latest antibiotic treatment on respiratory tract infections and
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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: - PowerPoint PPT PresentationTRANSCRIPT
Latest antibiotic treatment on
respiratory tract infections and
respiratory tract infection pathogens
Hospital Universitario Ramón y CajalSERVICIO DE MICROBIOLOGÍA Y PARASITOLOGÍA
Dr. Rafael Cantón
Antibiotic therapy in community acquired infections:strategies for optimal outcomes and
minimized resistance emergence
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
Ball et al. J Antimicrob Chemother 2002; 49:31-40
These recommendations are not out of date…
November, 18th
Antibiotic therapy in community acquired infections:strategies for optimal outcomes and
minimized resistance emergence
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
Ball et al. J Antimicrob Chemother 2002; 49:31-40
These recommendations are not out of date…
Respiratory tract infection pathogens
Micro-organismsAcute
Pneumonia
Pathogenic colonization
Exacerbation (COPD)
Bronchiectasis
Haemophilus influenzae + ++++ ++++
Streptococcus pneumoniae ++++ +++ ++
Staphylococcus aureus + +
Pseudomonas aeruginosa + ++
Other NFGNB
Mycoplasma pneumoniae +++
Chlamydophila pneumoniae ++
Legionella pneumophila + +
Viruses ++ ++ ++
M. pneumoniae
C. pneumoniae
L. pneumophila
S. pneumoniae
H. influenzae
M. catarrhalis
P. aeruginosa
With resistance problems
Without resistance problems
Respiratory tract infection pathogens
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; 30:546-50Reinert et al. Clin Microbiol Infect 2009; 15 (Suppl 3):7-11
Streptococcus pneumoniae
2000
2008
Invasive isolates Penicillin resistance (I+R)
http://www.rivm.nl/earss/
S. pneumoniae
Decrease of penicillin (I + R)resistance
http://www.rivm.nl/earss/
2000 2008
I 21.6 15.7
R 11.0 7.1
TOTAL 32.6 22.8
SPAIN
Australia
n = 657
Far East
n = 5155
LatinAmerican = 2889
NorthAmerican = 4155
NorthernEuropen = 7170
SouthernEuropen = 5479
South Africa
n = 1611
RTI pathogens: Streptococcus pneumoniae
Regional trends of penicillin resistance (PROTEKT Study)
China, Hong Kong, Japan, South Korea and Taiwan
Felmingham, Cantón, Jenkins. J Infec 2007; 55:111-8
RTI pathogens: Streptococcus pneumoniae
Regional trends of erythromycin resistance (PROTEKT Study)
Felmingham, Cantón, Jenkins. J Infec 2007; 55:111-8
Australia
n = 657
Far East
n = 5155
LatinAmerican = 2889
NorthAmerican = 4155
NorthernEurope
n = 7170
SouthernEurope
n = 5479
South Africa
n = 1611
China, Hong Kong, Japan, South Korea and Taiwan
Prev
alen
ce o
f res
ista
nce
(%)
RTI pathogens: Streptococcus pneumoniae
0
20
40
60
80
100
Su
scep
tibili
ty (%
)
PRSP
ERSP
0 0
29.0
0.20.10
69.2
84.9
34.4
21.8 21.8 21.9
99.199.4 98.1 98.3
Antibacterial susceptibility prevalence (PROTEKT study) among penicillin-R (PRSP; n=1696) and erythromycin-R (ERSP; n=2638) S. pneumoniae
Felmingham, Cantón, Jenkins. J Infec 2007; 55:111-8
Felmingham, Cantón, Jenkins. J Infec 2007; 55, 111e118
RTI pathogens: Streptococcus pneumoniae
Macrolide resistance mechanisms among erythromycin-R S. pneumoniae isolates collected in selected countries during the PROTEKT study
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
*Global Landscape On the Bactericidal Activity of Levofloxacin
Agent
Asia (n=564) 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 26.7CLSI breakpoints (M100-S17)
RTI pathogens: Haemophillus influenzae
GLOBAL* Surveillance study
