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Pr Ali Ben Kheder
The First annuel conference of LATA 24 March 2016- Beyrouth
Group 1: TB drugs of 1rst line
-
Isoniazide (H)
Rifampicine (R)
Ethambutol (E)
Pyrazinamide (Z)
Group 2: TB drugs injected
-
Kanamycine (Km)
Amikacine (Am)
Capréomycine (Cm)
Streptomycine (S)
Group 3: Fluoroquinolones
- Ofloxacine (Ofx)
- Moxifloxacine (Mfx)
- Lévofloxacine (Lfx)
Group 4: TB drugs bactériostatic de 2nd line
- Ethionamide (Eto)/ prothionamide (Pto)
- Cyclosérine (Cs)/ Terizidone (Trd)
- Acide p- aminosalicylique (PAS)
Group 5: TB Drugs with unproven effectivness
-
Clofazimine (Cfz)
Linezolide (Lzd)
Amoxicilline/Acide clavulanique (Amx/Clv)
Thioacétazone ((Thz)
Imipénème/ Cilastatine (Ipm/Cln)
Isoniazide à dose élevée
Clarithromycine (Clr)
Why do we need new drugs/ regimens?
• Decrease toxicity
Adverse effects are important
• Shorten therapy
Multidrug-resistant TB, or intolerance to first-line drugs
• Improve efficacy+++
Developing Drugs
Anne F. Luetkemeyer
AJRCCM 2011
MOXIFLOXACIN

Moxifloxacin is generally regarded as later
Of generation C-8-methoxy- fluoroquinolones.

This newer fluoroquinolones have potent antituberculosis activity, much of which is due to
fragment C-8-methoxy .
Common Structure of quinolones
Fluorine radical
Fluorine radical: improve the antibacterial activity
Fluoroquinolones : broad spectrum

Intracellulars Bacteria ++






L. pneumophila,
Mycoplasmes,
Chlamydia spp.,
Coxiella burnetii
Mycobacterium

M. tuberculosis (Moxiflo ++)

Some atypical mycobacterium (Cipro ++)
Francisella tularensis
Bioavailability
Molécule
Bioavail
t1/2 (h)
IV dose
Oral dose
Norfloxacine
50%
4-5
-
2 x 400 mg
2 x 400 mg
2 x 400 mg
Pefloxacine
Ciprofloxacine
>90%
60-80
10
%
3-5
2 x 200 mg ou 2 x 500 mg ou
2 x 400 mg
2 x 750 mg
2 x 200 mg
2 x 200 mg
Ofloxacine
85-95%
5-7
Levofloxacine
>90%
6-8
1 x 500 mg
1 x 500 mg
Moxifloxacine
90%
10
1 x 400 mg
1 x 400 mg
Drug Resistance : real problem
Labreche MJ, Am J Health-Syst Pharm 2012
What justifies the role of moxifloxacin in
treatment of tuberculosis ?
MOXIFLOXACIN
Tested in :
 Clinical trial Phase II by the CDC TB trials
Consortium
(center of diseases control and prevention)
 Clinical multicentric trial Phase III (WHO and
European community)
MOXIFLOXACIN
Clinical trial phase II
 Objective : to compare bactercidal activity of Moxifloxacin, Isoniazid
et Rifampcine
 Protocol : Monotherapy of Moxifl (400mg/j), INH (300mg/j) or R
(600mg/j) during 5 days
Collection of Sputum D0 , D2 and D5
 Evaluation :
◦ Early bactericidal activity (D2)
◦ Time required to Kill 50% of bacteria
Gosting RD. Am. J. Respir. Crit. Care Med 2003, 1; 168 (11) 1342-5
Conclusion
Moxifloxacin has a bactericidal activity
similar to that Rifampicin
MOXIFLOXACIN :Tolerance
38 patients (14 MDR) treated by Moxifloxacin +3 main TB drug
duration of Treatment : 6 + 5 months
Results
 12 patients (31%) have at least an adverse effect
◦ 8 digestive AE
◦ 8 neurologic AE
 4 patients (10.5%) have had Major AE  Stop of the
Moxifloxacin
 thérapeutic success : 81.6%
51.7% in TBC MDR
Codecasa LR. Respir. Med 2006 . Feb 13
Conclusion
Moxifloxacin has a good tolerance
• 26 Centers in USA and AFRICA
• 328 Patients with smear positive TB
-No antecedent of treatment
-No resistance known
-65% in Africa
-11% of HIV
- 76% of cavitary lesions
• Randomized ,double blind:
-DOT Moxifloxacin 400mg versus INH 300mg 5/7
During 8 weeks + RIF –PZA-EMB
Main Goal: Smear culture conversion after 8 WEEKS
Moxifloxacine vs INH
moxifloxacin could be an alternative to INH in case of
resistance or major side effect
Moxifloxacin as an Alternative or Additive Therapy
for Treatment of Pulmonary Tuberculosis
Option/Bio 20(420):7-7 · June 2009
Although a final conclusion can be put forward , the
available scientific data suggest that use of
moxifloxacin seems to be as effective as ethambutol
and possibly as effective as isoniazid for treatment of
pulmonary tuberculosis .
Given the limited availability of options in 2ndpulmonary
tuberculosis treatment line , moxifloxacin is an
attractive option as an alternative for treating
pulmonary tuberculosis.
Rifampicin-moxifloxacin interaction
in tuberculosis treatment: a real-life
study
1
1
2
2
Authors: Manika, K. ; Chatzika, K. ; Papaioannou, M. ; Kontou, P. ; Boutou,
1
1
1
A. ; Zarogoulidis, K. ; Kioumis, I.
The International Journal of Tuberculosis and Lung Disease,
Volume 19, Number 11, 1 November 2015, pp. 1383-1387(5)
Study Setting
Rifampicin (RMP) has been reported
to reduce moxifloxacin (MFX)
levels, which may interfere with
the effectiveness of MFX in treating
tuberculosis (TB).
Study Objective
To study the MFX/RMP interaction in patients
receiving MFX with or without RMP as part of
their anti-tuberculosis treatment regimen
Study Design
 Patients with pulmonary TB followed up by the Tuberculosis Outpatient Clinic of the Pulmonary Department, Aristotle University
of Thessaloniki, Greece, who underwent treatment with MFX
during the periods 1 May 2012-30 April 2014 and 1 January-31
March 2015, were included in the study.

