New Antituberculous Drugs

1. New Antituberculous Drugs Hail M. Al-Abdely, MD Consultant, Infectious Diseases King Faisal Specialist Hospital and Research Center

2. Driving forces behind Drug development • Good market • Common NOT rare (pseudomonas versus Burkhelderia) • Common in the rich (HIV versus Tuberculosis) • Difficult to treat with current agents • Emerging new organisms (Fungi in immune suppressed patients) • Resistance in old organisms (several bacteria) • Better kinetics and safety (Ampho B versus Azoles) • Basic Human need

3. The Fact • Despite this enormous market in terms of patients, only 5% of the 16 million people currently sick with TB can pay for treatment - a lack of buying power that has dissuaded investors for decades. Alliance against TB.org

4. 1940 1950 1960 1970 1980 1990 2000 2010 Timeline Development of Antituberculous Drugs Rifampin-1963 Ethambutol-1962 Pyrazinamide-1954 INH-1952 Streptomycin-1944

5. Why do we need new drugs? • Current therapy • Too long • Too toxic • Too complex • Resistance

6. Geographic region No. of MDR TB cases (% of all new cases) All countries (n = 136) 272,906 (3.2) Established market economies 882 (0.7) Latin America 8508 (2.2) Eastern Europe 17,269 (5.5) Africa, low HIV 15,014 (1.9) Africa, high HIV 25,199 (1.8) Eastern Mediterranean 45,964 (7.9) Southeast Asia 75,062 (2.5) Western Pacific 85,008 (4.5) Dye et al. Global Burden of Multidrug-Resistant TB. JID 185(8), 2002 Epidemiology of MDR TB

7. WHO Surveillance and Incidence of MDR TB Dye et al. Global Burden of Multidrug-Resistant TB. JID 185(8), 2002

8. WHO Estimates of MDR TB in Some Arabian Countries * Surveyed Dye et al. Global Burden of Multidrug-Resistant TB. JID 185(8), 2002

9. The target Drug For TB • Effective • Quick-acting sterilizing agent • Kills persisting bacilli • Avoid cross-resistance with existing drugs • Low toxic side-effects

10. New Chemotherapeutic Agents • Not many. Low interest from industry • Derivatives of Rifamycin • Rifabutin: Sensitive subset of Rifampin resistant strains • Rifapentine: Extended half-life but more mono-resistance to rifamycins • Rifazil. benzoxazinorifamycin. In vitro and animal models. High intra-cellular concentrations. • Nitroimidazoles • related to metronidazole. May work better against latent bacilli • Amoxicillin/Clavulenic acid • Anectodes of few cases

11. 1940 1950 1960 1970 1980 1990 2000 2010 Timeline Development of Antituberculous Drugs Rifampin-1963 Ethambutol-1962 Pyrazinamide-1954 INH-1952 Streptomycin-1944 Fluroquinolones

12. Fluoroquinolones • Ciprofloxacin • Levofloxacin • Sparfloxacin • Moxifloxacin • Gatifloxacin

13. MICs (µg/ml) of GAT, MXF, and LVX against 23 M. tuberculosis isolates Alvirez-Freites EJ. Antimicrob Agents Chemother. 2002 Apr;46(4):1022-5

14. Randomized controlled trial of a drug regimen that includes ciprofloxacin for the treatment of pulmonary tuberculosis ( Kenneday et al. CID 22:827, 1996) • INH-6, RIF-6, CIP-4 versus INH-6, RIF-6, PZA-4, ETH-2 (drug-duration in months) • Excluded previous exposure to any study drug • Smear/culture positive • 168 evaluable patients (HARZE 86, HRC 82) • The two groups matched well including number of HIV+ patients Kennedy N, et al. Clin Infect Dis. 1996 May;22(5):827-33.

15. Randomized controlled trial of a drug regimen that includes ciprofloxacin for the treatment of pulmonary tuberculosis … • Relapse rate At 6-12 months HRZE 0/81 (0.0%) HRC 7/75 (9.3%) Kennedy N, et al. Clin Infect Dis. 1996 May;22(5):827-33.

16. Kennedy N, et al. Clin Infect Dis. 1996 May;22(5):827-33.

18. Fuoroquinolones: Where do they stand in current recommendation? CDC, ATS, IDSA recommendation . MMWR, June 2003

19. Quinolones for Other infections and TB A 36-year-old man with AIDS presented with weight loss, flank pain, fever, and dysuria. Examination revealed prostatic nodules, and CT scan revealed abscesses. He received six days of levofloxacin therapy for prostatitis. There was no clinical improvement. He then received ciprofloxacin alone for seven days and afterward underwent transurethral prostatic resection; acid-fast smears were positive. A urine culture obtained four days before the initiation of levofloxacin therapy grew M. tuberculosis (isolate 1). A culture of a prostatic abscess subsequently also grew M. tuberculosis (isolate 2). Isolate 1 was sensitive to all fluoroquinolones Isolate 2 was resistant to all fluoroquinolones Ginsburg AS, et al. N Engl J Med. 2003 Nov 13;349(20):1977-8

20. 1940 1950 1960 1970 1980 1990 2000 2010 Timeline Development of Antituberculous Drugs Rifampin-1963 Ethambutol-1962 Pyrazinamide-1954 INH-1952 ? Oxazolidinone Streptomycin-1944 Fluroquinolones

