PENETRATION OF CEFTRIAXONE INTO THE MIDDLE EAR FLUID OF CHILDREN

Abstract

Ceftriaxone is a broad spectrum parenteral cephalosporin antibiotic with potent in vitro activity against a wide variety of Gram-positive and Gram-negative bacteria, including those most commonly causing otitis media.1 Ceftriaxone is rapidly and completely absorbed after intramuscular administration, with the peak plasma concentration occurring between 2 and 3 h after dosing. The plasma half-life of ceftriaxone in infants and young children is ∼6.5 h.2 When antibiotic treatment is indicated for acute otitis media (AOM) oral amoxicillin has been recommended as the first choice.3 A single 50-mg/kg intramuscular dose of ceftriaxone has been reported to be as effective clinically as 7 to 10 days of oral antibiotics for the treatment of otitis media.4-9 Fraschini et al.10 studied the pharmacokinetics and distribution of ceftriaxone in the middle ear mucosa in adults after an intramuscular injection of 1 g. They demonstrated that the concentration peaked at 3 h at 6.0 μg/ml, and the concentration exceeded the MIC at 24 h for the most common bacterial pathogens causing AOM. The penetration of ceftriaxone into the middle ear fluid (MEF) in children is not known. This information is important for understanding and predicting the clinical and bacteriologic efficacy of ceftriaxone in the treatment of otitis media. The aim of this study was to evaluate the penetration of ceftriaxone into the MEF in children after a single 50-mg/kg intramuscular dose of ceftriaxone. Methods.Study design. This was an open label, noncomparative randomized pharmacokinetic study. Ceftriaxone sodium (Hoffmann-La Roche), as a sterile powder, was dissolved with 3.5 ml of 1% lidocaine to produce a final solution with a total volume of 4 ml and a ceftriaxone concentration of 50 mg/0.2 ml. The child being treated received 0.2 ml/kg (50 mg/kg) as a single intramuscular injection. Any side effect possibly related to the administration of the antibiotic was recorded for each child. The study was approved by the Ethical Committee of the National University Hospital (Landspitalinn) of Iceland, the Scientific Ethical Committee of the Icelandic Medical Association, the State Committee on Pharmaceuticals, the Ethical Committee of the Reykjavik City Hospital and the State Department of Health. All children enrolled in the study had documented chronic middle ear effusion for at least 3 months requiring insertion of tympanostomy tubes. None of the children were receiving a concomitant medication at the time preceding administration of ceftriaxone. After written informed consent was obtained from a parent, a baseline blood sample was obtained and the child was randomly assigned to one of six groups, based on the time intervals between the administration of ceftriaxone to MEF and blood sampling. Group 1 had samples obtained 1 to <3 h after the administration of ceftriaxone, Group 2 at 3 to <5 h, Group 3 at 5 to 8 h, Group 4 at 10 to 16 h, Group 5 at 24 to 30 h and Group 6 at 48 to 52 h. The study was designed to include at least 48 children, 8 in each group. All children underwent general anesthesia (i.e. oxygen, nitrous oxide and fluothane) applied with a mask to the oropharyngeal airway. An otomicroscope was used to inspect the ear, and myringotomy was performed in the anteroinferior quadrant of the tympanic membrane. One MEF sample was obtained from each child (minimum, 0.3 ml) into a 1-ml tuberculin syringe connected to a suction pump immediately before the insertion of the tympanostomy tubes. To obtain enough MEF for analysis, fluid from one or both ears was collected in one syringe at the same time as the blood sampling. The syringe with the MEF was then frozen immediately at −20°C until analyzed. Based on the findings at the myringotomy, the effusions were classified as serous (clear/yellow liquid with low viscosity), mucoid (thick and gray liquid) or purulent (thick yellow pus). No MEF sample was grossly contaminated with blood. Blood samples were obtained by venipuncture or through an indwelling catheter into Vacutainer® tubes containing potassium oxalate-sodium fluoride as the anticoagulant. After collection, blood samples were immediately centrifuged for 15 min at 2500 rpm at 10°C, and the plasma samples were frozen at −20°C until analyzed. The plasma and MEF samples were analyzed at Medi-Lab A/S, Copenhagen, Denmark, by high performance liquid chromatographic assay.11 Ceftriaxone (free and bound) was extracted by combining 50 μl of MEF or plasma with 50 μl of acetonitrile containing the internal standard (cefazolin) and mixing by vortexing for 30 s. After centrifugation at 13 000 × g for 3 min at room temperature, a 10-μl aliquot of the supernatant was injected into a reverse phase high performance liquid chromatography system with ultraviolet light detection at 274 nm. The results were cross-validated against eight reference samples containing ceftriaxone. The assay could detect concentrations as low as 5 μg/ml. Data analysis. Since only one blood sample with a corresponding MEF sample was obtained from each child, mean concentration in each group was used to calculate the pharmacokinetic indices. The plasma and MEF concentration <5 μg/ml (i.e. lower limit of the assay) was assigned a value of 2.5 μg/ml for calculations. The ratio of MEF concentration to plasma concentration was calculated for each child with ceftriaxone concentrations of >5 μg/ml in plasma and MEF. The peak concentration (Cmax) and time to reach the peak concentration (Tmax) were recorded for plasma and