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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 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