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![Page 1: Prevention of Emergence of Resistance: A Pharmacodynamic Solution G.L. Drusano, M.D. Professor and Director Division of Clinical Pharmacology Clinical.](https://reader035.fdocuments.net/reader035/viewer/2022062515/56649ce35503460f949aeee0/html5/thumbnails/1.jpg)
Prevention of Emergence of Resistance:
A Pharmacodynamic Solution
G.L. Drusano, M.D.
Professor and Director
Division of Clinical Pharmacology
Clinical Research Institute
Albany Medical College &
New York State Department of Health
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Prevention of Emergence of Resistance: A Pharmacodynamic Solution
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Prevention of Emergence of Resistance: A Pharmacodynamic Solution
• Resistance to antimicrobial agents often occur as a function of single point mutations
• Other mechanisms include spread of plasmids with multiple resistance determinants
• Horizontal transmission also confuses the issue
• Examples of a point mutation providing drug resistance are stable derepression of AMP C beta lactamases for 3rd generation cephalosporins and target mutations or pump upregulation for fluoroquinolones
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Prevention of Emergence of Resistance: A Pharmacodynamic Solution
• As these occur at a frequency of 1/108 or less frequently, infection site populations exceed this frequency, often by multiple logs
• Consequently, such total populations do not behave as a single, sensitive population, but as a mixture of two populations of differing drug susceptibility
• This raises an important question:
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Prevention of Emergence of Resistance: A Pharmacodynamic Solution
Can a drug exposure be identified that will prevent the resistant subpopulation from
taking over the total population?
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The Team
N. L. Jumbe, A. Louie, W. Liu,V. Tam, T. Fazili, R. Leary, C. Lowry, M.H. Miller and
G. L. Drusano
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S. pneumoniae outcome studies
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P. aeruginosa outcome studies
Rf in vitro Rfin vivo MIC (g/mL) MBC (g/mL)
2.35x10-6 2.2x10-6 0.8 1.6
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Prevention of Emergence of Resistance: A Pharmacodynamic Solution
• Clearly, Pseudomonas and Pneumococcus differ in their response
• Pneumococcus has no inoculum effect; Pseudomonas has a major inoculum effect
• The explanation probably rests in the mutational frequency to resistance
• Pseudomonas has a high frequency, while Pneumococcus has a frequency that is not measurable at the bacterial densities used in these experiments with this fluoroquinolone
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Peripheral (thigh)Compartment (Cp)
Central Blood Compartment (Cc)
IPinjection
kcp kpc
+ Bacteria(XT/R)
f(c)
dCc= kaCa+kpcCp-kcpCc-keCc
dt
ke
dXS=KGS x XS x L - fKS(CcH ) x XS
dtdXR= KGR x XR x L- fKR(Cc
H ) x XR
dt
Kmax CcH
C H
50+CcH
f(CcH)=
Y1=XT=XS+XR
Y2=XR
[3]
[4]
[5]
[6]
[7]
, =K and = S,R
[1]
L = (1-(XS+XR)/POPMAX)
[8]
dCp = kcpCc - kpc Cp
dt
[2]
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KmaxGS
0.117
KmaxGR
0.163
KmaxKS
94.01
KmaxKR
12.16
HKS
6.26
HKR
2.37
C50KS
123.5
C50KR
129.8
KmaxG -maximum growth rate (hr-1) in the presence of drug
KmaxK -maximum kill rate (hr-1)
C50K -drug concentration (g/mL) to decrease kill rate by half
HK -rate of concentration dependent kill
Popmax -maximal population size
Mean Parameter Estimates of the Model.