MEF. The area under the plasma and MEF concentration time curves from time 1.5 to 47.9 h (AUC1.5→47.9) was calculated according to the trapezoidal rule. The apparent half-life of elimination of ceftriaxone (t1/2) was estimated by linear regression of the log-transformed data of the individual plasma concentration values of ceftriaxone in the apparent log linear phase of elimination. An estimate of half-life elimination from MEF was based on the mean ceftriaxone concentration in MEF in the sampling time intervals between 24 and 30 h and between 48 and 52 h. Results. Forty-eight children (6 groups each consisting of 8 children) were enrolled into the study. There were 25 boys and 23 girls. Their mean age was 37.8 months (range, 12 to 91 months). No adverse events were reported during the study period. Plasma concentrations were evaluated for 46 children and concentrations in MEF for 42. The plasma concentration in Child 17 was 2.5-fold higher than the standard deviation in that group. It was therefore considered to be an outlier and not included in the analysis. One child (Child 36) dropped out because of parental refusal of myringotomy. Five children (Children 9, 26, 29, 37 and 42) did not have enough MEF for analysis. All but 4 MEF specimens were classified as mucoid. The mean concentrations of ceftriaxone in plasma and MEF are presented in Table 1. After intramuscular administration plasma concentration peaked at 1.5 h (171 μg/ml) and then declined with an estimated half-life of ∼6 h. The concentration of ceftriaxone in MEF increased more slowly and persisted longer than plasma concentration. The concentration of ceftriaxone peaked in the MEF at 24.3 h (35 μg/ml), indicating a slow penetration of ceftriaxone into MEF. This also indicates a slow elimination of ceftriaxone from the MEF, with an estimated half-life of 25 h. The ratio of AUC1.5→47.9 for MEF to plasma was 0.59, indicating good penetration of ceftriaxone into the MEF. Assuming that MEF ceftriaxone concentration continued to decline with a half-life of 25 h, the predicted mean ceftriaxone concentrations in MEF at 72, 96, 120 and 144 h after a single 50-mg/kg intramuscular dose of ceftriaxone are 9.5, 4.8, 2.4 and 1.6 μg/ml, respectively.TABLE 1: Mean concentration of ceftriaxone in MEF and plasma (μg/ml) at various time intervals (hours) after a single 50-mg/kg intramuscular dose of ceftriaxone Discussion. The evaluation of antibiotic therapy for otitis media is difficult, because of the high rate of spontaneous cure.12, 13 Knowing the pharmacokinetics of antibiotics in the MEF is helpful in predicting antibacterial efficacy.14, 15 The pharmacokinetics of many antibiotics in MEF has been reported15 but is not known for ceftriaxone. Our results therefore add to the understanding of the possible role of ceftriaxone in the treatment of otitis media. The AUC ratio of MEF to plasma concentrations of ceftriaxone in our study indicates that ∼59% of ceftriaxone in plasma penetrates into the MEF after a single intramuscular dose of 50 mg/kg. Because of the young age of the children, it was difficult to collect many plasma and MEF samples from each child. Because plasma and MEF samples were randomly assigned, the Tmax and Cmax are estimates. However, the pharmacokinetic indices for ceftriaxone in plasma in our study were similar to that previously reported in other studies.2 The half-life of ceftriaxone in MEF was estimated to be ∼25 h. Because the majority of the MEF samples in our study were mucoid, the results may not represent the pharmacokinetics of ceftriaxone in the MEF of AOM. Studies have shown a higher concentration of antibiotics in the MEF of children with AOM than in those with chronic effusion.16 The ratio of antibiotic concentration in MEF:MIC and the time the concentration stays above MIC appear to predict bacteriologic efficacy of beta-lactams in the treatment of otitis media.15 Our results show that the Cmax of ceftriaxone in MEF is 35 to 580 times higher than the MIC90 for the three major causative pathogens of otitis media, including penicillin-resistant pneumococci. Furthermore the time in which the concentration of ceftriaxone is above MIC90 is between 100 and >200 h. These results predict good bacteriologic efficacy of a single 50-mg/kg intramuscular dose of ceftriaxone in the treatment of otitis media, including that caused by penicillin-resistant pneumococci. Clinical studies show that a single intramuscular dose of ceftriaxone compared favorably with the traditional oral course of various antibiotics for the treatment of AOM,4-9 supporting the pharmacokinetic prediction. Additionally a single 50-mg/kg intramuscular dose of ceftriaxone has shown a bacteriologic efficacy of 82% in the treatment of otitis media caused by penicillin-resistant pneumococci.17 The bacteriologic failures may be the result of inadequate penetration of ceftriaxone into the MEF, supported by the individual variation of penetration seen in our study. A single 50-mg/kg intramuscular dose of ceftriaxone may be a reasonable choice when an antibiotic is indicated in the treatment of complicated otitis media, including that caused by penicillin-resistant but ceftriaxone-susceptible pneumococci. Acknowledgment. This work was funded by Roche Laboratories Inc. Thorolfur Gudnason, M.D. Fridrik Gudbrandsson, M.D. Franco Barsanti, Pharm.D. Karl G. Kristinsson, M.D., Ph.D. Department of Pediatrics and Microbiology; National University Hospital; (Landspitalinn) of Iceland Department of Otolaryngology; Reykjavik City Hospital Reykjavik, Iceland Roche Laboratories Inc.; Nutley, NJ