Dosing of Fluoroquinolones in Urinary Tract Infections

K.G. Naber, F.M.E. WagenlehnerUrologic Clinic, St. Elisabeth Hospital,

Straubing, Germany

mod. Naber et. al., 1998

Classification of Fluoroquinolones

I Oral FQ, UTI only NorfloxacinPefloxacin

II Systemic use, (Enoxacin, oral)broad spectrum Fleroxacin(UTI, RTI, SSI, Sepsis) Ofloxacin

Ciprofloxacin

III Improved activity against LevofloxacinGram-positive and “atypicals“ Sparfloxacin

IV As III + anaerobes GatifloxacinMoxifloxacinGemifloxacin

Substance Dose

(mg)

Peak SerumConcentration

(mg/L)

SerumHalf-life

(h)

Urinary Excretionof Parent Drug

(%)

Group 1Norfloxacin 400 1.5 3.2 20Pefloxacin 400 3.2 10.5 14 + 18(N)

Group 2Enoxacin 400 3.1 4.9 53Fleroxacin 400 4.4 9.2 67Ofloxacin 400 4.2 5.4 81Lomefloxacin 400 5.2 75Ciprofloxacin 500 2.6 4.2 43

Group 3Levofloxacin 500 5.2 7.4 84Sparfloxacin 200 1.6 17 10

Group 4Gatifloxacin 400 3.4 8 80Moxifloxacin 400 2.5 13.1 20Gemifloxacin* 320 1.3 6.1 28

*not registered yet; (N) norfloxacin

Pharmacokinetics of Oral Fluoroquinolones

8.1

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

MIC

CMAX

AUC > MIC

T>MIC

Time (t)

Conc. (mg/l)

PK / PD Parameters

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

Prob

ability

(%)

Prob

ability

(%)

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

l acute uncomplicated cystitisl acute pyelonephritis

* uncomplicated* complicated

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

l sepsis syndrome - urosepsis

l 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) orTMP/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

Equivalent Daily Dosages of Oral F/Q

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

Ofloxacin 100 mg bidCiprofloxacin 100 mg bid

Standard dosage: Enoxacin 400 mg biduUTI/uCystitis Ofloxacin 200 mg bidAcute uncompl PN? Ciprofloxacin 250 mg bid

Cipro XR 500 mg odLevofloxacin 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 necessaryNaber KG 2001 Int J AntimicrAgents Chemother 17: 331-341

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

once

ntra

tion

(mg/

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 hPlasma-AUC > MIC ≅ 762.6 h

Ciprofloxacin 2 x 500 mg

AUCPlasma ≅ 18.2 µg • h/ml

MIC E.coli = 0.008 mg/l

Plasma-AUC / MIC ≅ 2275 hPlasma-AUC > MIC ≅ 2274.8 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 hPlasma-AUC > MIC ≅ 85.9 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 hPlasma-AUC > MIC ≅ 143.3 h

E. coli – Nx-resistant

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 91.491.4Other EnterobacteriaceaeOther Enterobacteriaceae 20/2320/23 87.087.0 22/2422/24 91.791.7Other GramOther Gram--negativesnegatives 2/22/2 100.0100.0 4/54/5 80.080.0Pseudomonas spp.Pseudomonas spp. 5/95/9 55.655.6 7/99 77.877.8Enterococcus spp.Enterococcus spp. 10/1710/17 58.858.8 14/2014/20 70.070.0Staphylococcus spp.Staphylococcus spp. 4/104/10 40.040.0 11/2111/21 52.452.4Other GramOther Gram--positivespositives - 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 ComplicatedUrinary 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 88.988.9Other EnterobacteriaceaeOther Enterobacteriaceae 20/2420/24 83.383.3 32/3532/35 91.491.4Other GramOther Gram--negativesnegatives 3/33/3 100.0100.0 2/32/3 66.766.7Pseudomonas spp.Pseudomonas spp. 4/64/6 66.766.7 4/44/4 100.100.0Enterococcus spp.Enterococcus spp. 10/1410/14 71.471.4 25/2925/29 86.286.2Staphylococcus spp.Staphylococcus spp. 8/138/13 61.561.5 13/2513/25 52.052.0Other GramOther Gram--positivespositives -- 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

nary

Con

cent

ratio

ns(m

g/l)

4.950

5.100

AUCUrin

(0-24)

(µg*h/ ml)

400 (80%)53045,8*6,366,44*LVX

430 (43%)69118,2*6,203,19*Cipro XR

UEmg (%)

Umax(µg/ ml)

AUCPlasma

(0-24h)

(µg*h/ ml)

t1/2

(h)Cmax

(µg/ ml)Substanz

*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

Plasma-AUC > MIC ≅ -25.1 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

Plasma-AUC > MIC ≅ 24.4 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

Urine-AUC > MIC ≅ 2‘463

Ciprofloxacin XR 1 x 1000 mg

AUCUrine ≅ 5‘100 µg • h/ml

MIC P.aerug. = 0.5 mg/l

Urine-AUC / MIC ≅ 10‘200

Urine-AUC > MIC ≅ 10‘188

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 48hours

Ciprofloxacin

Via

ble

cel

l co

un

ts

CPFX 64 MBCCPFX 32 MBCCPFX 16 MBCCPFX 8 MBCCPFX 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 48hours

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

Urine-AUC > MBC ≅ 744 h

Ciprofloxacin

Goto: (32 x MBC x 24 h)

Urine-AUC / MBC ≅ 768 h

Urine-AUC > MBC ≅ 744 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

nary

Bac

teri

cida

l 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 hUrine-AUC > MBC ≅ 744 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 hUrine-AUC > MBC ≅ 744 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

nary

Bac

teri

cida

l Tite

rs

AUC/MBC and AUC > MBCin Urine within 24 h

Levofloxacin 1 x 500 mg

Urine-AUC / MBC ≅ 1280° h(Range 352 – 3840)

Urine-AUC > MBC ≅ 1256 h

Ciprofloxacin XR 1 x 1000 mg

Urine-AUC / MBC ≅ 656° h(Range 480 – 3008)

Urine-AUC > MBC ≅ 632 h

Enterococcus faecalis

° p>0.05

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 theTreatment of Complicated/Nosocomial UTI