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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.