Cefditoren pivoxil:a new antibiotic for the treatment of respiratory infections

Cefditoren pivoxil:a new antibiotic for the treatment of respiratory infections

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  Cefditoren pivoxil: a newantibiotic for the treatment of respiratory infections Jordi Roig (SPAIN) Scientific Committee of SEPAR N. Sra. Meritxell Hospital Pulmonary Division (Andorra)
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  The “ideal” antibiotic •High activity against potential causative pathogens • Adequate pharmacodynamic profile (good penetration in tissues) • Safe • Easy posology • Favorable cost/benefit ratio
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  Antibiotics in theRTI • ß-lactams: - Aminopenicilins: amoxicillin +/-clavulanate - Cephalosporins: cefuroxime, cefaclor, cefixime, cefotaxime, cefpodoxime • Macrolides: erythromycin, clarithromycin, azithromycin • Quinolones: levofloxacin, moxifloxacin • Ketolides: telithromycin
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  Cephalosporins profile Gen. OralParenteral 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
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  S. pneumoniae inEurope penicillin erythromycin The European Antimicrobial Resistance Surveillance System (EARSS) Annual Report 2005
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  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
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  H. influenzae resistanceto β-lactams Surveillance studies (Libra, Alexander Project) 35% 21% 9% 35% 15% 23% 10%
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  Considering the currentsituation: 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
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  Key points onmicrobial 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.
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  Cefditoren pivoxil: PROFILE Cefditorenpivoxil 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
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  Antibacterial activity • CDTRis 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)
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  In vitro antibacterialactivity 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
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  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
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  S. pneumoniae: evolutionof 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
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  CONCLUSIONS on bactericidalactivity  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)
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  • Cmax: 2.6µg/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*
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  Pharmacodynamics Percentage of thedose 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
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  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
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  Clinical development inRTI » 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)
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  Acute otitis media Clinicalstudy (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%
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  Acute sinusitis (I) Clinicalstudies 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.
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  Acute sinusitis (II) Pivotalstudies (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,
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  Acute pharyngotonsillitis (I) Pivotalstudies (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
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  Acute pharyngotonsillitis (II) CodeCountry 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)
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  Acute Exacerbation ofChronic 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
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  AECB clinical studies CODECOUNTRY 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
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  Evolution of signsand 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
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  Economical Evaluation ofCDTR 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
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  S.pneumoniae S.aureus Legionella PA H.influenzae Enterobac. CAPCAP: Etiology Angus DCet 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”.
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  46,2 10,1 8,8 8,27,6 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”.
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  Is S. pneumoniaethe 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
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  30,1% 21,4% 0% 5% 10% 15% 20% 25% 30% 35% COPD Non COPD Mortalityrate(%) p=0.05 n=176n=176n=252n=252
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  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)
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  Treatment failure inCAP / 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
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  Is coverage ofatypical 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
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  Community Acquired Pneumonia PivotalstudiesPivotal 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
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  Community Acquired Pneumonia Distributionaccording 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%)
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  Cefditoren pivoxil INTERATIONSINTERATIONS » Itdoes 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
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  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