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Clinical Impact of PK/PD in Urinary Tract Infections

Clinical Impact of PK/PD in Urinary Tract Infections. K.G. Naber, F.M.E. Wagenlehner Urologic Clinic, St. Elisabeth Hospital, Straubing, Germany Inernational Congress of Chemotherapy (Manila, June 4-6, 2005) ISAP symposium. PK / PD Parameters. Conc. (mg/l). C MAX. AUC > MIC. MIC.

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Clinical Impact of PK/PD in Urinary Tract Infections

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  1. Clinical Impact of PK/PD in Urinary Tract Infections K.G. Naber, F.M.E. Wagenlehner Urologic Clinic, St. Elisabeth Hospital, Straubing, Germany Inernational Congress of Chemotherapy (Manila, June 4-6, 2005) ISAP symposium

  2. PK / PD Parameters Conc. (mg/l) CMAX AUC > MIC MIC T>MIC Time (t)

  3. Aims of antimicrobial treatment in UTI • inhibit growth or kill bacteria in the urine and tissues of urinary tract • prevent complications • abscesses • bacteremia • stone formation • scar formation • prevent emergence of resistance Niels Frimodt-Møller, Int J Antimicrob Agents 19 (2002) 546-553

  4. 100 90 80 70 60 Probability (%) 50 40 30 20 10 0 0 10 20 30 40 50 Peak/MIC ratio PHARMACODYNAMICS OF LEVOFLOXACIN Preston SL et al. JAMA 1998; 279: 125-129 Urinary tract infections Pulmonary infections Skin and soft tissues infections n = 272 500 mg OD for at least 3 doses BREAKPOINT = 12.2

  5. Classification of Urinary Tract Infections • acute uncomplicated cystitis • acute pyelonephritis • uncomplicated • complicated • complicated urinary tract infections • due to underlying diseases • due to urological disorders • sepsis syndrome - urosepsis • others • urethritis • prostatitis • epididymitis

  6. common pathogens Escherichia coli Klebsiella sp. Proteus sp. Staphylococci empirical oral treatment trimethoprim (TMP) or TMP/SMZ*(3 days) fluoroquinolones (3 days) Alternatives: fosfomycin trometamol (SD) pivmecillinam (7 days) nitrofurantoin (7 days) *regional resistance pattern ! duration of treatment: (1)-3-(7) days Acute Uncomplicated Cystitis Warren JW et al.Clinical Infectious Diseases 1999; 29: 745-758; EAU Guidelines on UTI 2001;

  7. Levofloxacin vs. Ciprofloxacin vs. Lomefloxacin in Acute Pyelonephritis (55/58) (60/64) Success rate (%) (83/89) (93/98) (37/39) (39/41) Ciprofloxacin 2 x 500 mg, 10d Levofloxacin 1 x 250 mg, 10d Lomefloxacin 1 x 400 mg, 14d Richard GA et al (1998) Urology 52:51-55

  8. Levofloxacin 500 mg Ciprofloxacin 500 mg Sparfloxacin 400 mg 0 2 4 6 8 10 12 14 16 18 20 22 24 Time (h) Plasma concentrations of fluoroquinolones (p.o.) 7 6 5 4 Serum Concentration (mg/l) 3 2 1 0 Chien et al., (1997), AAC 41: 2256 ff, Product Monograph Ciprobay (1986) und Zagam (1994)

  9. Levofloxacin 1 x 250 mg AUCPlasma 22.9 µg • h/ml MIC E.coli = 0.03 mg/l Plasma-AUC / MIC  763.3h Ciprofloxacin 2 x 500 mg AUCPlasma 18.2 µg • h/ml MIC E.coli = 0.008 mg/l Plasma-AUC / MIC  2275 h Plasma 0-24 hAUC and AUC/MIC E. coli ATTC 25922

  10. Levofloxacin 1 x 250 mg AUCPlasma 22.9 µg • h/ml MIC E.coliR-Nx = 0.25 mg/l Plasma-AUC / MIC  91.6h Ciprofloxacin 2 x 500 mg AUCPlasma 18.2 µg • h/ml MIC E.coliR-Nx = 0.125 mg/l Plasma-AUC / MIC  145.6 h Plasma 0-24hAUC and AUC/MIC E. coli – Nx-resistant

