Optimizing antimicrobial therapy for hospitalized pneumonia:

Focus on PK/PD profile of levofloxacin

Prof. Francesco Blasi, MD, FERS

Chairman Department of Pathophysiology and Transplantation,

University of Milan, Italy

Head Cardio-Thoracic Unit and Cystic Fibrosis Adult Center,

Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico Milan, Italy

Disclosures

• I have accepted grants, speaking and conference

invitations from Almirall, Angelini, AstraZeneca,

Bayer, Chiesi, GSK, Guidotti-Malesci, Menarini,

Novartis, Pfizer, Sandoz and Zambon

• I have had recent or ongoing consultancy with

Almirall, Angelini, AstraZeneca, Chiesi, GSK,

Menarini, Mundipharma, Novartis,Teva, Zambon

Power of Antibiotics

1IDSA Position Paper ‘08 Clin Infect Dis47(S3):S249-65; 2IDSA/ACCP/ATS/SCCM Position Paper ‘10 Clin Infect Dis In Press; 3Kerr AJ. Subacute

Bacterial Endocarditis. Springfield IL: Charles C. Thomas, 1955 & Lancet 1935 226:383-4; 4Lancet ‘38 231:733-4 & Waringet al. ‘48 Am J Med

5:402-18; 5Spellberg et al. ‘09 Clin Infect Dis49:383-91 & Madsen ‘73 Infection 1:76-81; 6‘88Lancet 2:349-60

Change in

Death Without

Treatment

+350%

+200%

+400%

+400%

+2200%

+165%

The miracle!

• Antibiotics

• Antifungals

• Antivirals

Early use of best antibiotic therapy is essential for improving mortality outcomes in critically ill patients.

1. I totally agree

2. I agree, but there is the risk of abuse of the last more active antimicrobials with high cost and emergence of resistance

3. I disagree, you can delay the therapy for 1-2 days in order to improve diagnosis

4

Luna et al. Chest 1997;111:676-85; Álvarez-Lerma. Intensive Care Med 1996;22:387-94; Rello et al. Am J Respir Crit Care

Med 1997;156:196-200;; Clec’h et al. Intensive Care Med 2004;30:1327-33; Garnacho-Montero et al. Intensive Care Med

2005;31:649-55

Ventilator-associated pneumonia

Mortality impact of inadequate therapy

Adequate

Inadequate

0 20 40 60 80 100

Garnacho-Montero

Luna

Álvarez-Lerma

Rello

Clec'h

In all of these studies adequate therapy means:

The bug is susceptible to the drug in vitro!

Patient mortality (%)

Dosing?Timing?

Tissue penetration?

Clinical Infectious Diseases 2007; 45:S191–5

ANTIBIOTICSITE ofINFECTION

BACTERIA

+

MIC

PATIENT

BACTERIA

+

MIC

ANTIBIOTIC

SITE OF INFECTION

PATIENT

THE PUZZLE OF ANTIMICROBIAL THERAPY

6

Improving the probabilityof positive outcomes

Window of opportunity• Early recognition of infection• adequate treatment

early ,early , soon, soon, very soon !!

Selection of appropriate antibiotic(not based on in vitro susceptibility only)

Therapy optimisation using PK/PD principles

7

Toxicity Efficacy Resistance

Dose optimisation

PK PD Correlation

(T>MIC AUC/MIC Cmax/MIC)

PK / PD : pharmacological view

0

40

30

10

20

Cmax/MIC

Co

nce

ntr

atio

n (

mg/

L)

0 248 16

MIC

T>MIC

AUC/MIC

0.5 10

Hours

PAE

β-lactams

Aminoglycosides

Fluoroquinolones

Tigecycline

GlycopeptidesDaptomycin

Linezolid

8

What about the timing ?

Mortality (%)

0

25

35

5

15

Appropriate therapyat beginning

Inappropriate therapyat all timepoints

20

30

10

Appropriate early antibiotic therapy reduces

mortality rates in patients with bloodstream

infection

Weinstein et al. Clin Infect Dis 1997;24:584–602

RR = 1.0

RR = 2.46

RR = 3.18

RR = relative risk of death

Appropriate therapyonly after susceptibility

determined

Mortality risk (expressed as adjusted odds ratio of death) with increasing

delays in initiation of effective antimicrobial therapy. Bars represent 95%

confidence interval.