*Global Landscape On the Bactericidal Activity of Levofloxacin
CLSI breakpoints (M100-S17): **29.8% β-lactamase (+); 0.8 amp-R β-lactamase (-)
Agent
Asia (n=497) 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
Ceftriaxone ≤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
RTI pathogens: Pseudomonas aeruginosa
GLOBAL* Surveillance study
*Global Landscape On the Bactericidal Activity of Levofloxacin
CLSI breakpoints (M100-S17)
Antibiotic therapy in community acquired infections:strategies for optimal outcomes and
minimized resistance emergence
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
Ball et al. J Antimicrob Chemother 2002; 49:31-40
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; 14:336-63Miravitlles. Eur Respir J 2002; 20 (Suppl 36):9-19
Mensa & Trilla Clin Microbiol Infect 2006; (Suppl 3):42-54
Bacterial inoculum and RTI
Mensa & Trilla Clin Microbiol Infect 2006; (Suppl 3):42-54
Vicious Cycle
Bacterial inoculum and RTI
Meta-analysis: 12 studies, 16 antibioticsR=0.83
Rate of eradication failure
% o
f clin
ica
l fa
ilure
Pechère. Infect Med1998;15 (Suppl E): 46–54
Failure in bacterial eradication determines clinical failure in AECB
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?
antibiotic treatment
Low bacterial load (susceptible)
Decrease of bacterial load
Acute exacerbation resolution
Decrease of neutrophil inflammation
Decrease of bacterial injury
antibiotic treatment
Selection of resistant mutant
High bacterial
load (susceptible)
natural resistant mutants
(10-8)
Decline in pulmonary function
Recurrent exacerbation status
Increase of bacterial injury
Increase the risk of resistance
Increase of bacterial variation
the bronchitis exacerbation model
Antibiotic therapy in community acquired infections:strategies for optimal outcomes and
minimized resistance emergence
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
Ball et al. J Antimicrob Chemother 2002; 49:31-40
These recommendations are not out of date…
Antibiotic resistance: mutational events
A natural resistant population (resistant mutants) is alwayspresent (frequency of mutation) in all bacterial populations
The number of resistant mutants increases with the inoculum
Under antibiotic pressure the susceptible subpopulation isinhibited and the resistant mutants can survive and become dominant within the population (selection)
resistant bacteria
susceptible bacteria
bacterial inoculum
The resistant subpopulation may emerge under the action of anantimicrobial agent due to the
inhibition of the susceptible population
antibiotic
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
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
Mutant prevention concentration and window of selection
Blondeau et al. Antimicrob Agents Chemother 2001; 45:433-8
S. pneumoniae, mutant prevention concentration (MPC)
Potential for restricting the selection of resistant mutants
moxifloxacin > gatifloxacin > levofloxacin
0
5
10
15
20
25
30
35
40
45
.06 0.1 0.2 0.5 1 2 4 8 16 32 64 128
MPC (µg/ml)
0
5
10
15
20
25
30
35
40
45
.06 0.1 0.2 0.5 1 2 4 8 16 32 64 128
MPC (µg/ml)
putative parC mutations
null parC mutations
unsequenced isolates
0
5
10
15
20
25
30
35
40
45
.06 0.1 0.2 0.5 1 2 4 8 16 32 64 128
MPC (µg/ml)
% of isolates % of isolates % of isolates
This data should be analyzed with pharmacokinetic data
Streptocccus pneumoniae
Plasma and intrapulmonary concentrations of levofloxacin
0
5
10
15
20
25
30
35
40
45
.06 0.1 0.2 0.5 1 2 4 8 16 32 64 128
