Later Generation Fluoroquinolones
in treatment of XDR Tuberculosis
Karen Jacobson, MD, MPH
Massachusetts General Hospital
Harvard Medical School
October 27, 2012
Standard TB Therapy
ISONIAZID
RIFAMPIN
PYRAZINAMIDE
ETHAMBUTOL
MDR
MDR Tuberculosis Therapy
FLUOROQUINOLONE
INJECTABLE AGENT
XDR
PYRAZINAMIDE
ETHIONAMIDE
CYCLOSERINE or PAS
± ETHAMBUTOL
WHO guidelines programmatic management
drug-resistant tuberculosis: 2011 update
Tugela Ferry, KwaZulu-Natal, South
Africa
• First described 2006
• 53 patients, all coinfected with HIV and
XDR TB
• Survived median 16
days
• Mortality 98%
Gandhi NR et al. Lancet 2006;368:1575-80
Fluoroquinolones
Early Generation
Later Generation
Ciprofloxacin
Gatifloxacin
Ofloxacin
Levofloxacin
Moxifloxacin
Sparfloxacin
Fluoroquinolone Mechanism
• Kill bacteria by altering DNA gyrase and
topoisomerase IV
• DNA gyrase: 2 A and 2 B subunits encoded by
gyrA and gyrB genes
• Quinolone resistance determining region
(QRDR)
• Also shown in lab strains: efflux pumps and
DNA mimicry
Mean Inhibitory Concentrations
and Structure
• Ofloxacin ≥ 2.0 ug/ml
• Moxifloxacin ≥ 0.25-0.5 ug/ml
Ofloxacin
Moxifloxacin
Aims
• Assess XDR TB treatment outcomes
• Identify therapeutic approaches
associated with favorable treatment
outcomes
XDR TB treatment outcomes
• All XDR treatment outcome studies (13)
Proportion of patients with favorable outcomes
Proportion Favorable Outcomes
(95% CI)
Study
Banerjee et al18
0.41 (0.18, 0.65)
Blaas et
al19
0.50 (0.01, 0.99)
Chan et
al20
0.20 (-0.05, 0.45)
Condos et al21
0.50 (0.11, 0.89)
Eker et al22
0.57 (0.20, 0.94)
al23
0.18 (0.12, 0.24)
Jeon et
Keshavjee et al9
0.48 (0.30, 0.67)
Kim H et al5
0.54 (0.39, 0.68)
Kim D et al24
0.29 (0.19, 0.40)
Kliiman et
al25
0.43 (0.29, 0.56)
Kwon et al26
0.67 (0.49, 0.85)
Mitnick et al27
0.62 (0.48, 0.76)
Shah et
al28
0.44 (0.33, 0.55)
Overall (I-squared = 84.3%)
0.44 (0.33, 0.55)
NOTE: Weights are from random effects analysis
0
.45
1
Proportion of patients who died
Study
Proportion Died
(95% CI)
Banerjee et al18
0.29 (0.07, 0.51)
Blaas et
al19
0.25 (0.0, 0.68)
Chan et
al20
0.50 (0.19, 0.81)
Condos et
al21
0.50 (0.11, 0.89)
Eker et al22
0.14 (0.0, 0.39)
Jeon et al23
0.23 (0.17, 0.29)
Keshavjee et al9
0.07 (-0.02, 0.16)
Kim H et al5
0.27 (0.17, 0.37)
Kim D et al24
0.14 (0.04, 0.24)
Kliiman et
Kwon et
0.19 (0.09, 0.29)
al26
Mitnick et
Shah et
al25
0.00 (0.00, 0.12)
al27
0.21 (0.09, 0.33)
al28
0.35 (0.25, 0.45)
Overall (I-squared = 67.7%)
0.21 (0.14, 0.27)
NOTE: Weights are from random effects analysis
0
.25
1
Univariate meta-regression of
individual study characteristics
Favorable outcomes, stratified on FQ use
Proportion Favorable Outcomes
(95% CI)
At least 50% Patients Received Later
Generation Fluoroquinolones
Blaas et al
0.50 (0.01, 0.99)
Condos et al
0.50 (0.11, 0.89)
Kim H et al
0.54 (0.39, 0.68)
Kwon et al
0.67 (0.49, 0.85)
Mitnick et al
0.62 (0.48, 0.76)
Overall (I-squared = 0.0%)
0.59 (0.51, 0.68)
0
0.6
1
Fewer than 50% Patients Received
Later Generation Fluoroquinolones
Chan et al
0.20 (-0.05, 0.45)
Eker et al
0.57 (0.20, 0.94)
Jeon et al
0.18 (0.12, 0.24)
Keshavjee et al
0.48 (0.30, 0.67)
Kim D et al
0.29 (0.19, 0.40)
Overall (I-squared = 73.7%)
0.31 (0.18, 0.43)
0
0.3
1
Specific gyrA mutations
• Codons 94, 88 = higher level resistance
• Codons 90, 91, 89 = lower level resistance
• 96% of isolates with genetic alterations had MICs ≤ 2.0
ug/mL for moxifloxacin, within achievable serum levels
Genotype MTBDRsl
• Second-line and
ethambutol testing
• GyrA codons A90V,
S91P, D94A, D94N/Y,
D94G, D94H
Murine model
GyrB D500N mutation
GyrA A90V mutation
Future
• Moxifloxacin in MDR and/or XDR regimens
• Should moxifloxacin doses be higher if MIC
higher (current dose 400mg/day)
• Develop molecular test to diagnose
fluoroquinolone resistance and distinguish
early and later generation efficacy
Thank you