New drugs and regimens are needed for tuberculosis (TB) to decrease toxicity, shorten therapy duration, and improve efficacy, especially for multidrug-resistant TB (MDR-TB). The document discusses several promising new drugs and regimens that are being studied or used compassionately, including bedaquiline, delamanid, clofazimine in the "Bangladesh regimen", and repurposing of existing drugs like metformin and linezolid. However, most new drugs still need larger trials to establish safety and efficacy before being used widely. Shortening standard TB treatment also requires further study of alternative regimens using high-dose rifapentine or rifampin in combination with other drugs.

1. New drugs and regimens for TB:
2015 update
Scott K. Heysell MD, MPH
(no disclosures)

2. Why do we need new drugs/ regimens?
▪Isoniazid and pyrazinamide remain some of the most toxic
antibiotics prescribed for infectious disease
-decrease toxicity
▪Even in U.S., completion of therapy in 12 months ~ 90% …
but completion in 6 months is actually the minority of DS-TB
-shorten therapy
▪Multidrug-resistant TB, or intolerance to first-line drugs
-improve efficacy

3. +
+
+
+
ethambutol pyrazinamide
ofloxacin cycloserine PAS granules
kanamycin (8+ months)
minimum
20 months!
pyridoxine
+ ?
truvada
+
efavirenz
+
TMP/sulfa
who.int/tb/challenges

4. Cost of treating a patient with MDR-TB in the United States?
$134,000 to $430,000 [for extensively drug-resistant (XDR)-TB]!
In European Union
The economic loss in disability adjusted life years was
10 times greater than the treatment cost itself
Marks et al. EID 2014
Diel et al. Euro Respir J 2013

5. Retooling conventional TB drugs or other non-TB drugs
▪Higher dose or
later generation
fluoroquinolones
(eg. moxifloxacin)
▪clofazimine
▪linezolid
▪High-dose rifampin or
rifapentine
lepromatous leprosy
(at U of Virginia)

6. Dorman et al. AJRCCM 2015
13-26% improvement in 2 month
sputum culture conversion!
High dose rifamycins may ultimately
shorten TB treatment duration
335 patients: TB Trials Consortium

7. Weekly moxifloxacin and rifapentine in the continuation phase
RIFAQUIN trial
Jindani et al. NEJM 2014
Equivalent
Inferior

8. Smythe et al. AAC 2013
AUC ↓~14.3%
following multiple
400-mg daily doses
of gatifloxacin
REMox and OFLOTUB failed in replacing ethambutol or isoniazid
with fluoroquinolone to shorten tx to 4 months total:
Importance of pharmacokinetics and M. tuberculosis MIC?
All “susceptible” by conventional DST
400mg
600mg
800mg

9. 515 patients
84.5% cure!
5.6% death
Remainder with default or relapse
Aung et al, Int J Tuberc Lung Dis 2014
9+ months:
high-dose gatifloxacin,
EMB, PZA, clofazimine
plus
first 4+ months:
KM, PTO, high-dose INH
The ‘Bangladesh Regimen’ for MDR-TB

10. Father Damien ultimately
canonized in 1995: when asked
what miracle he had performed,
Mother Theresa answered,
“Damien himself is a miracle.”

11. Criticisms of ‘Bangladesh’ regimen, reasons for larger multinational trial:
▪Observational study, many patients were excluded
▪No HIV
▪Treated in Damien Foundation centers with consequent attention to nutrition,
careful management of side effects, occupational training and family support
With permission, Mymensingh

12. 5 years (2009-2014)
10 cases of MDR-TB in Virginia
if susceptible to fluoroquinolone then cure rate 6/7*
3 cases were resistant to fluoroquinolone or all injectable agents  pre-XDR
All 3 pre-XDR received linezolid
2 were given 600 mg daily and were cured*
Heysell et al. Tuberc Respir Dis 2015
We use linezolid (with caution) in MDR-TB patients with additional
resistance to fluoroquinolones and/or injectable agents
(pre-XDR and XDR-TB)
*Thanks to everyone at
!

13. bedaquiline
sutezolid
delamanid
pretomanid

14. ▪Drug-induced phospholipidosis (like amiodorone) in organs and other tissues
Safety concerns with bedaquiline
metabolized in liver CYP3A4
▪can’t give with rifampin as will significantly lower bedaquiline concentrations;
protease inhibitors, macrolides etc will increase bedaquiline concentrations
half life 24 hours, terminal elimination half life of 5.5 months
▪Drug-related hepatic disorders (8.8% bedaquiline v. 1.9% placebo)
▪ Not to be used together with delaminid (both with QT prolongation)
prolongs the QTc
▪ the mean increase in QTc was greater for patients taking bedaquiline and
clofazimine (32-ms increase) than for bedaquiline alone (12.3 ms). No TdP

15. Cure rates at 120 weeks:
bedaquiline group 58%
placebo group 32%
(p = 0.003)
Diacon et al. NEJM 2014
*Death 10/79 (13%) bedaquiline v. 2/81 2% in placebo
(p=0.02)
*QTc increase more common with bedaquiline
Bedaquiline + optimized background regimen faster time
to culture conversion and higher rate of 120 week cure

16. bedaquiline
sutezolid
delamanid
pretomanid

17. Gler et al. NEJM 2012
Delamanid with improved
2 month culture conversion
QT prolongation more common
than with placebo
▪Novel nitro-dihydro-
imidazo-oxazole derivative
▪More M. tuberculosis
specific minimal drug
interactions
▪High volume of distribution
▪Dose dependent activity in
vitro similar to rifampin
Delamanid

18. 2 mo delamanid
Favorable outcome 55%
Cure 48%
Death 8.3%
6 mo delamanid
Favorable outcome 74.5%
Cure 57.3%
Death 1.0%
6 months of delamanid is more efficacious and tolerable
421 patients

19. How new drugs are currently being used:
we need a new regimen
First compassionate use delamanid in Europe (pediatric XDR-TB)
Esposito et al. ERJ 2014

20. Metformin:
Enhances killing of M. tuberculosis
in the laboratory
In Virginia, what you are doing for diabetes may be most important
*HgbA1c to rule-in or rule-out diabetes and
refer to care: don’t rely on self-report
*Early therapeutic drug monitoring for
diabetics
*Educational flip-chart
Singhal et al, Sci Trans Med 2014

21. ▪Clofazimine and the ‘Bangladesh regimen’ may be here to stay for
MDR-TB await STREAM trial
▪High dose Rifapentine planned for treatment shortening in DS-TB
▪Rifapentine/ Moxifloxacin a future option for once weekly dosing
in continuation phase?
▪Get to know Bedaquiline and Delamanid but not ready for prime-time
in the U.S.
▪Let’s continue to prioritize diabetes here in Virginia
Summary