Penicillin and ceftriaxone susceptibility of Streptococcus pneumoniae isolated from cerebrospinal fluid of children with meningitis hospitalized in a tertiary hospital in Israel.

BACKGROUND: Streptococcus pneumoniae is now the predominant pathogen causing meningitis. The resistance of S. pneumoniae to penicillin and third-generation cephalosporins has grown steadily. OBJECTIVES: To assess the antibiotic susceptibility of S. pneumoniae isolated from the cerebrospinal fluid of children with meningitis, and determine the antibiotic regimen appropriate for suspected bacterial meningitis in Israel. METHODS: The study group included 31 children with 35 episodes of meningitis hospitalized from 1998 to 2006. S. pneumoniae isolates from the cerebrospinal fluid were tested for susceptibility to penicillin and ceftriaxone. RESULTS: Of the 35 isolates, 17 (48.6%) showed resistance to penicillin (minimum inhibitory concentration > or = 0.12 microg/ml). Only 3 isolates (8.6%) showed intermediate resistance to ceftriaxone (> or = 0.5 and < (2 microg/ml), and none showed complete resistance (MIC > or = 2 microg/ml). The rates of antibiotic resistance were higher in children who were treated with antibiotics prior to admission (penicillin 88.9% vs. 34.6%, P = 0.007; ceftriaxone 22.2% vs. 3.8%, P = 0.156). CONCLUSIONS: The rate of penicillin resistance is high in children with S. pneumoniae meningitis in Israel, especially in those treated with oral antibiotics prior to admission. Resistance to ceftriaxone is infrequent though not negligible. On the basis of these findings, current recommendations to empirically treat all children with suspected bacterial meningitis with ceftriaxone in addition to vancomycin until the bacterial susceptibility results become available are justified also in Israel.

[Penetration of ceftriaxone into the cerebrospinal fluid and its relationship to inflammatory markers during bacterial meningitis]. / Prunik ceftriaxonu do likvoru a jeho v vztah k markerum zánetu v prubehu invazivní bakteriální infekce.

AIM: To evaluate the penetration of ceftriaxone into the cerebrospinal fluid (CSF) in patients with invasive bacterial infection and to define correlation between the penetration and laboratory markers of inflammation. MATERIAL AND METHODS: Levels of ceftriaxone in the serum and CSF of 17 patients with purulent meningitis were examined. Serum concentrations of ceftriaxone before and after its administration were measured in 9 patients (18 samples, 52.9 %) by microbiological assay based on the agar diffusion test. In all patients, the CSF/serum quotient for ceftriaxone was calculated and correlated with laboratory markers of inflammation (C-reactive protein, fibrinogen and neutrophils). The CSF from nine patients with positive culture for bacteria was used for a modified bactericidal test. RESULTS: Ceftriaxone levels in the serum before and after administration (31.2 mg/l -/+ SD 12.29 and 300.0 mg/l -/+ SD 125.9, respectively) were different (p = 0.000156). The decrease of ceftriaxone levels in the CSF was gradual. There was also a significant difference between the levels of inflammatory markers and CSF/serum quotient of ceftriaxone. Patients with the values higher than 0.1 had higher CRP serum levels (p = 0.00192), fibrinogen serum levels (p = 0.0178) as well as neutrophil count in the CSF (p = 0.0112). However, no inflammatory markers (or their combinations) predicted the extent of penetration of ceftriaxone into the CSF. CONCLUSION: High serum concentration of ceftriaxone causes higher penetration through the inflamed blood-brain barrier. Higher antibiotic penetration correlated with the extent of systemic inflammatory response. However, no inflammatory marker predicted the rate of ceftriaxone crossing the blood-brain barrier. Ceftriaxone penetration, with a 24-hour regimen of administration, remains reliable and efficient therapy of purulent meningitis.

Encephalopathy Induced by High Plasma and Cerebrospinal Fluid Ceftriaxone Concentrations in a Hemodialysis Patient.

