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Mutant Prevention Concentration and the Selection Window Hypothesis Karl Drlica, Xilin Zhao, and Tao Lu Public Health PowerPoint Presentation
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Mutant Prevention Concentration and the Selection Window Hypothesis Karl Drlica, Xilin Zhao, and Tao Lu Public Health Research Institute Newark, NJ. Selecting a treatment plan for a particular patient. Individual patient issues Probability of “cure” without serious side effects.

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slide1

Mutant Prevention Concentration

and the

Selection Window Hypothesis

Karl Drlica, Xilin Zhao, and Tao Lu

Public Health Research Institute

Newark, NJ

slide2

Selecting a treatment plan for a particular patient

Individual patient issues

Probability of “cure” without serious side effects

Public health issues

Probability for avoiding enriching a resistant bacterial subpopulation

slide3

Blocking Growth of Single Mutants Forces Cells to Have a Double Mutation to Overcome Drug

attack by drug

frequency ~ 10-7

frequency ~ 10-7

wild type

double mutant

single mutant

frequency ~ 10-14

(number of bacteria during infection: < 1010)

slide4

Introduction to MPC

  • Mutant Selection Window
    • Dosing above the MPC
    • Closing the Window
  • Combination Therapy
  • Comparison with Traditional PK/PD
  • Application to S. pneumoniae
  • Application to S. aureus
  • Other antimicrobial-pathogen combinations
slide5

Introduction to MPC:

Fluoroquinolone studies with mycobacteria

slide6

Intracellular Consequences of Fluoroquinolone Treatment

+

DNA

Gyrase

(a)

Gyrase

mutations

(b)

Quinolone

Blocks DNA replication

and cell growth (MIC)

Cell lysis

SDS

Cm

(c)

(d)

Cell death

slide7

O

O

O

O

F

F

OH

H5C2

OH

H5C2

N

N

N

N

HN

O

HN

H3C

Fluoroquinolone Structure

C-8-methoxy compound

C-8-H compound

slide8

Bacteriostatic Activity with M. bovis BCG

Fluoroquinolone C-8-moiety ID50 (mg/ml)

gyrA+gyrAr

ciprofloxacin H 0.15 6.1

PD161148 OMe 0.05 0.61

PD160793 H 0.08 7.0

slide9

C-8-OMe

C-8-H

Bactericidal Activity of Fluoroquinolones

with M. bovis BCG

gyrA mutant

wild type

A

B

103

102

Survival (%)

10

1

10-1

10-2

10

1

10

100

0.01

0.1

1

[Fluoroquinolone] (mg/ml)

Incubation time: 6 days

slide10

Effect of Fluoroquinolone Concentration on Mutant Recovery

A

B

C

D

1

100

10-2

80

Percent recovered

10-4

Fraction of cells recovered

60

A

10-6

40

B

10-8

C

D

20

0.01

0.1

1

10

0

D95G

G89C

D95H

D95G

G89C

D95Y

D95A

D95N

D95G

A91V

D95H

[Fluoroquinolone] (mg/ml)

non-gyrA

Mycobacterium smegmatis

slide12

Mutant Prevention Concentration (MPC)

C-8-H

MIC99

C-8-OMe

10-1

MIC99

10-3

10-5

Fraction of cells recovered

10-7

MPC

MPC

10-9

0.01

0.1

1

10

[Fluoroquinolone] (µg/ml)

M. bovis BCG

slide13

A

MIC

MPC

C-8-methoxy

Fraction of colonies recovered (log10)

Mutant Selection Window

C-8-hydrogen

MPC

MIC

Drug Concentration (log10)

Mutant Selection Window

B

Cmax

Serum or tissue drug concentration

MPC

Mutant

Selection

Window

MIC

Time post-administration

slide14

A

10

1

MPC

MIC

0.1

Selection Window Demonstrated by Dynamic, in vitro Model

Dosing Protocol

Analysis of recovered cells

0.3

0.2

0.1

0

0.3

B

[Moxifloxacin] (μg/ml)

10

0.2

MIC (mg/ml)

1

MPC

0.1

MIC

0.1

0

0.3

C

10

0.2

1

MPC

0.1

MIC

0.1

0

before treatment

24

48

72

96

120

at 24 h

Time (h)

Data from Firsov et al.

Organism: Staphylococcus aereus

at 48 h

at 72 h

slide15

Traditional Explanation for Enrichment of Mutants

Concentration

MIC

Sele

ctive

Pres

Selective Pressure

Time

slide16

Mutants are not selected

at concentrations below MIC

slide17

Strategies for Restricting the

Development of Resistance

Dose above MPC

Narrow the window

2-drug therapy

Serum or tissue drug concentration

MPC

MPC~MIC

MPC=MIC

MIC

Time post-administration

slide19

Dose above MPC

Serum or tissue drug con.

Time post-administration

Relationship of Pharmacokinetics and

MPC in M. tuberculosis

Antibiotic MPC Cmax MPC/Cmax

Rifampicin >80 9.5 >8

Streptomycin >320 34 >9

Isoniazid 20 7.6 2.6

Ethionamide 35 20 1.8

Ethambutol 50 6 8.3

Capreomycin 160 33 4.8

Kanamycin >800 21 >38

Cycloserine 70 35 2

Fluoroquinolones

Ciprofloxacin 8.0 4.4 1.8

Levofloxacin 7.5 5.7 1.3

Sparfloxacin 2.5 1.4 1.6

Moxifloxacin 2.5 4.5 0.55

Gatifloxacin 1.5 3.7 0.41

slide21

Narrow the window

Serum or tissue drug con.

O

O

Time post-administration

F

OH

N

N

N

O

H3C

O

O

F

OH

O

O

N

N

N

F

OH

N

N

HN

O

O

F

OH

N

N

HN

O

H3C

Narrowing the Selection Window with S. aureus

MPC MIC(99) MPC/MIC(99)

(mg/ml) (mg/ml)

0.6 0.05 12

1.7 0.05 34

4 0.3 13

0.45 0.08 6

slide23

Closing The Mutant Selection Window

Mutant Selection Window

open

closed

open

#2

#3

#1

Serum or tissue drug concentration

MIC

Drug 1

Drug 2

Time post-administration

slide24

Treatment Protocol for a Dual-drug Failure

HIV+ TB patients (drug-susceptible)

Treat with INH, Rif, Pz, Em (2 months; DOT)

INH/Rif

(2/wk, 4 months; DOT)

INH/Rifapentine

(1/wk, 4 months; DOT)

3/31 relapse

5/30 relapse

4/5 Rif-resistant

0/3 Rif-resistant

Source: A. Vernon et al. Lancet 353: 1843-1847 (1999)

slide25

Pharmacodynamic Comparison of Rifampicin and Isoniazid

1000

Plasma drug concentration

(fold of MIC)

100

Isoniazid

10

Rifampicin

MIC

1

0

10

20

30

Time post-administration (hr)

M. tuberculosis

slide26

Pharmacokinetic mismatch between rifapentine and isoniazid

1000

Rifapentine

100

Plasma drug concentration (fold of MIC)

Isoniazid

10

MIC

1

0

10

20

30

40

50

60

70

Time post-administration (hr)

M. tuberculosis

slide27

Normalized pharmacokinetic profiles of Rifater

500

100

INH

10

Serum drug concentration (fold of MIC)

Rifampicin

1

MIC

Pyrazinamide

(M. tuberculosis)

0.1

0

2

4

6

8

10

12

14

Time post-administration (hr)