Popmax = 3.6 x 1010
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Prevention of Emergence of Resistance: A Pharmacodynamic Solution
• All regimens were simultaneously fit in a large population model
• The displayed graph is the predicted-observed plot for the total population after the Maximum A-posteriori Probability (MAP) Bayesian step
![Page 14: Prevention of Emergence of Resistance: A Pharmacodynamic Solution G.L. Drusano, M.D. Professor and Director Division of Clinical Pharmacology Clinical.](https://reader035.fdocuments.net/reader035/viewer/2022062515/56649ce35503460f949aeee0/html5/thumbnails/14.jpg)
Prevention of Emergence of Resistance: A Pharmacodynamic Solution
• All regimens were simultaneously fit in a large population model
• The displayed graph is the predicted-observed plot for the resistant population after the Maximum A-posteriori Probability (MAP) Bayesian step
![Page 15: Prevention of Emergence of Resistance: A Pharmacodynamic Solution G.L. Drusano, M.D. Professor and Director Division of Clinical Pharmacology Clinical.](https://reader035.fdocuments.net/reader035/viewer/2022062515/56649ce35503460f949aeee0/html5/thumbnails/15.jpg)
Prevention of Emergence of Resistance: A Pharmacodynamic Solution
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Prevention of Emergence of Resistance: A Pharmacodynamic Solution
• In this experiment, a dose was selected to generate an exposure that would prevent emergence of resistance
• As this was at the limit of detection, the measured population sometimes had “less than assay detectable” for the colony count
• These were plotted at the detection limit
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Prevention of Emergence of Resistance: A Pharmacodynamic Solution
• We were able to determine how the overall (sensitive plus resistant) population responds to pressure from this fluoroquinolone
• More importantly, we were able to model the resistant subpopulation and choose a dose based on simulation to suppress the resistant mutants
• The prospective validation demonstrated that the doses chosen to encourage and suppress the resistant mutants did, indeed, work
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Prevention of Emergence of Resistance: A Pharmacodynamic Solution
• Now, for Pneumococcus
• We were unable to recover resistant mutants with levofloxacin as the selecting pressure in the mouse thigh model
• However, we then examined ciprofloxacin as the selecting agent
• Now, selecting mutants was straightforward
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Study Design: Mouse Thigh Infection Model- Ciprofloxacin Studies [50mg/kg BID ~
AUC/MIC 100:1]
Begin therapy
Sacrifice, harvest,homogenize muscle
-2 hr 0 hr1. Microbial eradication
2. Selection of resistance
Infect
24 hr
BID
+ 2xMIC Cipro - Drug + 4xMIC Cipro + 3xMIC Levo
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Drug #58 RC2
Cipro/±Reserpine 0.6/0.6 3.5/1.0
Levo/±Reserpine 0.6/0.6 0.6/0.6
Prevention of Emergence of Resistance: A Pharmacodynamic Solution
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Prevention of Emergence of Resistance: A Pharmacodynamic Solution
• Strain 58, the RC2 and RC4 mutants were sequenced through Gyr A, Gyr B, Par C & Par E.
• The entire open reading frames were sequenced.
• No differences were seen between parent and the RC2 daughter strain.
• This, coupled with the decrement in ciprofloxacin MIC with reserpine exposure (3.5 mg/L 1.0 mg/L), implies RC2 is a pump mutant.
• For RC4, a mutation was found in parC (aa 79, sertyr) and this strain also decreased its MIC with addition of reserpine.
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Prevention of Emergence of Resistance: A Pharmacodynamic Solution
• We have examined other new fluoroquinolones in this system or in our hollow fiber pharmacodynamic system
• All resemble levofloxacin and do not allow emergence of resistance for wild type isolates
• Why is ciprofloxacin different?
• Likely because it is the most hydrophilic drug and is most efficiently pumped by the PMRA pump
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Prevention of Emergence of Resistance: A Pharmacodynamic Solution
• Are there other factors that can alter the probability of emergence of resistance?
• The most likely is duration of therapy
• Fluoroquinolones induce an SOS response
• This resembles a “hypermutator phenotype”
• Therapy intensity and therapy duration should influence the probability of having the resistant population becoming ascendant
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Prevention of Emergence of Resistance: A Pharmacodynamic Solution
• Hollow fiber System allows simulation of human PK in vitro
• Useful for dose ranging and schedule dependency determinations
• Allows examination of different classes (beta lactams, fluroquinolones, etc.)
