Clinical Impact of PK/PD in Urinary Tract Infections

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 gt MIC
MIC
TgtMIC
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
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-p
  ositive and atypicals Sparfloxacin
• IV As III anaerobes Gatifloxacin Moxifloxacin
  Gemifloxacin

mod. Naber et. al., 1998
5
Pharmacokinetics of Oral Fluoroquinolones
Urinary Excretion
Substance
Dose
Peak Serum
Serum
Half-life
Concentration
of Parent Drug
(mg/L)
()
(mg)
(h)
Group 1

Norfloxacin
1.5
20
400
3.2

Pefloxacin
3.2
14 18(N)
400
10.5
Group 2

Enoxacin
3.1
53
400
4.9

Fleroxacin
4.4
67
400
9.2

Ofloxacin
4.2
81
400
5.4

Lomefloxacin
5.2
75
8.1
400

Ciprofloxacin
2.6
4.2
43
500
Group 3

Levofloxacin
5.2
7.4
84
500

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 279 125-129
Urinary tract infections
Pulmonary infections
Skin and soft tissues infections
n 272 500 mg OD for at least 3 doses
BREAKPOINT 12.2
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 !

Warren JW et al.Clinical Infectious Diseases
1999 29 745-758 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-p
  ositive and atypicals Sparfloxacin
• IV As III anaerobes Gatifloxacin Moxifloxacin
  Gemifloxacin

mod. Naber et. al., 1998
10
Pharmacokinetics of Oral Fluoroquinolones
Urinary Excretion
Substance
Dose
Peak Serum
Serum
Half-life
Concentration
of Parent Drug
(mg/L)
()
(mg)
(h)
Group 1

Norfloxacin
1.5
20
400
3.2

Pefloxacin
3.2
14 18(N)
400
10.5
Group 2

Enoxacin
3.1
53
400
4.9

Fleroxacin
4.4
67
400
9.2

Ofloxacin
4.2
81
400
5.4

Lomefloxacin
5.2
75
8.1
400

Ciprofloxacin
2.6
4.2
43
500
Group 3

Levofloxacin
5.2
7.4
84
500

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
(55/58)
(60/64)
Success rate ()
(83/89)
(93/98)
(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 5251-55
12
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)
13
Plasma 0-24 hAUC 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 ? 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

14
Plasma 0-24hAUC 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 0.125 mg/l
• Plasma-AUC / MIC ? 145.6 h

15
Plasma 0-24hAUC 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 ? 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

16
Plasma 0-24hAUC 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. 0.125 mg/l
• Plasma-AUC / MIC ? 36.5 h

17
Acute Uncomplicated Pyelonephritis
randomized double-blind trial
Talan et al 2000 JAMA 283 1583 1583-90
18
Acute Uncomplicated Pyelonephritis
bacteriological eradication
p 0.002
Talan et al 2000 JAMA 283 1583 1583-90
19
Acute Uncomplicated Pyelonephritis
bacteriological eradication at 4-11 days after
oral therapy with only TMP/SMZ
TMP/SMZ TMP/SMZ susceptible resistant Uropathog
ens 59/63 (94) 2/9 (22)
E. coli
Talan et al 2000 JAMA 283 1583 1583-90
20
Minimal inhibitory concentrations (mg/l) of
Trimethoprim
21
Acute Uncomplicated Pyelonephritis
adverse events
Talan et al 2000 JAMA 283 1583 1583-90
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
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
1581494-1499
24
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
1581494-1499
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 (n12) Levofloxacin
(500mg) vs. Ciprofloxacin XR (1000mg)
29
Ciprofloxacin XR (1000 mg) vs. Levofloxacin (500
mg) bei Probanden (n 12) nach einer
EinmalgabePharmakokinetik(mediane Werte)
Substanz Cmax (µg/ ml) t1/2 (h) AUCPlasma (0-24h) (µgh/ ml) Umax (µg/ ml) AUCUrin (0-24) (µgh/ 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 lt 0,05
30
Plasma 0-24hAUC, AUC/MIC, AUCgtMIC
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 0-24hAUC, AUC/MIC, AUCgtMIC
Pseudomonas aeruginosa

• Levofloxacin 1 x 500 mg
• AUCUrine ? 4950 µg h/ml
• MIC P.aerug. 2.0 mg/l
• Urine-AUC / MIC ? 2475

• Ciprofloxacin XR 1 x 1000 mg
• AUCUrine ? 5100 µg h/ml
• MIC P.aerug. 0.5 mg/l
• Urine-AUC / MIC ? 10200

32
Experimental Setup of Catheter-associated
Infection Model
Goto et al 1999 IJAA 11227-232
33
Teflon Catheters and Biofilmformation
Pre.
4th
8th day
Goto et al 1999 IJAA 11227-232
34
Goto et al 1999 IJAA 11227-232
35
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 11227-232
CPFX 0.5 MBC
36
AUC/MBC and AUC gt MBCin 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 (n11) Levofloxacin
(500mg) vs. Ciprofloxacin XR (1000mg)
38
AUC/MBC and AUC gt MBCin Urine within 24 h
Pseudomonas aeruginosa

• Levofloxacin
• 1 x 500 mg
• Urine-AUC / MBC ? 896 h
• Urine-AUC gt 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 gt MBC ? 1384 h
• Goto (32 x MBC x 24 h)
• Urine-AUC / MBC ? 768 h

plt0.05
39
Urin - Bakterizidietiter (n11) Levofloxacin
(500mg) vs. Ciprofloxacin XR (1000mg)
40
AUC/MBC and AUC gt MBCin 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)

pgt0.05
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 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
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