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
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
Epidemiology of MDR TB
7
WHO Surveillance and Incidence of MDR TB
Country MDR TB of all new cases
Estonia 14.1
Latvia 9.0
China (non-DOTS) 7.7
China (DOTS) 2.8
Russia 6.0
India 3.4
Iran 5.8
Dominican 6.6
Ivory Cost 5.3
Dye et al. Global Burden of Multidrug-Resistant
TB. JID 185(8), 2002
8
WHO Estimates of MDR TB in Some Arabian Countries
Country MDR TB of all new cases
Morocco 2.2
Oman 0.8
Algeria 0.7
Egypt 5.6
Jordan 2.8
Kuwait 3.3
Lebanon 3.4
Saudi Arabia 3.0
Sudan 10.1
Syria 6.7
Yemen 12.4
Dye et al. Global Burden of Multidrug-Resistant
TB. JID 185(8), 2002
Surveyed
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
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
Antimicrobial agent MICs (µg/ml) MICs (µg/ml) MICs (µg/ml)
Antimicrobial agent 50 90 Range
GAT 0.031 0.031 0.007-0.12
MXF 0.062 0.125 0.031-0.12
LVX 0.5 1 0.12-1
Alvirez-Freites EJ. Antimicrob Agents Chemother.
2002 Apr46(4)1022-5
14
Randomized controlled trial of a drug regimen
that includes ciprofloxacin for the treatment of
pulmonary tuberculosis ( Kenneday et al. CID
22827, 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
May22(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
May22(5)827-33.
16
Kennedy N, et al. Clin Infect Dis. 1996
May22(5)827-33.
17
(No Transcript)
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 Is
olate 2 was resistant to all fluoroquinolones
Ginsburg AS, et al. N Engl J Med. 2003 Nov
13349(20)1977-8
20
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

M. tuberculosis isolates (no. of isolates)
M. tuberculosis isolates (no. of isolates) Range 50 90 Geometric mean

Susceptible to first-line drugs (73) 0.25-1 0.5 0.5 0.524
Resistant to first-line drugs (44)   0.125-1 0.5 1 0.477
Resistant to one first-line drug (25)   0.125-1 0.5 1 0.529
Resistant to multiple first-line drugs (19) 0.25-1 0.5 0.5 0.417
All (117)   0.125-1 0.5 1 0.506

Alcala L, at al. Antimicrob Agents Chemother.
2003 Jan47(1)416-7
23
Oxazolidinones in Animal Model
Cynamon MH, et al. Antimicrob Agents Chemother.
1999 May43(5)1189-91
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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-clavulana
  te
• 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
Timeline Development of Antituberculous Drugs
Rifampin-1963
Ethambutol-1962
Pyrazinamide-1954
Novel Compounds
INH-1952
? Oxazolidinone
Streptomycin-1944
Fluoroquinolones
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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 2005307223-7.
28
Activity of the novel compound R20910 against
Mycobacterium tuberculosis.
Andries K, Verhasselt P, Guillemont J, et al.
Science 2005307223-7.
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
  200275720727

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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
199734915131515
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