The original hollow fiber system was used by Blaser & Zinner
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Prevention of Emergence of Resistance: A Pharmacodynamic Solution
• A 10 day hollow fiber experiment was performed for MSSA and MRSA (CS) for 6 regimens
• The time to complete replacement of the population with resistant organisms was recorded
• CART was employed to look for a breakpoint in the exposure
• > 200/1 AUC/MIC ratio was identified
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Prevention of Emergence of Resistance: A Pharmacodynamic Solution
• A stratified Kaplan-Meier analysis was performed with this breakpoint
• The breakpoint was significant (Mantel test p = 0.0007); Tarone-Ware and Breslow Gahan tests were also significant
• To prevent resistance, hit hard (> 200 AUC/MIC) and stop early (< 7 days)
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Prevention of Emergence of Resistance: A Pharmacodynamic Solution
• The intensity of therapy and the duration of therapy have an impact upon the probability of emergence of resistance
• Short duration therapy trials should examine an endpoint of resistance frequency
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Prevention of Emergence of Resistance: A Pharmacodynamic Solution
Placebo
0
2
4
6
8
10
12
0 6 12 18 24 30 36 42 48Time (h)
Total
ToyamaresistantCiproresistant
Tam et al ICAAC 2001
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Prevention of Emergence of Resistance: A Pharmacodynamic Solution
Cipro (AUC/MIC 65.6)
0
1
2
3
4
5
6
7
8
9
10
0 6 12 18 24 30 36 42 48
Time (h)
Total
ToyamaresistantCiproresistant
Tam et al ICAAC 2001
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Prevention of Emergence of Resistance: A Pharmacodynamic Solution
T600 (AUC/MIC 3.2)
0
2
4
6
8
10
0 6 12 18 24 30 36 42 48Time (h)
Log1
0 CFU
/mL
Total
Toyamaresistant
Ciproresistant
Tam et al ICAAC 2001
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Prevention of Emergence of Resistance: A Pharmacodynamic Solution
T1800 (AUC/MIC 10.4)
0
1
2
3
4
5
6
7
8
9
10
0 6 12 18 24 30 36 42 48 Time (h)
Log1
0 CF
U/m
L
Total
ToyamaresistantCiproresistant
Tam et al ICAAC 2001
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Prevention of Emergence of Resistance: A Pharmacodynamic Solution
T13500 (AUC/MIC 88.6)
0
1
2
3
4
5
6
7
8
9
0 6 12 18 24 30 36 42 48
Time (h)
Total
ToyamaresistantCiproresistant
Tam et al ICAAC 2001
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Prevention of Emergence of Resistance: A Pharmacodynamic Solution
T18000 (AUC/MIC 108.3)
0
1
2
3
4
5
6
7
8
9
0 6 12 18 24 30 36 42 48
Time (h)
Total
ToyamaresistantCiproresistant
Tam et al ICAAC 2001
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Prevention of Emergence of Resistance: A Pharmacodynamic Solution
T36000 (AUC/MIC 200.8)
0
1
2
3
4
5
6
7
8
9
0 6 12 18 24 30 36 42 48
Time (h)
Total
ToyamaresistantCiproresistant
Tam et al ICAAC 2001
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Central Compartment (Cc)Infusion + Bacteria
(XT/R)
f(c)
dCc=Infusion-(SCl/V)xCc
dt
SCl
dXS=KGS x XS x L - fKS(CcH ) x XS
dtdXR= KGR x XR x L- fKR(Cc
H ) x XR
dt
Kmax CcH
C H 50 +Cc
H
f(CcH)=
Y1=XT=XS+XR, IC(1)=2.4x108
Y2=XR , IC(2)= 30
[2]
[3]
[4]
[5]
[6]
, =K and = S,R
[1]
L = (1-X/POPMAX)
[7]
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KmaxGS
0.745
KmaxGR
0.614
KmaxKS
27.85
KmaxKR
31.72
HKS
2.24
HKR
3.50
C50KS
16.94
C50KR
107.0
KmaxG -maximum growth rate (hr-1) in the presence of drug
KmaxK -maximum kill rate (hr-1)
C50K -drug concentration (g/mL) to decrease kill rate by half
HK -rate of concentration dependent kill
Popmax -maximal population size
Mean Parameter Estimates of the Bacterial Growth/Kill Model.
