optimizing antimicrobial therapy for hospitalized pneumonia: focus on pk/pd profile of levofloxacin...
TRANSCRIPT
![Page 1: Optimizing antimicrobial therapy for hospitalized pneumonia: Focus on PK/PD profile of levofloxacin - Slideset by Professor Francesco Blasi](https://reader031.vdocuments.mx/reader031/viewer/2022021814/589df9471a28ab1e718b5765/html5/thumbnails/1.jpg)
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
![Page 2: Optimizing antimicrobial therapy for hospitalized pneumonia: Focus on PK/PD profile of levofloxacin - Slideset by Professor Francesco Blasi](https://reader031.vdocuments.mx/reader031/viewer/2022021814/589df9471a28ab1e718b5765/html5/thumbnails/2.jpg)
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
![Page 3: Optimizing antimicrobial therapy for hospitalized pneumonia: Focus on PK/PD profile of levofloxacin - Slideset by Professor Francesco Blasi](https://reader031.vdocuments.mx/reader031/viewer/2022021814/589df9471a28ab1e718b5765/html5/thumbnails/3.jpg)
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
![Page 4: Optimizing antimicrobial therapy for hospitalized pneumonia: Focus on PK/PD profile of levofloxacin - Slideset by Professor Francesco Blasi](https://reader031.vdocuments.mx/reader031/viewer/2022021814/589df9471a28ab1e718b5765/html5/thumbnails/4.jpg)
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
![Page 5: Optimizing antimicrobial therapy for hospitalized pneumonia: Focus on PK/PD profile of levofloxacin - Slideset by Professor Francesco Blasi](https://reader031.vdocuments.mx/reader031/viewer/2022021814/589df9471a28ab1e718b5765/html5/thumbnails/5.jpg)
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
![Page 6: Optimizing antimicrobial therapy for hospitalized pneumonia: Focus on PK/PD profile of levofloxacin - Slideset by Professor Francesco Blasi](https://reader031.vdocuments.mx/reader031/viewer/2022021814/589df9471a28ab1e718b5765/html5/thumbnails/6.jpg)
ANTIBIOTICSITE ofINFECTION
BACTERIA
+
MIC
PATIENT
BACTERIA
+
MIC
ANTIBIOTIC
SITE OF INFECTION
PATIENT
THE PUZZLE OF ANTIMICROBIAL THERAPY
6
![Page 7: Optimizing antimicrobial therapy for hospitalized pneumonia: Focus on PK/PD profile of levofloxacin - Slideset by Professor Francesco Blasi](https://reader031.vdocuments.mx/reader031/viewer/2022021814/589df9471a28ab1e718b5765/html5/thumbnails/7.jpg)
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
![Page 8: Optimizing antimicrobial therapy for hospitalized pneumonia: Focus on PK/PD profile of levofloxacin - Slideset by Professor Francesco Blasi](https://reader031.vdocuments.mx/reader031/viewer/2022021814/589df9471a28ab1e718b5765/html5/thumbnails/8.jpg)
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
![Page 9: Optimizing antimicrobial therapy for hospitalized pneumonia: Focus on PK/PD profile of levofloxacin - Slideset by Professor Francesco Blasi](https://reader031.vdocuments.mx/reader031/viewer/2022021814/589df9471a28ab1e718b5765/html5/thumbnails/9.jpg)
What about the timing ?
