June 2015 THE JAPANESE JOURNAL OF ANTIBIOTICS 68 3 189 49 1 : 14 1 2 2 3 1 2 3 2015 4 3 1 : 14 CVA/AMPC 1 : 14 27 CVA/AMPC 1 : 14 88.5% Streptococcus pneumoniae, Haemophilus influenzae, Moraxella catarrhalis β- BLNAR β- BLPAR β- / BLPACR 80% CVA/AMPC 1 : 14 MIC BLNAR BLPAR BLPACR 1 4 μg/ml 19% 5/27 CVA/AMPC 1 : 14 M. catarrhalis β- I. 1
190 50 THE JAPANESE JOURNAL OF ANTIBIOTICS 68 3 June 2015 Streptococcus pneumoniae, Haemophilus influenzae, Moraxella catarrhalis 5 3 90% 2 S. pneumoniae M. catarrhalis, H. influenzae M. catarrhalis 3 S. pneumoniae Penicillin intermediately resistant S. pneumoniae: PISP S. pneumoniae Penicillin resistant S. pneumoniae: PRSP M. catarrhalis BRO β - β- H. influenzae CVA/AMPC 1 : 14 β- CVA AMPC 1 : 14 CVA AMPC AMPC β- Staphylococcus H. influenzae, M. catarrhalis, Klebsiella Proteus β- PRSP CVA AMPC 4 β- CVA/AMPC 1 : 14 S. pneumoniae, M. catarrhalis, H. influenzae 2012 3 CVA/AMPC 5 2010 CVA/AMPC 1, 6 3 15 CVA/ AMPC 1 : 14 CVA/AMPC 1 : 14 II. 3 good clinical practice GCP ClinicalTrials. gov ID: NCT01934231 1. 2013 8 11 2010 1 3 15 6 kg 40 kg 27 12 12
June 2015 THE JAPANESE JOURNAL OF ANTIBIOTICS 68 3 191 51 2. CVA/AMPC 1 : 14 7 7 14 Day 1 Day 4 Day 8 Day 15 4 CVA 6.4 mg / kg/ AMPC 90 mg /kg/ CVA/AMPC 1 : 14 1 6 kg 11 kg 1.01 g 11 kg 17 kg 2.02 g 17 kg 24 kg 3.03 g 24 kg 31 kg 4.04 g 31 kg 37 kg 5.05 g 37 kg 40 kg 6.06 g 1 2 12 CVA/AMPC 7 7 3. 1 2 2010 1 3 3, 2, 1, FEW, NEG 4 S. pneumoniae, H. influenzae, M. catarrhalis, Staphylococcus aureus, Streptococcus pyogenes CVA/AMPC 1 : 14, AMPC, cefditoren CDTR, cefcapene CFPN, clarithromycin CAM 5 S. pneumoniae, H. influenzae, S. aureus benzylpenicillin PCG, ampicillin ABPC, oxacillin MPIPC
192 52 THE JAPANESE JOURNAL OF ANTIBIOTICS 68 3 June 2015 Clinical and Laboratory Standards Institute CLSI 7 a. S. pneumoniae PCG Minimum Inhibitory Concentration MIC MIC 2 μg/ml Penicillin susceptible S. pneumoniae: PSSP MIC 4 μg/ml PISP MIC 8 μg/ml PRSP b. H. influenzae ABPC MIC β- MIC 2 μg/ml β- β-lactamase non-producing ABPC susceptible strain: BLNAS MIC 4 μg/ml β- β-lactamase nonproducing ABPC resistant strain: BLNAR β - β-lactamase producing ABPC resistant strain: BLPAR c. S. aureus MPIPC MIC MIC 2 μg/ml methicillin susceptible S. aureus: MSSA MIC 4 μg/ml methicillin resistant S. aureus: MRSA 4. CVA/AMPC 1 : 14 5. CVA/ AMPC 1 : 14 6. 1 Full Analysis Set FAS FAS 3 80 100% Per Protocol Set PPS PPS Bacteriology PPS 1 Safety Population SP MIC ICH MedDRA Version 16.1 SOC PT % SP
