Antibiotic in Community Acquired Pneumonia - 2007 -

1. Cefditoren pivoxil:
a new antibiotic for the
treatment of respiratory
infections
Jordi Roig (SPAIN)
Scientific Committee of SEPAR
N. Sra. Meritxell Hospital
Pulmonary Division (Andorra)

2. The “ideal” antibiotic
• High activity against potential causative
pathogens
• Adequate pharmacodynamic profile (good
penetration in tissues)
• Safe
• Easy posology
• Favorable cost/benefit ratio

3. Antibiotics in the RTI
• ß-lactams:
- Aminopenicilins: amoxicillin +/-clavulanate
- Cephalosporins: cefuroxime, cefaclor, cefixime,
cefotaxime, cefpodoxime
• Macrolides: erythromycin, clarithromycin,
azithromycin
• Quinolones: levofloxacin, moxifloxacin
• Ketolides: telithromycin

4. Cephalosporins profile
Gen. Oral Parenteral
1st
cefalexine, cefadroxil cefazolin, cefalotin,
cefradin cefapirin
2nd
cefaclor, cefprozil cefuroxime, cefoxitin,
cefonicid, cefamandole
3rd
cefpodoxime, cefixime cefotaxime, ceftriaxone
ceftibuten ceftazidime
Cefditoren
4th
cefepime, cefpirone
G + G -
↑↑↑ ↑
↑↑ ↑↑
↑↑ ↑↑↑
↑↑↑ ↑↑↑
↑↑ ↑↑↑*
*active against P. aeruginosa

5. S. pneumoniae in Europe
penicillin erythromycin
The European Antimicrobial Resistance Surveillance System (EARSS) Annual Report 2005

6. Streptococcus pneumoniae
Antibiotic resistance (%) in Saudi Arabia
Peni resistant
Author, year,
nº isolates
Peni
Susceptible Total I H
Macrolide
resistant
Ery Rox Azt
Others
Shibl Am,
2005; 350
51 19 (total)
Al-Tawfiq,
2004; 162
51 49 20
Memish ZA,
2004; 154
59 15
9,amoxy/clav;
32 cefuroxime;
40 cepfrozil
Fouda SI,
2004; 336
44,6 55 36 20 22 18 18 18

7. H. influenzae resistance to β-lactams
Surveillance studies (Libra, Alexander Project)
35%
21%
9%
35%
15%
23%
10%

8. Considering the current situation:
1. S. peumoniae resistance*:
58% Cefixime 37% Azithromycin
47% Cefaclor 35% Clarithromycin
40% Cefuroxime axetil 10% Amoxicillin/ clav
2. Suboptimal activity of macrolides
and ketolides against H. influenzae.
*Pérez- Trallero et al. Antimicrob Agents Chemother, 2001
New
antibiotics are
necessary

9. Key points on microbial etiology and
resistance
• Selection of antimicrobial resistance appears
to be strongly associated with suboptimal
antimicrobial therapy
• Shortening the length of antibiotic treatment
helps to reduce the emergence of
multiresistant bacteria
Rello J & Roig J. In: Respiratory infections. Chapter 40; Hodder Arnold
Pub, London, 2006.

10. Cefditoren pivoxil: PROFILE
Cefditoren pivoxil Cefditoren
• Administered orally as cefditoren pivoxil (CDTR-PI)
• Intestinal esterases release the active drug into the
blood stream
• Acts by inhibiting the synthesis of bacterial wall
• The β-lactam with the lowest MIC values against
bacterial respiratory pathogens

11. Antibacterial activity
• CDTR is the oral cephalosporin showing the highest in vitro
activity against:
– S. pneumoniae: more active than:
– H. influenzae
– M. catarrhalis
– S. aureus (MS) and Staphylococcus coagulase (-)
– S. pyogenes
– N. meningitidis and N. gonorrhoeae (incl. β-lactamase (+)
– Enterobacteriaceae
profile comparable to cefotaximeprofile comparable to cefotaxime
but…..orally administeredbut…..orally administered
•cefpodoxime (2-3 times)
•cefuroxime (4-8 times)
•cefixime (16-32 times)

