Ceftriaxone Levels Research Articles

Passage of cefotaxime and ceftriaxone into cerebrospinal fluid of patients with uninflamed meninges

Cefotaxime and ceftriaxone have proven to be effective in pyogenic infections of the central nervous system. Since in some bacterial central nervous system infections the blood-cerebrospinal fluid (CSF) barrier is either minimally impaired or recovers in the course of the illness, we studied the penetration of both antibiotics in the absence of inflamed meninges. Patients who had undergone external ventriculostomies for noninflammatory occlusive hydrocephalus received either cefotaxime (2 g/30 min) or ceftriaxone (2 g/30 min) to treat extracerebral infections. Serum and CSF were drawn repeatedly after the first dose. With ceftriaxone, they were also drawn after the last dose. The concentrations of cefotaxime, its metabolite desacetylcefotaxime, and ceftriaxone were determined by high-performance liquid chromatography with UV detection. Maximum concentrations of cefotaxime in CSF were reached 0.5 to 8 h (median = 3 h; n = 6) after the end of the infusion and ranged from 0.14 to 1.81 mg/liter (median = 0.44 mg/liter; n = 6). Maximum levels of ceftriaxone in CSF ranging from 0.18 to 1.04 mg/liter (median = 0.43 mg/liter; n = 5) were seen 1 to 16 h (median = 12 h; n = 5) after the infusion. The elimination half-life of cefotaxime in CSF was 5.0 to 26.9 h (median = 9.3 h; n = 5), and that of ceftriaxone was 15.7 to 18.4 h (median = 16.8 h; n = 3). It is concluded that after a single dose of 2 g, maximal concentrations of cefotaxime and ceftriaxone in CSF do not differ substantially. The long elimination half-lives guarantee uniform concentrations in CSF. These concentrations reliably inhibit highly susceptible bacteria but cannot be relied on to inhibit staphylococci and penicillin G-resistant Streptococcus pneumoniae.

Influence of therapeutic plasmapheresis on elimination of ceftiaxone

To study the plasma elimination rate of ceftriaxone given to patients undergoing plasmapheresis, a single 2-g intravenous dose of ceftriaxone was given to 11 patients who underwent plasmapheresis 3 h (early group) or 15 h (late group) later. Even though the early patient group had twofold more ceftriaxone removed than the late group, all individual patients had 24-h ceftriaxone levels of 9 micrograms/ml or higher. We conclude that patients undergoing plasmapheresis lasting 150 min or less may safely be treated with 2 g of ceftriaxone once daily without risking periods of subtherapeutic plasma ceftriaxone levels.

Maternal and fetal serum and tissue levels of ceftriaxone following preoperative prophylaxis in emergency cesarean section.

The use of antibiotic prophylaxis in emergency cesarean section has become the standard of care. Concern over fetal exposure has been the reason that antibiotics are traditionally given post cord clamping, but this does not allow adequate antibiotic levels in maternal blood and tissue to be achieved at the stage of incision and during surgery. We evaluated by bioassay maternal and fetal serum and placental ceftriaxone concentrations following the intravenous administration of 1.0 g of ceftriaxone upon the decision to perform cesarean section. The preoperative prophylaxis with ceftriaxone resulted in adequate protective levels in the mother and very low fetal blood levels.

Pharmacokinetics and tissue penetration of a single dose of ceftriaxone (1,000 milligrams intravenously) for antibiotic prophylaxis in thoracic surgery.

The pharmacokinetics and tissue penetration of ceftriaxone after a single intravenous injection of 1,000 mg to 17 patients for antibiotic prophylaxis in thoracic surgery were studied. The patients were scheduled for elective noncardiac thoracic surgery. Adequate levels in serum (higher than or equal to the MIC for 90% of isolates of Staphylococcus aureus, Streptococcus spp., Escherichia coli, Haemophilus influenzae, and Klebsiella pneumoniae) were found for all patients throughout the surgical procedures. Mean maximal (5-min) and final (24-h) ceftriaxone levels in serum were 157 +/- 42 and 8.6 +/- 4.5 mg/liter, respectively. The beta-phase elimination half-life was 8.6 +/- 3 h, the plasma clearance was 18.4 +/- 6.25 ml/min, and the apparent volume of distribution at steady state was 0.21 +/- 0.07 liters/kg. At the time of the thoracotomy, the ceftriaxone concentrations were 13.5 +/- 7.8 micrograms/g in thoracic wall fat and 27 +/- 9 micrograms/g in lung tissue. At the time of closure, the ceftriaxone concentration was 15 +/- 9 micrograms/g in thoracic wall fat. During the different steps of the surgical procedures, 100% of patients had adequate levels in tissue (higher than or equal to the MIC for 90% of isolates of Streptococcus spp., E. coli, H. influenzae, and K. pneumoniae). For S. aureus, 90 to 100% of patients had adequate tissue ceftriaxone levels.

