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Editor's Pick Pharmacology

Fluoroquinolone Efficacy against Tuberculosis Is Driven by Penetration into Lesions and Activity against Resident Bacterial Populations

Jansy Sarathy, Landry Blanc, Nadine Alvarez-Cabrera, Paul O’Brien, Isabela Dias-Freedman, Marizel Mina, Matthew Zimmerman, Firat Kaya, Hsin-Pin Ho Liang, Brendan Prideaux, Jillian Dietzold, Padmini Salgame, Radojka M. Savic, Jennifer Linderman, Denise Kirschner, Elsje Pienaar, Véronique Dartois
Jansy Sarathy
aPublic Health Research Institute, New Jersey Medical School, Rutgers, The State University of New Jersey, Newark, New Jersey, USA
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Landry Blanc
aPublic Health Research Institute, New Jersey Medical School, Rutgers, The State University of New Jersey, Newark, New Jersey, USA
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Nadine Alvarez-Cabrera
aPublic Health Research Institute, New Jersey Medical School, Rutgers, The State University of New Jersey, Newark, New Jersey, USA
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Paul O’Brien
aPublic Health Research Institute, New Jersey Medical School, Rutgers, The State University of New Jersey, Newark, New Jersey, USA
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Isabela Dias-Freedman
aPublic Health Research Institute, New Jersey Medical School, Rutgers, The State University of New Jersey, Newark, New Jersey, USA
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Marizel Mina
aPublic Health Research Institute, New Jersey Medical School, Rutgers, The State University of New Jersey, Newark, New Jersey, USA
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Matthew Zimmerman
aPublic Health Research Institute, New Jersey Medical School, Rutgers, The State University of New Jersey, Newark, New Jersey, USA
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Firat Kaya
aPublic Health Research Institute, New Jersey Medical School, Rutgers, The State University of New Jersey, Newark, New Jersey, USA
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Hsin-Pin Ho Liang
aPublic Health Research Institute, New Jersey Medical School, Rutgers, The State University of New Jersey, Newark, New Jersey, USA
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Brendan Prideaux
aPublic Health Research Institute, New Jersey Medical School, Rutgers, The State University of New Jersey, Newark, New Jersey, USA
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Jillian Dietzold
bDepartment of Medicine, New Jersey Medical School, Rutgers, The State University of New Jersey, Newark, New Jersey, USA
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Padmini Salgame
bDepartment of Medicine, New Jersey Medical School, Rutgers, The State University of New Jersey, Newark, New Jersey, USA
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Radojka M. Savic
cDepartment of Bioengineering and Therapeutic Sciences, University of California San Francisco, San Francisco, California, USA
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Jennifer Linderman
dDepartment of Chemical Engineering, University of Michigan, Ann Arbor, Michigan, USA
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Denise Kirschner
eDepartment of Microbiology and Immunology, University of Michigan Medical School, Ann Arbor, Michigan, USA
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Elsje Pienaar
dDepartment of Chemical Engineering, University of Michigan, Ann Arbor, Michigan, USA
eDepartment of Microbiology and Immunology, University of Michigan Medical School, Ann Arbor, Michigan, USA
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Véronique Dartois
aPublic Health Research Institute, New Jersey Medical School, Rutgers, The State University of New Jersey, Newark, New Jersey, USA
bDepartment of Medicine, New Jersey Medical School, Rutgers, The State University of New Jersey, Newark, New Jersey, USA
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DOI: 10.1128/AAC.02516-18
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  • FIG 1
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    FIG 1

    Modeling and simulation of the distribution of moxifloxacin (MXF), gatifloxacin (GFX), and levofloxacin (LVX) at human-equivalent doses in cellular granulomas and in caseum. Solid and dashed lines show means and standard deviations, respectively, for 100 lesions of each type. PK profiles in plasma and cellular granulomas were simulated using drug concentration data generated by high-pressure liquid chromatography and tandem mass spectrometry (LC/MS-MS) in plasma and tissue homogenates. PK profiles in caseum were simulated using data generated by laser capture microdissection coupled to LC-MS/MS.

