clinical use of fluoroquinolones -...

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Clinical Use of Fluoroquinolones

Cheng-Yi Liu,M.D.Taipei Veterans General Hospital

- 1928Alexander Fleming1898-1968

Penicillium notatum

1930-1940 Sulfar, penicillin, streptomycin

1950-1970 Cephalosporins, erythromycin, penicillins

1970-1980 Vancomycin, new macrolides

1990s New fluoroquinolones, carbapenem

2000s Oxazolidinones, Tigecycline

Alexander Fleming1898-1968

Nobel Prize 1945

The organism will find its way ! (to survive), !

Intracellular organism Spore formation

02468

10121416

1983-1987 1988-1992 1993-1997 1998-2003 Futurepipeline

Antibacterials licensed by the FDA

G(-) Targeting of DNA gyrase Lead to bacterial cell death No Cross-Resistance to -lactam antibiotics

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Nalidixic Acid

Ciprofloxacin, Norfloxacin, Ofloxacin

Levofloxacin, Sparfloxacin

Gatifloxacin, Gemifloxacin, Moxifloxacin

Trovafloxacin, Clinafloxacin

Limited gram-negatives

Expanded gram-negatives

Gram-positives

Expanded gram-positives + atypicals

Anaerobes

I

II

II

III

IV

The Evolution of The Evolution of QuinolonesQuinolones

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FluoroquinolonesFluoroquinolonesGroups (I, II, III)

Group I (1960s): limited spectrum Nalidixic acid, pipemidic acid, oxolinic acid Enteric or urinary tract infections

Group II (1970s-1980s): extended spectrum Norfloxacin, fleroxacin, enoxacin, ciprofloxacin,

ofloxacin, and levofloxacin GNR (P. aeruginosa), S. pneumoniae, atypicals Nosocomial and community-acquired infection

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FluoroquinolonesFluoroquinolonesGroups (I, II, III)

Group III (1990s): respiratory spectrum Levofloxacin, moxifloxacin, gatifloxacin, gemifloxacin,

grepafloxacin, clinafloxacin, temofloxacin, trovafloxacin, sitafloxacin, garenoxacin

GNR (P. aeruginosa ), GPB (S. pneumoniae ), atypicals, anaerobes

Respiratory tract infections (CAP, ABECB, sinusitis)

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Quinolone Avaliable in TaiwanGeneration

1st Pipemidic Acid(Docol)

2nd(I)

2nd(II)

Norfloacin(Baccidal)Ciprofloxacin(Ciproxin)Levofloxacin(Cravit)Sparfloxacin

3rd Moxifloxacin(Avelox)Galtifloxaicn,Gemifloxacin

4th Travafloxacin,Clinafloxaicn

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Classification of Fluoroquinolones

First generation: Ciproxin

Second generation: Cravit

Third generation: Avelox

G(+):Pneumococcus

PseudomonasG(-):

Emerging Infectious. 9 Disease Vol no.1 P1-8, 2003

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Pharmacology Pharmacology of Antimicrobial Therapyof Antimicrobial Therapy

Dosingregimen

Concentrationsin serum

Concentrationsin tissues and

body fluids

Concentrationsat site of infection

Pharmacologic and toxicologic

effect

Antimicrobialeffect

AbsorptionAbsorptionDistributionDistributionEliminationElimination

Pharmacokinetics (PK)Pharmacokinetics (PK) PharmacodynamicsPharmacodynamics (PD)(PD)

MIC, MBCCmax/MIC,

T>MIC, AUIC

G(-)Time

MIC

Time > MIClo

g C

once

ntra

tion

Time-Dependent(Maximize time above MIC)

Maximum killing

Cmax = 3-4x MIC

T > MIC

MIC

Peak (Cmax)

-lactamsMacrolides

40-50% interval

G(-)Time

MIClog

Con

cent

ratio

n

Cmax/MICPeak (Cmax)

Concentration-Dependent(Achieve Highest Possible Dose Without Toxicity)

