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

MIC

CMAX

AUC > MIC

T>MIC

Time (t)

Conc. (mg/l)

PK / PD Parameters

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

PHARMACODYNAMICS OF LEVOFLOXACINPreston SL et al. JAMA 1998; 279: 125-129

Pro

bab

ilit

y (

%)

Pro

bab

ilit

y (

%)

Peak/MIC ratioPeak/MIC ratio0 10 20 30

0

10

20

30

40

70

60

50

90

80

100

40 50

Urinary tract infections

Pulmonary infections

Skin and soft tissues infections

BREAKPOINT = 12.2 n = 272

500 mg OD for at least 3 doses

acute uncomplicated cystitisacute pyelonephritis

uncomplicated complicated

complicated urinary tract infections due to underlying diseases due to urological disorders

sepsis syndrome - urosepsis

others urethritis prostatitis epididymitis

Classification of Urinary Tract Infections

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: 745-758;EAU Guidelines on UTI 2001;

duration of treatment:

(1)-3-(7) days

93 95 95 94 95 95

0

20

40

60

80

100

Clinical success Bacteriologic success

Levofloxacin1 x 250 mg, 10d

Ciprofloxacin2 x 500 mg, 10d

Richard GA et al (1998) Urology 52:51-55

Su

cces

s ra

te (

%)

(83/89) (55/58)(93/98) (60/64)

Levofloxacin vs. Ciprofloxacin vs. Lomefloxacin in Acute Pyelonephritis

Lomefloxacin1 x 400 mg, 14d

(37/39) (39/41)

7

0

Seru

m C

on

cen

trati

on

(m

g/l

)

6

5

4

3

2

1

24Time (h)

0 2 4 6 8 10 12 14 16 18 20 22

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.)

Plasma 0-24 hAUC and AUC/MIC

Levofloxacin 1 x 250 mg

AUCPlasma 22.9 µg • h/ml

MIC E.coli = 0.03 mg/l

Plasma-AUC / MIC 763.3 h

Ciprofloxacin 2 x 500 mg

AUCPlasma 18.2 µg • h/ml

MIC E.coli = 0.008 mg/l

Plasma-AUC / MIC 2275 h

E. coli ATTC 25922

Plasma 0-24hAUC and AUC/MIC

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 = 0.125 mg/l

Plasma-AUC / MIC 145.6 h

E. coli – Nx-resistant

Plasma 0-24hAUC and AUC/MIC

Levofloxacin 1 x 500 mg

AUCPlasma 45.8 µg • h/ml

MIC E.coliR-Nx = 0.25 mg/l

Plasma-AUC / MIC 183.2 h

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

E. coli – Nx-resistant

Plasma 0-24hAUC and AUC/MIC

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. = 0.125 mg/l

Plasma-AUC / MIC 36.5 h

Pseudomonas aeruginosa

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

SpeciesSpecies fleroxacinfleroxacin200 mg qd*200 mg qd*

fleroxacinfleroxacin400 mg qd400 mg qd

N/NN/Ntot %% N/NN/Ntot %%

Escherichia coliEscherichia coli 27/3227/32 84.484.4 53/5853/58 91.491.4

Other EnterobacteriaceaeOther Enterobacteriaceae 20/2320/23 87.087.0 22/2422/24 91.791.7

Other Gram-negativesOther Gram-negatives 2/22/2 100.0100.0 4/54/5 80.080.0

Pseudomonas spp.Pseudomonas spp. 5/95/9 55.655.6 7/99 77.877.8

Enterococcus spp.Enterococcus spp. 10/1710/17 58.858.8 14/2014/20 70.070.0

Staphylococcus spp.Staphylococcus spp. 4/104/10 40.040.0 11/2111/21 52.452.4

Other Gram-positivesOther Gram-positives - 1/21/2 50.050.0

TotalTotal 68/9368/93 73.173.1 113/119113/119 81.381.3

Frankenschmidt, Naber et. al. (1997) J Urol 158:1494-1499

*loading dose 400 mg

Eradication of Uropathogens in Complicated Urinary Tract Infections

SpeciesSpecies ciprofloxacinciprofloxacin250 mg bid250 mg bid

ciprofloxacinciprofloxacin500 mg bid500 mg bid

N/NN/Ntot % N/NN/Ntot %%

Escherichia coliEscherichia coli 28/3228/32 87.587.5 52/6352/63 88.988.9

Other EnterobacteriaceaeOther Enterobacteriaceae 20/2420/24 83.383.3 32/3532/35 91.491.4

