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Clinical Impact of PK/PD in Urinary Tract Infections

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Presentation on theme: "Clinical Impact of PK/PD in Urinary Tract Infections"— 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 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)

4 Classification of Fluoroquinolones
I Oral FQ, UTI only Norfloxacin Pefloxacin II Systemic use, (Enoxacin, oral) broad spectrum Fleroxacin (UTI, RTI, SSI, Sepsis) Ofloxacin Ciprofloxacin III Improved activity against Levofloxacin Gram-positive and “atypicals“ Sparfloxacin IV As III + anaerobes Gatifloxacin Moxifloxacin Gemifloxacin mod. Naber et. al., 1998

5 Pharmacokinetics of Oral Fluoroquinolones
Substance Dose Peak Serum Serum Urinary Excretion Concentration Half-life of Parent Drug (mg) (mg/L) (h) (%) Group 1 Norfloxacin 400 1.5 20 3.2 Pefloxacin 400 3.2 (N) 10.5 Group 2 Enoxacin 400 3.1 53 4.9 Fleroxacin 400 4.4 67 9.2 Ofloxacin 400 4.2 81 5.4 Lomefloxacin 400 5.2 8.1 75 Ciprofloxacin 500 2.6 4.2 43 Group 3 Levofloxacin 500 5.2 7.4 84 Sparfloxacin 200 1.6 17 10 Group 4 Gatifloxacin 400 3.4 8 80 Moxifloxacin 400 2.5 13.1 20 Gemifloxacin* 320 1.3 6.1 28 * not registered yet; (N) norfloxacin

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

7 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

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

9 Classification of Fluoroquinolones
I Oral FQ, UTI only Norfloxacin Pefloxacin II Systemic use, (Enoxacin, oral) broad spectrum Fleroxacin (UTI, RTI, SSI, Sepsis) Ofloxacin Ciprofloxacin III Improved activity against Levofloxacin Gram-positive and “atypicals“ Sparfloxacin IV As III + anaerobes Gatifloxacin Moxifloxacin Gemifloxacin mod. Naber et. al., 1998

10 Pharmacokinetics of Oral Fluoroquinolones
Substance Dose Peak Serum Serum Urinary Excretion Concentration Half-life of Parent Drug (mg) (mg/L) (h) (%) Group 1 Norfloxacin 400 1.5 20 3.2 Pefloxacin 400 3.2 (N) 10.5 Group 2 Enoxacin 400 3.1 53 4.9 Fleroxacin 400 4.4 67 9.2 Ofloxacin 400 4.2 81 5.4 Lomefloxacin 400 5.2 8.1 75 Ciprofloxacin 500 2.6 4.2 43 Group 3 Levofloxacin 500 5.2 7.4 84 Sparfloxacin 200 1.6 17 10 Group 4 Gatifloxacin 400 3.4 8 80 Moxifloxacin 400 2.5 13.1 20 Gemifloxacin* 320 1.3 6.1 28 * not registered yet; (N) norfloxacin

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

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

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

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

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

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

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

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

19 Acute Uncomplicated Pyelonephritis
bacteriological eradication at 4-11 days after oral therapy with only TMP/SMZ TMP/SMZ TMP/SMZ susceptible resistant Uropathogens 59/63 (94%) 2/9 (22%)* *E. coli Talan et al 2000 JAMA 283: 1583:

20 Minimal inhibitory concentrations (mg/l) of Trimethoprim

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

22 Nosocomial - Complicated UTI: Causes, Localisations and Complications
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 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:

24 Eradication of Uropathogens in Complicated Urinary Tract Infections
Species ciprofloxacin ciprofloxacin 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. 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:

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

26 European study: not equivalent
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 Ciprofloxacin XR (1000 mg) vs
Ciprofloxacin XR (1000 mg) vs. Levofloxacin (500 mg) bei Probanden (n = 12) nach einer Einmalgabe Pharmakokinetik (mediane Werte) Substanz Cmax (µg/ ml) t1/2 (h) AUCPlasma (0-24h) (µg*h/ ml) Umax AUCUrin (0-24) UE mg (%) Cipro XR 3,19* 6,20 18,2* 691 5.100 430 (43%) LVX 6,44* 6,36 45,8* 530 4.950 400 (80%) *P < 0,05

30 Plasma 0-24h AUC, AUC/MIC, AUC>MIC
Pseudomonas aeruginosa Levofloxacin 1 x 500 mg AUCPlasma  45.8 µg • h/ml MIC P.aerug. = 2.0 mg/l Plasma-AUC / MIC  22.9 h 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

31 Urine 0-24h AUC, AUC/MIC, AUC>MIC
Pseudomonas aeruginosa 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

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

33 Teflon Catheters and Biofilmformation
Pre. 4th 8th day Goto et al 1999 IJAA 11:

34 Goto et al 1999 IJAA 11:

35 Time-kill courses of Ciprofloxacin and Levofloxacin against biofilm cells of P. aeruginosa No. 02 in artificial urine 109 109 Ciprofloxacin Levofloxacin 108 108 107 107 106 106 Viable cell counts 105 Viable cell counts 105 104 104 103 103 102 102 101 101 100 100 6 12 18 24 30 36 42 48 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: CPFX 0.5 MBC

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

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

38 AUC/MBC and AUC > MBC in Urine within 24 h
Pseudomonas aeruginosa 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 *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
Enterococcus faecalis 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) ° p>0.05

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

42 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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