Experimental treatment of · streptomycin (SM), AMK, RIF, and AMK+RIF * Assess the “growth...
Transcript of Experimental treatment of · streptomycin (SM), AMK, RIF, and AMK+RIF * Assess the “growth...
Experimental treatment of M.ulcerans disease
Jacques H. Grosset, MD
Center for TB ResearchJohns Hopkins UniversitySchool of MedicineBaltimore, MD
March 13-14, 2006
Relationship between Cmax & MIC MIC** (µg/ml)Cmax
(µg/ml)
0.5 - 12-3
10-20
15 - 252 - 4
15 - 208 - 10
0.06>162.0
2.00.5
0.52.0
MIC 90
0.03160.5
≤0.015 - 0.12≤4.0 - >16≤0.25 - 4.0
New compounds:Diarylquinoline (TMC207) 100Nitroimidazopyran (PA-824) 600Linezolid* 600
0.50.12
0.25 - 2.00.015 - >0.5
Other drugs: Amikacin* 500Moxifloxacin* 400
0.250.5
≤0.12 - 1.0≤0.12 - 4.0
TB drugs:Streptomycin*500 (7.5m/kg)Rifampicin* 600 (10mg/kg)
MIC50RangeAntibiotic and dose in mg
*Cost in the USA: from Medicare [SM, $5.60/g; AMK, $26.00/g]; from drugstore.com [RIF, $ 1.66/300mg; MXF, $ 10/400mg; Linezolid, $ 58.90/600mg]** From Ji et al., 2006, in press
In vivo data in the mouse model
Using Shepard’s kinetic method*, we assessed the activity of:
• 8-week daily (5/7) treatment with minocycline, sparfloxacin, clarithromycin, rifampicin (R, RIF), rifabutin (RBT), and amikacin (AMK)
• 4-week daily treatment with clari (as +ve control) streptomycin (SM), AMK, RIF, and AMK+RIF
* Assess the “growth delay” induced by treatment initiated one week after infection with 105 M. ulcerans and given for a limited period.
Onset of foot pad swelling in mice infected with 5x105 AFB of M.ulcerans and daily treated for 8 weeks
0102030405060708090
100
0 5 10 15 20 25
Week
Cum
ulat
ive
prob
abili
ty o
f hav
ing
afo
ot p
ad fr
ee o
f sw
ellin
g
ControlMinoSparfloClariR,Rbt,Amk
8-wk treatment
8 weeks
Onset of foot pad swelling in mice infected with 105 AFB of M.ulcerans and daily treated for 4 weeks
0102030405060708090
100
0 5 10 15 20 25 30 35Weeks
Cum
ulat
ive
prob
abili
ty o
f ha
ving
no
swol
len
foot
pad
controlclariSMAMKRIFAMK+RIF
treatment4w
Onset of foot pad swelling in mice infected with 105 AFB of M.ulcerans and daily treated for 4 weeks
0102030405060708090
100
0 5 10 15 20 25 30 35Weeks
Cum
ulat
ive
prob
abili
ty o
f ha
ving
no
swol
len
foot
pad
controlclariSMAMKRIFAMK+RIF
4w
Conclusion I• Minocycline and levofloxacin had no activity• Moxifloxacin had limited bacteriostatic activity• Sparfloxacin and clarithromycin had potent
bacteriostatic activity• Streptomycin, amikacin, rifampicin and rifabutin had
bactericidal activity (no relapse within the 4 months after completion of 2-month treatment)
• The combination AMK-RIF was strongly bactericidal but given for one month did not prevent relapse in 50% of mice. It was therefore used to treat mice with established M. ulcerans disease for 3 months
Evolution of the average lesion index (ALI) in mice infected with Mycobacterium ulcerans
and started on treatment when foot pads were swollen
0
1
2
3
4
5
6
0 4 8 12 16Week
ALI
of t
he fo
ot p
ad
ControlRR+CL+SPR+AMK
Death
(ALI of foot pad: 0, no lesion; 1, not inflammatory swelling; 2, inflammatory swelling; 3, inflammatory hind foot; 4, inflammatory trunk swelling; 5, death)
Treatment
Long-term follow-up of mice with M. ulceransdisease and treated for 3 months
Activities of the rifampicin-amikacin (R+A) combination given for 4 weeks at once, twice or five times weekly as
measured by the proportional bactericidal test
0.001
0.01
0.1
1
10
100
0 4
weeks
% o
f log
10 v
iabl
e M
.ulc
eran
s
R+A 1/7
R+A 2/7
R+A 5/74.2 log
3.2 log
2.5 log
*
* P<0.01
Conclusion II
• The combination AMK-RIF given for 3 months cured the M. ulcerans disease and was not followed by relapse within the 6 months after treatment completion
• The oral combination RIF+SPX+Clari was less rapidly active and followed by relapse
• RIF alone stabilized the disease and selected resistant mutants in the hands of Marsollier& Carbonnelle (AAC 2003:47: 1228-32)
Next steps?
• Potential of existing drugs? Moxifloxacin
• Potential of new drugs? TMC207, LZD: alone or in combination with RIF
Log10 M.ulcerans CFU per footpad in treated mice
012345678
-6 0 2 4 8 Week
Log 1
0 CFU
controlRIF alone STR aloneMXF aloneRIF+STRRIF+MXF
(Ji et al., 2006, in press)
pretreatment
Rx initiation
MXF
RIF
RIF+MXF
Reduction of log10 M.ulcerans CFU per footpad in treated mice
0
1
2
34
5
6
7
8
-6 0 2 4 8 Week
Log 1
0 CFU control
LZDTMC207RIF+LZDRIF alone RIF+TMC
(Ji et al., 2006, in press)
pretreatment
Rx initiation
R+L
LZD
RIF+TMC
TMC
RIF
To conclude• Existing drugs :
No clear bactericidal benefit of adding MXF to RIF (except for prevention of resistance)
• New drugs:- Nitroimidazopyran (PA-824): not active- Diarylquinoline (TMC207): active but still in development- Linezolid: active
But, no clear benefit of adding TMC207 or LZD to RIF
Conclusion: There is no basis from in vitro and animal studies at present for proceeding with comparative controlled trials to find an alternative to RIF+SM