title: Pharmacokinetic and pharmacodynamic assessment of co-amoxiclav in the treatment of melioidosis.
abstract: OBJECTIVE
  We conducted a prospective pharmacokinetic study of oral co-amoxiclav in patients with melioidosis to determine the optimal dosage and dosing interval in this potentially fatal infection.
  
  
  METHODS
  Serial plasma concentrations were measured after administration of two 1 g tablets of Augmentin (1750 mg of amoxicillin and 250 mg of clavulanate) to 14 adult patients with melioidosis. Monte Carlo simulation was used to predict the concentration of each drug following multiple doses of co-amoxiclav at different dosages and dose intervals. The proportion of the dose-interval above MIC (T > MIC) was calculated from 10,000 simulated subject plasma concentration profiles together with chequerboard MIC data from 46 clinical isolates and four reference strains of Burkholderia pseudomallei.
  
  
  RESULTS
  The median (range) observed maximum plasma concentrations of amoxicillin and clavulanate were 11.5 (3.3-40.2) mg/L and 5.1 (0.8-12.1) mg/L, respectively. The median (range) elimination half-lives were 94 (73-215) and 89 (57-140) min, respectively. Simulation indicated that co-amoxiclav 1750/250 mg given at 4, 6, 8 or 12 hourly dosing intervals would be associated with a T > MIC of < or = 50% in 0.7%, 2.8%, 8.6% and 33.2% of patients, respectively. Corresponding proportions for T > MIC of > or = 90% were 95.8%, 78.6%, 50.2% and 10.8%, respectively.
  
  
  CONCLUSIONS
  The dosing interval for co-amoxiclav (750/250 mg) in melioidosis should not be greater than 6 h.
authors.affiliation: Department of Clinical Tropical Medicine, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand. tmwcr@mahidol.ac.th
authors.forename: Wirongrong
authors.initials: W
authors.lastname: Chierakul
authors.forename: Jinda
authors.initials: J
authors.lastname: Wangboonskul
authors.forename: Thida
authors.initials: T
authors.lastname: Singtoroj
authors.forename: Wirichada
authors.initials: W
authors.lastname: Pongtavornpinyo
authors.forename: Jennifer M
authors.initials: JM
authors.lastname: Short
authors.forename: Bina
authors.initials: B
authors.lastname: Maharjan
authors.forename: Vanaporn
authors.initials: V
authors.lastname: Wuthiekanun
authors.forename: David A B
authors.initials: DA
authors.lastname: Dance
authors.forename: Prapit
authors.initials: P
authors.lastname: Teparrukkul
authors.forename: Niklas
authors.initials: N
authors.lastname: Lindegardh
authors.forename: Sharon J
authors.initials: SJ
authors.lastname: Peacock
authors.forename: Nicholas P
authors.initials: NP
authors.lastname: Day
authors.forename: Wipada
authors.initials: W
authors.lastname: Chaowagul
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: White
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000658:Amoxicillin / Q000097:blood; D019980:Amoxicillin-Potassium Clavulanate Combination / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use; D019818:Clavulanic Acid / Q000097:blood; D006801:Humans; D008554:Melioidosis / Q000188:drug therapy* / Q000382:microbiology; D008875:Middle Aged; D013997:Time Factors
chemical_list: D019818:Clavulanic Acid; D019980:Amoxicillin-Potassium Clavulanate Combination; D000658:Amoxicillin