Transcript Slide 1

New Antituberculous
Drugs
Hail M. Al-Abdely, MD
Consultant, Infectious Diseases
King Faisal Specialist Hospital and
Research Center
Driving forces behind Drug
development
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Good market
– Common NOT rare (pseudomonas versus
Burkhelderia)
– Common in the rich (HIV versus Tuberculosis)
– Difficult to treat with current agents
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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
The Fact
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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
Timeline Development of Antituberculous Drugs
Rifampin-1963
Ethambutol-1962
Pyrazinamide-1954
INH-1952
Streptomycin-1944
1940
1950
1960
1970
1980
1990
2000
2010
Why do we need new drugs?
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Current therapy
– Too long
– Too toxic
– Too complex
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Resistance
Epidemiology of MDR TB
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
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
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
* Surveyed
Dye et al. Global Burden of Multidrug-Resistant TB. JID 185(8), 2002
The target Drug For TB
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Effective
Quick-acting sterilizing agent
Kills persisting bacilli
Avoid cross-resistance with existing
drugs
Low toxic side-effects
New Chemotherapeutic
Agents
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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.
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Nitroimidazoles
– related to metronidazole. May work better against latent bacilli
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Amoxicillin/Clavulenic acid
– Anectodes of few cases
Timeline Development of Antituberculous Drugs
Rifampin-1963
Ethambutol-1962
Pyrazinamide-1954
INH-1952
Streptomycin-1944
1940
1950
1960
Fluroquinolones
1970
1980
1990
2000
2010
Fluoroquinolones
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Ciprofloxacin
Levofloxacin
Sparfloxacin
Moxifloxacin
Gatifloxacin
MICs (µg/ml) of GAT, MXF, and LVX against 23 M. tuberculosis isolates
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 Apr;46(4):1022-5
Randomized controlled trial of a drug regimen that
includes ciprofloxacin for the treatment of pulmonary
tuberculosis ( Kenneday et al. CID 22:827, 1996)
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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.
Randomized controlled trial of a drug regimen
that includes ciprofloxacin for the treatment of
pulmonary tuberculosis …
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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.
HIV positive
100
HRZE
80
HRC
60
40
20
0
0
1
2
3
Months
4
5
6
% culture positive
% culture positive
HIV negative
100
HRZE
80
HRC
60
40
20
0
0
1
2
3
4
5
6
Months
Kennedy N, et al. Clin Infect Dis. 1996 May;22(5):827-33.
Fuoroquinolones: Where do they stand in
current recommendation?
CDC, ATS, IDSA recommendation . MMWR, June 2003
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
Timeline Development of Antituberculous Drugs
Rifampin-1963
Ethambutol-1962
Pyrazinamide-1954
INH-1952
? Oxazolidinone
Streptomycin-1944
1940
1950
1960
Fluroquinolones
1970
1980
1990
2000
2010
Linezolid
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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
In vitro activities (MIC (µg/ml) of linezolid against 117 clinical isolates of
M. tuberculosis
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 Jan;47(1):416-7
Oxazolidinones in Animal Model
Cynamon MH, et al. Antimicrob Agents Chemother. 1999 May;43(5):1189-91
Linezolid in Human
Tuberculosis
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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
Linezolid in Human
Tuberculosis
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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 amoxicilinclavulanate
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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
Timeline Development of Antituberculous Drugs
Rifampin-1963
Ethambutol-1962
Pyrazinamide-1954
Novel Compounds
INH-1952
? Oxazolidinone
Streptomycin-1944
1940
1950
1960
Fluoroquinolones
1970
1980
1990
2000
2010
Diarylquinoline (R207910)
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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.
Activity of the novel compound R20910 against
Mycobacterium tuberculosis.
Before treatment
After treatment
10000000
Surviving bacteria
1000000
100000
10000
1000
100
10
1
INH, RIF, PZA
R207910, RIF, PZA
Andries K, Verhasselt P, Guillemont J, et al. Science 2005;307:223-7.
Family of diamines
(Dipiperidines) SQ109, SQ609,
SQ619
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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 100fold lower doses
NIKONENKO, et al. Abstract B-693, 44th ICAAC, Washington DC, 2004
Immunotherapy
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Cytokine therapy
–  interferon
– Interleukin-2
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Vaccine
– Killed organism (M. vaccae)-did not work
– DNA vaccine
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Nutrition
– Zinc, Vit A, Vit D
(Dolmans WM, et al. A double-blind, placebocontrolled 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
Cytokine therapy
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 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
DNA vaccine
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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
Conclusion
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New drug development against M. tuberculosis has been unjustifiably
slow
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Fluroquinolones and oxazolidinones are promising and may become a
cornerstone in salvage therapy for MDR-TB
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The wide use of FQ and OZ for bacterial infection can alter the
epidemiology of TB resistance to these agents
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Few Investigational drugs are under development with promising
potential
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Immunotherapy can be synergistic to antituberculous therapy for MDRTB
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Cost and delivery will remain the main obstacle in future therapy of
tuberculosis in endemic areas