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PK/PD of Antibiotics in relation to resistance Otto Cars MD Department of Medical Sciences Infectious diseases Uppsala University Sweden. Question: Can the PK/PD and dosage of antibiotics influence the emergence of antibiotic resistance ?. What is resistance?. Genotype

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  1. PK/PD of Antibioticsin relation to resistanceOtto Cars MDDepartment of Medical SciencesInfectious diseasesUppsala UniversitySweden

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

  3. 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

  4. Ecological • compartments • Oropharyngeal • Skin • Peri-urethral • Faecal • Intracellular

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

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

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

  8. Lomefloxacin Therapy for Pseudomonas Sepsis in Neutropenic Rats:Effect of Dose Fractionation (N=50/Group) Drusano GL, et al. Antimicrob Agents Chemother. 1993;37:483-490.

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

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

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

  12. MIC and MPC in theory MIC 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

  13. Cells 0.5 McFarland 16-18 hrs, 37ºC MIC (Etest) MIC 0.1 µg/ml 0.3 µg/ml 0.5 µg/ml MPC Dong, Zhao, Domagala, Drlica AAC, 43: 1756-1758, 1999 Cells 1010 48 hrs, 37ºC MPC MIC and MPC in practice

  14. 22 Sensitive Clinical UTI E.coli isolates Marcusson et al , JAC, accepted for publication MIC MPC MIC Mutants Clinical UTI Strains

  15. 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

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

  17. 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)

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

  19. Firsov et al

  20. Firsov et al

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

  22. 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

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

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

  25. 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 1998 42:521

  26. 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 1998 42:521

  27. Beta-lact. Prod. Thomas et al, AAC 1998 42:521

  28. Cefuroxime axetil 90 Cefaclor 80 70 60 50 40 30 20 10 0 Pneumococci Bacteriologic Failures vs. MIC to Penicillin. Otitis Media (double tap studies) (N=78) 4/5 80 3/7 43 2/6 Failure rate (%) 33 3/13 23 2/22 1/25 9 4 MIC <0.1 0.125 - 0.25 0.38 - 1.0 Chi-square for linear trend in proportion, P < 0.001

  29. Relationship between shift in the use of aminopenicillins–cephalosporins and emergence of penicillin resistance in S. pneumoniae 6 30 25 5 4 20 Ratiaoof aminopenicillins:cephaalosporins % of resistant strains 3 15 2 10 1 5 0 0 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

  30. Long half-life macrolides Short half-life macrolides New macrolides may be ‘driving’ selection of macrolide resistance in S. pneumoniae 5 R=0.896 4.5 4 3.5 3 Prescriptions / 1000 2.5 2 R=0.099 1.5 1 0.5 0 0 10 20 30 40 50 % macrolide resistance The Alexander Project 1992–1996 IMS data 1992–1996

  31. Erythromycin-Resistant Streptococcus pneumoniae and Consumption of Erythromycin and Azithromycin, Denmark, 1994-2002 Source: DANMAP, 2003 in EPI-NEWS 2004,3. Available from: URL: ww.ssi.dk

  32. 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 1012-1014 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

  33. 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

  34. 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

  35. 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

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