Intraosseous administration of antibiotics: Same-dose comparison with intravenous administration in the weanling pig

To assess the reliability of the intraosseous route of administration for delivery of a loading dose of broad-spectrum antibiotics in a pediatric animal model. Serum levels achieved within 90 minutes of equivalent intraosseous (IO) and IV bolus dosing of ceftriaxone, cefotaxime, and a combination of ampicillin and gentamicin were compared in the weanling pig. Twelve female weanling pigs were studied in the Animal Facilities Laboratory at the University of Mississippi Medical Center. Through a proximal tibial IO catheter, each anesthetized animal received one of the following: 50 mg/kg ceftriaxone, 50 mg/kg cefotaxime, or 300 mg/kg ampicillin followed immediately by 2.5 mg/kg gentamicin. Venous blood was obtained for antibiotic assay at 15, 30, 45, 60, and 90 minutes after IO injection. The animals were allowed to recover, and, after a one-week washout period, each received the same antibiotic and dose as before through a peripheral IV. Levels were assayed at the same intervals and IO versus IV were compared. Comparable serum levels of all four antibiotics were achieved by the two routes. Gentamicin levels were statistically indistinguishable IO versus IV at all assay intervals. Ampicillin and cefotaxime levels achieved by the two routes were equivalent within one hour of dosing. Serum levels of ceftriaxone after IO administration paralleled those after IV dosing but remained significantly lower at all time intervals. In the weanling pig model, the IO route was used to deliver serum levels of broad-spectrum antibiotics comparable to those attained after IV administration. The data support the use of standard parenteral doses for IO administration. To overcome potential avid protein binding of ceftriaxone in the bone marrow, we recommend using ceftriaxone at its highest recommended IO loading dose. Consistent with many other medications that have been similarly tested, these data indicate that initial or empiric antibiotic coverage in hypodynamic and shock states in infants and young children need not await the establishment of traditional IV access.

Determination of ceftriaxone in biological material by differential-pulse adsorptive stripping voltammetry

Differential-pulse adsorptive stripping voltammetry was used to determine sub-micromolar concentrations of ceftriaxone in plasma. A hanging mercury drop electrode was chosen as the working electrode. A simple clean-up procedure was developed in which ceftriaxone was extracted from blood plasma with the non-ionic resin Amberlite XAD-2 and eluted with methanol. The recovery from plasma was 97.6% using a 1.52 x 10(-4) M stock ceftriaxone solution. The method was applied to caesarean cases, and total ceftriaxone levels were measured in the maternal and umbilical cord blood. The amount of ceftriaxone transmitted to the baby on administration of the drug to the mother before the caesarean operation was found to be in the range 0.067-0.17%.

Pharmacokinetic and clinical studies on ceftriaxone in the perinatal period

The pharmacokinetics of ceftriaxone (CTRX) and its clinical efficacy in perinatal infections were studied. The obtained results are summarized as follows. 1. Concentrations of CTRX in maternal serum, umbilical cord serum and amniotic fluid were determined following intravenous injection with 1 g of CTRX. Maternal serum levels were not lower than 100 micrograms/ml immediately after administration, and gradually decreased to about 10 micrograms/ml in 12 hours, and to 4 micrograms/ml in 24 hours. The half-life of CTRX in maternal serum was 5.6 hours. CTRX levels in umbilical cord serum were about 7 micrograms/ml at 10 minutes after injection, increasing to 12 to 13 micrograms/ml in 12 hours and decreasing to 5 micrograms/ml in 24 hours. CTRX levels in amniotic fluid were slightly lower than those in the umbilical cord serum, and about 2 micrograms/ml at 10 minutes after injection, and they remained at 4 to 8 micrograms/ml thereafter for 28 hours. 2. CTRX (1 g) was intravenously administered twice daily to 9 patients with perinatal infections for 3 to 7 days. Clinical efficacies of CTRX were judged excellent in 2 cases and good in 7, suggesting that CTRX was effective in all cases. No side effects or laboratory abnormalities were observed in any case. As a result of these findings, CTRX may be considered a very useful antibiotic in perinatal infections.

Penetration of ceftriaxone into human pleural fluid.

The pharmacokinetics of ceftriaxone were studied for seven patients with pleural effusion of various etiologies. All patients received 1 g of antibiotic, administered as an intravenous bolus. The pleural fluid had a high total protein content (6.0 g/dl). Ceftriaxone levels in plasma and in pleural fluid were determined by the agar well diffusion technique. Total and free drug concentrations in pleural fluid reached 7 to 8.7 and 3.8 to 2.3 micrograms/ml, respectively, in 4 to 6 h. The disappearance of the drug from the pleural fluid was very slow. In these patients, therapeutic ceftriaxone levels were present for at least 53 h in pleural fluid.

