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Clinical Impact of PK/PD in Urinary Tract Infections K.G. Naber, F.M.E. Wagenlehner Urologic Clinic, St. Elisabeth Hospital, Straubing, Germany Inernational.

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Presentation on theme: "Clinical Impact of PK/PD in Urinary Tract Infections K.G. Naber, F.M.E. Wagenlehner Urologic Clinic, St. Elisabeth Hospital, Straubing, Germany Inernational."— Presentation transcript:

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

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)

4 mod. Naber et. al., 1998 Classification of Fluoroquinolones I Oral FQ, UTI onlyNorfloxacin Pefloxacin II Systemic use,(Enoxacin, oral) broad spectrumFleroxacin (UTI, RTI, SSI, Sepsis)Ofloxacin Ciprofloxacin III Improved activity againstLevofloxacin Gram-positive and “atypicals“Sparfloxacin IV As III + anaerobesGatifloxacin Moxifloxacin Gemifloxacin

5 SubstanceDose (mg) Peak Serum Concentration (mg/L) Serum Half-life (h) Urinary Excretion of Parent Drug (%) Group 1 Norfloxacin Pefloxacin (N) Group 2 Enoxacin Fleroxacin Ofloxacin Lomefloxacin Ciprofloxacin Group 3 Levofloxacin Sparfloxacin Group 4 Gatifloxacin Moxifloxacin Gemifloxacin* *not registered yet; (N)norfloxacin Pharmacokinetics of Oral Fluoroquinolones 8.1

6 PHARMACODYNAMICS OF LEVOFLOXACIN Preston SL et al. JAMA 1998; 279: Probability (%) Peak/MIC ratio Urinary tract infections Pulmonary infections Skin and soft tissues infections BREAKPOINT = 12.2 n = mg OD for at least 3 doses

7 lacute uncomplicated cystitis lacute pyelonephritis *uncomplicated *complicated lcomplicated urinary tract infections *due to underlying diseases *due to urological disorders lsepsis syndrome - urosepsis lothers *urethritis *prostatitis *epididymitis Classification of Urinary Tract Infections

8 Acute Uncomplicated Cystitis 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 ! Warren JW et al.Clinical Infectious Diseases 1999; 29: ; EAU Guidelines on UTI 2001; duration of treatment: (1)-3-(7) days

9 mod. Naber et. al., 1998 Classification of Fluoroquinolones I Oral FQ, UTI onlyNorfloxacin Pefloxacin II Systemic use,(Enoxacin, oral) broad spectrumFleroxacin (UTI, RTI, SSI, Sepsis)Ofloxacin Ciprofloxacin III Improved activity againstLevofloxacin Gram-positive and “atypicals“Sparfloxacin IV As III + anaerobesGatifloxacin Moxifloxacin Gemifloxacin

10 SubstanceDose (mg) Peak Serum Concentration (mg/L) Serum Half-life (h) Urinary Excretion of Parent Drug (%) Group 1 Norfloxacin Pefloxacin (N) Group 2 Enoxacin Fleroxacin Ofloxacin Lomefloxacin Ciprofloxacin Group 3 Levofloxacin Sparfloxacin Group 4 Gatifloxacin Moxifloxacin Gemifloxacin* *not registered yet; (N)norfloxacin Pharmacokinetics of Oral Fluoroquinolones 8.1

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

12 7 0 Serum Concentration (mg/l) Time (h) Levofloxacin 500 mg Ciprofloxacin 500 mg Sparfloxacin 400 mg Chien et al., (1997), AAC 41: 2256 ff, Product Monograph Ciprobay (1986) und Zagam (1994) Plasma concentrations of fluoroquinolones (p.o.)

