Transcript Quinolonas”

Latest antibiotic treatment
on
respiratory tract infections
and
respiratory tract infection pathogens
Dr. Rafael Cantón
Hospital Universitario Ramón y Cajal
SERVICIO DE MICROBIOLOGÍA Y PARASITOLOGÍA
Antibiotic therapy in community acquired infections:
strategies for optimal outcomes and
minimized resistance emergence
Ball et al. J Antimicrob Chemother 2002; 49:31-40
 Antibiotic use only in bacterial infections (!)
 Adequate the antimicrobial treatment strategy to
- the etiology
- local susceptibility profiles
 Attempt maximal reduction in bacterial load, with the ultimate
aim of bacterial eradication
 Avoidance of selection processes
 Antibiotic used based in PK/PD (pharmacokinetic/
pharmacodynamic) knowledge
These recommendations are not out of date…
November, 18th
Antibiotic therapy in community acquired infections:
strategies for optimal outcomes and
minimized resistance emergence
Ball et al. J Antimicrob Chemother 2002; 49:31-40
 Antibiotic use only in bacterial infections (!)
 Adequate the antimicrobial treatment strategy to
- the etiology
- local susceptibility profiles
 Attempt maximal reduction in bacterial load, with the ultimate
aim of bacterial eradication
 Avoidance of selection processes
 Antibiotic used based in PK/PD (pharmacokinetic/
pharmacodynamic) knowledge
These recommendations are not out of date…
Respiratory tract infection pathogens
Micro-organisms
Acute
Pneumonia
Pathogenic colonization
Exacerbation
(COPD)
Bronchiectasis
+
++++
++++
++++
+++
++
Staphylococcus aureus

+
+
Pseudomonas aeruginosa

+
++
Other NFGNB



Mycoplasma pneumoniae
+++


Chlamydophila pneumoniae
++


Legionella pneumophila

+
+
Viruses
++
++
++
Haemophilus influenzae
Streptococcus pneumoniae
Respiratory tract infection pathogens
S. pneumoniae
H. influenzae
M. catarrhalis
M. pneumoniae
C. pneumoniae
L. pneumophila
P. aeruginosa
With
resistance problems
Without
resistance problems
RTI pathogens: Streptococcus pneumoniae
 Europe & North America
- Decrease penicillin resistance but
… emergence of very high level resistant clones (Pen≥ 8 mg/L)
- Maintenance of erythromycin resistance rates but
… increase of isolates with dual mechanisms [mef+erm(B)]
- Low rates of fluoroquinolone resistance but…
… emergence of specific resistant clones
 Asia
- Maintenance of penicillin resistance (high level resistant clones)
- Extremely high resistance rates to macrolides, including
isolates with dual resistance mechanism
- Low rates of fluoroquinolone resistance but emergence of
specific resistant clones
Cantón et al. Int J Antimicrob Agents. 2007; 30:546-50
Reinert et al. Clin Microbiol Infect 2009; 15 (Suppl 3):7-11
Streptococcus pneumoniae
Invasive isolates
Penicillin resistance (I+R)
2000
http://www.rivm.nl/earss/
2008
S. pneumoniae
Decrease of penicillin (I + R)
resistance
2000
2008
I
21.6
15.7
R
11.0
7.1
TOTAL 32.6
22.8
SPAIN
http://www.rivm.nl/earss/
RTI pathogens: Streptococcus pneumoniae
 Regional trends of penicillin resistance (PROTEKT Study)
China, Hong Kong, Japan,
South Korea and Taiwan
90
80
PISP
PRSP
Prevalence (%)
70
60
50
40
30
20
10
0
Y3
Y4
Y5
Y3
Y4
Y5
Australia
Far East
n = 657
n = 5155
Y3
Y4
Y5
Latin
America
n = 2889
Y3
Y4
Y5
North
America
n = 4155
Y3
Y4
Y5
Northern
Europe
n = 7170
Y3
Y4
Y5
Southern
Europe
n = 5479
Y3
Y4
Y5
South
Africa
n = 1611
Felmingham, Cantón, Jenkins. J Infec 2007; 55:111-8
RTI pathogens: Streptococcus pneumoniae