Kumar, A. crit.care med 34(6), 2006,

Epithelial lining fluid

Neutrophil

Colonisingencapsulated

bacteria

Edema

Alveolarlumen

Alveolar macrophages

Capillarylumen Interstitium

Antibiotics

Capillary endothelium

Capillarybasementmembrane

Infectedlung

Alveolarbasementmembrane

Alveolarepithelium

Epithelial lining fluid

EPITHELIAL LINING FLUID

Intensive care patient

13

Sepsis

Increased cardiac index

• Increased capillary permeability• Fluid shifts

End organ dysfunction

Increased clearances

Increased volume of distribution

Low serum drug concentrations

Increased drug half-lives

Decreasedclearances

High serum drugconcentrations

Consider an increaseof dose

Consider a decreaseof dose

Effects of sepsis on serum drug concentrations

14Scaglione and Paraboni.Int J Antimicrob Agents 2008;32:294-301

Do you consider your choice and dose of antimicrobials in response to physiological changes that are occurring in your critically ill patients ?

1. No

2. Yes

3. Is interesting , but how can I choose/dosing during physiological changes?

15

Theoretical concentrationof an antibiotic

Time

Co

ncen

trati

on

MIC

Serum

Interstitial fluid

Large volume

compartment

16Scaglione and Paraboni.Int J Antimicrob Agents 2008;32:294-301

• Low Vd• Predominant renal CL• Low intracellular penetration

• High Vd• Predominant hepatic CL• Good intracellular penetration

• ↑ Vd• CL ↑ or ↓ dependent on renal

function

• Vd largely unchanged• CL ↑ or ↓ dependent on hepatic

function

• β-lactam• Aminoglycosides• Glycopeptides• Colistin

• Fluoroquinolones• Macrolides• Lincosamides• Tigecycline• Linezolid

General PK

Altered ICU PK

Examples

Hydrophilic and lipophilic antibioticsHydrophilic Lipophilic

Roberts and Lipman. Crit Care Med 2009;37:840-51

Vd, volume of distribution;CL, clearance; ICU, intensive care unit

17

18

Resistance is a Global Issue

North AmericaVRE ( E.faecium ) **MRSAESBL -K.pneumoniae 9.7%A.baumannii (Carb- R)a 22.1%P.aeruginosa 8.7%Enterobacter spp

North AmericaVRE ( E.faecium ) MRSA 50.8%ESBL -K.pneumoniaeA.baumannii (

Enterobacter spp (Triax-R) 25.4%

(Carb- R)a

LatinLatin AmericaAmerica

VRE (VRE ( E.faeciumE.faecium ) ) 46,3%

MRSAMRSA 46,6%

ESBLESBL --K.pneumoniaeK.pneumoniae %35.4%

A.baumanniiA.baumannii --R) 55.9%

P.aeruginosaP.aeruginosa (IMP - 35,8%24.9%

EnterobacterEnterobacter sppspp -R) 43,4%

LatinLatin AmericaAmerica

VRE (VRE ( E.faeciumE.faecium ) ) %39.8%

MRSAMRSA %46.9%

ESBLESBL --K.pneumoniaeK.pneumoniae

A.baumanniiA.baumannii

P.aeruginosaP.aeruginosa

EnterobacterEnterobacter sppspp %45.5%

(Carb- R)a

(Carb- R)a

(Triax-R)

** Results pending. a = Imipenem and/or meropenem resistant.

Triax-R = Ceftriaxone resistant

Source: www.testsurveillance.com (last access March 2, 2011)1Rice LB. J Infect Dis 2008; 197:1079 –81

EuropeVRE (E.faecium) MRSAESBL-K.pneumoniaeA.baumanniiP.aeruginosa 13.8%Enterobacterspp 41.2%

EuropeVRE (E.faecium) 14.2%MRSA 25.5%ESBL-K.pneumoniae 21.0%A.baumannii 27.4%P.aeruginosaEnterobacterspp

(Carb- R)a

(Carb- R)a

(Triax-R)

Asia PacificAsia Pacific

VRE (VRE ( E.faeciumE.faecium ) ) 22,5%

MRSAMRSA 40,7%

ESBLESBL --K.pneumoniaeK.pneumoniae 19,7%

A.baumanniiA.baumannii (IMP- 32,6%

P.aeruginosaP.aeruginosa (IMP- 18,1%

EnterobacterEnterobacter sppspp - 42,8%

Asia PacificAsia Pacific

VRE (VRE ( E.faeciumE.faecium ) ) %21.9%

MRSAMRSA %43.7%

ESBLESBL --K.pneumoniaeK.pneumoniae %23.1%

A.baumanniiA.baumannii %42.8%

P.aeruginosaP.aeruginosa %16.0%

EnterobacterEnterobacter sppspp %45.7%

(Carb- R)a

(Carb- R)a

(Triax-R)

What can we do ?