Human pharmacokinetics and distribution in various tissues of ceftriaxone.

Multiple-dose pharmacokinetics of ceftriaxone were investigated in 7 patients with bronchopneumonia using an intramuscular regimen of 1 g given every 24 h for 7 days. Serum, sputum, and urine samples were collected serially following the first dose (day 1) and last dose (day 7). Mean peak serum concentrations of ceftriaxone occurred at 2 h on both days and were 67.8 and 75.1 micrograms/ml, respectively, on day 1 and day 7. Ceftriaxone had a half-life of 6.9 h on day 1 and 7.4 h on day 7. The half-life of ceftriaxone in sputum was 5.9 and 6.6 h, respectively, on days 1 and 7. Approximately 50% of the dose of ceftriaxone was recovered in the urine within 24 h on day 1, 60% on day 7. Tissue distribution of ceftriaxone was determined in 103 patients following intramuscular administration of a single 1-gram dose at different times up to 24 h prior to surgery. High concentrations of ceftriaxone were found in lung, tonsil, middle ear mucosa, and nasal mucosa, and therapeutic levels of ceftriaxone persisted for 24 h after administration.

Once-daily ceftriaxone therapy for serious bacterial infections in children.

Ceftriaxone administered as a single daily dose of 50 mg/kg was evaluated in the treatment of 35 children with a variety of nonmeningitic bacterial infections. In two of the patients, the drug was discontinued before the response to the drug could be evaluated. All of the remaining patients had a satisfactory response. In 22 of the patients, plasma was available for the determination of ceftriaxone levels 1 h after a dose and immediately before the next dose. All but one of these patients had trough ceftriaxone levels which exceeded the MIC of the infecting organism, although marginally so for Staphylococcus aureus. Ceftriaxone appears to be safe and effective in the treatment of a variety of bacterial pathogens in children when administered at a single daily dose of 50 mg/kg. This drug may be especially useful in those patients in whom outpatient antibiotic therapy is contemplated or in whom maintenance of intravenous access is difficult.

Pharmacokinetic analysis of intravitreal ceftriaxone in monkeys.

Ocular toxic effects of intravitreally injected ceftriaxone sodium and its rate of clearance after a single dose were studied in rhesus and cynomolgus monkeys. Doses of 2, 2.5, and 3 mg/0.1 mL were injected into the vitreous cavity. Electroretinograms performed 15 minutes, 24 hours, one week, and two weeks after injection were not significantly different from preinjection electroretinograms. Lens opacification occurred in one eye receiving 2.5 mg of ceftriaxone. Histopathologic findings in the retina were normal in all eyes injected intravitreally. Levels of ceftriaxone after a 2-mg intravitreal dose were 609 mg/L at 0 hours, 434 mg/L at 24 hours, and 19 mg/L at 100 hours in the vitreous; and 1 mg/L at 0 hours, 116 mg/L at 24 hours, and 9 mg/L at 100 hours in the aqueous.

The penetration of ceftriaxone into synovial fluid of the inflamed joint.

Fifteen patients with acute exacerbation of rheumatoid arthritis each received a 1 g bolus intravenous injection of ceftriaxone. Serum and synovial fluid was sampled at intervals between 1 h and 24 h later and assayed for ceftriaxone. Synovial fluid leucocyte counts and albumin content were measured concomitantly. Detectable levels of ceftriaxone were found in synovial fluid and serum 24 h after injection. Synovial fluid ceftriaxone concentration ranged between 66% and 100% of the concomitant serum levels. No correlation was observed between synovial fluid ceftriaxone concentration and synovial fluid leucocyte count and albumin concentration.

Intravitreal ceftriaxone in a rabbit model. Dose- and time-dependent toxic effects and pharmacokinetic analysis.

Ceftriaxone's toxic effects were assessed in albino rabbits after intravitreal injection. Doses up to 5 mg did not alter the B-wave amplitude. Following 7.5-and 20-mg doses, B-wave amplitude ratios were depressed at 24 hours and normal at seven and 14 days. A 50-mg dose caused a temporarily flat B-wave 24 hours after injection. At two weeks this ratio exhibited a moderate increase but remained 2 SDs below the mean preinjection ratio. Eyes receiving up to 20 mg were normal histologically at 14 days. A 50-mg dose induced generalized retinal edema and disruption of the retinal layers 24 hours after injection; at two weeks there were no histologic changes in the retina. Immediately after a 2-mg intravitreal injection, vitreous ceftriaxone levels were 1,345 +/- 4.9 mg/L; by 72 hours they had decreased to 17.6 +/- 1.4 mg/L. The mean peak aqueous level was 80.2 +/- 12.2 mg/L at 72 hours.

Ceftriaxone levels in blood and tissue during cardiopulmonary bypass surgery.