12. In vitro antibacterial activity
The ARISE* (Antimicrobial Resistant Isolates in Shouthern
Europe) project . Soriano et al. Int J. of Antimicrobial Agents 2004
CDTR is the oral β-lactam with the highest intrinsic activity
against the most prevalent bacterial respiratory pathogens

13. Activity of S. pneumoniae strains non-
susceptible (NS) to common oral antibiotics
n=600
cefditoren concentrations (µg/mL)
≤0.06 0.12 0.25 0.5 1 2
PEN-NS 8.2 15.0 35.6 97.4 99.7 100
AMX-NS 0.5 1.9 20.1 97.6 100 100
CFX-NS 0.3 4.0 25.8 97.0 99.7 100
AZT-NS 41.5 47.6 62.8 98.5 100 100
LVX-NS 67.4 73.9 80.4 97.8 100 100
Fenoll A. et al. Int J Antimicrob Agents, 2007
Cumulative percentage

14. S. pneumoniae: evolution of cefditoren
MIC90 in Japan
0,5
0,78
0,390,39 0,5
0
1
1,5
2
1996 1998 2000 2002
35% of S. pneumoniae strains showed diminished susceptibility to penicillin
Chemotherapy, 44, 610-25, 1998 Chemotherapy, 51, 179-208, 2003
Chemotherapy, 48, 585-609, 2000 Chemotherapy, 54, 330-54, 2006

15. CONCLUSIONS on bactericidal activity
 Against Penicillin resistant S. pneumoniae (MICpeni= 2-4µg/mL) CDTR
was the only antibiotic showing bactericidal activity at 12 and 24 hours
vs. Cefuroxime and Amox/Clav 875/125 bid or tid (Gonzalez et al. ECC,
Budapest 2006; submitted to Int J. of Antimicrobial Chemother)
 Against H. influenzae with different resistance phenotypes CDTR was
the only antibiotic showing bactericidal activity at 12 and 24 hours vs.
Cefuroxime and Amox/Clav 875/125 bid or tid. in press: Int. J. of
Antimicrobial Chemother.)
A remarkable result in an environment where the BLNAR phenotype is
increasing
 Bactericidal activity of CDTR was mantained in the presence of 90%
human serum at 24 h. despite of the protein binding of CDTR is 88%
(Califi et al. ECC, Budapest 2006; submitted to Int. J. Antimicrob. Chemother)
 CDTR in preformed Biofilms (S.pneumoniae and H. influenzae) shows
bactericidal activity in initial and mature biofilms. (Roveta S, Marchese A.,
Schito G.C. 34 Congresso Nazionale della Societá Italiana di Microbiologia. Genova,
15-18 Oct. 2006)

16. • Cmax: 2.6 µg/ml (200 mg), 4.1 µg/ml (400 mg)
• tmax: 2.5 h
• t1/2: 1.5 h
• AUC: 7.9 µg.h/mL (200 mg), 14.6 µg.h/mL(400 mg)
• Vd: 40-65 L
• Absolute bioavailability: 20%
• Binding to proteins: 88%
• Absorption increases with food
• Elimination of cefditoren mainly in urine and
metabolites in urine and faeces
* Data from the approved European SPC
Pharmacokinetics*

17. Pharmacodynamics
Percentage of the dose interval during plasma
concentrations of CDTR exceed MIC.
Dose MIC90
(µg/ml)
0.008 0.015 0.03 0.06 0.12 0.25 0.5 1 2
Mean 98.5 95.2 88.1 77.2 63.5 49.6 37.3 24.6 9.2
200
mg bid
SD 4.6 7.3 10.8 12.0 10.8 8.5 6.9 6.3 6.5
Mean 100.0 99.8 98.0 91.5 79.4 64.8 51.3 38.7 24.8
400
mg bid
SD 0.3 1.3 3.9 8.9 11.6 10.8 9.3 7.9 7.7