  11. Levofloxacin 1 x 500 mg AUCPlasma 45.8 µg • h/ml MIC E.coliR-Nx = 0.25 mg/l Plasma-AUC / MIC  183.2h Ciprofloxacin 2 x 500 mg AUCPlasma 18.2 µg • h/ml MIC E.coliR-Nx = 0.125 mg/l Plasma-AUC / MIC  145.6 h Plasma 0-24hAUC and AUC/MIC E. coli – Nx-resistant

  12. Levofloxacin 1 x 500 mg AUCPlasma 45.8 µg • h/ml MIC P.aerug = 2.0 mg/l Plasma-AUC / MIC  22.9h Ciprofloxacin 2 x 500 mg AUCPlasma 18.2 µg • h/ml MIC P. aerug. = 0.125 mg/l Plasma-AUC / MIC  36.5 h Plasma 0-24hAUC and AUC/MIC Pseudomonas aeruginosa

  13. Nosocomial - Complicated UTI: Causes, Localisations and Complications • Causes: • complicating factors (e.g. obstruction, stone) • urologic interventions • catheters or splints • Localisations: • lower urinary tract • upper urinary tract • Complications: • change of pathogen • development of resistance • biofilm infection

  14. Eradication of Uropathogens in Complicated Urinary Tract Infections Species fleroxacin fleroxacin 200 mg qd* 400 mg qd N/N % N/N % tot tot Escherichia coli 27/32 84.4 53/58 91.4 Other Enterobacteriaceae 20/23 87.0 22/24 91.7 Other Gram-negatives 2/2 100.0 4/5 80.0 Pseudomonas spp. 5/9 55.6 7/ 9 77.8 Enterococcus spp. 10/17 58.8 14/20 70.0 Staphylococcus spp. 4/10 40.0 11/21 52.4 Other Gram-positives - 1/2 50.0 Total 68/93 73.1 113/119 81.3 *loading dose 400 mg Frankenschmidt, Naber et. al. (1997) J Urol 158:1494-1499

  15. Eradication of Uropathogens in Complicated Urinary Tract Infections ciprofloxacin ciprofloxacin Species 250 mg bid 500 mg bid N/N % N/N % tot tot Escherichia coli 28/32 87.5 52/63 88.9 Other Enterobacteriaceae 20/24 83.3 32/35 91.4 Other Gram-negatives 3/3 100.0 2/3 66.7 Pseudomonas spp. 4/6 66.7 4/4 100. 0 Enterococcus spp. 10/14 71.4 25/29 86.2 Staphylococcus spp. 8/13 61.5 13/25 52.0 Other Gram-positives - 0/1 0.0 Total 74/92 78.7 132/161 82.0 Frankenschmidt, Naber et. al. (1997) J Urol 158:1494-1499

  16. Acute Pyelonephritis and Complicated UTI Gemifloxacin (320mg od) vs. Ciprofloxacin (500mg bid) US-Study: equivalent European study: not equivalent

  17. Acute Pyelonephritis and Complicated UTI Gemifloxacin (320mg od) vs. Ciprofloxacin (500mg bid) • US-Study: equivalent • European study: not equivalent • Stratification of the Patients • Acute uncomplicated pyelonephritis in women • cUTI without need for urological intervention (e.g. diabetes, • postmenopause) • cUTI with successful urological intervention (e.g. ureteral • stone with extraction during therapy) • cUTI with partially or no successful • urological intervention (e.g. staghorn stone, catheter)

  18. Median concentrations in plasma of ciprofloxacin XR (1000 mg) vs. levofloxacin (500 mg) in healthy volunteers (n = 12) receiving a single oral dose

  19. Urin - Konzentrationen (n=12) Levofloxacin (500mg) vs. Ciprofloxacin XR (1000mg)

  20. Ciprofloxacin XR (1000 mg) vs. Levofloxacin (500 mg) bei Probanden (n = 12) nach einer EinmalgabePharmakokinetik(mediane Werte) *P < 0,05

  21. Levofloxacin 1 x 500 mg AUCPlasma 45.8 µg • h/ml MIC P.aerug. = 2.0 mg/l Plasma-AUC / MIC  22.9h Ciprofloxacin XR 1 x 1000 mg AUCPlasma 18.2 µg • h/ml MIC P.aerug. = 0.5 mg/l Plasma-AUC / MIC  36.4 h Plasma 0-24hAUC, AUC/MIC, AUC>MIC Pseudomonas aeruginosa