MPC (µg/ml)
putative parC mutations
null parC mutations
unsequenced isolates
% of isolates
Compartment
Concentrations of levofloxacin at
4h after administration
500 mg 750 mg
Plasma 5.29 11.98
ELF 9.94 22.12
AMs 97.90 105.10ELF: epithelial lining fluid
AM: alveolar macrophages
Gotfried et al. Chest 2001; 119:1114-22
Blondeau et al. Antimicrob Agents Chemother 2001; 45:433-8
0,01
0,1
1
10
100
µg/m
l
Pen-S Pen-I Pen-R Pen-S Pen-I Pen-R Pen-S Pen-I Pen-R
MIC MPC
0,01
0,1
1
10
100
µg/m
l
Pen-S Pen-I Pen-R Pen-S Pen-I Pen-R Pen-S Pen-I Pen-R
MIC MPC
S. pneumoniae – MPC and pharmacokinetics of different fluoroquinolones
MOXIFLOXACIN GATIFLOXACIN LEVOFLOXACIN
Hernsen et al. Antimicrob Agents Chemother 2005; 49:1633-35
Compartment
Concentrations of levofloxacin at
4h after administration
500 mg 750 mg
Plasma 5.29 11.98
ELF 9.94 22.12
AMs 97.90 105.10ELF: epithelial lining fluid
AM: alveolar macrophages
Gotfried et al. Chest 2001; 119:1114-22
P. aeruginosa – mutant prevention concentration (MPC)
García-Castillo, Morosini, Baquero, Oliver, Baquero, Cantón. 15th ECCMID, Prague, 2004Hansen et al. Int J Clin Microbiol Infect Dis 2006; 27: 120-140
MIC (µg/ml) MPC (µg/ml) range mode range mode
LEVO García-Castillo et al. (n=14)
0.06-0.5 0.25 0-5-8 8
Hansen et al. (n=151)
0.12-8 1.3* 2-64 8
CIPRO García-Castillo et al.
(n=14) 0.03-0.12 0.12 0.25-8 2
Hansen et al (n=151)
0.06-4 0.4* 0.5-32 2
*mean value
P. aeruginosa: fluoroquinolone MPCs and ELF concentrations
García-Castillo, Morosini, Baquero, Oliver, Baquero, Cantón. 15th ECCMID, Prague, 2004
Epithelial lining fluid
concentration (ELF)
Gotfried et al. Chest
2001; 119:1114-22
Boselli et al. Crit Care
Med 2005; 33:104-9
CIPROFLOXACIN
0.01
0.1
1
10
100
1000
µg
/ml
1.8 µg/ml (500 mg/12h)
MIC
MPC
LEVOFLOXACIN
0.01
0.1
1
10
100
1000
22.1 µg/ml (750 mg/24h)
9.9 µg/ml (500 mg/24h)
µg
/ml
strains
17.8 µg/ml (500 mg/12h)
2.3 µg/ml (750 mg/24h)
Antibiotic therapy in community acquired infections:strategies for optimal outcomes and
minimized resistance emergence
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
Ball et al. J Antimicrob Chemother 2002; 49:31-40
These recommendations are not out of date…
Co
nce
ntr
atio
n
Time
t1/2
Cmax
tmax
PK / PD parameters of clinical efficacy
MIC
AUC : MIC
Cmax : MIC
Texposition
Aminoglycosides
Fluoroquinolones
Tetracyclines
Glicopeptides
Fluoroquinolones
Beta-lactams
Macrolides
Linezolid
Metlay et al. Emerg Infect Dis 2006; 12:183-190
• 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
Target (AUC:MIC) attainment values for ciprofloxacin and levofloxacin and different pathogens
Fluoroquinolones
Dose P. aeruginosa
Enterobacteriaceae S. pneumoniae
Ciprofloxacin
200 mg/12 h or 400 mg/8h i.v.
125
500 mg/12 h oral or 400 mg/12 h iv
34
Levofloxacin 750 mg/24 h i.v. 87 500 mg/24 h oral 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; 45:2793-7Ambrose 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
Lister PD. Diagn Microbiol Infect Dis 2002; 44:43-9
AUC:MIC
Levofloxacin MIC (µg/ml) Levofloxacin
500 mg dose Levofloxacin 750 mg dose
1.4 33 49 1.8 29 43 3.2 18 27 2.6 14 22
In vitro pharmacokinetic simulated model
CMI
3.2
2.6
1.81.4
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
Which is the influence of these recommendations on current antimicrobial guideline for RTI infections
Antibiotic therapy in community acquired infections:strategies for optimal outcomes and
minimized resistance emergence
Antibiotic use only in bacterial infections (!)