June 2015 THE JAPANESE JOURNAL OF ANTIBIOTICS 68 3 193 53 III. β-lactamase producing AMPC/CVA resistant strain: BLPACR M. catarrhalis β- S. aureus MSSA 1 1. CVA/ AMPC 1 : 14 27 FAS SP PPS 3 1 26 Bacteriology PPS 2 24 PPS 6.5 1 12 23.07 kg 11.0 36.5 kg 58% 14/24 2 13% 3/24 3 29% 7/24 3 39 S. pneumoniae 9 23% H. influenzae 14 36% M. catarrhalis 6 15% S. aureus 5 13% S. pneumoniae 9 8 89% PSSP 1 11% PISP PRSP H. influenzae 14 10 71% BLNAS 3 21% BLNAR 1 7% BLPAR BLPAR 1 CVA/AMPC MIC 8 μg/ml β- / 2. 1 96.2% 25/26 2 88.5% 23/26 2 1 PSSP, BLNAS, M. catarrhalis 3 1. 2. PPS
194 54 THE JAPANESE JOURNAL OF ANTIBIOTICS 68 3 June 2015 2 1 M. catarrhalis 1 PSSP, BLPAR, M. catarrhalis 3 BLPAR 2 92% 24/26 77% 20/26 96% 25/26 4 91% 20/22 3 77% 54% 58% 81% 92% 69% 78% 92% 3 S. pneumoniae 88.9% 8/9 M. catarrhalis 6/6 AMPC β- 100% H. influenzae BLNAS 80% 8/10 BLNAR 3 BLPAR 1 4 CVA/AMPC BLPAR 1 CVA/AMPC MIC 8 μg/ml H. influenzae BLPACR 8 4 MIC CVA/AMPC 1 : 14 MIC PSSP 8 0.06 2 μg/ml 3. PPS
June 2015 THE JAPANESE JOURNAL OF ANTIBIOTICS 68 3 195 55 4. Bacteriology PPS PISP 1 2 μg/ml BLNAS 10 0.5 2 μg/ml β- M. catarrhalis 6 0.06 0.25 μg/ml MSSA 9 0.12 2 μg/ml BLNAR 3 MIC 2 8 μg/ml BLPACR 1 MIC 8 μg/ml AMPC β- M. catarrhalis 6 MIC 0.12 2 μg/ml 5 3. 41% 11/27 19% 5/27 6 1 5 4. PPS 26.9% 7/26 38.5% 10/26 65.4% 17/26 80 100% IV. 3 15
196 56 THE JAPANESE JOURNAL OF ANTIBIOTICS 68 3 June 2015 5. MIC Bacteriology PPS
June 2015 THE JAPANESE JOURNAL OF ANTIBIOTICS 68 3 197 57 6. 27 CVA/AMPC 1 : 14 9 6.5 0 5 S. pneumoniae 33.3% H. influenzae 33.3% M. catarrhalis 20.8% 6 19 S. pneumoniae 7.7% H. influenzae 15.4% M. catarrhalis 7.7% 3 2 S. pneumoniae 23% H. influenzae 36% M. catarrhalis 15% 88.5% 96.2% CVA/AMPC 1 : 14 94% 10 CVA/AMPC 1 : 14 2 CVA/AMPC 1 : 14
198 58 THE JAPANESE JOURNAL OF ANTIBIOTICS 68 3 June 2015 CVA/AMPC 1 : 14 3 4 7 Time above MIC T MIC % 40% 11 T MIC % CVA/AMPC 1 : 14 12 AMPC MIC 4 μg/ml T MIC 46% CVA/ AMPC 1 : 14 MIC 4 μg/ml 10 CVA/ AMPC 1 : 14 80% MIC range S. pneumoniae PSSP 87.5%: 0.06 2 μg/ml PISP 100%: 2 μg/ml CVA/AMPC 1 : 14 H. influenzae BLNAS 80.0%: 0.5 2 μg/ml β- M. catarrhalis 100%: 0.06 0.25 μg/ml S. aureus MSSA 100%: 0.12 2 μg/ml MIC 4 μg/ml AMPC β- M. catarrhalis AMPC MIC 0.12 2 μg/ml CVA/AMPC 1 : 14 MIC AMPC β- β- S. pneumoniae M. catarrhalis M. catarrhalis β- 12 M. catarrhalis S. pneumoniae M. catarrhalis β- CVA/AMPC 1 : 14 13 β- M. catarrhalis CVA/ AMPC 1 : 14 100% MIC M. catarrhalis CVA/AMPC 1 : 14 β- MIC CVA/ AMPC 1 : 14 MIC 14 MIC 8 μg/ml 2 BLNAR 1 BLPAR BLPACR 1 HOSHINO H. influenzae BLPACR 2007 1.6%, 2010 4.8% 8 CVA/AMPC 1 : 14 BLPACR 9 CVA/AMPC 1 : 14 CVA/AMPC 1 : 14 β-
June 2015 THE JAPANESE JOURNAL OF ANTIBIOTICS 68 3 199 59 3 50 1 2010 49: 143 198, 2010 2 4 26: 15 26, 2008 3 clavulanic acid/amoxicillin Jpn. J. Antibiotics 52: 613 627, 1999 4 BROOK, I.; P. A. FOOTE & J. N. HAUSFELD: Eradication of pathogens from the nasopharynx after therapy of acute maxillary sinusitis with low- or high-dose amoxicillin/clavulanic acid. Int. J. Antimicrob. Agents 26: 416 419, 2005 5 CHOW, A. W.; M. S. BENNINGER, I. BROOK, et al.: ISDA clinical practice guideline for acute bacterial rhinosinusitis in children and adults. Clin. Infect. Dis. 54: e72 e112, 2012 6 2010 53: 103 160, 2014 7 Clinical and Laboratory Standards Institute. Performance standards for antimicrobial susceptibility testing; twenty-third informational supplement. 