Maximize Bactericidal

Cmax/MIC, 8-10:1

MIC

QuinolonesAminoglycosides

G(-)Time

MIC90

L

24h-AUC

og C

once

ntra

tion 24h-AUC/MIC90 (24h-AUIC)

Area under the Serum-Time Curve (AUC)

MIC

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Days of therapy

0 2 4 6 8 10 12 140

100

75

50

25

AUIC 125-AUIC >25

AUIC 250AUIC >250

32 days32 days

1.9 days1.9 days6.6 days6.6 days

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Peak (Cmax)

AUC

0 4 8 12 16 20 24

T > MIC MIC

40

30

20

10

0

Time (h)

Con

cent

ratio

n (m

g/L)

PK/PD Surrogate RelationshipsPK/PD Surrogate Relationships

24h-AUC/MICCmax/MICTime>MIC

MIC90

Definite therapy

Empirical therapy

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FluoroquinolonesFluoroquinolonesPK/PD-Optimized Therapy

Cmax/MIC ratio 8

24-h AUC/MIC ratio 125 (GPB, GNB); 25-30 (GPB): efficacy

125 (all): resistance prevention

Do not over-fractionate the daily dose

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AUIC of FluoroquinolonesAUIC of Fluoroquinolones

Antimicrobial-Therapy and Vaccines. Dr Victor L. Yu 1999

Fluoroquinolone Ofloxacin Levofloxacin Ciprofloxacin Moxifloxacin

Oral Dose (mg/24h) 800 500 1500 400

AUC24 (mg.h/L) 133 138 64 32

Breakpoint MIC for

AUIC 125 1.0 1.0 0.5 0.25

P. aeruginosa MIC90 2.0 2.0 0.5 2.0

S. aureus MIC90 0.25 0.5 0.5 0.25

E.coli MIC90 0.125 0.05 0.01 0.05

S. pneumoniae MIC90 2.0 1.0 2.0 0.25

AUIC (area under the inhibitory curve), AUC24/MIC90

PD breakpoint

Worldwide Epidemiology of Resistant-GNB (SMART)

Study for Monitoring Antimicrobial Resistance Trends

Paterson, et al. J Antimicrob Chemother 2005

Bacteria / Antibiotic % IPM CRO CAZ FEP TZP AMK CIP

Escherichia coli 99 90 89 91 95 97 77

Klebsiella pneumoniae 99 84 84 85 86 94 84

Enterobacter cloacae 100 59 58 83 72 93 83

Proteus mirabilis 98 98 99 100 99 99 86

Morganella morganii 100 94 80 96 96 96 86

Serratia marcescens 98 83 83 94 86 91 84

Pseudomonas aeruginosa 82 17 80 81 72 93 86

Acinetobacter baumannii 64 22 26 26 32 41 25

Stenotrophomonas maltophilia 6 6 35 6 14 14 24

Fluoroquinolone-Resistance among Gram-negative Bacilli in Taiwan

Example of ciprofloxacin sensitivity E. coli K. pneumoniae Proteus mirabilis Morganella morganii Serratia marcescens Enterobacter cloacae Pseudomonas aeruginosa

50% FQ-resistant bacterial infection without previous exposure to FQs !

Diagn Microb Infect Dis 2002

1985 1997100% 81%100% 93%100% 96%100% 81%99% 80%

100% 83%97% 87%

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MICsMICs of Fluoroquinolonesof Fluoroquinolones55--Centers, ICUs, 2000, TaiwanCenters, ICUs, 2000, Taiwan

MIC50/MIC90 (g/ml)

Bacteria Ciprofloxacin Moxifloxacin Levofloxacin Gemifloxacin

E. coli 0.03/16 0.06/16 0.06/8 0.12/16

K. pneumoniae 0.03/0.25 0.12/1 0.06/1 0.03/0.25

E. cloacae 0.03/1 0.06/2 0.06/2 0.03/4

S. marcescens 1/16 2/16 2/16 2/16

C. freundii 0.12/1 1/4 0.25/1 0.5/1

Hsueh PR et al. Microb Drug Resist 2001;7:345-54.