MFX levels were compared between 12
patients who were receiving RMP (Group 1)
and 10 who were not (Group 2)
Conclusion
 Decrease in MFX level was observed in
the RMP-treated group,
 the effect was lower than previously
There
is interaction
between
RMP and MFX
reported
in a real-life
setting.
leading to readjustement of MFX dose
 The large variability observed in MFX
pharmacokinetics in both groups may
suggest the need for dose readjustment
in some patients, regardless of RMP coadministration
Concerning Shortening of Treatment
Moxifloxacin could shorten duration
of tuberculosis treatment
The Pharmaceutical Journal3 APR 2009
Study Design
In a randomised trial conducted in Rio de
Janeiro, Brazil, 80% of the 170 tuberculosis
patients enrolled in the study who had received
400mg of MFX five days a week tested negative
on the eighth week, compared with 63% in the
group receiving just 15–20mg/kg ethambutol
(P=0.03).
Results
 After one week, 13 % of 69 patients in the
moxifloxacin group had sputum cultures that
converted to negative compared with 3 % of
those in the ethambutol group (P=0.03).
 At every week after enrolment, patients
assigned to moxifloxacin had a significantly
higher rate of culture conversion than those
assigned to ethambutol
Conclusion
Additional studies are required to confirm
 the safety of using moxifloxacin for longer periods,
 as well as to assess whether shorter courses of the
antibiotic can cure tuberculosis as well as or better
than the current six-month regimen.
« the study authors say. »
Four-Month Moxifloxacin-Based
Regimens for Drug-Sensitive
Tuberculosis
Stephen H. Gillespie, M.D., D.Sc., Angela M. Crook, Ph.D., Timothy
D. McHugh, Ph.D., Carl M. Mendel, M.D., Sarah K. Meredith, M.B.,
B.S., Stephen R. Murray, M.D., Ph.D., Frances Pappas, M.A., Patrick
P.J. Phillips, Ph.D., and Andrew J. Nunn, M.Sc., for the REMoxTB
Consortium*
N Engl J Med 2014; 371:1577-1587October 23, 2014
The REMoxTB study was a collaboration
between :
The TB Alliance, Bayer HealthCare AG, the University College
London (UCL) ,Centre for Clinical Microbiology, the Medical
Research Council Clinical Trials Unit at UCL and the University
of St. Andrews.
It enrolled 1,931 patients at 50 sites in nine countries
(Kenya, Mexico, Tanzania, South Africa, China, India,
Thailand, Malaysia and Zambia).
Methods
a randomized, double-blind, placebo-controlled, phase 3 trial
to test the non-inferiority of two moxifloxacin-containing
regimens as compared with a control regimen (1931 patients
enrolled)
 One group of patients received isoniazid, rifampin,
pyrazinamide, and ethambutol for 8 weeks, followed
by 18 weeks of isoniazid and rifampin (control group).
 In the second group, we replaced ethambutol with
moxifloxacin for 17 weeks, followed by 9 weeks of
placebo (isoniazid group),
 and in the third group, we replaced isoniazid with
moxifloxacin for 17 weeks, followed by 9 weeks of
placebo (ethambutol group).
Objective
a randomized, double-blind, placebocontrolled, phase 3 trial to test the noninferiority
of
two
moxifloxacincontaining regimens as compared with a
control regimen (1931 patients enrolled)
End point
 The primary end point was treatment
failure or relapse within 18 months after
randomization
RESULTS OF PHASE III REMOXTB
CLINICAL TRIAL PUBLISHED
 Results of the Phase III REMoxTB clinical trial were published in
the New England Journal of Medicine on September 7th, 2014. REMox
or Rapid Evaluation of Moxifloxacin in
 Tuberculosis (REMoxTB) was a trial designed to determine whether
replacement of either ethambutol or isoniazid with moxifloxacin
