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)

The “ideal” antibiotic

• High activity against potential causative pathogens

• Adequate pharmacodynamic profile (good penetration in tissues)

• Safe• Easy posology• Favorable cost/benefit ratio

Antibiotics in the RTI

• ß-lactams:- Aminopenicilins: amoxicillin +/-clavulanate- Cephalosporins: cefuroxime, cefaclor, cefixime,

cefotaxime, cefpodoxime• Macrolides: erythromycin, clarithromycin,

azithromycin• Quinolones: levofloxacin, moxifloxacin• Ketolides: telithromycin

Cephalosporins profile

Gen. Oral Parenteral1st 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

S. pneumoniae in Europe

penicillin erythromycin

The European Antimicrobial Resistance Surveillance System (EARSS) Annual Report 2005

Streptococcus pneumoniaeAntibiotic resistance (%) in Saudi Arabia

Peni resistantAuthor, year,

nº isolatesPeni

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

59 159,amoxy/clav;32 cefuroxime;

40 cepfrozil

Fouda SI,2004; 336

44,6 55 36 20 22 18 18 18

H. influenzae resistance to -lactams

Surveillance studies (Libra, Alexander Project)

35%

21%

9%

35%

15%

23%

10%

Considering the current situation:

1. S. peumoniae resistance*:

58% Cefixime 37% Azithromycin47% Cefaclor 35% Clarithromycin40% 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

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 ArnoldPub, London, 2006.

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 -lactam with the lowest MIC values against

bacterial respiratory pathogens

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. -lactamase (+)– Enterobacteriaceae

profile comparable to cefotaximeprofile comparable to cefotaximebut…..orally administeredbut…..orally administered

•cefpodoxime (2-3 times)•cefuroxime (4-8 times)•cefixime (16-32 times)

In vitro antibacterial activityThe ARISE* (Antimicrobial Resistant Isolates in Shouthern

Europe) project . Soriano et al. Int J. of Antimicrobial Agents 2004

CDTR is the oral -lactam with the highest intrinsic activity against the most prevalent bacterial respiratory pathogens

Activity of S. pneumoniae strains non-susceptible (NS) to common oral antibioticsn=600

cefditoren concentrations (g/mL)

0.06 0.12 0.25 0.5 1 2PEN-NS 8.2 15.0 35.6 97.4 99.7 100AMX-NS 0.5 1.9 20.1 97.6 100 100CFX-NS 0.3 4.0 25.8 97.0 99.7 100AZT-NS 41.5 47.6 62.8 98.5 100 100LVX-NS 67.4 73.9 80.4 97.8 100 100

Fenoll A. et al. Int J Antimicrob Agents, 2007

Cumulative percentage

S. pneumoniae: evolution of cefditoren MIC90 in Japan

0,5

0,780,390,39 0,5

0

11,5

2

1996 1998 2000 2002

35% of S. pneumoniae strains showed diminished susceptibility to penicillin

Chemotherapy, 44, 610-25, 1998 Chemotherapy, 51, 179-208, 2003Chemotherapy, 48, 585-609, 2000 Chemotherapy, 54, 330-54, 2006

CONCLUSIONS on bactericidal activity

Against Penicillin resistant S. pneumoniae (MICpeni= 2-4g/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)

• Cmax: 2.6 g/ml (200 mg), 4.1 g/ml (400 mg)• tmax: 2.5 h• t1/2: 1.5 h• AUC: 7.9 g.h/mL (200 mg), 14.6 g.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*

Pharmacodynamics

Percentage of the dose interval during plasma concentrations of CDTR exceed MIC.

Dose MIC90(g/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 9.2200mg 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 24.8400mg bid SD 0.3 1.3 3.9 8.9 11.6 10.8 9.3 7.9 7.7

Susceptibility of S. pneumoniae to cefditoren

MIC (g/ 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 g/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

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)

Acute otitis media

Clinical study (France) n= 295Inclusion 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/ CLAV8mg/ 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%

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.

Acute sinusitis (II)Pivotal studies (US) and EU study

Code Country CDTR-PI dose Comparator n200 mg bid, 10 days AMOX/CLAV400 mg bid, 10 days 875/125 mg bid 10 days

200 mg bid, 10 days AMOX/CLAV400 mg bid, 10 days 500/125 mg tid 10 days

CXM-AX250 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,

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

Acute pharyngotonsillitis (II)Code Country CDTR-PI dose Comparator n

CEF 97-008 US200 mg bid,

10 days(95% - 92%)

PEN-V250 mg qid, 10 days

(92% - 81%)503

CEF 97-010 US200 mg bid,

10 days(93% - 88%)

PEN-V250 mg qid, 10 days

(89% - 85%)508

ME 309 EU200 mg bid,

5 days(94% - 86%)

PEN-V400 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)

Acute Exacerbation of Chronic Bronchitis

Tissue penetration of cefditoren into bronchial Tissue penetration of cefditoren into bronchial mucosa and epithelial lining fluidmucosa and epithelial lining fluid

Concentration ratios

Collection Interval(h)

BronchialMucosa/Plasma

Epithelial LiningFluid/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 AntimicrobialsAgents and Chemotherapy; 2001Dec16-19; Chicago

AECB clinical studiesCODE COUNTRY TREATMENT COMPARATOR n

CDTR 200 bid10 days

CEF97-003 USCDTR 400 bid

10 days

CXM 250 bid10 days

537

CDTR 200 bid10 days

CEF97-005 USCDTR 400 bid

10 days

CLR 500 bid10 days

903

ME303 *(Pivotal)

EUCDTR 200 bid

5 daysCXM 250 bid

10 days568

* Inclusion criteria* Inclusion criteria» > 18 years old» Anthonisen I and II» FEV1<80% , FEV/FVC<65%

Kardos et al. Antimicrob Agents Chemother, 2006

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

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

S.pneumoniaeS.aureusLegionellaPAH.influenzaeEnterobac.

CAPCAP: Etiology

Angus DC et al . Am J Respir Crit Care Med 2002;166:717-723

““S.pneumoniae S.pneumoniae is the is the principal microorganism principal microorganism responsible of CAP”responsible of CAP”

““The etiologic pattern was The etiologic pattern was similar in both ICU and non-similar in both ICU and non-ICU patients”.ICU patients”.

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

ShockNo 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”.

Is S. pneumoniae the leading cause of pneumonia of unknown etiology?

Ruiz-Gonzalez A. A microbiologic study with lung Ruiz-Gonzalez A. A microbiologic study with lung aspirates in consecutive patients with CAP. Am J aspirates 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

30,1%

21,4%

0%

5%

10%

15%

20%

25%

30%

35%

COPD Non COPD

Mor

talit

y ra

te (%

) p=0.05

n=176n=176 n=252n=252

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)

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

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 2006Mills GD et al. BMJ 2005Shefet D et al. Arch Intern Med 2005

Community Acquired PneumoniaPivotal 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 patientsFogarty et al. Clin Ther, 200. Van Zyl et al. Clin Ther, 2002

Community Acquired Pneumonia

Distribution according to Fine (blue)(blue) andClinical efficacy (red)(red)

Fine CDTR200 mg bid

CDTR400 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%)

Cefditoren pivoxilINTERATIONSINTERATIONS» 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 -lactam antibiotics, mainly gastrointestinal according to SPC

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