 Regional trends of erythromycin resistance (PROTEKT Study)
China, Hong Kong, Japan,
South Korea and Taiwan
Prevalence of
resistance
(%)
Prevalence
(%)
90
80
70
60
50
40
30
20
10
0
Y3 Y4 Y5
Y3 Y4 Y5
Australia
Far East
n = 657
n = 5155
Y3 Y4 Y5
Latin
America
n = 2889
Y3 Y4 Y5
North
America
n = 4155
Y3 Y4 Y5
Northern
Europe
n = 7170
Y3 Y4 Y5
Southern
Europe
n = 5479
Y3 Y4 Y5
South
Africa
n = 1611
Felmingham, Cantón, Jenkins. J Infec 2007; 55:111-8
RTI pathogens: Streptococcus pneumoniae
Antibacterial susceptibility prevalence (PROTEKT study) among penicillin-R
(PRSP; n=1696) and erythromycin-R (ERSP; n=2638) S. pneumoniae
99.1 99.4
100
98.1 98.3
84.9
80
Susceptibility (%)
69.2
60
PRSP
ERSP
34.4
40
29.0
21.8
21.8
21.9
20
0.2
ro
xi
m
e
ef
u
at
e
C
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A
m
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ic
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ill
in
ni
c
Pe
0
Er
yt
hr
om
yc
in
A
zi
th
ro
m
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C
in
la
rit
hr
om
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in
lit
hr
om
yc
in
Le
vo
flo
xa
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n
0
0
0
Felmingham, Cantón, Jenkins. J Infec 2007; 55:111-8
RTI pathogens: Streptococcus pneumoniae
Macrolide resistance mechanisms among erythromycin-R S. pneumoniae
isolates collected in selected countries during the PROTEKT study
Felmingham, Cantón, Jenkins. J Infec 2007; 55, 111e118
Dispersion of specific clonal complexes
RTI pathogens: Streptococcus pneumoniae
Resistance profiles in Shanghai (China)
 High penicillin and erythromycin resistance rates (2004-2005)
 High rate (42%) of isolates with dual erythromycin-R genes
 Absence of fluoroquinolone resistance
 Population structure:
- 75% of the isolates belonging to
19F, 14, 23F, 6B and 19A serotypes
- dispersion of international
resistant clonal complexes:
- Taiwan19F-14 - Spain23F-1,
- Spain6B-2
- Taiwan23F-15
Yang et Int J Antimicrob Agenst Chemother 2008; 32:386-91
RTI pathogens: Streptococcus pneumoniae
GLOBAL* Surveillance study
Asia (n=564)
Agent
China (n=105)
MIC90 (mg/L)
S (%)
MIC90 (mg/L)
S (%)
Penicillin
4
40.1
4
53.3
Amox-clavulanate
>4
80.9
>4
84.8
Cefuroxime-axetil
>4
46.5
>4
62.9
Ceftriaxone
2
74.1
2
81.0
Azithromycin
>4
22.5
>4
10.5
Levofloxacin
1
98.0
1
99.0
Trimeth-sulfa
>4
38.3
>4
26.7
CLSI breakpoints (M100-S17)
*Global Landscape On the Bactericidal Activity of Levofloxacin
RTI pathogens: Haemophillus influenzae
GLOBAL* Surveillance study
Asia (n=497)
Agent
China (n=138)
MIC90 (mg/L)
S (%)
MIC90 (mg/L)
S
Ampicillin
>8
69.4**
1
92.8
Amox-clavulanate
2
99.6
1
92.8
Cefuroxime-axetil
>4
98.4
1
62.9
≤0.015
100
≤0.015
100
Clarithromycin
16
67.8
16
62.3
Azithromycin
2
99.8
4
99.3
Levofloxacin
0.03
99.6
0.03
100
Trimeth-sulfa
>4
52.7
>4
46.4
Ceftriaxone
CLSI breakpoints (M100-S17): **29.8% β-lactamase (+); 0.8 amp-R β-lactamase (-)
*Global Landscape On the Bactericidal Activity of Levofloxacin
RTI pathogens: Pseudomonas aeruginosa
GLOBAL* Surveillance study
Asia
(n=144)
Agent
S (%)
Piper/tazb
76.8
Ceftazidime
68.7
Imipenem
75.7
Amikacin
88.2
Levofloxacin
77.1
Ciprofloxacin
71.5
CLSI breakpoints (M100-S17)
*Global Landscape On the Bactericidal Activity of Levofloxacin
Antibiotic therapy in community acquired infections:
strategies for optimal outcomes and
minimized resistance emergence
Ball et al. J Antimicrob Chemother 2002; 49:31-40
 Antibiotic use only in bacterial infections (!)
