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G(-)
Clinical Use of Fluoroquinolones
Cheng-Yi Liu,M.D.Taipei Veterans General Hospital
- 1928Alexander Fleming1898-1968
Penicillium notatum
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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
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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
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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
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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
Pseudo +ve:APA + Cipro
or
APA + AG +FQ or macrolide
Pseudo +ve:APA + Cipro
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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Ciprofloxacin (Ciproxin)
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
Ciprofloxacin (Ciproxin)
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-