The single-dose and steady-state pharmacokinetics of cefpodoxime were assessed in plasma and skin blister fluid (SBF) after oral dosing of 200 mg (n = 8) and 400 mg (n = 8) of cefpodoxime proxetil (doses are expressed as cefpodoxime equivalents) in healthy subjects in an open-label, parallel-design study. Skin blisters were formed by air suction on the midvolar forearm by a previously validated method. After single-dose administration, serial plasma and SBF samples were collected over 24 h for measurement of cefpodoxime by microbiological assays. After a 1-week washout, subjects received the same doses of antibiotic every 12 h for 5 days, with plasma and SBF sampling on day 5. After 200 mg of cefpodoxime proxetil, average peak concentrations (Cmax) in plasma and SBF were 2.18 +/- 0.52 and 1.55 +/- 0.59 micrograms/ml, respectively, after a single dose and 2.33 +/- 0.74 and 1.56 +/- 0.55 micrograms/ml, respectively, at steady state. After 400 mg of cefpodoxime proxetil, Cmax in plasma and SBF averaged 4.16 +/- 1.04 and 2.94 +/- 0.71 micrograms/ml, respectively, following a single dose and 4.10 +/- 0.95 and 2.84 +/- 0.88 micrograms/ml, respectively, at steady state. Cmax occurred 1.1 to 1.6 h later in SBF than in plasma. There was no accumulation of cefpodoxime in plasma or SBF when dosing was done every 12 h. Cefpodoxime blister fluid penetration was estimated to be 67 to 101%, consistent with the relatively low serum protein binding of the drug. Cefpodoxime levels exceeding the MIC for 90% of many skin pathogens, such as Streptococcus species (<1 microgram/ml) or Staphylococcus species (2 to 4 micrograms/ml), were achieved in plasma and SBF following the 200- and/or 400-mg dosing regimens.