title: Comparative bacteriological efficacy of pharmacokinetically enhanced amoxicillin-clavulanate against Streptococcus pneumoniae with elevated amoxicillin MICs and Haemophilus influenzae.
abstract: A new pharmacokinetically enhanced formulation of amoxicillin-clavulanate (2,000 mg of amoxicillin/125 mg of clavulanate twice a day; ratio 16:1) has been designed, with sustained-release technology, to allow coverage of bacterial strains with amoxicillin-clavulanic acid MICs of at least 4/2 mug/ml. The bacteriological efficacy of amoxicillin-clavulanate, 2,000/125 mg twice a day, ratio 16:1, was compared in a rat model of respiratory tract infection versus four other amoxicillin-clavulanate formulations: 8:1 three times a day (1,000/125 mg), 7:1 three times a day (875/125 mg), 7:1 twice a day (875/125 mg), and 4:1 three times a day (500/125 mg); levofloxacin (500 mg once a day); and azithromycin (1,000 mg on day 1 followed thereafter by 500 mg once a day). Bacterial strains included Streptococcus pneumoniae, with amoxicillin-clavulanic acid MICs of 2/1 (one strain), 4/2, or 8/4 microg/ml (three strains each), and Haemophilus influenzae, one beta-lactamase-positive strain and one beta-lactamase-negative, ampicillin-resistant strain. Animals were infected by intrabronchial instillation. Antibacterial treatment commenced 24 h postinfection, with doses delivered by computer-controlled intravenous infusion to approximate the concentrations achieved in human plasma following oral administration. Plasma concentrations in the rat corresponded closely with target human concentrations for all antimicrobials tested. Amoxicillin-clavulanate, 2,000/125 mg twice a day, ratio 16:1, was effective against all S. pneumoniae strains tested, including those with amoxicillin-clavulanic acid MICs of up to 8/4 microg/ml and against beta-lactamase-producing and beta-lactamase-negative ampicillin-resistant H. influenzae. These results demonstrate the bacteriological efficacy of pharmacokinetically enhanced amoxicillin-clavulanate 2,000/125 mg twice a day (ratio 16:1) against S. pneumoniae with amoxicillin-clavulanic acid MICs of at least 4/2 microg/ml and support clavulanate 125 mg twice a day as sufficient to protect against beta-lactamase in this rat model.
authors.affiliation: GlaxoSmithKline, Collegeville, PA, USA.
authors.forename: Valerie
authors.initials: V
authors.lastname: Berry
authors.forename: Jennifer
authors.initials: J
authors.lastname: Hoover
authors.forename: Christine
authors.initials: C
authors.lastname: Singley
authors.forename: Gary
authors.initials: G
authors.lastname: Woodnutt
mesh_terms: D000658:Amoxicillin / Q000493:pharmacokinetics / Q000494:pharmacology; D019980:Amoxicillin-Potassium Clavulanate Combination / Q000494:pharmacology*; D000818:Animals; D017963:Azithromycin / Q000494:pharmacology; D019818:Clavulanic Acid / Q000493:pharmacokinetics / Q000494:pharmacology; D006193:Haemophilus influenzae / Q000187:drug effects*; D006801:Humans; D064704:Levofloxacin; D008826:Microbial Sensitivity Tests; D015242:Ofloxacin / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013296:Streptococcus pneumoniae / Q000187:drug effects*
chemical_list: D019818:Clavulanic Acid; D064704:Levofloxacin; D019980:Amoxicillin-Potassium Clavulanate Combination; D000658:Amoxicillin; D017963:Azithromycin; D015242:Ofloxacin
references.citation: J Antimicrob Chemother. 2000 Apr;45 Suppl 1:79-85
references.pmid: 10824037
references.citation: Antimicrob Agents Chemother. 1999 Jan;43(1):35-40
references.pmid: 9869562
references.citation: Clin Ther. 2001 Apr;23(4):578-84
references.pmid: 11354391
references.citation: Ann Pharmacother. 2001 Jun;35(6):687-90
references.pmid: 11408985
references.citation: Antimicrob Agents Chemother. 2001 Sep;45(9):2585-93
references.pmid: 11502533
references.citation: N Engl J Med. 2002 Mar 7;346(10):747-50
references.pmid: 11882730
references.citation: Pharmacotherapy. 2002 Mar;22(3):395-9
references.pmid: 11898897
references.citation: Clin Infect Dis. 2002 Sep 1;35(5):556-64
references.pmid: 12173129
references.citation: Antimicrob Agents Chemother. 2003 Mar;47(3):1017-22
references.pmid: 12604536
references.citation: Int J Infect Dis. 2003 Mar;7 Suppl 1:S13-20
references.pmid: 12839703
references.citation: J Antimicrob Chemother. 2003 Aug;52(2):229-46
references.pmid: 12865398
references.citation: Clin Microbiol Infect. 2003 Jul;9(7):590-9
references.pmid: 12925097
references.citation: Diagn Microbiol Infect Dis. 2003 Sep;47(1):373-6
references.pmid: 12967753
references.citation: South Med J. 2003 Oct;96(10):974-85
references.pmid: 14570341
references.citation: J Antimicrob Chemother. 2004 Jan;53 Suppl 1:i3-20
references.pmid: 14726431
references.citation: Clin Microbiol Infect. 2004 Apr;10 Suppl 2:6-11
references.pmid: 14759228
references.citation: J Antimicrob Chemother. 1990 Jan;25 Suppl A:73-82
references.pmid: 2154441
references.citation: J Antimicrob Chemother. 1990 Sep;26(3):371-80
references.pmid: 2121699
references.citation: Antimicrob Agents Chemother. 1997 Oct;41(10):2256-60
references.pmid: 9333057
references.citation: Clin Infect Dis. 1998 Jan;26(1):1-10; quiz 11-2
references.pmid: 9455502
references.citation: Antimicrob Agents Chemother. 1998 Sep;42(9):2385-90
references.pmid: 9736568
references.citation: Antimicrob Agents Chemother. 1998 Dec;42(12):3193-9
references.pmid: 9835514
references.citation: Antimicrob Agents Chemother. 1999 Jan;43(1):29-34
references.pmid: 9869561
references.citation: J Antimicrob Chemother. 2000 Jul;46 Suppl T1:25-31
references.pmid: 10997596