 Adequate the antimicrobial treatment strategy to
- the etiology
- local susceptibility profiles
 Attempt maximal reduction in bacterial load, with the ultimate
aim of bacterial eradication
 Avoidance of selection processes
 Antibiotic used based in PK/PD (pharmacokinetic/
pharmacodynamic ) knowledge
These recommendations are not out of date…
Bacterial inoculum and RTI
 Why is so important the reduction of the bacterial load or
the bacterial erradication for the clinical outcome in RTI?
… the acute exacerbation of chronic bronchitis model
Sethi and Murphy. Clin Microbiol Rew 2001; 14:336-63
Miravitlles. Eur Respir J 2002; 20 (Suppl 36):9-19
Mensa & Trilla Clin Microbiol Infect 2006; (Suppl 3):42-54
Bacterial inoculum and RTI
Vicious Cycle
Mensa & Trilla Clin Microbiol Infect 2006; (Suppl 3):42-54
Bacterial inoculum and RTI
 Failure in bacterial eradication determines clinical failure in AECB
% of clinical failure
Meta-analysis: 12 studies, 16 antibiotics
R=0.83
Rate of eradication failure
Pechère. Infect Med1998;15 (Suppl E): 46–54
Bacterial load and FEV1 decline in AECB
 30 COPD patients with 1 year of lung function follow-up
 Sputum sampling at the beginning and the end of the study
 increase in bacterial load (107.47 cfu/ml to 107.93 cfu/ml, p=0.019)
 decline in pulmonary function (FEV1) (p=0.001)
Wilkinson et al. Am J Resp Crit Care Med 2003; 167:1090-5
Bacterial inoculum in RTI
 Why is so important erradication for the clinical outcome?
the bronchitis exacerbation model
Acute exacerbation resolution
antibiotic
treatment
Low bacterial
load (susceptible)
natural
resistant
mutants
(10-8)
High bacterial
load (susceptible)
Decrease of neutrophil inflammation
Decrease of
bacterial load
Decrease of bacterial injury
Decline in pulmonary function
Recurrent exacerbation status
antibiotic
treatment
Selection of
resistant mutant
Increase of bacterial injury
Increase the risk of resistance
Increase of bacterial variation
Antibiotic therapy in community acquired infections:
strategies for optimal outcomes and
minimized resistance emergence
Ball et al. J Antimicrob Chemother 2002; 49:31-40
 Antibiotic use only in bacterial infections (!)
