Old and new: How MDR-TB treatment requires drugs of all ages

Issue: August 2016

ByRachel S. Bacher, PharmD

ByStephen M. Small, PharmD

With the disturbing advent of multidrug-resistant tuberculosis, or MDR-TB, the medical field is scrambling to find ways to effectively treat affected patients. With an already limited array of pharmaceuticals, we have now needed to take an “all hands on deck” approach, where antiquated drugs are being dusted off as researchers discover new medicines to combat this insidious disease. This review covers the pharmacology of some of the drugs, both new and old, now being included in our arsenal against MDR-TB.

Dated drugs

Lamprene (clofazimine, Novartis): Clofazimine was originally approved as an orphan drug by the FDA in 1986 as an oral treatment of leprosy. Although never formally approved to treat TB, its use to treat the disease has increased due to the rise in MDR-TB.

Clofazimine is a member of the riminophenazine class of drugs originally studied in the 1950s. Proposed mechanisms of action against Mycobacterium tuberculosis include generation of intracellular hydrogen peroxide, binding to guanine DNA bases, and accumulation of lysophospholipids via stimulation of phospholipase A2.

One advantage of clofazimine is the inability of M. tuberculosis to effectively generate resistance to the drug. Furthermore, at serum concentrations considered subtherapeutic, clofazimine may actually prevent isoniazid resistance.

Clofazimine suffers from poor oral absorption as well as considerable accumulation into tissues and phagocytes rather than the serum. This accumulation contributes to the drug’s half-life of approximately 70 days. These kinetic factors are some of the reasons for its limited utility in favor of other anti-TB drugs. The advent of MDR-TB, however, has created new interest in the drug despite its perceived pharmacokinetic downfalls.

Aside from small observational studies, a randomized controlled study in 2015 compared the treatment outcomes and adverse effects of using clofazimine vs. nonclofazimine drug regimens for MDR-TB for 21 months. In 105 patients, the clofazimine group success rate was higher than the control group (73.6% vs. 53.8%, P = .035). Furthermore, the rate of cavitation closure was faster in the clofazimine group (P = .047).

There are at least four open clinical trials, including three phase 3 trials, analyzing clofazimine in the treatment of MDR-TB. These studies are focused on clofazimine in combination with other TB drugs to produce less toxic and shorter regimens for MDR-TB infections.

The adverse effects of clofazimine are relatively minor. The drug commonly causes a reversible orange-brown discoloration of the skin. However, case reports have shown an association of this side effect with depression and suicide. Other common adverse effects include nausea, vomiting and diarrhea.

Para-aminosalicylic acid: Discovered in 1946, para-aminosalicylic acid (PAS) was one of the first medications used to treat TB. After powerful drugs like isoniazid and pyrazinamide were discovered, PAS became a second-line agent. Still, a delayed-release oral granule formulation was approved by the FDA in the 1990s under the brand name Paser (Jacobus), even though efficacy studies were lacking.

PAS is believed to act as a bacteriostatic prodrug that inhibits mycobacterial dihydrofolate reductase enzyme used to synthesize folate. Studies have aimed to optimize dosing strategies for PAS to improve its pharmacokinetics and patient compliance, but data still support giving PAS as 4 g (one packet) two or three times daily to treat MDR-TB. PAS resistance is possible via enzyme mutations and efflux pumps. Thankfully, such resistance is rare when PAS is used in combination with other drugs against MDR-TB.

Few studies have analyzed the efficacy of PAS in MDR-TB. There was a prospective, uncontrolled study of 39 patients with MDR-TB treated with kanamycin, Trecator (ethionamide, Pfizer), isoniazid, Seromycin (cycloserine, Purdue GMP) and PAS. With this regimen, a majority (74.3%) of the patients became culture-negative at 6 months; however, two of these patients relapsed. At this time, there is also one phase 2 study of MDR-TB that includes PAS in the treatment regimen.