18. Susceptibility of S. pneumoniae to
cefditoren
MIC (µg/ mL)
N ≤0.03 0.06 0.1 0.2 0.5 1 2 4
Pen S 723 96.4 97.6 99.8 99.8 99.9 - - -
Pen I 243 17.3 29.2 48.5 75.2 95.3 99.8 - -
Pen R 226 - - 3.5 19.9 67.7 96.9 99.5 99.9
Total 1192 62.0 65.2 71.1 79.9 92.9 99.3 99.8 99.9
CDTR at 0.5 µg/mL inhibits around
93% of S. pneumoniae including
Pen-R strains (Breakpoint in
European SPC) Martínez Beltrán et al, ICAAC 1994
Soriano et al. J Chemother 2003

19. Clinical development in RTI
» More than 500 subjects (Phase I)
» More than 9.200 patients (Phases II and III, with 5,900 of CDTR
arm) (RTI and SSI).
» Conducted in Europe (Austria, France, Italy, Germany, Hungary,
Rumania, Spain, Switzerland, UK), United States and South
Africa according to European and American Guidelines.
Upper RTUpper RT
» Acute otitis media
» Bacterial pharyngitis/tonsillitis
» Bacterial sinusitis
Lower RTLower RT
» Acute exacerbation of chronic bronchitis
» Community acquired pneumonia (mild-moderate)

20. Acute otitis media
Clinical study (France) n= 295
Inclusion criteriaInclusion criteria
» Infants 6-30 months of age with clinical diagnosis of AOM with otorrhea
» Microbiologic samples obtained by paracentesis or nasopharyngeal
aspiration.
» Treatment duration 10 days
ResultsResults
222 (32%) strains of S.
pneumoniae isolated:
25% S, 25% I, and 50% R.
Efficacy
CDTR 6mg/ kg x 3 days
Clinical
82
Microbiological
72.5
CDTR 8mg/ kg x 3 days
AMOXI / CLAV
8mg/ kg / day
80
82
76.1
72.6
Bacterial origin in the 55%
of the cases:
S. pneumoniae, 50%
H. influenzae, 25%
M. catarrhalis, 15%

21. Acute sinusitis (I)
Clinical studies US and EU
Inclusion CriteriaInclusion Criteria
» ≥ 12 y.o (US) and ≥ 18 y.o (EU)
» Clinical diagnosis of acute maxillary sinusitis
» Sinus x- Ray or CT scan
» Microbiological sample by swab or sinus puncture
EtiologyEtiology
• Bacterial origin in the 60% of the cases*
– S. pneumoniae 43%,
– H. influenzae 35%,
– M. catarrhalis 10%
* Rev Esp Quimioter, 2003.

22. Acute sinusitis (II)
Pivotal studies (US) and EU study
Code Country CDTR-PI dose Comparator n
200 mg bid, 10 days AMOX/CLAV
400 mg bid, 10 days 875/125 mg bid 10 days
200 mg bid, 10 days AMOX/CLAV
400 mg bid, 10 days 500/125 mg tid 10 days
CXM-AX
250 mg bid, 10 days
205200 mg bid, 10 daysEUME 305
CEF 97-004 US
775
837CEF 97-007 US
CONCLUSIONSCONCLUSIONS::
• Cefditoren (200 mg bid or 400 mg bid during 10 days) was as effective as the
combined comparator group. Confidence intervals show that both CDTR groups
are equivalent with the comparators and between them.
• No Serious Adverse Reactions were reported.
Wellington et al. Drugs,

23. Acute pharyngotonsillitis (I)
Pivotal studies (US) and EU study**
Inclusion criteriaInclusion criteria
≈ ≥ 12 y.o (US) and ≥ 18 y.o (EU).
» Clinical diagnosis of acute pharyngotonsillitis (sore throat, erythema/
exudate, tenderness, fever).
» S. pyogenes rapid immunoassay test (US).
EtiologyEtiology
• Bacterial origin up to a 23% of the cases.
Streptococcus pyogenes is the most frequent pathogen*
* Rev Esp Quimioter 2003..
**Kaplan et al. J Respir Dis, 2001. Wellington et al. Drugs, 2004

