title: In vitro pharmacodynamics of human-simulated exposures of ampicillin/sulbactam, doripenem and tigecycline alone and in combination against multidrug-resistant Acinetobacter baumannii.
abstract: OBJECTIVE
  Multidrug resistance is common among Acinetobacter baumannii, limiting the available options used to treat infections caused by this organism. The objective of this study was to compare monotherapy and combination therapy with ampicillin/sulbactam, doripenem and tigecycline against multidrug-resistant A. baumannii using an in vitro pharmacodynamic model.
  
  
  METHODS
  Human free-drug concentration profiles of clinically relevant ampicillin/sulbactam, doripenem and tigecycline were simulated alone and in two-drug combinations against four clinical A. baumannii isolates (MICs: ampicillin/sulbactam, 4/2-64/32 mg/L; doripenem, 16 to ≥64 mg/L; and tigecycline, 1-4 mg/L) over 24 h. Microbiological response was measured as log10 cfu/mL and the area under the bactericidal curve (AUBC).
  
  
  RESULTS
  Control strains grew to 7.11 ± 0.13 log10 cfu/mL. Except for ampicillin/sulbactam-containing regimens against the single ampicillin/sulbactam-susceptible isolate, all A. baumannii demonstrated regrowth to 24 h control levels against all mono and combination regimens. Using AUBC as an endpoint, the most active regimens were 9 g of ampicillin/sulbactam every 8 h (3 h infusion) + 2 g of doripenem every 8 h (4 h infusion; 87.8 ± 21.0), 9 g of ampicillin/sulbactam every 8 h (3 h infusion) + 200 mg of tigecycline every 12 h (30 min infusion; 100.6 ± 33.0) and 9 g of ampicillin/sulbactam every 8 h (3 h infusion) monotherapy (116.7 ± 31.6), followed by 3 g of ampicillin/sulbactam every 6 h (30 min infusion) + 200 mg of tigecycline every 12 h (30 min infusion; 134.0 ± 31.5) and 2 g of doripenem every 8 h (4 h infusion) + 200 mg of tigecycline every 12 h (30 min infusion; 142.7 ± 16.9).
  
  
  CONCLUSIONS
  Although specific combination regimens displayed additive activity at aggressive doses against these multidrug-resistant A. baumannii, none of the regimens could maintain cfu reductions against the more resistant isolates.
authors.affiliation: Center for Anti-Infective Research and Development, Hartford Hospital, Hartford, CT, USA.
authors.forename: Seth T
authors.initials: ST
authors.lastname: Housman
authors.forename: Mao
authors.initials: M
authors.lastname: Hagihara
authors.forename: David P
authors.initials: DP
authors.lastname: Nicolau
authors.forename: Joseph L
authors.initials: JL
authors.lastname: Kuti
mesh_terms: D000151:Acinetobacter Infections / Q000188:drug therapy; D040981:Acinetobacter baumannii / Q000187:drug effects*; D000667:Ampicillin / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D000900:Anti-Bacterial Agents / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D058491:Bacterial Load; D015780:Carbapenems / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D000077726:Doripenem; D004338:Drug Combinations; D024901:Drug Resistance, Multiple, Bacterial; D006801:Humans; D066298:In Vitro Techniques; D008911:Minocycline / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D008962:Models, Theoretical; D013407:Sulbactam / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D000078304:Tigecycline
chemical_list: D000900:Anti-Bacterial Agents; D015780:Carbapenems; D004338:Drug Combinations; C035444:sultamicillin; D000078304:Tigecycline; D000667:Ampicillin; D000077726:Doripenem; D008911:Minocycline; D013407:Sulbactam
keywords: antibiotics; in vitro modelling; pharmacokinetics; serum concentrations