2013 8 HOSHINO, T.; Y. SATO, Y. TOYONAGA, et al.: Nationwide survey of the development of drug resistance in the pediatric field in 2007 and 2010: drug sensitivity of Haemophilus influenzae in Japan second report J. Infect. Chemother. 19: 495 503, 2013 9 2007 10 54: 1056 1072, 2005 11 CRAIG, W. A. & D. ANDES: Pharmacokinetics and pharmacodynamics of antibiotics in otitis media. Pediatr. Infect. Dis. J. 15: 255 259, 1996 12 42: 119 141, 2012 13 MB ENT 142: 9 17, 2012 14 Clavulanic acid/amoxicillin 1 : 14 Jpn. J. Antibiotics 66: 141 158, 2013
200 60 THE JAPANESE JOURNAL OF ANTIBIOTICS 68 3 June 2015 Efficacy and safety of clavulanic acid/amoxicillin 1 : 14 dry syrup in the treatment of children with acute bacterial rhinosinusitis RINYA SUGITA 1, SHUICHI YAMAMOTO 2, HIDEKATSU MOTOYAMA 2 and MASAO YARITA 3 1 Sugita ENT Clinic 2 Medicines Development, Japan Development & Medical Affairs Division, GlaxoSmithKline K.K. 3 Clinical Platforms & Sciences, Japan Development & Medical Affairs Division, GlaxoSmithKline K.K. To demonstrate clinical value of clavulanic acid/amoxicillin CVA/AMPC 1 : 14 combination dry syrup for acute bacterial rhinosinusitis ABRS, the efficacy and safety were evaluated in a multicenter, open-label, uncontrolled study in 27 children with ABRS. The proportion of subjects who were cured at the test of cure as the primary endpoint was 88.5%. In subjects with a major pathogenic bacteria at baseline i.e., Streptococcus pneumoniae, Haemophilus influenzae and Moraxella catarrhalis bacterial eradication was achieved in 80% of the subjects with the exception of β-lactamase non-producing ampicillin resistant H. influenzae: BLNAR and β-lactamase producing ampicillin resistant H. influenzae: BLPAR β-lactamase producing amoxicillin/clavulanic acid resistant H. influenzae: BLPACR. The MIC of CVA/AMPC 1 : 14 was not higher than 4 μg/ml for all pathogens except one strain each of BLNAR and BLPAR BLPACR. Drug-related adverse events were reported in 19% of patients 5/27 patients. All of the reported drug-related adverse events were classified as gastrointestinal disorders that have been commonly reported with antibacterial drugs. These results indicate that CVA/AMPC 1 : 14 was clinically useful for the treatment of ABRS and is also suggested that was effective especially for the treatment of ABRS in children caused by beta-lactamase-producing bacteria including M. catarrhalis.