Resistance in the ICU: risk factors• > 7 days of mechanical ventilation

• Previous use of 3rd generation cephalosporins, fluoroquinolones, carbapenems (< 1 month)

• Inadequate choice

• Inadequate dosing

• Inadequate infection control– Workload of staff

– For example contamination of equipment

• Invasive devices– Endotracheal tubes

– Intravascular catheters

– Urinary catheters

• Prolonged hospital stay– Horizontal nosocomial transmission

– Endogenous emergence 19

Critically ill patients

Increased volumeof distribution

Clearance variations

Fluid extravasation• Sepsis• Trauma• Severe hypoalbuminaemia• Fluid therapy• Parenteral nutrition• Reduced cardiac output

Fluid loss(Apparent increased Vd)• Post-surgical drainage• Burns (early phase)

Compartmental fluid accumulation• Pleural effusion• Ascites• Mediastinitis

Increased clearance• Burns (late phase)• Acute leukaemia• Hyperdynamic sepsis phase

Reduced clearance• Renal failure• Age >75 years

Scaglione and Paraboni.Int J Antimicrob Agents 2008;32:294-301 20

What is the value of fixed doses in the light of pathophysiological changes in the critically ill?

• Increased clearance• Decreased clearance• Increased volume of distribution• High inoculum• MICs close to breakpoint

Critically ill patients

Conclusions: antimicrobial PK/PD

• What information is required for rational antibiotic selection and dosing optimisation?

– Drug exposure at target site (what do you wish to achieve?)

– Patient population PK (severe vs not severe infection)

– Tissue penetration may be relevant in critically ill patients (lipophilic vs hydrophilic antibiotics)

Probability of developing resistance

Thomas et al. Antimicrob Agents Chemother 1998;42:521–527

Probability of remaining

susceptible (%)

AUC0–24h:MIC 100

AUC0–24h:MIC <100

Days from initiation of therapy

0 5 10 15 200

20

40

60

80

100

Data from 107 acutely ill patients with

nosocomial RTIs treated with 5 different

antibiotic regimens (ciprofloxacin,

cefmenoxime, ceftazidime, ciprofloxacin plus

piperacillin, ceftazidime plus tobramycin)

Bugs of Hosp-acquired pneumonia

Early Middle Late

1 3 5 10 15 20

Strep

H flu

Staph aureus MRSA

Enterobacter

Klebsiella, E coli

Pseudomonas aeruginosa

Acinetobacter sp

Stenotrophomonas

Days in Hospital

LATE

29

31

Ciprofloxacin

FluoroquinolonesChemical structures

Levofloxacin Grepafloxacin Trovafloxacin

Moxifloxacin Gemifloxacin

Fluoroquinolones

Mechanism of action

Fluoroquinolones bind these 2 enzymes with

variable affinity,inhibiting DNA

replication.

Topoisomerase IV

(parC, parE)

Fluoroquinolone

DNA gyrase (gyrA, gyrB)

THIRD GENERATION QUINOLONESMechanism of action

DNA gyraseenzyme that catalyzes

DNA negative supercoiling

1º Target

in Gram-negativesTopoisomerase IVEnzyme with a potent

decatenating activity

on DNA

1º Target

in Gram-positives

Fluoroquinolones

Structure/activity relationship

J.M. Domagala, JAC, 1994, mod.

Controls gyrase

and bacterial

potency

Controls potency.

Adds Gram-positive

activity

Controls potency,

spectrum and

pharmacokinetics

Controls

pharmacokinetics

and anaerobe activity

Controls potency.

Some effect on pharmacokinetics

for activity

Close to gyrase binding

site. H is optimal. Small

rings to R1 or C3 acid

are active

Essential for gyrase binding and

bacterial transport.