Other Gram-negativesOther Gram-negatives 3/33/3 100.0100.0 2/32/3 66.766.7

Pseudomonas spp.Pseudomonas spp. 4/64/6 66.766.7 4/44/4 100.100.0

Enterococcus spp.Enterococcus spp. 10/1410/14 71.471.4 25/2925/29 86.286.2

Staphylococcus spp.Staphylococcus spp. 8/138/13 61.561.5 13/2513/25 52.052.0

Other Gram-positivesOther Gram-positives -- 0/10/1 0.00.0

Total 74/9274/92 78.778.7 132/161132/161 82.082.0

Eradication of Uropathogens in Complicated

Urinary Tract Infections

Frankenschmidt, Naber et. al. (1997) J Urol 158:1494-1499

Acute Pyelonephritis and Complicated UTI Gemifloxacin (320mg od) vs. Ciprofloxacin

(500mg bid)

US-Study: equivalentEuropean study: not equivalent

Acute Pyelonephritis and Complicated UTI Gemifloxacin (320mg od) vs. Ciprofloxacin

(500mg bid)

US-Study: equivalentEuropean 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)

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

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

0-6 6-12 12-24 24-36 36-48 48-72 72-96 96-120

5.0

50.0

500.0

1

10

100.0

Levofloxacin

Ciprofloxacin

Time (h)

Med

ian

Uri

nar

yC

on

cen

trat

ion

s(m

g/l)

Substanz Cmax

(µg/ ml)

t1/2

(h)

AUCPlasma

(0-24h)

(µg*h/ ml)

Umax

(µg/ ml)

AUCUrin

(0-24)

(µg*h/ ml)

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

Ciprofloxacin XR (1000 mg) vs. Levofloxacin (500 mg) bei Probanden (n = 12) nach einer Einmalgabe

Pharmakokinetik(mediane Werte)

Plasma 0-24hAUC, AUC/MIC, AUC>MIC

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

Pseudomonas aeruginosa

Urine 0-24hAUC, AUC/MIC, AUC>MIC

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

Pseudomonas aeruginosa

Experimental Setup of Catheter-associated Infection Model

Goto et al 1999 IJAA 11:227-232

Teflon Catheters and Biofilmformation

Pre. 4th 8th day

Goto et al 1999 IJAA 11:227-232

Goto et al 1999 IJAA 11:227-232

Time-kill courses of Ciprofloxacin and Levofloxacin against biofilm cells of P. aeruginosa No. 02 in artificial urine

109

108

107

106

105

104

103

102

101

100

0 6 12 18 24 30 36 42 48

hours

Ciprofloxacin

Via

ble

cel

l co

un

ts

CPFX 64 MBCCPFX 32 MBCCPFX 16 MBCCPFX 8 MBC

CPFX 4 MBCCPFX 1 MBCCPFX 0.5 MBC

109

108

107

106

105

104

103

102

101

100

0 6 12 18 24 30 36 42 48

hours

Levofloxacin

LVFX 32 MBCLVFX 16 MBCLVFX 4 MBCLVFX 1 MBCLVFX 0.5 MBC

Via

ble

cel

l co

un

ts

Goto et al 1999 IJAA 11:227-232

AUC/MBC and AUC > MBCin 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

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

0-4 4-8 8-12 12-16 16-24 24-28 28-32 32-3601248

163264

128256512

1024

LEV; MIC 2.0 mg/l

CIP; MIC 0.5 mg/l

Pseudomonas aeruginosa (# 568)

Time (h)

Med

ian

Uri

nar

yB

acte

rici

dal

Tite

rs

AUC/MBC and AUC > MBCin Urine within 24 h

Levofloxacin 1 x 500 mg

Urine-AUC / MBC 896* hUrine-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* hUrine-AUC > MBC 1384 h

Goto: (32 x MBC x 24 h)

Urine-AUC / MBC 768 h

Pseudomonas aeruginosa

*p<0.05

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

0-4 4-8 8-12 12-16 16-24 24-28 28-32 32-3601248

16326464

128256512

1024

CIP, MIC 1.0 mg/lLEV, MIC 1.0 mg/l

Enterococcus faecalis (# 60)

Time (h)

Med

ian

Uri

nar

yB

acte

rici

dal

Tite

rs

AUC/MBC and AUC > MBCin 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

Equivalent Daily Dosages of Oral F/Q

Low dosage: Norfloxacin 400 mg biduUTI/uCystitis (?) Enoxacin 200 mg bid

Ofloxacin 100 mg bid Ciprofloxacin 100 mg bid

Standard dosage: Enoxacin 400 mg biduUTI/uCystitis Ofloxacin 200 mg bidAcute 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 odcUTI Levofloxacin 500 mg qd *

*Dosage can be increased if necessary

Naber KG 2001 Int J Antimicr Agents Chemother 17: 331-341

PK / PDPlasma?

PK / PDUrine?

WhichPK / PD

Parameters?

Clinical Studies including PK / PD in Plasma and Urinecorrelated with therapeutic outcome and emergence of resistance

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