Encephalopathy is a rare side effect of cephalosporin treatment. We herein present a case of encephalopathy induced by ceftriaxone, a third-generation cephalosporin, in a patient with renal failure. An 86-year-old woman on maintenance hemodialysis received ceftriaxone for Helicobacter cinaedi bacteremia. Her mental status deteriorated during antibiotic treatment, and an electroencephalogram revealed triphasic waves predominantly in the frontal area. Her consciousness improved after the discontinuation of the antibiotic due to the suspicion of ceftriaxone-induced encephalopathy. This is the first reported case of encephalopathy associated with high plasma and cerebrospinal fluid ceftriaxone concentrations, and provides significant evidence for a causal relationship between the administration of ceftriaxone and the onset of encephalopathy.

Determination of ceftriaxone concentration in human cerebrospinal fluid by high-performance liquid chromatography with UV detection.

Determination of ceftriaxone (CTRX) concentration in human cerebrospinal fluid (CSF) is required to clarify whether a high concentration of CTRX in CSF is associated with CTRX-induced encephalopathy (CIE). In our study, in order to perform an accurate analysis of CSF sample from CIE patient, we proposed HPLC with UV detection (HPLC-UV) using an octadecylsilica (ODS) column, a methanol and 10 mM phosphoric acid (25:75, v/v) mixture solution as a mobile phase, and a detection wavelength at 280 nm. The linear range was from 0.1 to 100 µg/mL (r = 0.999) in the present HPLC-UV. In the recovery tests using blank samples of human CSF and control serum spiked with CTRX, the recoveries of CTRX were >95.3%, and the RSD (n = 3) was <5.8%. We applied the proposed HPLC-UV system to determine CTRX in the CSF and serum samples obtained from a patient diagnosed as having CIE, and it was revealed that the CTRX concentrations in the CSF sample and the serum were 2.61 and 37.35 µg/mL, respectively. To the best of our knowledge, this is the first report describing the determination of CTRX concentration in a CSF sample obtained from a peritoneal dialysis patient diagnosed as having CIE.

Effect of ABCC2 and ABCG2 Gene Polymorphisms and CSF-to-Serum Albumin Ratio on Ceftriaxone Plasma and Cerebrospinal Fluid Concentrations.

We measured ceftriaxone pharmacokinetics in patients' plasma and cerebrospinal fluid (CSF) and assessed the influence of biometric, demographic, genetic (ABCB1, ABCC2, ABCB11, ABCG2, and SLCO1A2 polymorphisms) and pathological features. Adult patients with signs and symptoms of central nervous system infections, receiving intravenous ceftriaxone, were enrolled. Ceftriaxone plasma and CSF concentrations were measured by high-precision liquid chromatographic methods; allelic discrimination was performed by real-time polymerase chain reaction. Forty-three patients were included: median ceftriaxone maximal concentration was 15,713 ng/mL in plasma and 3512 ng/mL in CSF with a CSF-to-plasma ratio of 0.3. ABCC2 1249 rs2273697 (P = .027) and ABCG2 1194+928 rs13120400 (P = .015) variants were significantly associated with CSF concentrations and CSF-to-plasma ratios. At linear regression analysis, CSF-to-serum albumin ratio was an independent predictor of ceftriaxone CSF concentrations (P = .001; also in those with intact blood-brain barrier: P = .031) and CSF-to-plasma ratio (P = .001; also in those with blood-brain barrier impairment: P = .040). We here report the role of transporters' genetic variants as well as of blood-brain barrier permeability in predicting ceftriaxone exposure in the central nervous system.

Comparison of the probability of target attainment between ceftriaxone and cefepime in the cerebrospinal fluid and serum against Streptococcus pneumoniae.

Although the disposition of ceftriaxone and cefepime in the cerebrospinal fluid (CSF) has been described, the ability of these agents to achieve critical pharmacodynamic targets against Streptococcus pneumoniae in CSF has not been reported. Plasma and CSF pharmacokinetic data were obtained from hospital patients with external ventricular drains and receiving ceftriaxone or cefepime. Concentration-time profiles in plasma and CSF were modeled using a 3-compartment model with 0-order infusion and 1st-order elimination and transfer. The model parameters were identified with population pharmacokinetic analysis (Big Non-Parametric Adaptive Grid with adaptive gamma). A Monte Carlo Simulation (9999 subjects) estimated the probability of target attainment (PTA) for total drug CSF concentrations at 50% and 100% T>MIC for ceftriaxone 2G IV Q12H and cefepime 2G IV Q8H. The S. pneumoniae bloodstream infection isolates from the SENTRY Antimicrobial Surveillance Program (USA) provided the distribution of contemporary (2003-2004) MICs. Post-Bayesian measures of bias and precision, observed-predicted plots, and R2 values were highly acceptable for both drugs. The probabilities of achieving 50% and 100% T>MIC in the CSF for ceftriaxone were 76% and 65%, respectively. For cefepime, the PTA at 50% and 100% T>MIC in the CSF were 91.8% and 82%, respectively. The CSF pharmacodynamics against S. pneumoniae for cefepime were superior to that of ceftriaxone. The implications of these findings need to be reexamined in the clinical setting.

