New antituberculous agents for drug-resistant resistant TB Symposium Belgian Society of Infectiology and Clinical Microbiology November 9 Jens Van Roey, MD - Tibotec Definitions MDR-TB multidrug resistance to, at least, isoniazid and rifampicin. Primary or acquired. XDR-TB is MDR-TB plus resistance to a fluoroquinolone and, at least, one second-line injectable agent (amikacin, kanamycin, capreomycin) Due to: poorly managed TB care and patient non- adherence. incorrect prescribing, poor quality of drugs, erratic supply, inadequate laboratory infrastructure, human resources constraints and limited access to health services WHO MDR-TB Estimates 8 MDR-TB drugs per WHO guidelines Total Global Estimate = 511, Estimates MDR 1 High Burden Countries MDR TB WHO GLOBAL 8 1 1 1 8 China India Russia Pakistan Bangladesh South Africa Ukraine Indonesia Phillipines Nigeria Market Economies All other Series1 China India Russia Pakistan Bangladesh South Africa Ukraine Indonesia Phillipines Nigeria Market Economies All other RANK ANTIBIOTICS ANTIMYCOBACTERIAL ACTIVITY 1 AMINOGLYCOSIDES Bactericidal on replicating organisms a b c d Streptomycin Kanamycin Amikacin Capreomycine ETHIONAMIDE Bactericidal 3 PYRAZINAMIDE Bactericidal at acidic ph OFLOXACIN Low bactericidal Market economies include n=159 from USA Global Plan to Stop TB : 1.Mi MDR patients to be treated by 15 5 ETHAMBUTOL Bacteriostatic CYCLOSERINE Bacteriostatic 7 P.A.S. Bacteriostatic
Treatment outcomes in MDR-TB 85 pts/33 studies Success Failure Default Death Individualized 1 11 standardized 5 18 1 11 Criteria leading to enhanced success, if combined 9% success rate Treatment duration of at least 18 months Use of DOT strategy throughout Criteria with no effect on treatment outcome Number of resistant drugs in the regimen Number of drugs % receiving fluoroquinolones HIV prevalence Overview new MDR-TB drugs Fluoroquinolones: moxi- and gatifloxacin Oxazolidinone: Linezolid, PNU-18 Nitro-imidazoles: imidazoles: PA-8 and OPC-783 Diamines or Ethambutol derivatives: SQ19 Diarylquinolines: TMC7 E. Orenstein et al. Lancet Inf Dis, March 9 5 Moxifloxacin vs. Ethambutol Chaisson ICAAC 7 HRZ+ethambutol or moxifloxacin 17 patients, 1 analyzed % negative cultures p=.1 Fluoroquinolones weeks 7 8
Moxifloxacin, gatifloxacin vs. EMB (OFLOTUB Study) Moxifloxacin vs. INH Dorman,, ICAAC 7 RZE + isoniazid or moxifloxacin 33 patients, 3 (79%) analyzed 5 (73%) excavation+, 3 (11%) VIH+ Moxifloxacin : % (13/171) culture negative at months Isoniazid : 55% (93/173) cultures negative at months p=,37 poor results due to improved culture techniques Rustomjee et al. 8. IJTLD. 9 1 Moxi-, Gatifloxacin MIC:.3.5 µg/ml Mainly being investigated for DS-TB and treatment shortening potential (time to conversion analysis) M substitutes H or E, G substitutes E in phase II/III trials Cross-class resistance issues Concerns M has QT prolongation effect and G has dysglycemia effects 11 Oxazolidinones 1
Linezolid MIC =.5 µg/ml (Alcala, AAC 3) Mechanism of action : inhibition of the synthesis of proteins by blocking the initiation complex Pharmacokinetics (Gee, AAC 1) at mg x /day Cmax = 18 µg/ml Half-life life = 5 hours Time dependant activity? (%>MIC) Absorption interaction with H and Z 13 CFU counts (log1) in the lungs 9 8 7 5 Placebo Linezolid, 5 3 Linezolid, 1 PNU, 5 1 PNU,1 Weeks Activity of Oxazolidinones in the mouse model. Cynamon et al. 1999. AAC. 1 PNU-18 Currently in Phase I trials In murine model both bactericidal and sterilizing activity, resulting in treatment shortening potential R+PNU is equally effective as R+H+PNU in continuation phase No cross-resistance resistance with existing TB-drugs Relapse assessment Linezolid vs PNU-18 Proportion (%) of mice with relapse after treatment Treatment group 3 mths mths mths RHZ + RH n.d. 18 of (9) of () RHZU + RHU 9 of (5) 1 of (5) n.d. RHZU + RU 7 of (35) 1 of (5) n.d. RHZU + RH 17 of (85) 7 of (35) n.d. RHZL + RHL n.d. of (1) n.d. 15 RHZL + RH n.d. of (1) n.d. 1
Conclusions Linezolid displays a limited (bacteriostatic) activity in vitro, in the mouse model and in patients. PNU-18 has sterilizing activity in the murine model and may be capable of shortening treatment duration for DS as well as MDR-TB Nitro-imidazoles imidazoles 17 18 PA-8 and OPC-783 Activity of PA-8 alone against M. tuberculosis in mice MIC vs. M. tuberculosis H37Rv (μg/ml) g/ml) Isoniazid.5 PA-8.15-.5.5 OPC-783.-.. Rifampicin.5 Metronidazole derivatives Active on DS-TB and MDR-TB strains. Inhibition of cell wall lipids and protein synthesis No cross resistance with standard TB-drugs Cross resistance with PA-8 CFU counts (log1) in the lungs 1 1 8-5 control RHZ H PA-8 H + PA Days Tyagi et al. 5. AAC. 19