![Page 10: Optimizing antimicrobial therapy for hospitalized pneumonia: Focus on PK/PD profile of levofloxacin - Slideset by Professor Francesco Blasi](https://reader031.vdocuments.mx/reader031/viewer/2022021814/589df9471a28ab1e718b5765/html5/thumbnails/10.jpg)
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
![Page 11: Optimizing antimicrobial therapy for hospitalized pneumonia: Focus on PK/PD profile of levofloxacin - Slideset by Professor Francesco Blasi](https://reader031.vdocuments.mx/reader031/viewer/2022021814/589df9471a28ab1e718b5765/html5/thumbnails/11.jpg)
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,
![Page 12: Optimizing antimicrobial therapy for hospitalized pneumonia: Focus on PK/PD profile of levofloxacin - Slideset by Professor Francesco Blasi](https://reader031.vdocuments.mx/reader031/viewer/2022021814/589df9471a28ab1e718b5765/html5/thumbnails/12.jpg)
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
![Page 13: Optimizing antimicrobial therapy for hospitalized pneumonia: Focus on PK/PD profile of levofloxacin - Slideset by Professor Francesco Blasi](https://reader031.vdocuments.mx/reader031/viewer/2022021814/589df9471a28ab1e718b5765/html5/thumbnails/13.jpg)
Intensive care patient
13
![Page 14: Optimizing antimicrobial therapy for hospitalized pneumonia: Focus on PK/PD profile of levofloxacin - Slideset by Professor Francesco Blasi](https://reader031.vdocuments.mx/reader031/viewer/2022021814/589df9471a28ab1e718b5765/html5/thumbnails/14.jpg)
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
![Page 15: Optimizing antimicrobial therapy for hospitalized pneumonia: Focus on PK/PD profile of levofloxacin - Slideset by Professor Francesco Blasi](https://reader031.vdocuments.mx/reader031/viewer/2022021814/589df9471a28ab1e718b5765/html5/thumbnails/15.jpg)
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
![Page 16: Optimizing antimicrobial therapy for hospitalized pneumonia: Focus on PK/PD profile of levofloxacin - Slideset by Professor Francesco Blasi](https://reader031.vdocuments.mx/reader031/viewer/2022021814/589df9471a28ab1e718b5765/html5/thumbnails/16.jpg)
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
![Page 17: Optimizing antimicrobial therapy for hospitalized pneumonia: Focus on PK/PD profile of levofloxacin - Slideset by Professor Francesco Blasi](https://reader031.vdocuments.mx/reader031/viewer/2022021814/589df9471a28ab1e718b5765/html5/thumbnails/17.jpg)
• 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
![Page 18: Optimizing antimicrobial therapy for hospitalized pneumonia: Focus on PK/PD profile of levofloxacin - Slideset by Professor Francesco Blasi](https://reader031.vdocuments.mx/reader031/viewer/2022021814/589df9471a28ab1e718b5765/html5/thumbnails/18.jpg)
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 ?
![Page 19: Optimizing antimicrobial therapy for hospitalized pneumonia: Focus on PK/PD profile of levofloxacin - Slideset by Professor Francesco Blasi](https://reader031.vdocuments.mx/reader031/viewer/2022021814/589df9471a28ab1e718b5765/html5/thumbnails/19.jpg)
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
![Page 20: Optimizing antimicrobial therapy for hospitalized pneumonia: Focus on PK/PD profile of levofloxacin - Slideset by Professor Francesco Blasi](https://reader031.vdocuments.mx/reader031/viewer/2022021814/589df9471a28ab1e718b5765/html5/thumbnails/20.jpg)
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
![Page 21: Optimizing antimicrobial therapy for hospitalized pneumonia: Focus on PK/PD profile of levofloxacin - Slideset by Professor Francesco Blasi](https://reader031.vdocuments.mx/reader031/viewer/2022021814/589df9471a28ab1e718b5765/html5/thumbnails/21.jpg)
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
![Page 22: Optimizing antimicrobial therapy for hospitalized pneumonia: Focus on PK/PD profile of levofloxacin - Slideset by Professor Francesco Blasi](https://reader031.vdocuments.mx/reader031/viewer/2022021814/589df9471a28ab1e718b5765/html5/thumbnails/22.jpg)
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)