21. Linezolid • First agent of the Oxazolidinones • Mainly a gram positive antibacteria agent • Developed mainly for VRE and MRSA • Showed good activity against mycobacteria including M. tuberculosis

22. In vitro activities (MIC (µg/ml)of linezolid against 117 clinical isolates of M. tuberculosis Alcala L, at al. Antimicrob Agents Chemother. 2003 Jan;47(1):416-7

23. Oxazolidinones in Animal Model Cynamon MH, et al. Antimicrob Agents Chemother. 1999 May;43(5):1189-91

24. Linezolid in Human Tuberculosis • A small series of 5 patients with MDR TB (isoniazid, rifampin, pyrazinamide, ethambutol, streptomycin and ciprofloxacin) • Three patients had prior pneumonectomies • All received linezolid, 600 mg orally twice a day for 4 to 33 months and aerosol interferon-gamma therapy (4 of 5 patients) three times a week in addition to their failing drug regimen • Five of five patients treated with linezolid achieved culture conversion in an average of 40 days • One patient converted in 7 days • one patient had the drug stopped because of toxicity (neutropenia) • Two of the five patients have completed 24 months of linezolid treatment and remained in remission. • Two more are still taking and remain in remission on linezolid • One patient died from an unrelated condition • Twice-daily treatment with linezolid costs $100 a day W Rom, T Harkin. 99th American Thoracic Society, Seattle, Abstract P621. 2003

25. Linezolid in Human Tuberculosis • Four patients MDR TB • Two M. bovis resistant to 12 anti-TB and 2 M. tuberculosis resistant to INH, rifampin, streptomycin, ethambutol, cycloserine, ethionamide ofloxacin • All the patients received linezolid with thiacetazone, clofamizine and amoxicilin-clavulanate • Patient #1: Lost at 5 months • Patient #2: Cured after 14 months • Patient #3: cured after 15 months • Patient #4: Cured after 24 months Fortún et Abstract L-921.- J. 44th ICAAC, Washington DC, 2004

26. 1940 1950 1960 1970 1980 1990 2000 2010 Timeline Development of Antituberculous Drugs Rifampin-1963 Ethambutol-1962 Pyrazinamide-1954 Novel Compounds INH-1952 ? Oxazolidinone Streptomycin-1944 Fluoroquinolones

27. Diarylquinoline (R207910) • Novel target, ATP synthase inhibiter • Rapidly bacteriocidal • No cross resistance with other agents • Not toxic to mice • No human experiments Andries K, Verhasselt P, Guillemont J, et al. Science 2005;307:223-7.

28. Activity of the novel compound R20910 against Mycobacterium tuberculosis. Andries K, Verhasselt P, Guillemont J, et al. Science 2005;307:223-7.

29. Family of diamines (Dipiperidines) SQ109, SQ609, SQ619 • Analogues of Ethambutol. • They emerged from the synthesis and screening of a 100,000 compound library of Ethambutol analogues • Interfere with cell-wall synthesis • As effective in vivo as Ethambutol at 100-fold lower doses • NIKONENKO, et al. Abstract B-693, 44th ICAAC, Washington DC, 2004

30. Immunotherapy • Cytokine therapy •  interferon • Interleukin-2 • Vaccine • Killed organism (M. vaccae)-did not work • DNA vaccine • Nutrition • Zinc, Vit A, Vit D (Dolmans WM, et al. A double-blind, placebo-controlled study of vitamin A and zinc supplementation in persons with tuberculosis in Indonesia: effects on clinical response andvnutritional status. Am J Clin Nutr 2002;75:720–727

31. Cytokine therapy •  interferon • As aerosol 3xwk given to 5 patients with smear-positive MDR TB • Failing regimen continued • Duration= 4wks • 4 of 5 became smear-negative • 1 of 5 smear from 4+ to 1+ • Wt stabilized or increased • After stoppage of interferon 4 of 5 became smear-positive. • Culture remained positive but the mean time to positive was extended from 17 to 24 days • Patients had radiological improvement Condos R, Rom WN, Schluger NW. Lancet 1997;349:1513–1515

32. DNA vaccine • A plasmid DNA encoding the Mycobacterium leprae 65 kDa heat-shock protein (hsp65) • in order to boost the efficiency of the immune system, is a valuable adjunct to antibacterial chemotherapy to shorten the duration of treatment, improve the treatment of latent TB infection and be effective against multidrug-resistant bacilli (MDR-TB). We also showed that the use of DNA-hsp65 alone or in combination with other drugs influence the pathway of the immune response or other types of inflammatory responses and should augment our ability to alter the course of immune response/inflammation as needed, evidencing an important target for immunization or drug intervention. C L Silva et al. Gene Therapy (2005) 12, 281-287

33. Conclusion • New drug development against M. tuberculosis has been unjustifiably slow • Fluroquinolones and oxazolidinones are promising and may become a cornerstone in salvage therapy for MDR-TB • The wide use of FQ and OZ for bacterial infection can alter the epidemiology of TB resistance to these agents • Few Investigational drugs are under development with promising potential • Immunotherapy can be synergistic to antituberculous therapy for MDR-TB • Cost and delivery will remain the main obstacle in future therapy of tuberculosis in endemic areas