 Adequate the antimicrobial treatment strategy to
- the etiology
- local susceptibility profiles
 Attempt maximal reduction in bacterial load, with the ultimate
aim of bacterial eradication
 Avoidance of selection processes Surpass the MPCs
 Antibiotic used based in PK/PD (pharmacokinetic/
pharmacodynamic ) knowledge
These recommendations are not out of date…
Antibiotic resistance: mutational events
 A natural resistant population (resistant mutants) is always
present (frequency of mutation) in all bacterial populations
 The number of resistant mutants increases with the inoculum
bacterial inoculum
susceptible bacteria
resistant bacteria
 Under antibiotic pressure the susceptible subpopulation is
inhibited and the resistant mutants can survive and become
dominant within the population (selection)
antibiotic
The resistant subpopulation may
emerge under the action of an
antimicrobial agent due to the
inhibition of the susceptible population
 if the susceptible bacteria (
) are inhibited
by a concentration which is lower than that
of necessary to inhibit the resistant
subpopulation (
)…
… a concentration able to inhibit both
susceptible and resistant populations
can be defined
MPC (mutant prevention concentration)
- a concentration which is able to inhibit the resistant subpopulation
… and also can inhibit the susceptible population
- concentration that prevents the emergence of resistance mutants
- MIC of the resistant population
Mutant prevention concentration and window of selection
Baquero & Negri. BioEssays 1997; 19: 731-6
Drlica K. ASM News 2001; 67:27-33
Cantón et al. Inter J Antimicrob Chemother 2006; 28 (Suppl 2):S115-27
S. pneumoniae, mutant prevention concentration (MPC)
 Potential for restricting the selection of resistant mutants
moxifloxacin
45
% of isolates
>
45
gatifloxacin
% of isolates
>
45
40
putative parC mutations
40
40
35
null parC mutations
35
35
30
unsequenced isolates
30
30
25
25
25
20
20
20
15
15
15
10
10
10
5
5
5
0
0
0
.06 0.1 0.2 0.5 1
2
4
8
MPC (µg/ml)
16 32 64 128
.06 0.1 0.2 0.5 1
2
4
8
MPC (µg/ml)
16 32 64 128
levofloxacin
% of isolates
.06 0.1 0.2 0.5 1
2
4
8
16 32 64 128
MPC (µg/ml)
Blondeau et al. Antimicrob Agents Chemother 2001; 45:433-8
This data should be analyzed with pharmacokinetic data
Streptocccus pneumoniae
Plasma and intrapulmonary concentrations of levofloxacin
45
% of isolates
40
putative parC mutations
35
null parC mutations
30
unsequenced isolates
Compartment
500 mg
750 mg
Plasma
5.29
11.98
ELF
9.94
22.12
AMs
97.90
105.10
25
20
15
10
5
Concentrations of
levofloxacin at
4h after
administration
ELF: epithelial lining fluid
AM: alveolar macrophages
0
.06 0.1 0.2 0.5 1
2
4
8 16 32 64 128
MPC (µg/ml)
Blondeau et al. Antimicrob Agents Chemother 2001; 45:433-8
Gotfried et al. Chest 2001; 119:1114-22
S. pneumoniae – MPC and pharmacokinetics
of different fluoroquinolones
100
MIC
MPC
µg/ml
10
Compartment
1
0,1
0,01
Pen-S Pen-I Pen-R
MOXIFLOXACIN
Pen-S Pen-I Pen-R
Pen-S Pen-I Pen-R
GATIFLOXACIN
LEVOFLOXACIN
Hernsen et al. Antimicrob Agents Chemother 2005; 49:1633-35
Concentrations of
levofloxacin at
4h after
administration
500 mg
750 mg
Plasma
5.29
11.98
ELF
9.94
22.12
AMs
97.90
105.10
ELF: epithelial lining fluid
AM: alveolar macrophages
Gotfried et al. Chest 2001; 119:1114-22
P. aeruginosa – mutant prevention concentration (MPC)
LEVO
CIPRO
García-Castillo et al.
(n=14)
Hansen et al.
(n=151)
García-Castillo et al.