Cefotaxime and ceftriaxone cerebrospinal fluid levels during treatment of bacterial meningitis in children.

Cefotaxime (CTX) and ceftriaxone (CRO) were compared for cerebrospinal fluid (CSF) penetration and antimicrobial efficacy in cases of bacterial meningitis in children. This was a comparative study of CRO (100mg/kg once daily) and CTX (50 mg/kg 6 hourly) in the treatment of children with bacterial meningitis. The aetiological agents included Streptococcus pneumoniae (SPn), Haemophilus influenzae type b (Hib) and Neisseria meningitidis (NMen). Minimum inhibitory concentrations (MICs) were measured. In 33 patients from whom a second CSF specimen was obtained, CSF was cultured and assayed for antibiotic concentration. Median MICs of CTX and CRO for SPn, Hib and NMen were 0.01 and 0.01 microg/mL, 0.004 and 0.002 microg/mL and 0.008 and 0.004 microg/mL, respectively. All 33 repeat lumbar puncture specimens were sterile. The lowest CSF level recorded (0.45 microg/mL for CTX) was 45 times the MIC (0.01 microg/mL). The highest levels (24-35 microg/mL for CRO) were up to 8750 times the MIC of the patient's causative organism. A wide range of CSF levels for both antibiotics was observed. Levels varied with post-dose interval and duration of illness. On the basis of these findings, clinicians should be reassured that repeat lumbar puncture is not recommended for the causative organisms in this study (i.e., for Hib, NMen and penicillin/cefotaxime/ceftriaxone fully-susceptible SPn).

Determination of ceftriaxone in cerebrospinal fluid by ion-pair liquid chromatography.

An ion-pair liquid chromatographic assay was developed and validated for the determination of ceftriaxone in cerebrospinal fluid. Chromatographic separation was achieved on a C18 column (125 x 4 mm, 5 microm) with detection at 270 nm, a 1 mL/min flow rate and a 50 microL loop. The mobile phase consisted of 300 mL acetonitrile, 50 mL 0.1M phosphate buffer (pH 7.4), 3.2 g tetrabutylammonium bromide as the ion-pairing agent, and dilution with distilled deionized water to 1 L. Cephradine was used as the internal standard. The assay was linear for ceftriaxone concentrations of 0.5-50 microg/mL. The coefficients of variation for precision were <4.61%. The accuracy ranged from 96.07 to 102.42%. The detection and quantitation limits were 0.019 and 0.065 microg/mL, respectively. This method was used to quantify ceftriaxone in the cerebrospinal fluid of children with meningitis. The results showed that the method described here is useful for the determination of ceftriaxone in cerebrospinal fluid.

Ceftriaxone therapy of bacterial meningitis: cerebrospinal fluid concentrations and bactericidal activity after intramuscular injection in children treated with dexamethasone.

Antibiotic therapy is administered intravenously to children with bacterial meningitis to achieve the highest possible blood and cerebrospinal fluid (CSF) concentrations. However, intravenous access for the entire duration of therapy may be difficult in some children. Intramuscular therapy offers a more versatile option; however, CSF concentrations and bactericidal activity following im injection in children concurrently treated with dexamethasone have not been studied. We prospectively evaluated 37 children given an im dose of ceftriaxone on either the 3rd, 6th or 9th day of antibiotic therapy while receiving dexamethasone for the first 4 days of treatment. All children were required to have normal peripheral perfusion at the time of im injection. Four to 6 hours after im injection CSF was obtained. The average age of study patients was 28 months; Neisseria meningitidis, Streptococcus pneumoniae and Haemophilus influenzae type b were responsible for 95% of all infections. All children studied had detectable CSF ceftriaxone concentrations, with mean (+/- SD) concentrations (microgram/ml) on Days 3, 6 and 9 of therapy of 5.7 +/- 5.5 (n = 12), 5.2 +/- 5.0 (n = 14) and 2.0 +/- 2.6 (n = 10), respectively. All CSF bactericidal titers for N. meningitidis, S. pneumoniae and H. influenzae type b, regardless of day of im injection, were > or = 1:64. Intramuscular ceftriaxone therapy of bacterial meningitis may be a reasonable therapeutic option for the convalescing child with good peripheral perfusion.