  • FIG 2
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    FIG 2

    Lesion-centric pharmacokinetic-pharmacodynamic (PK/PD) parameters of the fluoroquinolones calculated using potency measured against intracellular M. tuberculosis in primary macrophages and extracellular M. tuberculosis in rabbit caseum. (A) Activated macrophages were infected with M. tuberculosis and treated with the fluoroquinolones for 3 days as indicated. Relative growth or survival rates on day 3 compared to pretreatment are shown (means ± standard deviation [SD], n = 3). (B) Bactericidal activity of the fluoroquinolones against ex vivo M. tuberculosis in cavity caseum, where tuberculous bacilli are rich in lipid inclusions and exhibit phenotypic drug resistance (45). Data are expressed as CFU per milliliter of homogenized caseum (diluted 1:3 in water), plotted on a log scale (means ± SD, n = 3). LOD, limit of detection. (C) Lesion-specific PK/PD parameters calculated as the ratios between the drugs’ area under the curve in cellular lesions (AUCcellular) or caseum (AUCcaseum) and the drugs’ inhibitory or cidal activity against the corresponding intracellular and extracellular M. tuberculosis bacilli. MacIC90, concentration that inhibits 90% of growth in macrophages; MacMBC90, concentration that kills 90% of M. tuberculosis bacilli in macrophages (A); WCC90, Wayne cidal concentration or concentration that kills 90% of extracellular M. tuberculosis under anaerobic conditions (47); casMBC90, concentration that kills 90% of M. tuberculosis bacilli in ex vivo rabbit caseum (45) (B). Means ± SD of data from 100 simulated granulomas or caseous foci are shown.

  • FIG 3
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    FIG 3

    (A) Steady-state AUC[0–24] distributions in plasma, uninvolved lung, cellular lesions, and caseum of rabbits receiving human-equivalent doses of MXF, LVX, and GTX as indicated. The PK variability was introduced by sampling 100 plasma PK parameter sets from the distributions given in Table S1. (B) Probability of target attainment for a PK/PD target AUC[0–24]/MIC of 125 to achieve 90% of maximal kill (15, 18, 19). The gray areas indicate the range of MIC as reported by Angeby et al. (48). Red, orange, olive, and green lines indicate the probability of target attainment in plasma, uninvolved lung, cellular lesions, and caseum, respectively. The minimum concentration required to achieve 90% growth inhibition of intracellular M. tuberculosis (MacIC90) and the concentration required to kill 90% of nonreplicating M. tuberculosis bacilli in caseum (casMBC) are indicated by arrows. These two potency values were determined using M. tuberculosis strains H37Rv and HN878; thus, the impact of potency variability on target attainment and efficacy predictions is unknown.

  • FIG 4
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    FIG 4

    Comparative efficacies of the three fluoroquinolones in the rabbit model of active TB. (A) Effect of MXF (blue), GTX (purple), and LVX (orange) daily treatment at human-equivalent doses on bacterial burden in uninvolved lung, cellular lesions and necrotic lesions, compared to vehicle-treated controls (gray), at 4 and 8 weeks of treatment. Data are presented as median ± 95% confidence interval; n = 4 to 6 rabbits or 13 to 59 lesions per lesion category and treatment group, with data determined using the two-tailed Mann-Whitney U (nonparametric) test. *, P < 0.05; **, P < 0.01; ***, P < 0.001; ****, P < 0.0001; ns, not significant. (B) Effect of MXF (blue), GTX (purple), and LVX (orange) treatment on sterilization of lung tissue and lesions, shown as proportions of sterile uninvolved lung samples and lesions. Actual ratios are shown above each bar. Sample size and P value categories correspond to those described for panel A. Fisher's exact test (two-sided) was performed for comparisons of treated versus untreated group pairs. (C) Effect of fluoroquinolone treatment on lesion weight. Sample size and statistical analysis correspond to those described for panel A. (D) Effect of MXF (blue), GTX (purple), and LVX (orange) treatment on bacterial kill in lung and lesions, calculated as the ratio between CEQ (chromosome equivalents; cumulative burden) and CFU (actual live burden at the time of sampling). Data points with undetectable CEQ were removed from the analysis since the CEQ LOD is approximately 100 (33) and the CFU LOD is 3 to 5. n = 4 to 6 rabbits or 7 to 54 lesions per lesion category and treatment group (2/4 MXF-treated rabbits had few lesions left after 2 months of treatment, hence the reduced number of lesions in this group), with data determined using the two-tailed Mann-Whitney U (nonparametric) test. *, P < 0.05; **, P < 0.01; ***, P < 0.001; ****, P < 0.0001; ns, not significant.

  • FIG 5
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    FIG 5

    Impact of suboptimal MXF plasma pharmacokinetics on tissue distribution and bacterial burden in lung and lesions. (A) Simulated plasma and lesion PK profiles at the ideal human-equivalent dose of 60 mg/kg (dark blue) and the suboptimal dose of 25 mg/kg reproducing exposure in the lower 5th percentile of the AUC range (light blue). (B and C) Effect of canonical and suboptimal MXF exposure on bacterial burden in uninvolved lung, cell, and necrotic lesions (B) and lesion sterilization (C). Color codes are identical in panels A, B, and C. Data are presented as median ± 95% confidence interval; n = 4 (MXF-treated) to 6 (vehicle-treated) rabbits or 16 to 59 lesions per lesion category and treatment group as determined using the two-tailed Mann-Whitney U (nonparametric) test. *, P < 0.05; **, P < 0.01; ***, P < 0.001; ****, P < 0.0001; ns, not significant.