No modifications possible

MIC90 (mg/l)

Strains Ciprofloxacin Levofloxacin Moxifloxacin

E. Coli ≤ 0.06 ≤ 0.06 0.06 – 1

K. pneumoniae 0.12 0.25 0.5 – 1

Enterobacter spp 0.06 – 0.12 0.12 – 0.25 0.5 – 1

S. marcescens 0.25 0.25 – 16 1 – 2

Proteus spp 0.06 – 1 0.25 – 1 2 – 4

P. aeruginosa 0.25 – 1 4 – 8 4 - >32

Haemophilus spp 0.03 − 0.03 – 0.125

Neisseria spp 0.008 0.008 – 0.1 0.03 – 0.125

Neu HC et al., 1992; Wise R et al., 1993; Wagstaff AJ & Balfour JA, 1997; Haria M & Lamb HM, 1997;

Brighty KE & Gootz TD, 1997; Thonsberry C, 1998; Balfour JA & Lamb HM, 2000

Fluoroquinolones

In vitro activity against Gram-negative strains

MIC90 (mg/l)

Strain Ciprofloxacin Levofloxacin Moxifloxacin

S. aureus 0.5 0.25 0.06 – 0.12

S. pyogenes 0.5 – 1 1 0.06 – 0.25

S. pneumoniae 1 – 2 2 0.06 – 0.25

E. faecalis 2 2 0.25 – 8

E. faecium 4 4 1 – 4

Wise R et al., 1993; Wagstaff AJ & Balfour JA, 1997; Haria M & Lamb HM, 1997; Brighty

KE & Gootz TD, 1997; Thonsberry C, 1998; Balfour JA & Haria M, 2000

Fluoroquinolones

In vitro activity against Gram-positive strains

Comparison of the relationships between

efficacy and 24-h AUC/MIC for fluoroquinolones

in animal models and infected patients

Animals – Literature review Seriously ill patients + ciprofloxacin

Andes D, Craig WA. Int J Antimicrob Agents. 2002;19:261-268; Forrest A, et al.

Antimicrob Agents Chemother. 1993;37:1073-1081.

0

20

40

60

80

100

0–62.5 62.5–125 125–250 250–500 >500

Effic

acy

Clinical

Microbiologic

24-h AUC/MIC24-h AUC/MIC

% M

ort

alit

y

2.5 10 25 100 250 1000

0

20

40

60

80

100

0 2 4 6 8 10 12 140

25

50

75

100

AUC/MIC < 125

AUC/MIC 125-250

AUC/MIC > 250

Days of therapy

% o

f p

ati

en

ts r

em

ain

ing

cu

ltu

re-p

osit

ive

A. Forrest et al., Antimicrob. Ag. Chemother., 1993

Relationship between ciprofloxacin AUC/MIC

and bacterial eradication rates (74 pts with RTI

in ICU)

Effect of bacterial species on AUC/MIC

AUC/MIC levofloxacin

S. pneumoniae P. aeruginosa

Stasis 16.5 45.2

-1 log10 cfu 32.9 81.5

-2 log10 cfu 54.8 130.0

Jumbe NL et al., 40th ICAAC, Toronto, Canada, 2000; Schentag JJ, J Chemother,

2002

What can be done in the clinical

setting

• Know the target pharmacokinetic/

pharmacodynamic parameter for

the specific drug in use

• Select the most appropriate

administration modality according

to pharmacokinetic/ pharmacody-

namic parameters

Adembri C and Novelli A, PK-PD and potential for providing dosing regimens that are less

vulnerable to resistance Clin Pharmacokinet, 2009

Ignác Fülöp Semmelweis

(1July 1818 – 13 August 1865)

LEVOFLOXACIN 750 OD or 500 BID?

750 OD

• Higher Cmax-Lower AUC

• Some peak-related sideeffects

• Good clinical results

• First choice in USA(1)

500 bid

• Lower Cmax-Higher AUC

• Some dose-related sideeffects

• Good clinical results

• In vitro data indicating apotential higher microactivity

• First choice in Europe (2)

1. Am J Respir Crit Care Med 2005;171:388-416 2. Clin Microbiol Infect 2011;17(Suppl 6):E1-59

CASE REPORT

Male, 74 y/o

Active smoker. Former parachutist.