![Page 23: Optimizing antimicrobial therapy for hospitalized pneumonia: Focus on PK/PD profile of levofloxacin - Slideset by Professor Francesco Blasi](https://reader031.vdocuments.mx/reader031/viewer/2022021814/589df9471a28ab1e718b5765/html5/thumbnails/23.jpg)
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)
![Page 24: Optimizing antimicrobial therapy for hospitalized pneumonia: Focus on PK/PD profile of levofloxacin - Slideset by Professor Francesco Blasi](https://reader031.vdocuments.mx/reader031/viewer/2022021814/589df9471a28ab1e718b5765/html5/thumbnails/24.jpg)
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
![Page 25: Optimizing antimicrobial therapy for hospitalized pneumonia: Focus on PK/PD profile of levofloxacin - Slideset by Professor Francesco Blasi](https://reader031.vdocuments.mx/reader031/viewer/2022021814/589df9471a28ab1e718b5765/html5/thumbnails/25.jpg)
![Page 26: Optimizing antimicrobial therapy for hospitalized pneumonia: Focus on PK/PD profile of levofloxacin - Slideset by Professor Francesco Blasi](https://reader031.vdocuments.mx/reader031/viewer/2022021814/589df9471a28ab1e718b5765/html5/thumbnails/26.jpg)
![Page 27: Optimizing antimicrobial therapy for hospitalized pneumonia: Focus on PK/PD profile of levofloxacin - Slideset by Professor Francesco Blasi](https://reader031.vdocuments.mx/reader031/viewer/2022021814/589df9471a28ab1e718b5765/html5/thumbnails/27.jpg)
![Page 28: Optimizing antimicrobial therapy for hospitalized pneumonia: Focus on PK/PD profile of levofloxacin - Slideset by Professor Francesco Blasi](https://reader031.vdocuments.mx/reader031/viewer/2022021814/589df9471a28ab1e718b5765/html5/thumbnails/28.jpg)
LATE
![Page 29: Optimizing antimicrobial therapy for hospitalized pneumonia: Focus on PK/PD profile of levofloxacin - Slideset by Professor Francesco Blasi](https://reader031.vdocuments.mx/reader031/viewer/2022021814/589df9471a28ab1e718b5765/html5/thumbnails/29.jpg)
29
![Page 30: Optimizing antimicrobial therapy for hospitalized pneumonia: Focus on PK/PD profile of levofloxacin - Slideset by Professor Francesco Blasi](https://reader031.vdocuments.mx/reader031/viewer/2022021814/589df9471a28ab1e718b5765/html5/thumbnails/30.jpg)
![Page 31: Optimizing antimicrobial therapy for hospitalized pneumonia: Focus on PK/PD profile of levofloxacin - Slideset by Professor Francesco Blasi](https://reader031.vdocuments.mx/reader031/viewer/2022021814/589df9471a28ab1e718b5765/html5/thumbnails/31.jpg)
31
![Page 32: Optimizing antimicrobial therapy for hospitalized pneumonia: Focus on PK/PD profile of levofloxacin - Slideset by Professor Francesco Blasi](https://reader031.vdocuments.mx/reader031/viewer/2022021814/589df9471a28ab1e718b5765/html5/thumbnails/32.jpg)
![Page 33: Optimizing antimicrobial therapy for hospitalized pneumonia: Focus on PK/PD profile of levofloxacin - Slideset by Professor Francesco Blasi](https://reader031.vdocuments.mx/reader031/viewer/2022021814/589df9471a28ab1e718b5765/html5/thumbnails/33.jpg)
![Page 34: Optimizing antimicrobial therapy for hospitalized pneumonia: Focus on PK/PD profile of levofloxacin - Slideset by Professor Francesco Blasi](https://reader031.vdocuments.mx/reader031/viewer/2022021814/589df9471a28ab1e718b5765/html5/thumbnails/34.jpg)
![Page 35: Optimizing antimicrobial therapy for hospitalized pneumonia: Focus on PK/PD profile of levofloxacin - Slideset by Professor Francesco Blasi](https://reader031.vdocuments.mx/reader031/viewer/2022021814/589df9471a28ab1e718b5765/html5/thumbnails/35.jpg)
![Page 36: Optimizing antimicrobial therapy for hospitalized pneumonia: Focus on PK/PD profile of levofloxacin - Slideset by Professor Francesco Blasi](https://reader031.vdocuments.mx/reader031/viewer/2022021814/589df9471a28ab1e718b5765/html5/thumbnails/36.jpg)
Ciprofloxacin
FluoroquinolonesChemical structures
Levofloxacin Grepafloxacin Trovafloxacin
Moxifloxacin Gemifloxacin
![Page 37: Optimizing antimicrobial therapy for hospitalized pneumonia: Focus on PK/PD profile of levofloxacin - Slideset by Professor Francesco Blasi](https://reader031.vdocuments.mx/reader031/viewer/2022021814/589df9471a28ab1e718b5765/html5/thumbnails/37.jpg)
Fluoroquinolones
Mechanism of action
Fluoroquinolones bind these 2 enzymes with
variable affinity,inhibiting DNA
replication.