shortened the duration of therapy.
 In summary, while the regimens with
moxifloxacin caused a more rapid decrease in
mycobacterial load, moxifloxacin containing
regimens did not shorten TB treatment to 4 months
as predicted.
Conclusion
 The two moxifloxacin-containing regimens
produced a more rapid initial decline in
bacterial load, as compared with the
control group.
 However, non-inferiority for these regimens
was not shown, which indicates that
shortening treatment to 4 months was not
effective in this setting. (Funded by the
Global Alliance for TB Drug Development and
others; REMoxTB ClinicalTrials.gov number,
NCT00864383
According to the researchers, REMoxTB was the most
rigorous TB trial ever conducted, and although the
experimental regimen wasn’t sufficient to reduce TB
treatment time by 2 months,
and CEO of TB Alliance
Mel Spigelman, MD, president
High-Dose Rifapentine with Moxifloxacin
for Pulmonary Tuberculosis
Amina Jindani, F.R.C.P., Thomas S. Harrison, F.R.C.P., Andrew J. Nunn, M.Sc.,
Patrick P.J. Phillips, Ph.D., Gavin J. Churchyard, Ph.D., Salome Charalambous, Ph.D.,
Mark Hatherill, M.D., Hennie Geldenhuys, M.B., Ch.B., Helen M. McIlleron, Ph.D.,
Simbarashe P. Zvada, M.Phil., Stanley Mungofa, M.P.H., Nasir A. Shah, M.B., B.S.,
Simukai Zizhou, M.B., Ch.B., Lloyd Magweta, M.B., Ch.B., James Shepherd, Ph.D.,
Sambayawo Nyirenda, M.D., Janneke H. van Dijk, Ph.D., Heather E. Clouting, M.Sc.,
David Coleman, M.Sc., Anna L.E. Bateson, Ph.D., Timothy D. McHugh, Ph.D.,
Philip D. Butcher, Ph.D., and Denny A. Mitchison, F.R.C.P.,
for the RIFAQUIN Trial Team*
n engl j med 371;17 nejm.org October 23, 2014
Methods
We randomly assigned patients with newly diagnosed, smearpositive, drug-sensitive tuberculosis to one of three regimens:
 a control regimen that included 2 months of ethambutol,
isoniazid, rifampicin, and pyrazinamide administered daily
followed by 4 months of daily isoniazid and rifampicin;
 4-month regimen in which the isoniazid in the control
regimen was replaced by moxifloxacin administered daily
for 2 months followed by moxifloxacin and 900 mg of
rifapentine administered twice weekly for 2 months
or a 6-month regimen in which isoniazid was replaced
by daily moxifloxacin for 2 months followed by one weekly
dose of both moxifloxacin and 1200 mg of rifapentine for
4 months.
Methods
Sputum specimens were examined on
microscopy and after culture at regular
intervals.
The primary end point was a composite
treatment failure and relapse, with noninferiority
 The 6-month regimen in which rifapentine and
moxifloxacin are administered once weekly
during the continuation phase is non inferior
to the standard regimen, which requires daily
administration of medication for 6 months.
 The new regimen could facilitate the strategy of
directly observed treatment and could be used
as first line treatment in certain settings, such
as those with low rates of HIV coinfection or
high ratesof isoniazid resistance.
JID JOURNAL SUPPLEMENT:
TUBERCULOSIS DRUG DEVELOPMENT
 A supplement dedicated to TB drug development
appears in the Journal of Infectious Diseases Volume
211, June 15, 2015. Topics include nonclinical models of
TB drug development, PKPD and dose response, drug
metabolism and interactions, and special populations.
 - See more at: http://www.newtbdrugs.org/blog/#sthash.AsmSs4iO.dpuf
Conclusion

MFX is an new interesting drug for fighting TB

Its role as a treament of second line is well
accepted

However , further studies are needed to
demonstrate its role in shortening of TB
treatment
Conclusion
First : We must better use FLD!!!