Past medical history:

10-year history of COPD (dystrophic bullae) in LTOT since 1 year (2 L/m-1.5 L/m). Chronic heart failure, pleural effusions since 4 years. Benign prostatic hyperplasia, depression, peptic ulcer.

Discharged 2 months before from the Internal Medicine Dpt with a diagnosis of UTI treated with ciprofloxacin.

FEV1: 64%76%

DLCO 47%

BGA (O2:1 L/m): pH: 7.49 PaCO2: 36 PaO2:64 HCO3: 22

Since the day before: fever (38 °C) and dyspnea.

BP: 150/60 mmHg HR: 80 bpm RR: 20 bpm T: 39 °C

Chest examination: non wheezing

K: 3.25 Na: 133 CRP: 5.8 WBC: 20.000

PNEUMONIA

LIVER

Diaphragm

PNEUMONIA

B LINES

Healthcare-associated pneumonia

• Ceftriaxone 2gr ev

• Azithromycin 500 mg ev

Since the day before: fever (38 °C) and SOB.

BP: 150/60 mmHg HR: 80 bpm RR: 20 bpm T: 39 °C

Chest examination: non wheezing

K: 3.25 Na: 133 CRP: 5.8 WBC: 20.000

D1

Ceftriaxone 2gr

20.000

5.8 ---

18.000

14.6

WBC

CRP

T

Azithromycina 500 stop

stop

D2 D3

Ab anti-Legionella pneumophila: negative

Swab: bacteria and fungi: neg

Urinary antigens LP and SP: negative

Hemoculture: negative

Ab anti-Mycoplasma: IgG negative and IgM negative

Naso-pharyngeal swab DNA CP, MP, LP: negative

Tracheal aspirate

• RESULT: POSITIVE

• VITEK : PSEUDOMONAS AERUGINOSA 106 cfu/ml

• ANTIBIOGRAM:

ANTIBIOTIC SIR MIC

– AMIKACIN R >64

– CEFTAZIDIME R 4

– PIP/TAZO S 1

– MEROPENEM S <1

– IMIPENEM S <1

– CIPROFLOXACIN S 1

– LEVOFLOXACIN S 1

Ceftriaxone 2gr

20.000

5.8 ---

18.000

14.6

15.000

---

14.200

5.6

WBC

CRP

T

Azithromycina 500 stop

stop

Imipenem 1g q8 EV

Levofloxacin 500 bid ev

D1 D2 D3 D4 D5

Ab anti-Legionella pneumophila: negative

Swab: bacteria and fungi: neg

Urinary antigens LP and SP: negative

Hemoculture: negative

Ab anti-Mycoplasma: IgG negative and IgM negative

Naso-pharyngeal swab DNA CP, MP, LP: negative

PNEUMONIA

LIVER

DIAPHRAGM

In VII giornataOn day 8

Pleural effusion

Ceftriaxone 2gr

20.000

5.8 ---

18.000

14.6

15.000

---

14.200

5.6

12.400

---

WBC

CRP

T

Azithromycina 500 stop

stop

Imipenem 1g q8 EV

D1 D2 D3 D4 D5 D6

Ab anti-Legionella pneumophila: negative

Swab: bacteria and fungi: neg

Urinary antigens LP and SP: negative

Hemoculture: negative

Ab anti-Mycoplasma: IgG negative and IgM negative

Naso-pharyngeal swab DNA CP, MP, LP: negative

Imipenem 1g q8 EV

Levofloxacin 500 bid ev

Discharged on Day 20…

CONCLUSIONS

• Levofloxacin is a valuable antimicrobial agent that has activity against a wide range of respiratory bacterial pathogens

• Levofloxacin have several beneficialproperties for the treatment of CAP. These include oral and intravenousadministration, good-to-excellent oralbioavailability and high concentrations in lung compartments.

• Levofloxacin covers the major causative organismsfor CAP and AECB and early onset HAP.

• Levofloxacin may have a role in Healthcare-associated pneumonia (HCAP) when administeredin combination with other antipseudomonal and anti-MRSA therapies

• High-dose, short-term therapy (levofloxacin 750 mg/day or 500 mg twice daily for 5-7 days) is the recommended dosing regimen for levofloxacin in the treatment of severe CAP and HAP in Europe.