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MICsMICs of Fluoroquinolonesof Fluoroquinolones5-Centers, ICUs, 2000, Taiwan

MIC50/MIC90 (g/ml)

Bacteria Ciprofloxacin Moxifloxacin Levofloxacin Gemifloxacin

MSSA 0.5/0.5 0.03/0.06 0.12/0.25 0.06/0.06

MRSA 16/16 1/2 4/8 2/4

S. pneumoniae 1/1 0.12/0.25 1/1 0.06/0.06

Enterococcus 1/4 0.25/2 2/8 0.12/2

Hsueh PR et al. Microb Drug Resist 2001;7:345-54.

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Guidelines on Antimicrobial Therapy of urinary tract infections in Taiwan

in Taiwan

J. Microbial Immunol Infect2000:33,271-272

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2000Guideline for antimicrobial therapy of urinary tract infections in

TaiwanJ. Microbial Immunol Infect2000:33,271-272

Indication Drug of Choice Alternative choice

-Chronic bacterial Baktar or

Prostatis Fluoroquinolone

-Nosocomial 3,4 cephalosporins Imipenem

/catheter-related Ureiodopenecillins MeropenemUTIS Fluoroquinolone

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Case Discussion

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Chief Complaint

Bilateral lower back pain with chills for one week

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Present Illness

This 65 y/o female patient was a case of 1.DM with OHA control (euglcon 1# bid, Glupizide 1# bid) for 5 years, 2.HTN with anti-hypertensive agent control, 3. Breast Ca s/p MRM & C/T.

She suffered from bilateral lower back pain with chills since one week ago. Nausea, poor appetite, general malaise, voiding pain and urgency were also noted.

She came to our ER for help (2/25)

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Lab data

T/P/R : 36.2/102/20, BP : 151/68 Breathing sound : clear WBC : 16900 (B/N=2/88) BUN/Cr : 64/3.2 U/A : WBC : numerous/HPF Cefmetazon was used after B/C & U/C

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Admission Course2/26

WBC : 20500 (B/N=2/85), CRP : 28.80 B/C : GNB No fever

2/28 WBC : 25000 (B/N=0/82), CRP : 13.60 No fever

3/1 U/C : E. coli U/A : WBC : numerous/HPF

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Admission Course

3/2 B/C : E. coli

Ampicillin [AM] S Augmentin [AMC] SChloroamphen. [C] S Ciprofloxacin [CIP] SCefmetazole [CMZ] S Cephalothin [CP] SCefotaxime [CTX] S Cefuroxime [CTM] SGentamicin [GM] S Lomefloxacin [LOM] STobramycin [NN] S Bactrim [STX] S

Renal echo : DM nephropathy

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Admission Course3/3

WBC : 23600 (B/N=6/79)3/4

Switch cefmetazon to ciproxin(100) 3vial IVD q12h3/7

WBC : 17400 (B/N=0/83), CRP : 1.61 U/A : WBC : 16 cells/HPF

3/10 WBC : 16200 (B/N=0/85), CRP : 1.39 U/A : WBC : 32 cells/HPF

3/14 WBC : 9800 (B/N=0/71)

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Ciprofloxacin in Prostatitis

Dosage: 500 mg, bid, 4 weeks Result:

94% showed clinical cure rate89% bacterial eradication rate

Conclusion: long term resolution of chronic bacterial prostatitis was achieved with orally administration ciprofloxacin

Drugs 1999,58 suppl.2 :341-343

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Oral Ciproxin demonstrated favourableoutcome in chronic osteomyelitis

Up to 95 % of osteomyelitis was cured when on Ciprofloxacin

The most common bacterial isolates were Pseudomonas aeruginosa and Enterobacteriaceae

Additional benefits low incidence of side effect

Rissing JP, Clin Infect Dis 25:1327-1333, 1997

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Guidelines for the Selection of Anti-infective