Early Bactericidal Activity of PA-8 in patients with pulmonary tuberculosis Conclusions 1 PA-8 : MIC:.15.5 µg/ml No cross resistance with anti-tb drugs but cross resistance with OPC-783. When used at 1 mg/kg in mice, similar activity than that of INH. Can not shorten DS-TB treatment in the mouse model. In patients, limited EBA. Phase II started. Activity of OPC-783 against M. tuberculosis in the mouse model. Early Bactericidal Activity of OPC-783 in patients with pulmonary tuberculosis 3
Conclusions OPC-783 : MIC.. µg/ml No cross resistance with anti-tb drugs but cross resistance with PA-8. Much more active than PA-8 in the mouse model. Potential to shorten treatment duration In patients, limited EBA. Phase II ongoing Ethambutol derivatives 5 Activity of SQ19 against M. tuberculosis in the mouse model Nikonenko et al. 7. AAC. Conclusions MIC:.1-..µg/ml DS and MDR-TB Inhibition cell wall synthesis No cross resistance with ethambutol or any first line TB drug (H, R, Z) In the mouse model, the addition of SQ19 to RHZ is more effective than RHZ. Phase I multidose safety study started in 9 7 8
J accelerates bacterial killing when added to SOC for MDR TB 7 Diarylquinolines 5 3 1 H = isoniazid R = rifampin Z = pyrazinamide J = R791 (TMC7) A= amikacin Et= Ethionamide M= moxifloxacin Z= pyrazinamide controls D1 HRZ HRZ+J wks AEtMZ AEtMZ+J 8 wks Lounis et al.. AAC. 3 EBA with TMC7 Activity of TMC7 in MDR-TB patients Changes in cfu counts over time with 95% CL start TMC7, placebo end TMC7, placebo double-blind phase BR alone for 1-18 m Confirmed MDR TB 8 weeks Stage I n=7 weeks Stage II n=15 y follow-up BR regimen: kanamycin, FQ, ethionamide, PZA, cycloserine 31 3
Time to culture conversion (MGIT) on ITT population (n=) Mean (±( SD) log 1 CFU count (SSCC) p =.3 (a) p-value from Cox proportional model adjusting for strata 33 3 Conclusions MIC:.3µg/ml No cross-resistance resistance with existing TB drugs Potential for treatment shortening Sterilizing activity in mouse model In patients : EBA limited activity, good activity in phase II BACK-UP SLIDES 35 3
EBA of linezolid Dietze et al. 8. AJRCCM. EBA of linezolid Dietze et al. 8. AJRCCM. AJRCCM. 37 38 Linezolid : in patients In vitro activity of TMC7 Clinical use of linezolid (Fortun, JAC 5) 5 patients treatead with linezolid + thiacetazone, clofazimine or o amoxicilline/clavulanate. All the isolates were sensitive in vitro (MIC.5 mg/l). Negativation of the sputum culture s after weeks of treatment. 3 cures (duration of treatment : 5-5 months). 1 lost to follow up after 5 months of treatment. 1 patient under treatment after 11 months. patients with anemia that need transfusions peripherial neuropathies 1 pancreatitis 39 Non-mycobacteria: MIC g/ml St. aureus Str. Pyogenes E. faecalis E. faecium S. typhimurium E. coli P. aeruginosa H. influenzae H. pylori M. pneumoniae Andries et al. 5, Science Br N O O H R791 TMC7 Compound J N Mycobacteria: MIC. g/ml M. tuberculosis MDR M. tuberculosis M. bovis M. avium M. kansasii M. fortuitum M. marinum M. smegmatis
ATP Synthase (cible du R791) Diarylquinoline : R791 (TMC7) Inhibition of ATP synthase Subunit c (atpe) 1 Andries et al. 5, Science Percentage of mice relapsing after treatment of MDR-TB Percentage of mice with positive cultures 5 3 1 RHZ+RH 11 Percentage of mice relapsing after treatment 1 JRZ+JR Relapse rates (%) months JMZ+JM 11 AEtMZ+EtM 58 Relapse rates (%) months JAEtMZ+JEtM 8 3 Ibrahim et al. 8, ICAAC 5 3 1 Activity of TMC7 in the mouse model TMC7 (J) in combination therapy Number of Bacteria in Lungs (Log 1CFU) Controls D1 R H Z R H Z J 5 logs drop in weeks R H J Z R = rifampin 1 mg/kg H = isoniazid 5 mg/kg Z = pyrazinamide 15 mg/kg J = JNJ 5 mg/kg R J Z Accelerated Drop in Bacterial Load H J H Z R 8 wks wks
Percentage of mice relapsing after treatment of Drug Susceptible -TB Microbiology data in mice and patients Percentage of mice with positive lung cultures 9 8 7 5 3 1 RHZ/RH 17 8 RMZ/RM 5 8 JRZ/JR 13 7 8 7 JHZ/JH 9 35 JRHZ/JRH mo 3mo mo mo Log CFU in lungs 8 7 5 3 1 Efficacy in Mice 8 weeks Lounis et al. AAC. AEtMZ AEtMZ+ TMC Log CFU in sputum 8 7 5 3 1 Efficacy in MDR TB patients KEtOZ+TMC KEtOZ 8 Weeks Diacon et al. NEJM. 9 5 Veziris et al. ICAAC, 7 A= amikacin Et=ethionamide M=moxifloxacin Z=pyrazinamide K= kanamycin O=ofloxacin