Adequate the antimicrobial treatment strategy to
-the etiology -local susceptibility profiles
Attempt maximal reductionin bacterial load, with the ultimate
aim of bacterial eradication
Avoidance of selection processes
Antibiotic used based in PK/PD (pharmacokinetic/
pharmacodynamic ) knowledge
Ball et al. J Antimicrob Chemother 2002; 49:31-40
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; 361-92Mandel et al. Clin Infec Dis 2007; 44:S27-72
3Dryden et al. J Antimicrob Chemoter 2009; 64:1123-54Lim et al. Thorax 2009; 24 (Suppl 3):iii1-55
Antimicrobial guidelines for RTI
Community acquired pneumonia (British Thoracic Society)
Severity Treatment site
First line treatment
Alternative treatment
Low HomeHospital
Amoxicillin Doxycicline
Moderate Hospital Amoxicillin + clarithromycin
Doxycicline
High Hospital (including ICU)
Amox/clavulanic Penicilin + levofloxacin or ciprofloxacin
Cefuroxime or cefotaxime + clarithromycin
Lim et al. Thorax 2009; 64 (Suppl 3): iii1-55
Antimicrobial guidelines for RTI
Community acquired pneumonia (Japanese Respiratory Society)
MaDOI: 10.2169/internalmedicine.45.1691
Outpatient Amoxicillin Penicillin + β-inhibitor
Inpatient Penicillin (iv) Cephems (iv)
Outpatient Macrolides Tetracyclines
Inpatient Minocycline (iv) Macrolides
Outpatient Amoxicillin High doses
Inpatient Penicillin (iv) Cephems (iv) Carbapenems
Adpated to speficic pathogen
Carbapanems (iv) +new quinolone (iv)
ormacrolide (iv)Minoclycline (ivi)
Antimicrobial guidelines for RTI
Community acquired pneumonia (ATS/IDSA)
Mandel et al. Clin Infec Dis 2007; 44:S27-72
Patient Treatment
Outpatient Previously healthy Macrolides or doxycycline
ComorbiditiesRegions with ↑ macrolideR
Fluoroquinoloneβ-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
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
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
Respiratory tract infections: CAP & AECB
Conclusions
Latest antibiotic treatment on
respiratory tract infections and
respiratory tract infection pathogens
Hospital Universitario Ramón y CajalSERVICIO DE MICROBIOLOGÍA Y PARASITOLOGÍA
Dr. Rafael Cantón
Fluoroquinolones
1st generation “old”
2nd generation “classic”
3rd/4th generation “new”
Nalidixic acid Norfloxacin Sparfloxacin
Oxolinic acid Pefloxacin Levofloxacin
Pipemidic acid Enoxacin Grepafloxacin
Cinoxacin Fleroxacin Gatifloxacin
Rosoxacin Tosufloxacina Moxifloxacin
Temafoxacin Trovafloxacin
Ciprofloxacin Clinafloxacin
Ofloxacin Sitafloxacin
Gemifloxacin
Garenoxacin
………………..