Agents for Complicated Intra-abdominal Infections

Clinical Infectious Diseases 2003; 37: 997-1005

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Selection of empiric antibiotic regimens

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ATS2001 IDSA 2003/2001

CAP Treatment Guideline

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Inpatient - WardIDSA CIDS-CTS ATS BTS

No Risk Factors:azithromycin

or doxycycline + -lactam

or

FQ

-lactam+ macrolide

FQRisk Factors:FQor

-lactam+

macrolide/doxycycline

FQ FQ

-lactam+ macrolide

-lactam+ macrolide

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Inpatient - ICU

IDSA CIDS-CTS ATS BTS

Pseudo ve:-lactam

+ FQ or macrolide

-lactam + macrolide

or

FQ

Pseudo +ve:APA + Cipro

Pseudo ve:-lactam

+ FQ or macrolide

Pseudo ve:FQ+

-lactam


or

APA + AG +FQ or macrolide


or

AG

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Initial Empiric Antibiotic Therapy for HAP, VAPInitial Empiric Antibiotic Therapy for HAP, VAPNo Risk Factors for MDRP, Early Onset, No Risk Factors for MDRP, Early Onset,

Any Disease SeverityAny Disease SeverityPotential pathogen Recommended antibioticS. pneumoniae CeftriaxoneH. influenzae orMSSA Levofloxacin, moxifloxacin,Antibiotic-susceptible GNB or ciprofloxacin

E. coli orK. pneumoniae Ampicillin-sulbactamEnterobacter spp. orProteus spp. ErtapenemS. marcescens

Bonten MJ et al. Am J Respir Crit Care Med 2005;171:388-416.

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Initial Empiric Antibiotic Therapy for HAP, VAP, HCAPInitial Empiric Antibiotic Therapy for HAP, VAP, HCAPRisk Factors for MDRP, Late Onset, Risk Factors for MDRP, Late Onset,

Any Disease SeverityAny Disease SeverityPotential pathogen Combination antibiotic therapyPathogens (early-onset) + Cefepime, ceftazidimeMDRP or

P. aeruginosa Imipenem or meropenemK. pneumoniae (ESBL) orAcinetobacter spp. Piperacillin-tazobactam

PLUSCiprofloxacin or levofloxacin

orAmikacin, gentamicin, or tobramicin

PLUSMRSA Linezolid or vancomycin

Bonten MJ et al. Am J Respir Crit Care Med 2005;171:388-416.

L. pneumophila+ a macrolide (azithromycin) or

a fluoroquinolone(CIP, LVX)

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Intravenous ,Adult Dosages of Antibiotics for Empiric Therapy ofHAP - VAP and HCAP Pneumonia in Patients with Late-Onset Disease or Risk Factors for Multi-Drug-Resistant Pathogens

Antibiotic Dosage*Antipseudomonal cephalosporinCefepime 12 g every 812 hCeftazidime 2 g every 8 hCarbepenemsImipenem 500 mg every 6 h or 1 g every 8 hMeropenem 1 g every 8 h-Lactam/-lactamase inhibitorPiperacillintazobactam 4.5 g every 6 hAminoglycosidesGentamicin 7 mg/kg per dTobramycin 7 mg/kg per dAmikacin 20 mg/kg per dAntipseudomonal quinolonesLevofloxacin 750 mg every dCiprofloxacin 400 mg every 8 hVancomycin 15 mg/kg every 12 hLinezolid 600 mg every 12 h* Dosages are based on normal renal and hepatic function. Trough levels for gentamicin and tobramycin should be less than 1 g/ml,and for amikacin they should be less than 45 g/ml. Trough levels for vancomycin should be 15 20 g/ml

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Susceptibility of Key AntibioticsSusceptibility of Key Antibioticsagainst against NosocomialNosocomial PathogensPathogens, , 2004, NTUH

