1. PK/PD of Antibiotics in relation to resistance Otto Cars MD Department of Medical Sciences Infectious diseases Uppsala University Sweden

3. Question:
Can the PK/PD and dosage of antibiotics influence the emergence of antibiotic resistance ?

4. What is resistance? Genotype
The bacteria carry certain resistance elements
Phenotype
The bacteria has an increased MIC in comparison
with the wild type
Clinical
The bacteria are able to multiply in humans
in the presence of drug concentrations
achievable during therapy

5. Ecological compartments Oropharyngeal Skin Peri-urethral Faecal
Intracellular

6. Infecting bacterial population
Antibiotic exposure
Clinical failure
and/or bacterial persistance
Infecting bacterial population
Selection of resistant
bacterial subpopulations R
Normal microflora
Gradual
change in
susceptibility

8. Bactericidal activity of two enoxacin regimens against K.pneumoniae
Blaser et.al. AAC 1987

9. Killing of P.aeruginosa at three different dosage
regimens of ciprofloxacin
Marchbanks et. Al. AAC 1993

10. Lomefloxacin Therapy for Pseudomonas Sepsis in Neutropenic Rats: Effect of Dose Fractionation (N=50/Group)
Drusano GL, et al. Antimicrob Agents Chemother. 1993;37:

12. Major risk factors for emergence
of antibiotic resistance during therapy
Mutation frequency / size of inoculum
Biological fitness cost and cost compensation
Selective antibiotic concentrations

14. Major risk factors for emergence
of antibiotic resistance during therapy
Mutation frequency / size of inoculum
Biological fitness cost and cost compensation
Selective antibiotic concentrations

15. Mutant Preventive
Concentration (MPC)
Mutant Selective
Window (MSW)

16. MIC MPC MIC and MPC in theory Antibiotic concentration that prevents
the growth of susceptible bacteria
A measure of the Majority of the Population
MPC
Antibiotic concentration that prevents the growth
of single-step resistant mutant
A measure of the Most Resistant Part of the Population

17. Dong, Zhao, Domagala, Drlica
MIC and MPC in practice
MIC (Etest)
Cells 0.5 McFarland
16-18 hrs, 37ºC
MIC
MPC
Dong, Zhao, Domagala, Drlica
AAC, 43: , 1999
0.1 µg/ml
0.3 µg/ml
0.5 µg/ml
Cells 1010
48 hrs, 37ºC

18. 22 Sensitive Clinical UTI E.coli isolates
Marcusson et al , JAC, accepted for publication
MIC
MPC
MIC Mutants
Clinical UTI Strains

19. MPC
The concept has similarities to agar dilution MICs. Both are measured at static concentrations
The last decade has clearly shown that the MIC alone is not predictive for outcome. MIC has to be related to dosing regimens, pk and PK/PD indices
It is not logical to use the MPC as a primary parameter

20. The concept of Mutant Selective Window
Time post-administration
MIC
MPC
Serum or tissue drug concentration
Mutant
Selection
Window
Cmax

21. PD and resistance: Endpoints
Regrowth of the population- increase in MICs
Change in the number of resistant bacteria during the
experiment e.g. time zero vs time X
(culture on antibiotic containing plates)
AUC of the population analysis profile
(serial plating on antibiotic plates during the experiments)
Specific measuring of the susceptible and resistant population
(competition assay using selective markers)

22. T> MPC TMSW AUCMSW Cmax /MIC Cmax/MPC AUC/MIC AUC/MPC
Pharmacodyamic indices used in resistance studies
T> MPC
TMSW
AUCMSW
Cmax /MIC
Cmax/MPC
AUC/MIC
AUC/MPC

23. Firsov et al

24. Firsov et al

25. Pharmacodynamics and MPC : Prevention of emergance of resistance
in E.coli vs ciprofloxacin
Resistance
Prevention of resistance
Olofsson et al, to be publ.