Popmax = 3.3 x 1010
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Prevention of Emergence of Resistance: A Pharmacodynamic Solution
• All regimens were simultaneously fit in a large population model
• The displayed graph is the predicted-observed plot for the drug concentrations after the Maximum A-posteriori Probability (MAP) Bayesian step
![Page 39: Prevention of Emergence of Resistance: A Pharmacodynamic Solution G.L. Drusano, M.D. Professor and Director Division of Clinical Pharmacology Clinical.](https://reader035.fdocuments.net/reader035/viewer/2022062515/56649ce35503460f949aeee0/html5/thumbnails/39.jpg)
Prevention of Emergence of Resistance: A Pharmacodynamic Solution
• All regimens were simultaneously fit in a large population model
• The displayed graph is the predicted-observed plot for the total bacterial counts after the Maximum A-posteriori Probability (MAP) Bayesian step
![Page 40: Prevention of Emergence of Resistance: A Pharmacodynamic Solution G.L. Drusano, M.D. Professor and Director Division of Clinical Pharmacology Clinical.](https://reader035.fdocuments.net/reader035/viewer/2022062515/56649ce35503460f949aeee0/html5/thumbnails/40.jpg)
Prevention of Emergence of Resistance: A Pharmacodynamic Solution
• All regimens were simultaneously fit in a large population model
• The displayed graph is the predicted-observed plot for the resistant bacterial counts after the Maximum A-posteriori Probability (MAP) Bayesian step
![Page 41: Prevention of Emergence of Resistance: A Pharmacodynamic Solution G.L. Drusano, M.D. Professor and Director Division of Clinical Pharmacology Clinical.](https://reader035.fdocuments.net/reader035/viewer/2022062515/56649ce35503460f949aeee0/html5/thumbnails/41.jpg)
Prevention of Emergence of Resistance:
A Pharmacodynamic Solution
•‘Inverted-U’ Phenomenon
– Resistant sub-populationis are initially amplified & then decline with increasing drug exposure 0
1
2
3
4
5
6
0 1 2 3 4 5 6 7
Therapeutic Intensity
Lo
g10
CF
U/m
L
ResistantSub-Population
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Prevention of Emergence of Resistance:
A Pharmacodynamic Solution P. aeruginosa - Prevention of Amplification of
Resistant Subpopulation• The amplification of the
resistant sub-population is a function of the AUC/MIC ratio
• The response curve is an inverted “U”.
• The AUC/MIC ratio for resistant organism stasis is circa 187/1
Tam et al ICAAC 2001
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Prevention of Emergence of Resistance:
A Pharmacodynamic Solution P. aeruginosa - Prevention of Amplification of
Resistant Subpopulation
Placebo
0
5
10
15
0 12 24 36 48 60 72 Time (h)
Lo
g10 C
FU
/mL
Total
Resistant
AUC/MIC 136.7
0
2
4
6
8
10
0 12 24 36 48 60 72 Time (h)
Lo
g10 C
FU
/mL
Total
Resistant
AUC/MIC 199.7
0
2
4
6
8
10
0 12 24 36 48 60 72 Time (h)
Lo
g10 C
FU
/mL
Total
Resistant
AUC/MIC 165.8
0
2
4
6
8
10
0 12 24 36 48 60 72 Time (h)
Lo
g10 C
FU
/mL
Total
Resistant
Prospective Validation
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Prevention of Emergence of Resistance:
A Pharmacodynamic Solution • This was the same strain as employed in the mouse
model, but a different fluoroquinolone
• The mouse model contained granulocytes, while the hollow fiber system does not
• The total drug target for the mouse model was 157 which is a free drug target of 110
• The hollow fiber system target is 187 (1.7 fold )
• Craig found that targets increase by 1.5 -2.0 fold when granulocytes are removed
• These results are concordant with this finding
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Prevention of Emergence of Resistance: A Pharmacodynamic Solution
Multiple Bacterial Populations Do Make a Difference!