0

20

40

60

80

100

E. coli Klebsiella Enterobacter P.aeruginosa

A. baumannii S.maltophilia

NFGNB

Ticarcillin-clavulanate Piperacillin-tazobactamCefepime CiprofloxacinAmikacin Imipenem%

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Efficacy of ciprofloxacin vsimipenem: outcomes

0

10

20

30

40

50

60

70

80

90

100

Perc

enta

ge

Bact Erad Clin Resp EnterobacErad

P.aeruginosa

CiprofloxacinImipenem

0

10

20

30

40

50

60

70

80

90

100

Perc

enta

ge

Bact Erad Clin Resp EnterobacErad

P.aeruginosa

CiprofloxacinImipenem

Mortality rate=20%; no difference between groupsMortality rate=20%; no difference between groups

**

*P

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Conclusions

Ciprofloxacin is superior to imipenem in terms of the with respect to the clinical response

Ciprofloxacin is equivalent to imipenem in terms of bacterial eradication

Antibiotic monotherapy is effective in the treatment of severe pneumonia in the hospital setting

Fink MP et al. Antimicrob Agents Chemother 1994; 38: 547557.

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Antimicrobial SpectrumAntimicrobial Spectrum

GNB NFGNB; GPC Atypical AnaerobicPsudomonas PathogenAeruginosa Myobactium

1st + - - - - -

2nd (I) ++ ++ + + -

2nd(II) ++ + ++ + -

3rd ++ + ++ ++ +

4th ++ + ++ ++ +

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Ciprofloxacin (Ciproxin)

Nosocomial infectionsPneumoniaIntra-abdominal infections, including biliarytract infection, acute cholecystitisUTI, including prostatitisAcute bacterial gastroenteritisSalmonellosisGonorrheaOsteomyelitis, ArthritisFUO (Aq-PCN ?+ Ciproxin)

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Normal renal function : 400mg IV q12h or 500-750mg po q12hCCr > 50-90 : 100%CCr 10-50 : 50-75%CCr

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Resistance to FluoroquinolonesMechanisms

Chrmosomal mutations DNA gyrase (A2B2 tetramer) GyrA, GyrB Topoisomerase IV (C2E2 tetramer) - ParC, ParE

Permeability (porin) Active efflux Increments in resistance vary among

different quinolones

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Time post-administration

MICMIC

MPCMPC

Seru

m o

r tis

sue

drug

con

cent

ratio

nMutation Selection Window (MSW)Mutation Selection Window (MSW)

MSWMSW

MPC90/MIC90 = 8-16MPC < Cmax

CmaxCmax

Urban C et al. J Infect Dis 2001;184:794-8.

MPC, mutation prevention MPC, mutation prevention concentrationconcentration

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Levo

floxa

cin

Levo

floxa

cin

Seru

m C

once

ntra

tion

(mg/

L)Se

rum

Con

cent

ratio

n (m

g/L)

Time (hrs)Time (hrs)Adapted from Adapted from levofloxacinlevofloxacin and ciprofloxacin PI 2004.and ciprofloxacin PI 2004.

00

11

22

33

44

55

66

00 66 1212 2424

77

88 750 mg 750 mg LevofloxacinLevofloxacin

Ciprofloxacin vs. LevofloxacinP. aeruginosa Pharmacokinetics

Ciprofloxacin Ciprofloxacin MICMIC9090 P. P. aeruginosaaeruginosa

400 mg Ciprofloxacin ,Q12h400 mg Ciprofloxacin ,Q12h

LevofloxacinLevofloxacinMICMIC9090 P. P. aeruginosaaeruginosa

LevofloxacinLevofloxacin 750 750 AUC below MIC AUC below MIC

~14 hrs~14 hrs

Ciprofloxacin Ciprofloxacin AUC below MICAUC below MIC

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Mutant Prevention ConcentrationP. aeruginosan S.pneumoniae

MPC(mg/L) MPC(mg/L)

Cipro 500mg bid 2 NR Levo 500mg qd 8 8 Avelox 400mgqd NR 2 Gati 400mgqd NR 4

Emerging Infectious Disease Vol. 9 no.1 ,P1-8 ,2003

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Levo

floxa

cin

Levo

floxa

cin

Seru

m C

once

ntra

tion

(mg/

L)Se

rum

Con

cent

ratio

n (m

g/L)

Time (hrs)Time (hrs)Adapted from Adapted from levofloxacinlevofloxacin and ciprofloxacin PI 2004.and ciprofloxacin PI 2004.