One gram of ceftriaxone was given intravenously to 15 patients approximately 2 h before cardiopulmonary bypass surgery. Ceftriaxone levels in plasma (mean +/- standard deviation) were 60.4 +/- 18.8 micrograms/ml (range, 17.0 to 96.0 micrograms/ml) at the beginning of bypass, 44.2 +/- 16.6 micrograms/ml (range, 9.4 to 78.6 micrograms/ml) at the end of bypass, and 19.6 +/- 9.6 micrograms/ml (range, 4.2 to 47.1 micrograms/ml) the following morning, 18.1 to 24.7 h after infusion of ceftriaxone. Concentrations in the sternal bone were 4.7 +/- 2.1 micrograms/g (range, 1.0 to 10.1 micrograms/g; tissue-to-plasma ratios, 0.066 +/- 0.036). Concentrations in the atrial appendage were 7.7 +/- 1.8 microgram/g (range, 3.6 to 10.2 micrograms/g; tissue-to-plasma ratios, 0.143 +/- 0.062). These data suggest that a single dose of ceftriaxone might be useful for prevention of infection due to susceptible pathogens.

Twice daily ceftriaxone therapy for serious bacterial infections in children.

The clinical efficacy and safety of ceftriaxone, a long half-life cephalosporin were evaluated in 48 children with a variety of serious bacterial infections. Clinical cure was achieved in 92% (44 of 48) of patients. Peak serum bactericidal titres for Haemophilus influenzae type b, Streptococcus pneumoniae, Str. pyogenes and Escherichia coli were greater than or equal to 1:1024. Mean peak and trough ceftriaxone levels were 173 and 42 mg/l, respectively. Mild and transient diarrhoea was observed in 10% of patients. Laboratory side effects encountered were eosinophilia, thrombocytosis and neutropenia in another 8%. Ceftriaxone is a useful antibiotic for common childhood infections. Its prolonged half-life allows twice daily administration which reduces problems related to intravenous therapy as well as the cost and personnel time.

Ceftriaxone therapy of serious bacterial infections in adults.

We evaluated the efficacy and safety of ceftriaxone in 50 adults with serious infections, usually giving 1 g every 12 h. Of the 35 patients who could be evaluated for clinical efficacy, 15 had failed on previous therapy, 15 had nosocomial infections, and all but 1 had underlying diseases. One patient had three sites of infection. Favorable responses were seen in 34 of 37 infections, including 11 of 13 respiratory tract infections, all 7 urinary tract infections, all 12 skin and soft tissue infections, 1 of 2 bone and joint infections, a catheter-related septicemia, a liver abscess, and an otitis media and externa. Favorable bacteriological responses were seen for 48 of 58 organisms. This included 6 of 7 Staphylococcus aureus strains, 14 of 16 other aerobic gram-positive cocci, 18 of 20 Enterobacteriaceae, 6 of 9 Pseudomonas aeruginosa, and 1 of 2 anaerobes. Peak plasma ceftriaxone levels on day 1 were 152 micrograms/ml by bioassay and 78 micrograms/ml by high-pressure liquid chromatography. Four of the 31 initial isolates of aerobic gram-negative rods developed resistance to ceftriaxone on disk diffusion testing. Diarrhea occurred in 3 of 50 patients. All three had received a higher than usual dose. Drug administration was stopped twice, once for a thrombocytopenia and once for a thrombocytopenia with leukopenia. Neither problem could be attributed exclusively to ceftriaxone. Other adverse reactions were eosinophilia, abdominal pain, inguinal candidiasis, and nonsuppurative phlebitis. Even among debilitated adults, ceftriaxone was safe and effective in a twice daily regimen.

Ceftriaxone diffusion into cerebrospinal fluid of children with meningitis.

We evaluated the diffusion of ceftriaxone into the cerebrospinal fluid of 27 infants and children with meningitis who were receiving conventional antimicrobic therapy. Ceftriaxone was administered as a single 75 mg/kg dose and was given early or late or both in the course of the illness. Three hours after a dose, the mean cerebrospinal fluid ceftriaxone level was 5.7 micrograms/ml in patients studied early in the course of meningitis and 2.1 micrograms/ml in patients studied later in the illness. Six hours after a dose, the mean cerebrospinal fluid ceftriaxone levels early and late in meningitis were 7.2 and 2.5 micrograms/ml, respectively. The diffusion did not correlate with the leukocyte count or the protein or glucose content of the cerebrospinal fluid. Serial, simultaneous cerebrospinal fluid and plasma ceftriaxone levels were also determined in three additional patients with ventriculo-peritoneal shunt infections and external ventriculostomy drainage. The cerebrospinal fluid ceftriaxone levels in these patients ranged from 0.7 to 8.3 micrograms/ml. Our data indicate that ceftriaxone diffuses sufficiently and consistently into the cerebrospinal fluid to warrant its assessment in the treatment of meningitis.