• In Vitro pharmacodynamic model investigations frequently only examine the total bacterial population
• The presence of a small pre-existent population more resistant to the selecting drug pressure has major implications, particularly as the bacterial population size increases to (near) clinical infection size
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0
2
4
6
8
10
0 50 100 150 200
Prevention of Emergence of Resistance: A Pharmacodynamic Solution
P aeruginosa
Lo
g10
CF
U/m
L
Daily AUC/MIC
Breakpoint = 187
![Page 47: Prevention of Emergence of Resistance: A Pharmacodynamic Solution G.L. Drusano, M.D. Professor and Director Division of Clinical Pharmacology Clinical.](https://reader035.fdocuments.net/reader035/viewer/2022062515/56649ce35503460f949aeee0/html5/thumbnails/47.jpg)
0
2
4
6
8
10
0 50 100 150 200
Prevention of Emergence of Resistance: A Pharmacodynamic Solution
K. pneumoniae
Lo
g10
CF
U/m
L
Daily AUC/MIC
Breakpoint = 93
![Page 48: Prevention of Emergence of Resistance: A Pharmacodynamic Solution G.L. Drusano, M.D. Professor and Director Division of Clinical Pharmacology Clinical.](https://reader035.fdocuments.net/reader035/viewer/2022062515/56649ce35503460f949aeee0/html5/thumbnails/48.jpg)
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1
2
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4
5
6
0 20 40 60 80 100 120 140 160
Prevention of Emergence of Resistance: A Pharmacodynamic Solution
MSSA
Lo
g10
CF
U/m
L
Daily AUC/MIC
Breakpoint = 66
![Page 49: Prevention of Emergence of Resistance: A Pharmacodynamic Solution G.L. Drusano, M.D. Professor and Director Division of Clinical Pharmacology Clinical.](https://reader035.fdocuments.net/reader035/viewer/2022062515/56649ce35503460f949aeee0/html5/thumbnails/49.jpg)
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4
6
8
0 20 40 60 80 100 120 140 160
Prevention of Emergence of Resistance: A Pharmacodynamic Solution
MRSA-CS
Lo
g10
CF
U/m
L
Daily AUC/MIC
Breakpoint = 143
![Page 50: Prevention of Emergence of Resistance: A Pharmacodynamic Solution G.L. Drusano, M.D. Professor and Director Division of Clinical Pharmacology Clinical.](https://reader035.fdocuments.net/reader035/viewer/2022062515/56649ce35503460f949aeee0/html5/thumbnails/50.jpg)
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8
10
12
0 100 200 300 400 500
Prevention of Emergence of Resistance: A Pharmacodynamic Solution
MRSA-CR
Lo
g10
CF
U/m
L
Daily AUC/MIC
Breakpoint = 484
![Page 51: Prevention of Emergence of Resistance: A Pharmacodynamic Solution G.L. Drusano, M.D. Professor and Director Division of Clinical Pharmacology Clinical.](https://reader035.fdocuments.net/reader035/viewer/2022062515/56649ce35503460f949aeee0/html5/thumbnails/51.jpg)
Prevention of Emergence of Resistance: A Pharmacodynamic Solution
• Some drug exposures allow amplification of the resistant subpopulations
• Exposures can be identified that will prevent this amplification and, functionally suppress emergence of resistance
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