Loracarbef concentrations in middle ear fluid

Abstract

Loracarbef concentrations in plasma and middle ear fluid (MEF) were measured in specimens obtained approximately 2 h after doses of 7.5 or 15 mg/kg. The mean + standard deviation concentrations in MEF were 2.0 + 2.6 mg/liter (48% of the concentration in plasma) after the smaller dose and 3.9 2.6 mg/liter (42% of the concentration in plasma) after the larger dose. With the larger dose, the concentrations in MEF were greater than the MIC for 90% of strains of the usual pathogens of acute otitis media tested in 16 of 17 specimens.Loracarbef (LY163892), a synthetic carbacephem antibiotic, has good in vitro activity against common respiratory pathogens (4). It is currently being tested in clinical trials for the treatment of acute otitis media and other respiratory infections. In this study, we assessed the penetration of loracarbef into middle ear fluid (MEF).Infants bacterial growth inhibition after 18 h of incubation were measured and read against a standard curve to calculate the concentration of drug. The lower limit of sensitivity of the assay was 0.25 mg/liter. The intra-assay variability of the standard curve was 3.4%, and the interassay variability was 2.1%. The concentrations at which variabilities were determined were 5.0, 3.0, 1.5, and 0.7 mg/liter.As controls, three specimens of MEF from children who were not receiving antibiotics were tested similarly and shown to cause no inhibition of the assay organism. In addition, a known quantity (4 mg/liter) of loracarbef was added to six similar MEF specimens; the assayed amounts ranged from 3.7 to 5.2 mg/liter.Twelve children taking the 7.5-mg/kg dose had a mean age of 32 months (range, 10 to 75 months). Nine were males and three were females. (Results from an additional child were discarded because the samples were grossly bloody.) Twenty MEF samples were obtained. Samples were obtained a mean of 135 min (range, 80 to 195 min) after the dose of loracarbef was given. The time between MEF sampling in cases of bilateral myringotomy was 6 min (range, 4 to 10 min). The time between plasma and MEF sampling was 9 min (range, 3 to 17 min). The mean ± standard deviation concentration of loracarbef in MEF was 2.0 ± 2.6 mg/liter (range, 0.2 to 5.6 mg/liter), and that in plasma was 4.2 ± 2.0 mg/liter (range, 1.4 to 6.8 mg/liter). The mean concentration in MEF was 48% of the mean concentration in plasma.The mean age of the 10 children taking the 15-mg/kg dose was 52 months (range, 21 to 82 months). Seven were males and three were females. (Results from an additional two patients were discarded because of grossly bloody samples in one and technical problems in the other.) Seventeen MEF samples were assayed. Samples were obtained a mean of 129 min (range, 60 to 165 min) after the dose of loracarbef was given. In cases of bilateral myringotomy, the time between sampling was 5 min (range, 3 to 8 min). The time between plasma and MEF sampling was 9 min (range, 5 to 15 min). The mean ± standard deviation concentration of loracarbef in MEF was 3.9 ± 2.6 mg/liter (range, 0.9 to 9....

Bactericidal titers of loracarbef (LY 163892) in serum and killing rates in volunteers receiving 400 versus 200 milligrams

“…However, oral absorption seemed to be variable among the volunteers, as indicated by the wide variation in peak concentrations in serum from one volunteer to another. A linearity between dose and concentration in serum was also reported in children who received 7.5 and 15 mg/kg of body weight (12,13 phradine. These antibiotics need to be administered three to four times daily (22).…”

“…Other species (Branhamella catarrhalis, Streptococcus anginosus, Staphylococcus aureus) were associated with lower bactericidal titers. Killing curves performed against 12 strains demonstrated that the bioactivity of loracarbef (measured by the reduction in the area under the control growth curve) was significantly correlated with the concentration/MIC ratio, whereas the initial rate of killing was not, once the concentration was greater than the MIC. Our results suggest that administration of 400 mg of loracarbef every 8 h might be associated with more favorable pharmacodynamic parameters against target bacteria.…”

Bactericidal activities of cefprozil, penicillin, cefaclor, cefixime, and loracarbef against penicillin-susceptible and -resistant Streptococcus pneumoniae in an in vitro pharmacodynamic infection model

“…Simulated pediatric dosage regimens and target peak concentrations in the central compartment were as follows: penicillin VK, 26 mg/kg of body weight every 6 h (q6h) and 14 g/ml; cefaclor, 13.4 mg/kg q8h and 16 g/ml; loracarbef, 15 mg/kg q12h and 19 g/ml; cefprozil, 15 mg/kg q12h and 11 g/ml; and cefixime, 8 mg/kg q24h and 4 g/ml (5,(7)(8)(9)14). Targeted half-lives of each agent were 1 h for penicillin, cefaclor, and loracarbef; 1.3 h for cefprozil; and 3.5 h for cefixime.…”

Pathogen Shifts and Changing Cure Rates for Otitis Media and Tonsillopharyngitis

“…Table 2 summarizes the penetration of antibiotics into middle ear fluids. [12][13][14][15][16][17][18][19][20][21][22] The important parameter is the ratio of middle ear fluid to serum, with higher ratios indicating enhanced penetration of the antibiotic into the middle ear fluid and, therefore, more capability of exerting an antibacterial effect. When this pharmacokinetic parameter is included with the pharmacodynamic modeling, one can rank antimicrobials for their relative activity against the 2 predominant pathogens of AOM.…”