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Aside from the compliance issues associated with the drug’s frequent dosing, the use of PAS is limited by its toxicity. The most common adverse effects of PAS include nausea, vomiting and diarrhea. PAS also may cause liver damage due to the formation of a hepatotoxic metabolite in the stomach, although the incidence has been reduced by the development of a delayed-release product. There are also several case reports of hypothyroidism associated with PAS.

Modern medicines

Sirturo (bedaquiline, Janssen Therapeutics): Bedaquiline is a new chemical entity approved by the FDA in 2012 for the treatment of adults with pulmonary MDR-TB (in combination with at least three other agents).

Bedaquiline is a member of the diarylquinoline class of antimicrobials and has a unique mechanism of action, targeting the adenosine triphosphate synthase enzyme of M. tuberculosis and preventing it from creating energy.

Studies have examined placebo in combination with drugs approved to treat MDR-TB vs. bedaquiline plus these same regimens in newly diagnosed patients with pulmonary MDR-TB. Results of these phase 2 trials have shown decreased time to culture conversion and improved culture conversion rates compared with the placebo group. Another study compared adults with smear-positive MDR-TB, which showed the same results but also a significantly higher rate of death in the bedaquiline arm for unknown reasons.

There are several ongoing phase 3 studies, including the STREAM II trial, that are comparing treatment durations, along with the NExT, NiX-TB and TB-PRACTECAL trials, which are examining various regimens such as bedaquiline.

Bedaquiline, which is metabolized by cytochrome P450 3A4, carries a black box warning for QTc prolongation, so it should be used cautiously in patients on medications that may cause additive QTc prolongation. Concomitant use of inhibitors or inducers of this enzyme should be avoided. It also carries a warning for increased risk for death, shown in a phase 2 trial, so it should be reserved for situations in which effective treatment cannot otherwise be provided.

Deltyba (delamanid, Otsuka): Delamanid was granted marketing authorization by the European Commission in 2014 (in combination with an optimized MDR-TB regimen) to be used when an effective treatment regimen is unavailable because of resistance or intolerability to other medications. Full approval is pending additional safety, efficacy and dosing studies. It is not yet approved in the United States.

Delamanid exerts its cytotoxic activity by inhibiting methoxy- and keto-mycolic acid syntheses, which prevent M. tuberculosis cell wall synthesis. Interruption of cellular respiration may be an additional mechanism of action.

Clinical trials are not yet as robust for delamanid, but results have shown that patients with pulmonary MDR-TB who received delamanid in combination with an approved drug regimen vs. placebo and the same regimen had an increase in sputum culture conversion at 2 months as well as a higher proportion of patients with culture conversion. An ongoing trial is examining the safety and efficacy of delamanid at 6 months in patients with MDR-TB.

Delamanid also carries a warning for QTc prolongation. Disallowing coadministration of delamanid and bedaquiline is strictly enforced. However, a phase 2 trial is studying the combined QT effects of the two new agents. Additionally, a recent case report detailed the clinical course of a man with pulmonary TB treated with a regimen containing bedaquiline and delamanid in combination. In this case, frequent electrocardiography was performed, and no QT interval prolongation was observed.

Conclusion

Although the threat of MDR-TB is certainly spreading around the world, not all hope has been lost. As described above, strides have been made with the discovery of medications such as bedaquiline. Still, as MDR-TB becomes more resistant to our backbone drugs, we have needed to bring back older medications that have faded from our collective clinical memory. We hope these medications, both new and old, continue to have success in beating MDR-TB. While some decades-old agents are providing useful treatment options, it is the development of new agents for the treatment of TB that is imperative for us to ultimately win this battle.

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For more information:
Rachel S. Bacher, PharmD, is a PGY1 pharmacy resident at Denver Health Medical Center.
Stephen M. Small, PharmD, is a pharmacy practice resident at Denver Health Medical Center.
Katherine C. Shihadeh, PharmD, is a clinical pharmacy specialist in infectious diseases at Denver Health Medical Center. She can be reached at katherine.shihadeh@dhha.org.

Disclosures: Bacher, Small and Shihadeh report no relevant financial disclosures.