Topoisomerase IV
(parC, parE)
Fluoroquinolone
DNA gyrase (gyrA, gyrB)
![Page 38: Optimizing antimicrobial therapy for hospitalized pneumonia: Focus on PK/PD profile of levofloxacin - Slideset by Professor Francesco Blasi](https://reader031.vdocuments.mx/reader031/viewer/2022021814/589df9471a28ab1e718b5765/html5/thumbnails/38.jpg)
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
![Page 39: Optimizing antimicrobial therapy for hospitalized pneumonia: Focus on PK/PD profile of levofloxacin - Slideset by Professor Francesco Blasi](https://reader031.vdocuments.mx/reader031/viewer/2022021814/589df9471a28ab1e718b5765/html5/thumbnails/39.jpg)
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
![Page 40: Optimizing antimicrobial therapy for hospitalized pneumonia: Focus on PK/PD profile of levofloxacin - Slideset by Professor Francesco Blasi](https://reader031.vdocuments.mx/reader031/viewer/2022021814/589df9471a28ab1e718b5765/html5/thumbnails/40.jpg)
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
![Page 41: Optimizing antimicrobial therapy for hospitalized pneumonia: Focus on PK/PD profile of levofloxacin - Slideset by Professor Francesco Blasi](https://reader031.vdocuments.mx/reader031/viewer/2022021814/589df9471a28ab1e718b5765/html5/thumbnails/41.jpg)
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
![Page 42: Optimizing antimicrobial therapy for hospitalized pneumonia: Focus on PK/PD profile of levofloxacin - Slideset by Professor Francesco Blasi](https://reader031.vdocuments.mx/reader031/viewer/2022021814/589df9471a28ab1e718b5765/html5/thumbnails/42.jpg)
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
![Page 43: Optimizing antimicrobial therapy for hospitalized pneumonia: Focus on PK/PD profile of levofloxacin - Slideset by Professor Francesco Blasi](https://reader031.vdocuments.mx/reader031/viewer/2022021814/589df9471a28ab1e718b5765/html5/thumbnails/43.jpg)
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)
![Page 44: Optimizing antimicrobial therapy for hospitalized pneumonia: Focus on PK/PD profile of levofloxacin - Slideset by Professor Francesco Blasi](https://reader031.vdocuments.mx/reader031/viewer/2022021814/589df9471a28ab1e718b5765/html5/thumbnails/44.jpg)
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
![Page 45: Optimizing antimicrobial therapy for hospitalized pneumonia: Focus on PK/PD profile of levofloxacin - Slideset by Professor Francesco Blasi](https://reader031.vdocuments.mx/reader031/viewer/2022021814/589df9471a28ab1e718b5765/html5/thumbnails/45.jpg)
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)
![Page 46: Optimizing antimicrobial therapy for hospitalized pneumonia: Focus on PK/PD profile of levofloxacin - Slideset by Professor Francesco Blasi](https://reader031.vdocuments.mx/reader031/viewer/2022021814/589df9471a28ab1e718b5765/html5/thumbnails/46.jpg)
![Page 47: Optimizing antimicrobial therapy for hospitalized pneumonia: Focus on PK/PD profile of levofloxacin - Slideset by Professor Francesco Blasi](https://reader031.vdocuments.mx/reader031/viewer/2022021814/589df9471a28ab1e718b5765/html5/thumbnails/47.jpg)
![Page 48: Optimizing antimicrobial therapy for hospitalized pneumonia: Focus on PK/PD profile of levofloxacin - Slideset by Professor Francesco Blasi](https://reader031.vdocuments.mx/reader031/viewer/2022021814/589df9471a28ab1e718b5765/html5/thumbnails/48.jpg)