Activity of different quinolones against
Group
Enterobact. S. aureus
S. pneumoniae H. influenzae
Atypical
pathogens P. aeruginosa Anaerobes
1st generation
Nalidixic acid + - - - - -
2nd generation
Norfloxacin ++ + ++ + + -
Pefloxacin ++ + ++ ++ + -
Ciprofloxacin ++++ ++ ++++ +++ ++++ +
Ofloxacin +++ ++ ++++ +++ ++ +
3rd/4th generation
Sparfloxacin ++ +++ +++ ++++ ++ +
Levofloxacin +++ ++++ ++++ +++ +++ +
Gatifloxacin +++ ++++ ++++ ++++ +++ ++
Moxifloxacin +++ ++++ ++++ ++++ ++ ++
Fluoroquinolones: spectrum of activity
quinolonic ring
levofloxacin
ciprofloxacin
moxifloxacin
garenoxacin
A well-balanced fluroquinolone …
- antimicrobial activity - pharmacokinetic/ pharmacodynamic parameters
- adverse effects
Levofloxacin
Pharmacokinetics• Absorption• Distribution• Metabolism• Excretion
Pharmacodynamics• Spectrum of activity• Bactericidal activity - Time-dependency - Concentration- dependency
Eff
ect
Time
PK - PDEffect vs time
Antibiotic
Clinical efficacy Resistance avoidance
Antimicrobial use…
Yu et al. Antimicrobial Therapy & Vaccines. 2005 (2nd ed)
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
% renal 60 95 20 90
Pharmacokinetics of fluoroquinolones
Pharmacokinetics of fluoroquinolones
Gotfried et al. Chest 2001; 119:1114-1122
0
5
10
15
20
25
30
CIP-500 bid LFX-500 od LFX-750 od MOX 400 od LFX-500 od
Ste
ad
y-s
tate
co
nc
en
tra
tio
ns
(m
g/m
l)
Plasma
Epithelial lining fluid
Capitano et al. Chest 2004; 125:965-73
Healthy adults Elderly patients
Steady-state concentrations (at 4 h after last dose of 5 days)
Gotfried et al. Chest 2001; 119:1114-22
0
20
40
60
80
100
CIP-500 bid LFX-500 od LFX-750 od MOX 400 od LFX-500 od
Ste
ad
y-s
tate
co
nc
en
tra
tio
ns
(m
g/m
l)
Macrophagues
Capitano et al. Chest 2004; 125:965-73
Healthy adults Elderly patients
Steady-state concentrations (at 4 h after last dose of 5 days)
Pharmacokinetics of fluoroquinolones
Levofloxacin: optimal bioavailability for sequential therapy
Furlanut et al. J Antimicrob Chemother 2003; 51:101-6
Pharmacokinetics of fluoroquinolones
1Gotfried 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
Penetration of levofloxacinin different compartments
Levofloxacin pharmacokinetics
Ratio to serum
Macrophages 18.51
Liver 3.72
Prostate 2.93
Sinus 2.54
Epithelial lining fluid 1.81
Gall bladder 1.85
Pleural fluid 1.35
Synovial fluid 1.26
Diabetic foot >17
Bone 16
Aqueous humor 0.38
CSF 0.39
accumulation of levofloxacin inmost compartments results in
concentrations 10-50-fold greaterthan the mean MIC of most
potential pathogens
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
Drussano et al. Antimicrob Agents Chemother 2002; 46: 586-9
Epithelial lining fluid/plasma concentration ratio (750 mg/24 h orally 5 days)
Montecarlo simulation
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
ELF
Cmax (mg/L) 11.9 17.8
Bosselli et al. Crit Care Med 2005; 33:104-9
Forrest et al. Antimicrob Agents Chemother 1993; 37:1073-81
0
20
40
60
80
100
0-62.5 62.5-125 125-250 250-500 500-5,541
% o
f cu
res
Clinical cure Microbiological cure
AUC : MIC>125
Ciprofloxacin (200 mg/12 h – 400 mg/8 h i.v.) clinical and microbiological outcome in critically ill ICU patients with Gram negative infections
Ciprofloxacin
9* 10
16 7 22*number of patients
0
20
40
60
80
100
21-30 31-40 41-100 110-150 151-200 201-250 251-300 301-350 >350
% o
f cu
res
Clinical cure Microbiological cure
AUC : MIC>33.7
Levofloxacin (500 mg/24 h) clinical and microbiological outcomes in patients
with community acquired S. pneumoniae respiratory tract infection
Levofloxacin
Ambrose et al. Antimicrob Agents Chemother 2001; 45:2793-7
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
Levofloxacin