  22. Levofloxacin 1 x 500 mg AUCUrine 4‘950 µg • h/ml MIC P.aerug. = 2.0 mg/l Urine-AUC / MIC  2‘475 Ciprofloxacin XR 1 x 1000 mg AUCUrine 5‘100 µg • h/ml MIC P.aerug. = 0.5 mg/l Urine-AUC / MIC  10‘200 Urine 0-24hAUC, AUC/MIC, AUC>MIC Pseudomonas aeruginosa

  23. Experimental Setup of Catheter-associated Infection Model Goto et al 1999 IJAA 11:227-232

  24. Teflon Catheters and Biofilmformation Pre. 4th 8th day Goto et al 1999 IJAA 11:227-232

  25. Goto et al 1999 IJAA 11:227-232

  26. Time-kill courses of Ciprofloxacin and Levofloxacin against biofilm cells of P. aeruginosa No. 02 in artificial urine 109 109 Levofloxacin Ciprofloxacin 108 108 107 107 106 106 105 Viable cell counts 105 Viable cell counts 104 104 103 103 102 102 101 101 100 100 0 6 12 18 24 30 36 42 48 0 6 12 18 24 30 36 42 48 hours hours LVFX 32 MBC CPFX 64 MBC LVFX 16 MBC CPFX 32 MBC LVFX 4 MBC CPFX 16 MBC LVFX 1 MBC CPFX 8 MBC LVFX 0.5 MBC CPFX 4 MBC CPFX 1 MBC Goto et al 1999 IJAA 11:227-232 CPFX 0.5 MBC

  27. Levofloxacin Goto: (32 x MBC x 24 h) Urine-AUC / MBC  768h Ciprofloxacin Goto: (32 x MBC x 24 h) Urine-AUC / MBC  768h AUC/MBC and AUC > MBCin Urine within 24 h Pseudomonas aeruginosa

  28. Urin - Bakterizidietiter (n=11) Levofloxacin (500mg) vs. Ciprofloxacin XR (1000mg)

  29. Levofloxacin 1 x 500 mg Urine-AUC / MBC  896* h Urine-AUC > MBC  872h Goto: (32 x MBC x 24 h) Urine-AUC / MBC  768h Ciprofloxacin XR 1 x 1000 mg Urine-AUC / MBC  1408* h Urine-AUC > MBC  1384 h Goto: (32 x MBC x 24 h) Urine-AUC / MBC  768h AUC/MBC and AUC > MBCin Urine within 24 h Pseudomonas aeruginosa *p<0.05

  30. Urin - Bakterizidietiter (n=11) Levofloxacin (500mg) vs. Ciprofloxacin XR (1000mg)

  31. Levofloxacin 1 x 500 mg Urine-AUC / MBC  1280°h (Range 352 – 3840) Ciprofloxacin XR 1 x 1000 mg Urine-AUC / MBC  656° h (Range 480 – 3008) AUC/MBC and AUC > MBCin Urine within 24 h Enterococcus faecalis ° p>0.05

  32. Equivalent Daily Dosages of Oral F/Q Low dosage: Norfloxacin 400 mg bid uUTI/uCystitis (?) Enoxacin 200 mg bid Ofloxacin 100 mg bid Ciprofloxacin 100 mg bid Standard dosage: Enoxacin 400 mg bid uUTI/uCystitis Ofloxacin 200 mg bid Acute uncompl PN (?) Ciprofloxacin 250 mg bid Cipro XR 500 mg od Levofloxacin 250 mg qd High dosage : Ciprofloxacin 500 mg bid * pyelonephritis Cipro XR 1,000 mg od cUTI Levofloxacin 500 mg qd * *Dosage can be increased if necessary Naber KG 2001 Int J Antimicr Agents Chemother 17: 331-341

  33. Which Parameters are Relevant for the Treatment of Complicated/Nosocomial UTI PK / PD Plasma? PK / PD Urine? Which PK / PD Parameters? Clinical Studies including PK / PD in Plasma and Urine correlated with therapeutic outcome and emergence of resistance

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