24. Acute pharyngotonsillitis (II)
Code Country CDTR-PI dose Comparator n
CEF 97-008 US
200 mg bid,
10 days
(95% - 92%)
PEN-V
250 mg qid, 10 days
(92% - 81%)
503
CEF 97-010 US
200 mg bid,
10 days
(93% - 88%)
PEN-V
250 mg qid, 10 days
(89% - 85%)
508
ME 309 EU
200 mg bid,
5 days
(94% - 86%)
PEN-V
400 mg tid, 10 days
(92% - 82%)
309
Clinical efficacy Microbiological Efficacy
CONCLUSIONS:CONCLUSIONS:
• The clinical efficacy was equivalent.
• The biological activity was higher in CDTR group (from statistical point of view)

25. Acute Exacerbation of Chronic Bronchitis
Tissue penetration of cefditoren into bronchialTissue penetration of cefditoren into bronchial
mucosa and epithelial lining fluidmucosa and epithelial lining fluid
Concentration ratios
Collection Interval
(h)
Bronchial
Mucosa/Plasma
Epithelial Lining
Fluid/Plasma
1.0 - 2.0 0.66 0.38
2.0 - 3.0 0.69 0.23
3.0 - 4.0 0.55 0.32
Kinzig-Schippers M. 41st Interscience Conference on Antimicrobials
Agents and Chemotherapy; 2001Dec16-19; Chicago

26. AECB clinical studies
CODE COUNTRY TREATMENT COMPARATOR n
CDTR 200 bid
10 days
CEF97-003 US
CDTR 400 bid
10 days
CXM 250 bid
10 days
537
CDTR 200 bid
10 days
CEF97-005 US
CDTR 400 bid
10 days
CLR 500 bid
10 days
903
ME303 *
(Pivotal)
EU
CDTR 200 bid
5 days
CXM 250 bid
10 days
568
* Inclusion criteria* Inclusion criteria
» > 18 years old
» Anthonisen I and II
» FEV1<80% , FEV/FVC<65%
Kardos et al. Antimicrob Agents Chemother, 2006

27. Evolution of signs and symptoms during
the study - ME 303
Cefditoren pivoxil (%)
5 DAYS
Cefuroxime axetil (%)
10 DAYS
Basal
(n=241)
Post-
treatment
(n=241)
Basal
(n=244)
Post-
tretment
(n=244)
Cough 100 88.0 100 93.4
Dyspnea 98.3 80.9 98.4 82.4
Wheezing 60.6 23.7 57.4 22.1
Rales and ronchi 77.2 31.1 77.0 32.4
Sputum volume >30 ml 75.9 10.0 76.2 7.8
Sputum purulence 87.1 13.7 87.7 9.4
69% of the patients were Anthonisen grade I69% of the patients were Anthonisen grade I

28. Economical Evaluation of CDTR in EACB
» In a cost minimization analysis, Cefditoren pivoxil 5
days has shown to be an effective treatment of
AECB and equivalent to Cefuroxime axetil 10 days.
» Favorable pharmacoeconomic analysis* results with
a cost saving per patient from 1 to 14 €
*Rubio-Terrés C, Pharmacoeconomics 2005; 2(2):45-54

29. S.pneumoniae
S.aureus
Legionella
PA
H.influenzae
Enterobac.
CAPCAP: Etiology
Angus DC et al . Am J Respir Crit Care Med 2002;166:717-723
““S.pneumoniaeS.pneumoniae is theis the
principal microorganismprincipal microorganism
responsible of CAP”responsible of CAP”
““The etiologic pattern wasThe etiologic pattern was
similar in both ICU and non-similar in both ICU and non-
ICU patients”.ICU patients”.

30. 46,2
10,1 8,8 8,2 7,6
59,3
4,3
7,6 5,9 8,4
0
10
20
30
40
50
60
70
S.pneumoniae S.aureus L.pneumophila P.aeruginosa H.influenzae
Shock
No Shock
CAPCAP: Etiology
(CAPUCI Study)(CAPUCI Study)
““The etiologic pattern was similar in both shock and non-shock patients”.The etiologic pattern was similar in both shock and non-shock patients”.