![Page 49: Optimizing antimicrobial therapy for hospitalized pneumonia: Focus on PK/PD profile of levofloxacin - Slideset by Professor Francesco Blasi](https://reader031.vdocuments.mx/reader031/viewer/2022021814/589df9471a28ab1e718b5765/html5/thumbnails/49.jpg)
![Page 50: Optimizing antimicrobial therapy for hospitalized pneumonia: Focus on PK/PD profile of levofloxacin - Slideset by Professor Francesco Blasi](https://reader031.vdocuments.mx/reader031/viewer/2022021814/589df9471a28ab1e718b5765/html5/thumbnails/50.jpg)
![Page 51: Optimizing antimicrobial therapy for hospitalized pneumonia: Focus on PK/PD profile of levofloxacin - Slideset by Professor Francesco Blasi](https://reader031.vdocuments.mx/reader031/viewer/2022021814/589df9471a28ab1e718b5765/html5/thumbnails/51.jpg)
![Page 52: Optimizing antimicrobial therapy for hospitalized pneumonia: Focus on PK/PD profile of levofloxacin - Slideset by Professor Francesco Blasi](https://reader031.vdocuments.mx/reader031/viewer/2022021814/589df9471a28ab1e718b5765/html5/thumbnails/52.jpg)
![Page 53: Optimizing antimicrobial therapy for hospitalized pneumonia: Focus on PK/PD profile of levofloxacin - Slideset by Professor Francesco Blasi](https://reader031.vdocuments.mx/reader031/viewer/2022021814/589df9471a28ab1e718b5765/html5/thumbnails/53.jpg)
![Page 54: Optimizing antimicrobial therapy for hospitalized pneumonia: Focus on PK/PD profile of levofloxacin - Slideset by Professor Francesco Blasi](https://reader031.vdocuments.mx/reader031/viewer/2022021814/589df9471a28ab1e718b5765/html5/thumbnails/54.jpg)
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
![Page 55: Optimizing antimicrobial therapy for hospitalized pneumonia: Focus on PK/PD profile of levofloxacin - Slideset by Professor Francesco Blasi](https://reader031.vdocuments.mx/reader031/viewer/2022021814/589df9471a28ab1e718b5765/html5/thumbnails/55.jpg)
CASE REPORT
![Page 56: Optimizing antimicrobial therapy for hospitalized pneumonia: Focus on PK/PD profile of levofloxacin - Slideset by Professor Francesco Blasi](https://reader031.vdocuments.mx/reader031/viewer/2022021814/589df9471a28ab1e718b5765/html5/thumbnails/56.jpg)
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
![Page 57: Optimizing antimicrobial therapy for hospitalized pneumonia: Focus on PK/PD profile of levofloxacin - Slideset by Professor Francesco Blasi](https://reader031.vdocuments.mx/reader031/viewer/2022021814/589df9471a28ab1e718b5765/html5/thumbnails/57.jpg)
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
![Page 58: Optimizing antimicrobial therapy for hospitalized pneumonia: Focus on PK/PD profile of levofloxacin - Slideset by Professor Francesco Blasi](https://reader031.vdocuments.mx/reader031/viewer/2022021814/589df9471a28ab1e718b5765/html5/thumbnails/58.jpg)
PNEUMONIA
LIVER
Diaphragm
![Page 59: Optimizing antimicrobial therapy for hospitalized pneumonia: Focus on PK/PD profile of levofloxacin - Slideset by Professor Francesco Blasi](https://reader031.vdocuments.mx/reader031/viewer/2022021814/589df9471a28ab1e718b5765/html5/thumbnails/59.jpg)
PNEUMONIA
B LINES
![Page 60: Optimizing antimicrobial therapy for hospitalized pneumonia: Focus on PK/PD profile of levofloxacin - Slideset by Professor Francesco Blasi](https://reader031.vdocuments.mx/reader031/viewer/2022021814/589df9471a28ab1e718b5765/html5/thumbnails/60.jpg)
![Page 61: Optimizing antimicrobial therapy for hospitalized pneumonia: Focus on PK/PD profile of levofloxacin - Slideset by Professor Francesco Blasi](https://reader031.vdocuments.mx/reader031/viewer/2022021814/589df9471a28ab1e718b5765/html5/thumbnails/61.jpg)