Streptococcal meningitis: effect of CSF filtration on inflammation and neuronal damage.

The effect of CSF filtration on inflammation and neuronal damage was studied in experimental Streptococcus pneumoniae meningitis. New Zealand white rabbits received either antibiotic therapy alone (ceftriaxone i.v., 20 mg/kg bolus, 10 mg/kg maintenance dose; n = 10) or ceftriaxone plus CSF filtration (n = 11) 12 h after intracisternal infection. Immediately after the onset of antibiotic therapy 300 microliters cisternal CSF was removed, passed through a miniaturized CSF-1 filter at a constant flow of 20 microliters/min, and then reinjected. This procedure was repeated six times at intervals of 20 min. Antibiosis plus CSF filtration caused a transient reduction in CSF bacterial titers and leukocyte counts compared with antibiosis alone (P = 0.04 and 0.02 5 h after initiation of therapy). CSF lipoteichoic acid concentrations were not reduced. The concentration of neuron-specific enolase in CSF and the density of apoptotic neurons in the dentate gyrus were almost equal 12 h after the onset of treatment. Adjuvant CSF filtration accelerated the elimination of viable bacteria from CSF in comparison to antibiotic treatment alone. Parameters of neuronal destruction, however, were not reduced.

Does dexamethasone affect ceftriaxone [corrected] penetration into cerebrospinal fluid in adult bacterial meningitis.

Trough cerebrospinal fluid (CSF) ceftriaxone concentrations were measured daily to investigate the effect of dexamethasone on ceftriaxone penetration into CSF in adult patients with acute bacterial meningitis. Patients were divided into two groups in this double blind randomized study. In group 1 (n=6) patients were given ceftriaxone with dexamethasone whereas in group 2 (n=6) patients were only administered ceftriaxone. Plasma and CSF samples were collected at 24, 48, 72, 96 and 264 h following the study treatments. The trough CSF ceftriaxone concentrations were measured using high performance liquid chromatography (HPLC) and microbiological assay. CSF ceftriaxone concentrations were 3.21 mg/l at 24 h in group 1 and 4.85 mg/l at the same time in group 2 by HPLC. Although microbiological assay results were lower than HPLC the trough CSF ceftriaxone concentrations in dexamethasone group were at least 10(3) times higher than the minimum inhibitory concentrations of the susceptible strains. It was concluded that the ceftriaxone concentration in CSF was adequate and ceftriaxone penetration was not significantly affected by concomitant dexamethasone use in adult patients with acute bacterial meningitis.

Influence of lipophilicity on the diffusion of cephalosporins into the cerebrospinal fluid.

The aim of this quantitative structure-activity relationship (QSAR) study was to investigate the influence of lipophilicity on the diffusion of cephalosporins into the cerebrospinal fluid (CSF). The lipophilicity was expressed as the chromatographic capacity factor (log k'w) determined by high-performance liquid chromatography in a reversed-phase system. The penetration of eight cephalosporins into CSF was studied in male Wistar rats receiving the drugs intramuscularly (1.5 mg/kg). One hour after administration, CSF and blood samples were collected, and concentrations of free drug were measured in CSF (CCSF) and in plasma (CP). A significant parabolic relationship was sought between lipophilicity (log k'w) and the capacity of diffusion across the blood-brain barrier expressed as log (CCSF/CP). The cephalosporins exhibiting a moderate lipophilicity diffused well into CSF. A pharmacokinetic study was performed at 1, 2 and 4 h after administration of three cephalosporins: cefazolin, ceftriaxone and cefsulodin. These compounds were choosen according to their lipophilicities (low, moderate and high values, respectively). The AUC0-4h for both free plasma (AUCP) and cerebrospinal fluid (AUCCSF) concentrations were determined. The AUCCSF/AUCP ratio presented a maximum value for a strongly albumin bound cephalosporin, ceftriaxone. In our experimental conditions, the ideal lipophilicity (log k'w) range for diffusion of cephalosporins from plasma into CSF was between 1.6 and 1.8.