(n=14)
Hansen et al
(n=151)
MIC (µg/ml)
range
mode
0.06-0.5
0.25
MPC (µg/ml)
range
mode
0-5-8
8
0.12-8
1.3*
2-64
8
0.03-0.12
0.12
0.25-8
2
0.06-4
0.4*
0.5-32
2
*mean value
García-Castillo, Morosini, Baquero, Oliver, Baquero, Cantón. 15th ECCMID, Prague, 2004
Hansen et al. Int J Clin Microbiol Infect Dis 2006; 27: 120-140
P. aeruginosa: fluoroquinolone MPCs and ELF concentrations
1000
LEVOFLOXACIN
µg/ml
100
22.1 µg/ml (750 mg/24h)
17.8 µg/ml (500 mg/12h)
9.9 µg/ml (500 mg/24h)
10
1
0.1
0.01
MPC
MIC
1000
CIPROFLOXACIN
µg/ml
100
Epithelial
lining fluid
concentration
(ELF)
Gotfried et al. Chest
2001; 119:1114-22
Boselli et al. Crit Care
Med 2005; 33:104-9
10
2.3 µg/ml (750 mg/24h)
1.8 µg/ml (500 mg/12h)
1
0.1
0.01
strains
García-Castillo, Morosini, Baquero, Oliver, Baquero, Cantón. 15th ECCMID, Prague, 2004
Antibiotic therapy in community acquired infections:
strategies for optimal outcomes and
minimized resistance emergence
Ball et al. J Antimicrob Chemother 2002; 49:31-40
 Antibiotic use only in bacterial infections (!)
 Adequate the antimicrobial treatment strategy to
- the etiology
- local susceptibility profiles
 Attempt maximal reduction in bacterial load, with the ultimate
aim of bacterial eradication
 Avoidance of selection processes
 Antibiotic used based in PK/PD (pharmacokinetic/
pharmacodynamic ) knowledge
These recommendations are not out of date…
PK / PD parameters of clinical efficacy
Concentration
Cmax
Aminoglycosides
Fluoroquinolones
Cmax : MIC
Tetracyclines
Glicopeptides
AUC : MIC
t1/2
Fluoroquinolones
MIC
Texposition
Beta-lactams
Macrolides
Linezolid
tmax
Time
• PK/PD breakpoints:
the highest MIC for which the antimicrobial drug concentrations (at
a defined dose) are sufficient to achieve the PK/PD target against
a specific organism and for which clinical data support their use
Metlay et al. Emerg Infect Dis 2006; 12:183-190
Fluoroquinolones
 Target (AUC:MIC) attainment values for ciprofloxacin and
levofloxacin and different pathogens
Dose
200 mg/12 h or
400 mg/8h i.v.
Ciprofloxacin
500 mg/12 h oral
or 400 mg/12 h iv
Levofloxacin
750 mg/24 h i.v.
500 mg/24 h oral
P. aeruginosa
Enterobacteriaceae
S. pneumoniae
125
34
87
33.5-33.7
Forrest et al. Antimicrob Agents Chemother 1993; 37:1073-81; Preston et al. JAMA 1998; 279:125-9
Ambrose et al. Antimicrobial Agents Chemother 2001; 45:2793-7
Ambrose et al. Infect Dis Clin North Am 2003; 17:529-43
Higher doses favors target PK/PD attainment despite MIC increase
AUC:MIC Levofloxacin and S. pneumoniae
AUC:MIC
Levofloxacin
MIC (µg/ml) Levofloxacin Levofloxacin
500 mg dose 750 mg dose
1.4
33
49
1.8
29
43
3.2
18
27
2.6
14
22
CMI
3.2
2.6
1.8
1.4
In vitro pharmacokinetic
simulated model
Lister PD. Diagn Microbiol Infect Dis 2002; 44:43-9
 Susceptibility rates (recent surveillance studiesa) among
respiratory pathogens based on PK/PD breakpoints
a: SENTRY, ARISE, Alexander Project, Protekt
Canut et al. J Antimicrob Chemother 2007; 60:607-12
Antibiotic therapy in community acquired infections:
strategies for optimal outcomes and
minimized resistance emergence
Ball et al. J Antimicrob Chemother 2002; 49:31-40
 Antibiotic use only in bacterial infections (!)