26. Pharmacodynamics of Penicillin G vs S.pneumoniae
with different suceptibility for penicillin
T>MIC
PSP 46%
PIP 6%
PRP 0%
Odenholt et al
AAC 47,518,2003

27. T>MIC
PSP 75%
PIP 38%
PRP 0%
T>MIC
PSP 100%
PIP 100%
PRP 48%

28. In vivo experimental pneumonia model in rabbits
Five pneumococcal strains with variable susceptibility to
fluoroquinolones
Simulated human kinetics of gatifloxacin
TMSW and AUCMSW significantly correlated
with emergence of resistance mutants
Croiser at al JAC 2004, 54:640

29. Retrospective, including 4 earlier studies
107 acutely ill patients, 128 pathogens, 5 antimicrobial regimens.
PK and MICs for every individual patient
Pharmacodynamic (PD) models probability of developing bacterial resistance.
Thomas et al, AAC :521

30. Overall, in 32 of 128 (25%) resistance developed during therapy.
AUC[0-24]/MIC was as a significant predictor.
This relationship was observed across all
treatments and within all organism groupings, with
the exception of beta-lactamase-producing gram-
negative organisms
Thomas et al, AAC :521

31. Beta-lact. Prod.
Thomas et al, AAC :521

32. Pneumococci
Bacteriologic Failures vs. MIC to Penicillin. Otitis Media (double tap studies) (N=78)
4/5 80 10 20 30 40 50 60 70 80 90
Cefuroxime axetil
Cefaclor
3/7 43
2/6
Failure rate (%) 33
3/13 23
2/22
1/25 9 4
MIC
<0.1
Chi-square for linear trend in proportion, P < 0.001

33. Ratiao of aminopenicillins:cephaalosporins
Relationship between shift in the use of aminopenicillins–cephalosporins and emergence of penicillin resistance in S. pneumoniae 30 6 25 5 20 4
Ratiao of aminopenicillins:cephaalosporins
% of resistant strains 15 3 10 2 5 1 84 85 86 87 88 89 90 91 92 93
Year
Ratio of aminopenicillins:cephalosporins per 1000 inhabitants in France
Penicillin resistance in S. pneumoniae
Baquero. JAC 1996; 38(Suppl A):117–132

34. New macrolides may be ‘driving’ selection of macrolide resistance in S
New macrolides may be ‘driving’ selection of macrolide resistance in S. pneumoniae 5
4.5
R=0.896 4
3.5
Short half-life macrolides
Long half-life macrolides 3
Prescriptions / 1000
2.5 2
R=0.099
1.5 1
0.5 10 20 30 40 50
% macrolide resistance
The Alexander Project 1992–1996
IMS data 1992–1996

35. Erythromycin-Resistant Streptococcus pneumoniae and Consumption of Erythromycin and Azithromycin, Denmark,
Source: DANMAP, 2003 in EPI-NEWS 2004,3. Available from: URL: ww.ssi.dk

36. Resistance to levofloxacin and failure
of treatment of pneumococcal pneumonia
First step mutations in parC occurs approx in one out of 107 pneumococci.
Total load of pneumococci in an infected lung
Low D, CID 2004:38,suppl4, 357
Increased used of levofloxacin,specifically, as opposed to other
fluoroquinolones was associated with increases in the MIC.
A failure of levofloxacin to achieve a highprobability of
PK-PD target attainment may be an important
contributing factor
Bhavani et al Diagn Micr and INf Dis 2005,51:31-37

37. Resistance to levofloxacin and failure
of treatment of pneumococcal pneumonia
Clinical failures in pneumonia caused by S.pneumoniae
resistant to levofloxacin confirm that resistance is
becoming clinically relevant for agents with marginal
PD indices.
Davidson et al NEJM 346:747, 2002
Urban et al J Inf Dis 184 : 794, 2001
To maximize the pharmacodynamic properties of levofloxacin,
A dosing regimen of 750 mg once daily seems more appropriate,
in adult patients than the current dosage of 500 mg.
Ferrara , Infection 2005,33:106

38. resistance will vary due to the infectious site,
Conclusions
Certain dosage regimens are clearly associated
with a risk for selective enrichment of a resistant
subpopulation
The selective pressure varies between bacterial
species, antibiotics, and resistance mechanisms
The pharmacdynamic indices to minimize
resistance will vary due to the infectious site,
bacterial species, antibiotics, and resistance
mechanisms

39. Potential clinical implications
Avoid monotherapy with drugs where Cmax does
not reach the MPC or where the MSW is very long
Adjust dosages regimens (dose, dose interval)
to reduce the TMSW
Include studies on prevention of resistance early in
drug development
Preferred properties:
- Low mutation rate
- High fitness cost of mutants
- Narrow MSW