Prevention of Emergence of Resistance: A Pharmacodynamic Solution
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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 &
NYSDOH
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Prevention of Emergence of Resistance: A Pharmacodynamic Solution
• Currently, the therapeutic armamentarium is amazingly limited for many Gram-negative pathogens
• Discovery programs do not promise any relief for at least 5 years
• We must learn to use available drugs more intelligently to preserve the susceptibility of the infecting flora to current agents
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Prevention of Emergence of Resistance: A Pharmacodynamic Solution
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Prevention of Emergence of Resistance: A Pharmacodynamic Solution
• Many organisms have resistance mechanisms that occur as a function of single point mutations
• Examples are stable derepression of type I beta lactamases for 3rd generation cephalosporins and target mutations or pump upregulation for fluoroquinolones
• As these occur at a frequency of 1/108 or greater, infection site populations exceed this frequency, often by multiple logs
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Prevention of Emergence of Resistance: A Pharmacodynamic Solution
• 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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Prevention of Emergence of Resistance: A Pharmacodynamic Solution
Let Us Compare and Contrast the Pharmacodynamics of Levofloxacin for Streptococcus pneumoniae and
Pseudomonas aeruginosa in a Mouse Thigh Infection Model
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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 Levofloxacin
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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
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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 resistant population after the Maximum A-posteriori Probability (MAP) Bayesian step
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Prevention of Emergence of Resistance: A Pharmacodynamic Solution
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Prevention of Emergence of Resistance: A Pharmacodynamic Solution
• We wished to evaluate the model prospectively
• Models, to be useful, need to predict the future
• We simulated a dose not previously studied that would encourage selection of resistance
• The study was carried out for 48, not 24 hours
• The model predicted the change in the resistant mutant population well
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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 Levofloxacin
• 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 sequences examined were: GyrA (ORF 822 aa) aa 4-229; Gyr B (ORF 648 aa) aa 346-579; ParC (ORF 823 aa) aa 1-178; ParE (ORF 647 aa) aa 359-561. 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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Begin therapy
Sacrifice, harvest,homogenize muscle
-2 hr 0 hr
+ 2xMIC Cipro - Drug
Infect
24 hr
BID
+ 4xMIC Cipro
Begin therapy
Sacrifice, harvest,homogenize muscle
-2 hr 0 hr
+ 3xMIC Levo - Drug
Infect
24 hr
BID
+ 3xMIC Cipro
#58-
RC
2#5
8-W
T
+ 3xMIC Levo
Study Design: Second Passage of First Stage Ciprofloxacin ResistantS. pneumoniae
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Total Counts
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Cipro Resistance
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Levo Resistance* = no colonies detected in any
sample. Sample size 4 animals
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Prevention of Emergence of Resistance: A Pharmacodynamic Solution
• What next?• We are currently examining the RC2 mutant in the
mouse thigh model• In preliminary data, exposures to levofloxacin that
would kill the wild-type isolate did not kill the mutant, even though the MIC has not changed
• This finding has been recreated with another later generation fluoroquinolone in a hollow fiber model
• This implies that, counter to the output of Resistance 2000, sometimes newer drugs preserve the sensitivity of the flora better than older drugs
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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
• 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
CONCLUSIONS
• Probability of emergence of resistance is impacted upon by the intensity of therapy and by the duration of therapy
• Short duration therapy trials should examine an endpoint of resistance frequency
• As importantly, doses should be chosen to provide resistance counterselection exposures for a large fraction of the population. An example follows:
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Prevention of Emergence of Resistance: A Pharmacodynamic Solution
Target Attainment
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Prevention of Emergence of Resistance: A Pharmacodynamic Solution
Target Attainment
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Prevention of Emergence of Resistance: A Pharmacodynamic Solution
• While this example is for microbiological outcome, a similar analysis could (and should!) be performed for a prevention of resistance target
• Such a dose choice, coupled with short duration therapy will yield the highest probability of a good clinical and microbiological outcome and the lowest probability of the resistant subpopulation taking over the whole population