 Adequate the antimicrobial treatment strategy to
- the etiology
- local susceptibility profiles
 Attempt maximal reduction in bacterial load, with the ultimate
aim of bacterial eradication
 Avoidance of selection processes
 Antibiotic used based in PK/PD (pharmacokinetic/
pharmacodynamic ) knowledge
Which is the influence of these recommendations
on current antimicrobial guideline for RTI infections
Antimicrobial guidelines for RTI: CAP & AECB
 Evidence- or consensus-based guidelines1
 Adapted to
- suspected or demonstrated pathogen
- severity of illness and co-moribities
- previous antibiotic use2
 Often recommend broad-spectrum agents but recent work in
antibiotic stewardship promotes narrow-spectrum agents3,4
 Not yet completely updated with recent Pk/Pd knowledge and
current resistance trends (should be locally revised)
1Blasi
et al. Pulm Pharm & Therap 2006; 361-9
et al. Clin Infec Dis 2007; 44:S27-72
3Dryden et al. J Antimicrob Chemoter 2009; 64:1123-5
4Lim et al. Thorax 2009; 24 (Suppl 3):iii1-55
2Mandel
Antimicrobial guidelines for RTI
Community acquired pneumonia (British Thoracic Society)
Severity Treatment
site
Low
Home
Hospital
First line
treatment
Alternative
treatment
Amoxicillin
Doxycicline
Moderate Hospital
Amoxicillin +
clarithromycin
Doxycicline
High
Amox/clavulanic Penicilin
+ levofloxacin or ciprofloxacin
Hospital
(including
ICU)
Cefuroxime or cefotaxime
+ clarithromycin
Lim et al. Thorax 2009; 64 (Suppl 3): iii1-55
Antimicrobial guidelines for RTI
Community acquired pneumonia (Japanese Respiratory Society)
Outpatient
Amoxicillin
Penicillin
+ β-inhibitor
Inpatient
Penicillin (iv)
Cephems (iv)
Outpatient
Macrolides
Tetracyclines
Outpatient
Amoxicillin
High doses
Inpatient
Minocycline (iv)
Macrolides
Inpatient
Penicillin (iv)
Cephems (iv)
Carbapenems
Adpated to
speficic
pathogen
Carbapanems (iv)
+
new quinolone (iv)
or
macrolide (iv)
Minoclycline (ivi)
MaDOI: 10.2169/internalmedicine.45.1691
Antimicrobial guidelines for RTI
Community acquired pneumonia (ATS/IDSA)
Patient
Outpatient
Treatment
Previously healthy
Macrolides or doxycycline
Comorbidities
Fluoroquinolone
Regions with ↑ macrolideR β-lactam + macrolides
Inpatients
Non-ICU
Fluoroquinolone
or β-lactam + macrolide
ICU
β-lactam + macrolide
or fluoroquinolone
Specific pathogens
P. aeruginosa
CA-MRSA
antipneumococcal-antipseudomonal
β-lactam + fluoroquinolone or
β-lactam + aminoglycoside + macrolide
+ vancomycin or linezolid
Mandel et al. Clin Infec Dis 2007; 44:S27-72
Antimicrobial guidelines for RTI
Exacerbation of COPD (GLOD*)
Group A: Patients not requiring hospitalization (Stage I-Mild COPD)
Group B & C: Patients addmitted to hospital (Stage II-IV: moderate to very severe COPD)
Global Initiative for Chronic Obstructive Lung Disease. http://www.goldcopd.com/ 2005
Respiratory tract infections: CAP & AECB
Conclusions
 Variable resistance rates in different geographic locations with
