title: Tissue penetration and antimicrobial activity of standard- and high-dose trimethoprim/sulfamethoxazole and linezolid in patients with diabetic foot infection.
abstract: OBJECTIVE
  The purpose of this study was to conduct a pharmacokinetic and pharmacodynamic evaluation of high (320/1600 mg) and standard (160/800 mg) doses of trimethoprim/sulfamethoxazole and linezolid in outpatients with mild diabetic foot infections (DFIs).
  
  
  METHODS
  Both viable skin/soft tissue from the infection site and serum were obtained at various times after antibiotic administration from 18 patients (6 per study group) being treated with linezolid, standard doses of trimethoprim/sulfamethoxazole or high doses of trimethoprim/sulfamethoxazole during a follow-up clinic visit. These samples were assayed for drug concentrations by liquid chromatography in tandem with mass spectrometry. Patient sera were also utilized in time-kill assays against two strains of Staphylococcus aureus and three strains of β-haemolytic streptococci.
  
  
  RESULTS
  The mean tissue/serum ratio for linezolid was 0.46 (range, 0.18-0.71). The mean tissue/serum ratio for trimethoprim was 1.2 (range, 0.3-4.5) for both standard and high doses, and 0.23 (range, 0.1-0.46) and 0.36 (range, 0.14-1.28) for standard and high doses of sulfamethoxazole, respectively. Linezolid exhibited inhibitory activity in time-kill assays against strains of S. aureus (0.45 ± 0.5 log10 cfu/mL) and β-haemolytic streptococci (2.2 ± 0.6 log10 cfu/mL), while trimethoprim/sulfamethoxazole exhibited bactericidal (>3 log kill) activity against all of these isolates. These findings were consistent for each sampling time and for high as well as standard doses of trimethoprim/sulfamethoxazole.
  
  
  CONCLUSIONS
  This pharmacokinetic/pharmacodynamic study found that trimethoprim/sulfamethoxazole exhibits good skin/soft tissue penetration in patients with DFIs as well as bactericidal activity in serum against strains of S. aureus and β-haemolytic streptococci.
authors.affiliation: Department of Medicine, Michigan State University, East Lansing, MI, USA.
authors.forename: Gary E
authors.initials: GE
authors.lastname: Stein
authors.forename: John K
authors.initials: JK
authors.lastname: Throckmorton
authors.forename: Amy E
authors.initials: AE
authors.lastname: Scharmen
authors.forename: William J
authors.initials: WJ
authors.lastname: Weiss
authors.forename: Laszlo
authors.initials: L
authors.lastname: Prokai
authors.forename: Curtis L
authors.initials: CL
authors.lastname: Smith
authors.forename: Daniel H
authors.initials: DH
authors.lastname: Havlichek
mesh_terms: D000081:Acetamides / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology; D000368:Aged; D000369:Aged, 80 and over; D000900:Anti-Bacterial Agents / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology; D001424:Bacterial Infections / Q000188:drug therapy*; D002853:Chromatography, Liquid; D017719:Diabetic Foot / Q000150:complications*; D005260:Female; D006801:Humans; D000069349:Linezolid; D008297:Male; D008875:Middle Aged; D010045:Outpatients; D023303:Oxazolidinones / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology; D044967:Serum / Q000737:chemistry; D012867:Skin / Q000737:chemistry; D013211:Staphylococcus aureus / Q000187:drug effects; D013291:Streptococcus / Q000187:drug effects; D053719:Tandem Mass Spectrometry; D013997:Time Factors; D015662:Trimethoprim, Sulfamethoxazole Drug Combination / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology
chemical_list: D000081:Acetamides; D000900:Anti-Bacterial Agents; D023303:Oxazolidinones; D015662:Trimethoprim, Sulfamethoxazole Drug Combination; D000069349:Linezolid
keywords: diabetes; pharmacokinetics; time–kill