Professor Blasi slideset is about the optimization of antimicrobial therapy for pneumonia and it underlines how the appropriate early antibiotic therapy reduces mortality rates in patients with bloodstream infection.

1. 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

2. 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

3. 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

4. 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

5. 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

6. ANTIBIOTIC
SITE of
INFECTION
BACTERIA
+
MIC
PATIENT
BACTERIA
+
MIC
ANTIBIOTIC
SITE OF
INFECTION
PATIENT
THE PUZZLE OF ANTIMICROBIAL THERAPY
6

7. Improving the probability
of 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

8. 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
Concentration(mg/L)
0 248 16
MIC
T>MIC
AUC/MIC
0.5 10
Hours
PAE
β-lactams
Aminoglycosides
Fluoroquinolones
Tigecycline
Glycopeptides
Daptomycin
Linezolid
8

9. What about the timing ?

10. Mortality (%)
0
25
35
5
15
Appropriate therapy
at beginning
Inappropriate therapy
at 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 therapy
only after susceptibility
determined

11. 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,

12. Epithelial
lining fluid
Neutrophil
Colonising
encapsulated
bacteria
Edema
Alveolar
lumen
Alveolar macrophages
Capillary
lumen Interstitium
Antibiotics
Capillary endothelium
Capillary
basement
membrane
Infected
lung
Alveolar
basement
membrane
Alveolar
epithelium
Epithelial
lining fluid
EPITHELIAL
LINING FLUID

13. Intensive care patient
13

14. 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
Decreased
clearances
High serum drug
concentrations
Consider an increase
of dose
Consider a decrease
of dose
Effects of sepsis on serum drug concentrations
14
Scaglione and Paraboni.Int J Antimicrob Agents 2008;32:294-301

15. 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

16. Theoretical concentration
of an antibiotic
Time
Concentration
MIC
Serum
Interstitial fluid
Large volume
compartment
16Scaglione and Paraboni.Int J Antimicrob Agents 2008;32:294-301

17. • 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 antibiotics
Hydrophilic Lipophilic
Roberts and Lipman. Crit Care Med 2009;37:840-51
Vd, volume of distribution;
CL, clearance; ICU, intensive care unit
17

18. 18
Resistance is a Global Issue
North America
VRE ( E.faecium ) **
MRSA
ESBL -K.pneumoniae 9.7%
A.baumannii (Carb- R)a 22.1%
P.aeruginosa 8.7%
Enterobacter spp
North America
VRE ( E.faecium )
MRSA 50.8%
ESBL -K.pneumoniae
A.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)
1
Rice LB. J Infect Dis 2008; 197:1079 –81
Europe
VRE (E.faecium)
MRSA
ESBL-K.pneumoniae
A.baumannii
P.aeruginosa 13.8%
Enterobacterspp 41.2%
Europe
VRE (E.faecium) 14.2%
MRSA 25.5%
ESBL-K.pneumoniae 21.0%
A.baumannii 27.4%
P.aeruginosa
Enterobacterspp
(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 ?

19. 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

20. Critically ill patients
Increased volume
of 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

21. 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

22. 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)

23. 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 20
0
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)

24. 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

28. LATE

29. 29

31. 31

36. Ciprofloxacin
Fluoroquinolones
Chemical structures
Levofloxacin Grepafloxacin Trovafloxacin
Moxifloxacin Gemifloxacin

37. Fluoroquinolones
Mechanism of action
Fluoroquinolones bind
these 2 enzymes with
variable affinity,
inhibiting DNA
replication.
Topoisomerase IV
(parC, parE)
Fluoroquinolone
DNA gyrase (gyrA, gyrB)

38. THIRD GENERATION QUINOLONES
Mechanism of action
DNA gyrase
enzyme that catalyzes
DNA negative supercoilin
1º Target
in Gram-negatives
Topoisomerase IV
Enzyme with a potent
decatenating activity
on DNA
1º Target
in Gram-positives

39. 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

40. 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

41. 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

42. 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
Efficacy
Clinical
Microbiologic
24-h AUC/MIC24-h AUC/MIC
%Mortality
2.5 10 25 100 250 1000
0
20
40
60
80
100

43. 0 2 4 6 8 10 12 14
0
25
50
75
100
AUC/MIC < 125
AUC/MIC 125-250
AUC/MIC > 250
Days of therapy
%ofpatientsremaining
culture-positive
A. Forrest et al., Antimicrob. Ag. Chemother., 1993
Relationship between ciprofloxacin AUC/MIC
and bacterial eradication rates (74 pts with RTI
in ICU)

44. 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

45. 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)

54. LEVOFLOXACIN 750 OD or 500 BID?
750 OD
• Higher Cmax-Lower AUC
• Some peak-related side
effects
• Good clinical results
• First choice in USA(1)
500 bid
• Lower Cmax-Higher AUC
• Some dose-related side
effects
• Good clinical results
• In vitro data indicating a
potential higher micro
activity
• 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

55. CASE REPORT

56. 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

57. 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

58. PNEUMONIA
LIVER
Diaphragm

59. PNEUMONIA
B LINES

61. Healthcare-associated pneumonia

62. • 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

64. 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

65. 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

66. 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

67. PNEUMONIA
LIVER
DIAPHRAGM

68. In VII giornataOn day 8
Pleural effusion

69. 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

70. Discharged on Day 20…

71. CONCLUSIONS
• Levofloxacin is a valuable antimicrobial agent
that has activity against a wide range of
respiratory bacterial pathogens
• Levofloxacin have several beneficial
properties for the treatment of CAP.
These include oral and intravenous
administration, good-to-excellent oral
bioavailability and high concentrations in
lung compartments.

72. • Levofloxacin covers the major causative organisms
for CAP and AECB and early onset HAP.
• Levofloxacin may have a role in Healthcare-
associated pneumonia (HCAP) when administered
in 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.