extremely high levels in some of these areas (i.e. macrolides
in S. pneumoniae in Asia, including China)
 Effective antimicrobial treatments should determine bacterial
eradication (CAP) or maximal reduction in bacterial load (AECB)
 Reduction of resistance development can be achieved with high
doses (surpass MPCs and avoidance of window of selection)
 Current antimicrobial guidelines should incorporate and be
updated with current Pk/Pd knowledge and Pk/Pd breakpoints
Latest antibiotic treatment
on
respiratory tract infections
and
respiratory tract infection pathogens
Dr. Rafael Cantón
Hospital Universitario Ramón y Cajal
SERVICIO DE MICROBIOLOGÍA Y PARASITOLOGÍA
Fluoroquinolones
1st generation
“old”
Nalidixic acid
2nd generation
“classic”
Norfloxacin
3rd/4th generation
“new”
Sparfloxacin
Oxolinic acid
Pefloxacin
Levofloxacin
Pipemidic acid
Enoxacin
Grepafloxacin
Cinoxacin
Fleroxacin
Gatifloxacin
Rosoxacin
Tosufloxacina
Moxifloxacin
Temafoxacin
Trovafloxacin
Ciprofloxacin
Clinafloxacin
Ofloxacin
Sitafloxacin
Gemifloxacin
Garenoxacin
………………..
Fluoroquinolones: spectrum of activity
Activity of different quinolones against
Group
Enterobact.
S. aureus
S. pneumoniae
H. influenzae
Atypical
pathogens
P. aeruginosa
Anaerobes
1st generation
+
-
-
-
-
-
Norfloxacin
++
+
++
+
+
-
Pefloxacin
++
+
++
++
+
-
Ciprofloxacin
++++
++
++++
+++
++++
+
Ofloxacin
+++
++
++++
+++
++
+
Sparfloxacin
++
+++
+++
++++
++
+
Levofloxacin
+++
++++
++++
+++
+++
+
Gatifloxacin
+++
++++
++++
++++
+++
++
Moxifloxacin
+++
++++
++++
++++
++
++
Nalidixic acid
2nd generation
3rd/4th generation
quinolonic
ring
ciprofloxacin
levofloxacin
moxifloxacin
garenoxacin
Levofloxacin
A well-balanced fluroquinolone …
- antimicrobial activity
- pharmacokinetic/ pharmacodynamic parameters
- adverse effects
Antimicrobial use…
Antibiotic
PK - PD
Pharmacokinetics
Absorption
Distribution
Metabolism
Excretion
Effect
•
•
•
•
Effect vs time
Clinical efficacy
Time
Pharmacodynamics
• Spectrum of activity
• Bactericidal activity
- Time-dependency
- Concentrationdependency
Resistance avoidance
Pharmacokinetics of fluoroquinolones
Ciprofloxacin
(750 mg bid)
Levofloxacin
(500 mg od)
Moxifloxacin
(400 mg od)
Gatifloxacin
(400 mg od)
Bioavailability
70
99
86
96
Serum Cmax
3.5
6.0
4.5
3.4
Protein binding
25
25
50
18
Vdss (L/Kg)
3.2
1.5
2.7
1.7
T1/2 (h)
4.0
6.0
12.7
8.4
AUC (mg.h/ml)
29
58
48
32
Clrenal (ml/min)
250
190
43
60
95
20
% renal
90
Yu et al. Antimicrobial Therapy & Vaccines. 2005 (2nd ed)
Pharmacokinetics of fluoroquinolones
Steady-state concentrations (at 4 h after last dose of 5 days)
Steady-state concentrations (mg/ml)
30
Plasma
25
Epithelial lining fluid
20
15
10
5
0
CIP-500 bid
LFX-500 od
LFX-750 od
Healthy adults
Gotfried et al. Chest 2001; 119:1114-1122
MOX 400 od
LFX-500 od
Elderly patients
Capitano et al. Chest 2004; 125:965-73
Pharmacokinetics of fluoroquinolones