Pharmacokinetics of ceftriaxone in healthy horses.

Five healthy Equidae (4 horses and one pony) were given a single i.v. dose of ceftriaxone (50 mg/kg bwt) to determine the pharmacokinetics and concentration in cerebrospinal fluid (CSF). Blood was drawn from an i.v. jugular catheter and CSF from a pre-placed, intrathecal catheter. Serum and CSF concentrations were determined by high performance liquid chromatography. The mean serum concentration of ceftriaxone was 144.7 micrograms/ml 15 min after injection and declined to 0.3 microgram/ml 10 h after injection. The elimination rate constant (lambda 2) was 0.63 +/- s.e. 0.23/h, the elimination half-life (t 1/2) was 1.62 +/- s.e. 0.42 h and the apparent volume of distribution at steady state (Vd(ss)) was 330.8 +/- 11.8 ml/kg bwt. Clearance was 312.7 +/- 38 ml/h/kg bwt and mean residence time was 1.13 +/- 0.14 h. Mean CSF concentration was 0.60 +/- 0.14 microgram/ml at 3 h after injection and 0.4 +/- 0.31 microgram/ml at 8 h. Ceftriaxone may be useful in the treatment of bacterial infections in horses. Its ability to penetrate the CSF should make it effective in the treatment of bacterial meningitis.

[Study on the penetration of ceftriaxone into cerebrospinal fluid].

Concentrations of ceftriaxone (CTRX) in the serum and the cerebrospinal fluid (CSF) were serially investigated after an intravenous drip infusion of 2 g per day to 14 patients with acute cerebrovascular diseases, as they were determined at 30 minutes, 3, 6, 24 hours, 3 and 7 days after first administration. The results obtained are summarized as follows: 1. Serum levels; Peak levels of CTRX in the serum were 162.0 +/- 51.2 (SD) micrograms/ml at 30 minutes after administration. Even at 24 hours after intravenous drip infusion, concentrations of CTRX were 14.9 +/- 6.15 (SD) micrograms/ml. 2. CSF levels; The CTRX concentrations in the CSF rose to 1.70 +/- 1.84 (SD) micrograms/ml at 30 minutes, 3.51 +/- 3.31 (SD) micrograms/ml at 3 hours and then decreased to 0.74 +/- 0.67 (SD) micrograms/ml at 24 hours after first infusion. 3. CTRX concentrations in serum in CSF after serially repeated infusion for 3 to 7 days were quite similar to the those obtained after the first administration. The above results indicates that CTRX is useful for the prevention of postoperative infections in the field of neurosurgery.

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.

Randomized comparison of ceftriaxone and cefotaxime in Lyme neuroborreliosis.

In this prospective, randomized, open trial, 33 patients with Lyme neuroborreliosis were assigned to a 10-day treatment with either ceftriaxone, 2 g intravenously (iv) every 24 h (n = 17), or cefotaxime, 2 g iv every 8 h (n = 16). Of the 33 patients, 30 were eligible for analysis of therapeutic efficacy. Neurologic symptoms improved or even subsided in 14 patients of the cefotaxime group and in 12 patients of the ceftriaxone group during the treatment period. At follow-up examinations after a mean of 8.1 months, 17 of 27 patients examined were clinically asymptomatic. In one patient Borrelia burgdorferi was isolated from the cerebrospinal fluid (CSF) 7.5 months after ceftriaxone therapy. CSF antibiotic concentrations were above the MIC 90 level for B. burgdorferi in nearly all patients examined. Patients with Lyme neuroborreliosis may benefit from a 10-day treatment with ceftriaxone or cefotaxime. However, as 10 patients were symptomatic at follow-up and borreliae persisted in the CSF of one patient, a prolongation of therapy may be necessary.

Bactericidal activity against cephalosporin-resistant Streptococcus pneumoniae in cerebrospinal fluid of children with acute bacterial meningitis.

