 11%), chest pain (11% vs. 7%), anorexia (9% vs. 4%), transaminases increased (9% vs. 1%), rash (8% vs. 4%), and blood amylase increased (3% vs. 1%).

Please see full Prescribing Information, including Boxed Warnings and Medication Guide, for more details.