Steady-state concentrations (mg/ml)
Steady-state concentrations (at 4 h after last dose of 5 days)
100
Macrophagues
80
60
40
20
0
CIP-500 bid
LFX-500 od
LFX-750 od
Healthy adults
Gotfried et al. Chest 2001; 119:1114-22
MOX 400 od
LFX-500 od
Elderly patients
Capitano et al. Chest 2004; 125:965-73
Pharmacokinetics of fluoroquinolones
Levofloxacin: optimal bioavailability for sequential therapy
Furlanut et al. J Antimicrob Chemother 2003; 51:101-6
Levofloxacin pharmacokinetics
Ratio to serum
Penetration of levofloxacin
in different compartments
accumulation of levofloxacin in
most compartments results in
concentrations 10-50-fold greater
than the mean MIC of most
potential pathogens
1Gotfried
Macrophages
Liver
Prostate
Sinus
Epithelial lining fluid
Gall bladder
Pleural fluid
Synovial fluid
Diabetic foot
Bone
Aqueous humor
CSF
18.51
3.72
2.93
2.54
1.81
1.85
1.35
1.26
>17
16
0.38
0.39
et al. Chest 2001; 119:1114-22; 2Weinrich et al. IJAA 2006; 28:221-5; 3 Drusano et al. AAC 2000; 2046-51;
4Pea et al. PR 2007; 55:38-41; 5Swoboda et al. JAC 2003; 51:459-62; 6Rimmele et al. JAC 2004; 533-5; 7Oberdorfer
et al. 2004; 54:836-9; 8García-Vázquez et al. EJCMID 2007; 26:137-40; 9Scotton et al. CID 2001; 33:e109-11
Levofloxacin
 The big issue ...
- 500 mg / 24 h versus 500 mg / 12 h bid
or
750 mg / 24 h
 The answers? ...
- PK/PD
- resistant development avoidance
Levofloxacin pharmacokinetics
Epithelial lining fluid/plasma concentration
ratio (750 mg/24 h orally 5 days)
Montecarlo simulation
Drussano et al. Antimicrob Agents
Chemother 2002; 46: 586-9
Levofloxacin
Steady-state concentrations (after 2 days of therapy) in critically
ill patients with severe community-acquired pneumonia
Levofloxacin 500 mg
(od)
(bid)
Plasma
Cmax (mg/L)
12.6
19.7
T1/2 (h)
11.5
17.0
AUC (mg.h/ml)
151
208
11.9
17.8
ELF
Cmax (mg/L)
Bosselli et al. Crit Care Med 2005; 33:104-9
Ciprofloxacin
 Ciprofloxacin (200 mg/12 h – 400 mg/8 h i.v.) clinical and microbiological
outcome in critically ill ICU patients with Gram negative infections
AUC : MIC
>125
100
*number of patients
16
7
22
% of cures
80
60
9*
40
10
20
0
0-62.5
62.5-125
Clinical cure
125-250
250-500
500-5,541
Microbiological cure
Forrest et al. Antimicrob Agents Chemother 1993; 37:1073-81
Levofloxacin
 Levofloxacin (500 mg/24 h) clinical and microbiological outcomes in patients
with community acquired S. pneumoniae respiratory tract infection
AUC : MIC
>33.7
100
% of cures
80
60
40
20
0
21-30
31-40
41-100
110-150 151-200 201-250 251-300 301-350
Clinical cure
>350
Microbiological cure
Ambrose et al. Antimicrob Agents Chemother 2001; 45:2793-7
Levofloxacin
 Probability of target attainment (AUC:MIC >33.7) for levofloxacin
(500 mg/24 h, orally) in patients with community acquired
Streptococcus pneumoniae respiratory tract infections
Classification and Regression Tree
(CART) analysis
Ambrose et al. Antimicrob Agents Chemother 2001; 45:2793-7