Latest antibiotic treatment on respiratory tract infections and

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These recommendations are not out of date…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These recommendations are not out of date…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