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  • TABLE 1

    Plasma PK/PD parameters in TB patients receiving the WHO-recommended doses of MXF, LVX, or GTX

    DrugDose
    (mg/day)
    MIC90
    (mg/liter)a
    MBC
    (mg/liter)b
    AUC[0–24]
    (mg*h/liter)a
    median (SD)
    fAUC[0–24]
    range
    (mg*h/liter)c
    fAUC/MIC
    rangec
    fAUC/MBC
    range
    (mg*h/liter)c
    Moxifloxacin4000.50.357 (12)23–4346–8677–143
    Levofloxacin1,0001.00.9129 (106)74–25874–25882–287
    Gatifloxacin4000.50.540 (7)22–3944–7844–78
    • ↵a Data are from reference 19.

    • ↵b Data are from reference 47.

    • ↵c Data were computed using MIC90 values from reference 19, MBC values from reference 47, and average human plasma protein binding values obtained as part of this work (Table S2).

  • TABLE 2

    Lesion PK/PD parameters in rabbits receiving the human-equivalent dose of MXF, LVX, or GTXa

    DrugMacIC90
    (mg/liter)
    MacMBC90
    (mg/liter)
    WCC
    (mg/liter)
    CasMBC90
    (mg/liter)
    Simulated
    AUCcellular[0–24]
    mean (95% CI)
    (mg*h/liter)
    Simulated
    AUCcaseum[0–24]
    mean (95% CI)
    (mg*h/liter)
    h 2, h 6,
    h 12
    caseum/cell
    ratiob
    MXF21643.2609 (584–635)276 (251–301)0.36, 0.79, 0.62
    GTX1.516182.2192 (166–218)103 (83–123)0.93, 0.98, 0.51
    LVX432184.0325 (259–392)238 (181–295)0.76, 1.16, 1.02
    • ↵a MacIC90 and MacMBC90, MIC90 and MBC90, respectively, against intracellular M. tuberculosis in murine bone marrow-derived macrophages (this work); WCC, Wayne cidal concentration (the concentration which kills 90% of viable bacilli under hypoxia-induced nonreplicating conditions) (from reference 47); casMBC90, MIC90 (1-log kill) against ex vivo M. tuberculosis from cavity caseum; AUCcellular[0–24], area under the concentration-time curve from 0 to 24 h in cellular granulomas at the human-equivalent dose as determined from the computational model; AUCcaseum[0–24], area under the concentration-time curve in caseum; CI, confidence interval.

    • ↵b Data were determined by laser capture microdissection and HPLC coupled to tandem mass spectrometry (55, 67).

Additional Files

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    • Supplemental file 1 -

      Supplemental figures and tables

      PDF, 1.1M

    • Supplemental file 2 -

      Data Set S1

      XLSX, 31K

    • Supplemental file 3 -

      Data Set S2

      XLSX, 18K

    • Supplemental file 4 -

      Data Set S3

      XLSX, 90K

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Fluoroquinolone Efficacy against Tuberculosis Is Driven by Penetration into Lesions and Activity against Resident Bacterial Populations
Jansy Sarathy, Landry Blanc, Nadine Alvarez-Cabrera, Paul O’Brien, Isabela Dias-Freedman, Marizel Mina, Matthew Zimmerman, Firat Kaya, Hsin-Pin Ho Liang, Brendan Prideaux, Jillian Dietzold, Padmini Salgame, Radojka M. Savic, Jennifer Linderman, Denise Kirschner, Elsje Pienaar, Véronique Dartois
Antimicrobial Agents and Chemotherapy Apr 2019, 63 (5) e02516-18; DOI: 10.1128/AAC.02516-18

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Fluoroquinolone Efficacy against Tuberculosis Is Driven by Penetration into Lesions and Activity against Resident Bacterial Populations
Jansy Sarathy, Landry Blanc, Nadine Alvarez-Cabrera, Paul O’Brien, Isabela Dias-Freedman, Marizel Mina, Matthew Zimmerman, Firat Kaya, Hsin-Pin Ho Liang, Brendan Prideaux, Jillian Dietzold, Padmini Salgame, Radojka M. Savic, Jennifer Linderman, Denise Kirschner, Elsje Pienaar, Véronique Dartois
Antimicrobial Agents and Chemotherapy Apr 2019, 63 (5) e02516-18; DOI: 10.1128/AAC.02516-18
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KEYWORDS

MDR-TB
fluoroquinolone
lesion-centric pharmacology
moxifloxacin
tuberculosis

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