00

11

22

33

44

55

66

00 66 1212 2424

77

88 750 mg 750 mg LevofloxacinLevofloxacin

Ciprofloxacin vs. LevofloxacinP. aeruginosa Pharmacokinetics

Ciprofloxacin Ciprofloxacin MICMIC9090 P. P. aeruginosaaeruginosa

400 mg Ciprofloxacin ,Q12h400 mg Ciprofloxacin ,Q12h

LevofloxacinLevofloxacinMICMIC9090 P. P. aeruginosaaeruginosa

LevofloxacinLevofloxacin 750 750 AUC below MIC AUC below MIC

~14 hrs~14 hrs

Ciprofloxacin Ciprofloxacin AUC below MICAUC below MIC

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Guide to Antimicrobial Therapy-

Flouro-quinolaones


Levofloxacin Moxifloxacin(Avelox)

Pathogen/ Year 02 03,04,05

02 03,04,05

03,04,05

+ +

+

+

02

Strep. pneumonia

+ +

Ps. aeruginosa

+ +

S. maltophilia

+

Guide to Antimicrobial Therapy 2002,2003,2004,2005

+ usually effective clinically or > 60% susceptible clinical trials lacking or 30-60% susceptible

Clinical Use of Fluoroquinolones - 1928FluoroquinolonesGroups (I, II, III)FluoroquinolonesGroups (I, II, III)Quinolone Avaliable in TaiwanPharmacology of Antimicrobial TherapyTime to Bacterial Eradication vs AUICFluoroquinolonesPK/PD-Optimized TherapyAUIC of FluoroquinolonesWorldwide Epidemiology of Resistant-GNB (SMART)Study for Monitoring Antimicrobial Resistance TrendsFluoroquinolone-Resistance among Gram-negative Bacilli in TaiwanMICs of Fluoroquinolones5-Centers, ICUs, 2000, TaiwanMICs of Fluoroquinolones5-Centers, ICUs, 2000, TaiwanGuidelines on Antimicrobial Therapy of urinary tract infections in Taiwanin Taiwan2000Guideline for antimicrobial therapy of urinary tract infections in TaiwanJ. Microbial Immunol Infect2000:33,271Case DiscussionChief ComplaintPresent IllnessLab dataAdmission CourseAdmission CourseAdmission CourseCiprofloxacin in ProstatitisOral Ciproxin demonstrated favourable outcome in chronic osteomyelitisGuidelines for the Selection of Anti-infective Agents for Complicated Intra-abdominal InfectionsSelection of empiric antibiotic regimensInpatient - WardInpatient - ICUInitial Empiric Antibiotic Therapy for HAP, VAPNo Risk Factors for MDRP, Early Onset, Any Disease SeverityInitial Empiric Antibiotic Therapy for HAP, VAP, HCAP Risk Factors for MDRP, Late Onset, Any Disease SeverityIntravenous ,Adult Dosages of Antibiotics for Empiric Therapy of HAP - VAP and HCAP Pneumonia in Patients with Late-Onset DiseSusceptibility of Key Antibioticsagainst Nosocomial Pathogens, 2004, NTUHEfficacy of ciprofloxacin vs imipenem: outcomesConclusionsAntimicrobial SpectrumCiprofloxacin (Ciproxin)Ciprofloxacin (Ciproxin)Resistance to FluoroquinolonesMechanisms Mutant Prevention Concentration Guide to Antimicrobial Therapy-

clinical use of fluoroquinolones -...

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