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

14 Plasma 0-24h AUC and AUC/MIC Levofloxacin 1 x 250 mg AUC Plasma  22.9 µg h/ml MIC E.coli R-Nx = 0.25 mg/l Plasma-AUC / MIC  91.6 h Ciprofloxacin 2 x 500 mg AUC Plasma  18.2 µg h/ml MIC E.coli R-Nx = mg/l Plasma-AUC / MIC  h E. coli – Nx-resistant

15 Plasma 0-24h AUC and AUC/MIC Levofloxacin 1 x 500 mg AUC Plasma  45.8 µg h/ml MIC E.coli R-Nx = 0.25 mg/l Plasma-AUC / MIC  h Ciprofloxacin 2 x 500 mg AUC Plasma  18.2 µg h/ml MIC E.coli R-Nx = mg/l Plasma-AUC / MIC  h E. coli – Nx-resistant

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

17 Acute Uncomplicated Pyelonephritis Talan et al 2000 JAMA 283: 1583: randomized double-blind trial

18 Acute Uncomplicated Pyelonephritis Talan et al 2000 JAMA 283: 1583: bacteriological eradication *p = 0.002

19 Acute Uncomplicated Pyelonephritis Talan et al 2000 JAMA 283: 1583: bacteriological eradication at 4-11 days after oral therapy with only TMP/SMZ *E. coli TMP/SMZ susceptibleresistant Uropathogens59/63 (94%)2/9 (22%)*

20 Minimal inhibitory concentrations (mg/l) of Trimethoprim

21 Acute Uncomplicated Pyelonephritis Talan et al 2000 JAMA 283: 1583: adverse events

22 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

23 Speciesfleroxacin 200 mg qd* fleroxacin 400 mg qd N/N tot %N/N % Escherichia coli 27/ / Other Enterobacteriaceae 20/ / Other Gram-negatives 2/ /580.0 Pseudomonas spp. 5/955.67/977.8 Enterococcus spp. 10/ / Staphylococcus spp. 4/ / Other Gram-positives -1/250.0 Total68/ / Frankenschmidt, Naber et. al. (1997) J Urol 158: *loading dose 400 mg Eradication of Uropathogens in Complicated Urinary Tract Infections

24 Species ciprofloxacin 250 mg bid ciprofloxacin 500 mg bid N/N tot %N/N % Escherichia coli 28/ / Other Enterobacteriaceae 20/ / Other Gram-negatives 3/ /366.7 Pseudomonas spp. 4/666.74/ Enterococcus spp. 10/ / Staphylococcus spp. 8/ / Other Gram-positives -0/10.0 Total74/ / Eradication of Uropathogens in Complicated Urinary Tract Infections Frankenschmidt, Naber et. al. (1997) J Urol 158:

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

26 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)

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

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

29 SubstanzCmax (µg/ ml) t 1/2 (h) AUC Plasma (0-24h) (µg*h/ ml) Umax (µg/ ml) AUC Urin (0-24) (µg*h/ ml) UE mg (%) Cipro XR3,19*6,2018,2* (43%) LVX6,44*6,3645,8* (80%) *P < 0,05 Ciprofloxacin XR (1000 mg) vs. Levofloxacin (500 mg) bei Probanden (n = 12) nach einer Einmalgabe Pharmakokinetik (mediane Werte)

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

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

32 Experimental Setup of Catheter-associated Infection Model Goto et al 1999 IJAA 11:

33 Teflon Catheters and Biofilmformation Pre.4th8th day Goto et al 1999 IJAA 11:

34

35 Time-kill courses of Ciprofloxacin and Levofloxacin against biofilm cells of P. aeruginosa No. 02 in artificial urine hours Ciprofloxacin Viable cell counts CPFX 64 MBC CPFX 32 MBC CPFX 16 MBC CPFX 8 MBC CPFX 4 MBC CPFX 1 MBC CPFX 0.5 MBC hours Levofloxacin LVFX 32 MBC LVFX 16 MBC LVFX 4 MBC LVFX 1 MBC LVFX 0.5 MBC Viable cell counts Goto et al 1999 IJAA 11:

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

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

38 AUC/MBC and AUC > MBC in Urine within 24 h Levofloxacin 1 x 500 mg Urine-AUC / MBC  896* h Urine-AUC > MBC  872 h Goto: (32 x MBC x 24 h) Urine-AUC / MBC  768 h 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  768 h Pseudomonas aeruginosa *p<0.05

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

40 AUC/MBC and AUC > MBC in Urine within 24 h 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) Enterococcus faecalis ° p>0.05

41 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 * pyelonephritisCipro XR 1,000 mg od cUTILevofloxacin 500 mg qd * *Dosage can be increased if necessary Naber KG 2001 Int J Antimicr Agents Chemother 17:

42 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 Which Parameters are Relevant for the Treatment of Complicated/Nosocomial UTI


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