Healthcare-associated pneumonia
![Page 62: Optimizing antimicrobial therapy for hospitalized pneumonia: Focus on PK/PD profile of levofloxacin - Slideset by Professor Francesco Blasi](https://reader031.vdocuments.mx/reader031/viewer/2022021814/589df9471a28ab1e718b5765/html5/thumbnails/62.jpg)
• 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
![Page 63: Optimizing antimicrobial therapy for hospitalized pneumonia: Focus on PK/PD profile of levofloxacin - Slideset by Professor Francesco Blasi](https://reader031.vdocuments.mx/reader031/viewer/2022021814/589df9471a28ab1e718b5765/html5/thumbnails/63.jpg)
![Page 64: Optimizing antimicrobial therapy for hospitalized pneumonia: Focus on PK/PD profile of levofloxacin - Slideset by Professor Francesco Blasi](https://reader031.vdocuments.mx/reader031/viewer/2022021814/589df9471a28ab1e718b5765/html5/thumbnails/64.jpg)
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
![Page 65: Optimizing antimicrobial therapy for hospitalized pneumonia: Focus on PK/PD profile of levofloxacin - Slideset by Professor Francesco Blasi](https://reader031.vdocuments.mx/reader031/viewer/2022021814/589df9471a28ab1e718b5765/html5/thumbnails/65.jpg)
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
![Page 66: Optimizing antimicrobial therapy for hospitalized pneumonia: Focus on PK/PD profile of levofloxacin - Slideset by Professor Francesco Blasi](https://reader031.vdocuments.mx/reader031/viewer/2022021814/589df9471a28ab1e718b5765/html5/thumbnails/66.jpg)
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
![Page 67: Optimizing antimicrobial therapy for hospitalized pneumonia: Focus on PK/PD profile of levofloxacin - Slideset by Professor Francesco Blasi](https://reader031.vdocuments.mx/reader031/viewer/2022021814/589df9471a28ab1e718b5765/html5/thumbnails/67.jpg)
PNEUMONIA
LIVER
DIAPHRAGM
![Page 68: Optimizing antimicrobial therapy for hospitalized pneumonia: Focus on PK/PD profile of levofloxacin - Slideset by Professor Francesco Blasi](https://reader031.vdocuments.mx/reader031/viewer/2022021814/589df9471a28ab1e718b5765/html5/thumbnails/68.jpg)
In VII giornataOn day 8
Pleural effusion
![Page 69: Optimizing antimicrobial therapy for hospitalized pneumonia: Focus on PK/PD profile of levofloxacin - Slideset by Professor Francesco Blasi](https://reader031.vdocuments.mx/reader031/viewer/2022021814/589df9471a28ab1e718b5765/html5/thumbnails/69.jpg)
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
![Page 70: Optimizing antimicrobial therapy for hospitalized pneumonia: Focus on PK/PD profile of levofloxacin - Slideset by Professor Francesco Blasi](https://reader031.vdocuments.mx/reader031/viewer/2022021814/589df9471a28ab1e718b5765/html5/thumbnails/70.jpg)
Discharged on Day 20…
![Page 71: Optimizing antimicrobial therapy for hospitalized pneumonia: Focus on PK/PD profile of levofloxacin - Slideset by Professor Francesco Blasi](https://reader031.vdocuments.mx/reader031/viewer/2022021814/589df9471a28ab1e718b5765/html5/thumbnails/71.jpg)
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.
![Page 72: Optimizing antimicrobial therapy for hospitalized pneumonia: Focus on PK/PD profile of levofloxacin - Slideset by Professor Francesco Blasi](https://reader031.vdocuments.mx/reader031/viewer/2022021814/589df9471a28ab1e718b5765/html5/thumbnails/72.jpg)
• 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.