31. Is S. pneumoniae the leading cause of
pneumonia of unknown etiology?
Ruiz-Gonzalez A. A microbiologic study with lungRuiz-Gonzalez A. A microbiologic study with lung
aspirates in consecutive patients with CAP. Am Jaspirates in consecutive patients with CAP. Am J
Med 1999.Med 1999.
• n= 109
• Conventional microbial work-up + in 54 cases (50%) 9 of
them S. pneumoniae
• Lung aspiration in remaining 55 provided diagnosis in 36:
– S. pneumoniae 18
– H. influenzae 6

32. 30,1%
21,4%
0%
5%
10%
15%
20%
25%
30%
35%
COPD Non COPD
Mortalityrate(%)
p=0.05
n=176n=176 n=252n=252

33. COPD (%) Non-COPD(%)
Streptoccoccus
pneumoniae
52 (54.1) 68 (51.5)
P. aeruginosa 13 (13.5) 1 (0.8)
Haemophillus
influenzae
11 (11.4) 7 (5.3)
Legionella spp. 4 (4.1) 15 (11.4)
Staphylococcus aureus 3 (3.1) 12 (9.0)
Enterobacteriaceae 3 (3.1) 9 (6.8)
Microorganisms isolated in COPD and non- COPD
immunocompetent patients with SCAP
ERJ 2006 (CAPUCI Study Investigators)

34. Treatment failure in CAP /
MORTALITY RATE
Menéndez R et al. Thorax 2004;59:960Menéndez R et al. Thorax 2004;59:960
0%
5%
10%
15%
20%
25%
30%
Failure No Failure
p<0.001p<0.001

35. Is coverage of atypical agents a
significant issue?
• Potential benefit of covering atypical
pathogens in the empiric approach of CAP
comes only from the subset of patients
with legionellosis
Roig J et al. Med Mal Infect 2006
Mills GD et al. BMJ 2005
Shefet D et al. Arch Intern Med 2005

36. Community Acquired Pneumonia
Pivotal studiesPivotal studies
Inclusion CriteriaInclusion Criteria
» Age ≥ 12 y.o. (US); ≥ 16 y.o. (SA)
» Clinical diagnosis of CAP
» Respiratory tract specimen, blood culture
Treatments(14 days):Treatments(14 days):
» CDTR-PI 200mg bid x 14 days
» CDTR-PI 400mg bid x 14 days
» comparatorscomparators: amoxi/clav 875/125 bid or
cefpodoxime proxetil 200 mg bid
n= 1653 patients
Fogarty et al. Clin Ther, 200. Van Zyl et al. Clin Ther, 2002

37. Community Acquired Pneumonia
Distribution according to Fine (blue)(blue) and
Clinical efficacy (red)(red)
Fine
CDTR
200 mg bid
CDTR
400 mg bid
Comparators
I
45%
(94%)
43%
(90%)
46%
(92%)
II
16%
(88%)
17%
(89%)
18%
(86%)
III
26%
(81%)
24%
(84%)
26%
(89%)
IV
14%
(78%)
15%
(80%)
10%
(83%)

38. Cefditoren pivoxil
INTERATIONSINTERATIONS
» It does not affect the pharmacokinetic of other drugs.
» It can be used with contraceptives
» I.v anti-H2 ↓ Cmax and AUC by 25%
» Interval > 2h after administration of antacids
POSOLOGY IN SPECIAL POPULATIONSPOSOLOGY IN SPECIAL POPULATIONS
» Renal insufficiency:
- Mild (CLCR > 50 mL/min): not adjustment
- Moderate (CLCR=30-50 mL/min): 200 mg/12h
- Severe (CLCR>30 mL/min): 200mg/24h
» Mild-moderate hepatic insufficiency (Child-Pugh A and B): not adjustment.
ADVERSE REACTIONS:ADVERSE REACTIONS:
» Similar to β-lactam antibiotics, mainly gastrointestinal according to SPC

39. Cefditoren pivoxil: conclusionsconclusions
• The most active oral cephalosporin against S. pneumoniae,
including resistant strains and H. influenzae with different
resistant phenotypes (BLNAR, BLPAR)
• Clinical trials results show the efficacy of CDTR
• Short course therapy in AECB
• Ideal for switch off therapy
• Good safety profile
• Favorable pharmacoeconomic analysis
• Wide post-marketing experience in other countries