There are reports of failure of extended-spectrum cephalosporin treatment in pneumococcal meningitis. On the basis of in vitro and animal experimental studies, the addition of vancomycin or rifampin to an extended-spectrum cephalosporin has been recommended for empiric treatment of these patients. Cerebrospinal fluid (CSF) was taken from 31 children with bacterial meningitis randomized to receive ceftriaxone alone (n = 11), ceftriaxone plus rifampin (n = 10), or ceftriaxone plus vancomycin (n = 10). The CSF from children receiving ceftriaxone alone was unable to kill intermediately ceftriaxone-resistant or fully resistant strains when the concentration of ceftriaxone in the CSF was less than 5 micrograms/ml. At higher concentrations bactericidal activity was present. We have shown that vancomycin penetrates reliably into the CSF of children with acute meningitis, which is in contrast to previous studies with adults. The addition of vancomycin or rifampin to ceftriaxone resulted in significantly enhanced CSF bactericidal activity compared with that of ceftriaxone alone against these resistant strains. Our data suggest that the addition of rifampin or vancomycin to ceftriaxone may be useful for the treatment of cephalosporin-resistant pneumococcal meningitis.

Concentrations of ceftriaxone in cerebrospinal fluid of children with meningitis receiving dexamethasone therapy.

The penetration of ceftriaxone into cerebrospinal fluid (CSF) was studied with 11 children (mean age: 2 years, 4 months; range: 4 months to 8 years) with meningitis, receiving dexamethasone (0.15 mg/kg of body weight intravenously four times daily) as adjunctive therapy. Ceftriaxone was given intravenously at doses of 50 mg/kg twice daily to patients < 18 months old and 100 mg/kg once daily to patients > or = 18 months old. CSF was collected after 1 day of treatment at the expected peak concentration of ceftriaxone in CSF. Concentrations of ceftriaxone in CSF ranged from 0.7 to 9.2 mg/liter, with a mean value of 4.0 (standard deviation [SD], 2.9) mg/liter. Values were significantly higher for patients with CSF glucose levels of < 1 mmol/liter on admission to the hospital than for patients with CSF glucose levels of > or = 1 mmol/liter (mean values of 7.1 [SD, 2.2] mg/liter versus 2.2 [SD, 1.1] mg/liter; P < 0.001). After 1 day of treatment, ceftriaxone concentrations in the CSF of children receiving dexamethasone are similar to the mean values reported for children not treated with dexamethasone.

Ceftriaxone kinetics and cerebrospinal fluid penetration in infants and children with meningitis.

20 patients (0.4-5.6 years old) receiving ceftriaxone for the treatment of bacterial meningitis were studied. Simultaneous serum and cerebrospinal fluid concentrations of ceftriaxone were determined by HPLC in 15 patients at 11.4-12.8 h after an intravenous loading dose of 75 mg/kg. Serum and cerebrospinal fluid concentrations ranged from 20.5 to 44.9 (31.3 +/- 7.8) and from 1.1 to 8.0 (3.7 +/- 1.8) micrograms/ml, respectively. Cerebrospinal fluid concentrations ranged from 3 to 25% (12 +/- 6%) of the simultaneous serum concentrations. In 6 patients, serum and cerebrospinal fluid concentrations were determined after maintenance doses of 50 mg/kg/12 h. Serum and cerebrospinal fluid concentrations ranged from 120 to 144 and 2.3-4.9 micrograms/ml at 1.8-5.5 h after the first maintenance dose in 2 patients; 74-139 and 5.7-7.9 micrograms/ml at 1.3-5.8 h after the second dose in 3 patients and was 101 and 4.1 micrograms/ml at 4 h after the 3rd dose in 1 patient. Multiple blood samples were collected after the loading dose in 5 patients and after 9-10 days of maintenance doses in 3 patients. Steady-state peak and trough serum concentrations ranged from 295 to 440 and 32.6-44.8 micrograms/ml, respectively. After the loading and maintenance dose at steady-state, total body clearance averaged 1.17 and 0.64 ml/min (p = 0.01); apparent volume of distribution averaged 0.37 and 0.26 l/kg (p greater than 0.05); and elimination half-life averaged 3.7 and 4.6 h (p = 0.01), respectively. These results suggest that (1) adequate cerebrospinal fluid concentrations of ceftriaxone can be achieved in patients with meningitis with the dosage regimen studied.(ABSTRACT TRUNCATED AT 250 WORDS)