Penetration of Cefotaxime into Cerebrospinal Fluid in Neonates and Young Infants.

Cefotaxime is the first-line treatment for meningitis in neonates and young infants. However, limited data on cefotaxime cerebrospinal fluid (CSF) concentrations in neonates and young infants were available. The aim of the present study was to evaluate the penetration of cefotaxime into CSF in neonates and young infants. Blood and CSF samples were collected from neonates and young infants treated with cefotaxime using an opportunistic pharmacokinetic sampling strategy, and concentrations were quantified by high-performance liquid chromatography-tandem mass spectrometry. The analysis was performed using NONMEM and R software. Thirty neonates and young infants (postmenstrual age range, 25.4 to 47.4 weeks) were included. A total of 67 plasma samples and 30 CSF samples were available for analysis. Cefotaxime plasma and CSF concentrations ranged from 2.30 to 175.42 mg/liter and from 0.39 to 25.38 mg/liter, respectively. The median ratio of the CSF concentration to the plasma concentration was 0.28 (range, 0.06 to 0.76). Monte Carlo simulation demonstrated that 88.4% and 63.9% of hypothetical neonates treated with 50 mg/kg of body weight three times a day (TID) would reach the pharmacodynamic target (the percentage of the dosing interval that the free antimicrobial drug concentration remains above the MIC, 70%) using the standard EUCAST MIC susceptibility breakpoints of 2 mg/liter and 4 mg/liter, respectively. The penetration of cefotaxime into the CSF of neonates and young infants was evaluated using an opportunistic sampling approach. A dosage regimen of 50 mg/kg TID could cover the most causative pathogens with MICs of <2 mg/liter. Individual dosage adaptation was required for more resistant bacterial strains, such as Staphylococcus aureus.

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).

Cefotaxime therapy. Evaluation of its effect on bacterial meningitis, CSF drug levels, and bactericidal activity.

Cefotaxime sodium was evaluated in the treatment of ten patients with bacterial meningitis. Seven of the patients were infected with unusual and difficult to eradicate pathogens. Eight of the ten patients had a favorable clinical response and rapid sterilization of their CSF. Trough CSF levels of cefotaxime (range, 5.6 to 44.3 micrograms/mL) and desacetylcefotaxime (3.7 to 44.0 micrograms/mL) were manyfold greater than the minimal bactericidal concentrations of the causative pathogens with the exception of the one Pseudomonas aeruginosa isolate. Trough CSF bactericidal titers ranged from 1:16 to 1:4,096 or more (median, 1:256) in the nine patients with susceptible pathogens. Trough cefotaxime and desacetylcefotaxime levels and bactericidal titers were maintained or actually increased over the course of therapy. Cefotaxime appears to be a promising new agent for the treatment of bacterial meningitis.

Potential value of cefoperazone in bacterial meningitis: experimental studies.

To assess the potential value of cefoperazone in treating bacterial meningitis, its pharmacokinetics in the cerebrospinal fluid of rabbits were studied. Cefoperazone penetrated poorly into the cerebrospinal fluid of rabbits with uninflamed meninges, but in the presence of meningitis concentrations increased 2- to 3-fold. These concentrations were above the minimum inhibitory concentrations for the majority of Enterobacteriaceae, indicating the potential value of cefoperazone in treating bacterial meningitis. The half-lives of cefoperazone and moxalactam in cerebrospinal fluid, measured by a bioassay, were marked prolonged by meningeal inflammation. In contrast, the half-life of cefotaxime in cerebrospinal fluid was short. Consequently both cefoperazone and moxalactam provided significantly better antibacterial effect in cerebrospinal fluid than did cefotaxime.

Meningoencephalitis due to penicillin-resistant Streptococcus pneumoniae.

The case of a 68-year-old man suffering from pneumococcal meningoencephalitis is reported. Antibacterial susceptibility tests revealed a multiply resistant pneumococcal strain. High doses of cefotaxime were necessary to sterilize the cerebrospinal fluid despite the achievement of a satisfactory level of antibiotic in the cerebrospinal fluid with moderate dosage. In France, as well as in many countries, high doses of third-generation cephalosporins such as cefotaxime or ceftriaxone should be administered for the initial therapy of suspected pneumococcal meningitis.

Cefotaxime in treatment of meningitis and ventriculitis? Evaluation of drug concentrations in human cerebrospinal fluid.

In three groups of patients levels of cefotaxime in serumand cerebrospinal fluid were determined. Therapeutic value and efficacy are discussed in meningitis patients. Nine concentrations of cefotaxime in lumbar and ventricular CSF out of 19 in a group of seven neurosurgical patients with mild to moderate impairment of the blood-CSF-barrier were higher than 0.5 micrograms/ml. In seven determinations in a second group of six patients with no or very little dysfunction of the blood-cerebrospinal-fluid barrier only twice cefotaxime was not detectable in lumbar CSF. Concentrations of cefotaxime in 25 determinations of lumbar or ventricular CSF in six patients with bacterial meningitis ranged from 1.1 micrograms/ml to 19.2 micrograms/ml. Treatment with cefotaxime alone was successful in a patient with E. coli meningitis and ventriculitis after infection of a ventriculo-atrial shunt and in another patient with pneumococcal meningitis and penicillin allergy. The other four patients with bacterial meningitis were treated successfully by antibiotics including cefotaxime.

Kinetic and biochemical analysis of carrier-mediated efflux of drugs through the blood-brain and blood-cerebrospinal fluid barriers: importance in the drug delivery to the brain.

In this manuscript, our recent studies on the transporters on the blood-brain barrier and blood-cerebrospinal fluid (CSF) barrier responsible for the excretion of ligands from the central nervous system (CNS) to the blood are summarized. By comparing the brain entry of quinidine in normal and mdr 1a knock out mice, the predominant role of P-glycoprotein in the brain distribution of this compound was demonstrated. In addition to P-glycoprotein, the presence of transporters responsible for the efflux of organic anions from the brain has been suggested by a pharmacokinetic analysis of the CNS distribution of cefodizime, a third generation cephalosporin antibiotic. This suggestion was confirmed by demonstrating the presence of a specific mechanism for the elimination of p-aminohippuric acid from the brain after microinjection into the cerebral hemisphere. In vitro, the energy-dependent luminal preferential efflux of glutathione-bimane was demonstrated in a monolayer of MBEC4 cells which were derived from mouse brain endothelial cells. Studies with isolated membrane vesicles from MBEC4 cells suggested the presence of a primary active transporter(s) for organic anions, and Western blot analysis indicated the presence of multidrug resistance associated protein (MRP1) and/or its related transporters on MBEC4 cells and freshly isolated rat cerebral endothelial cells. The transcellular transport of 17beta estradiol 17beta-D-glucuronide (E(2)17betaG) across the choroid plexus was also demonstrated by examining the efflux of this compound from CSF after intracerebroventricular administration. The functional significance of organic anion transporting polypeptide (oatp-1) on the brush border membrane of the choroid plexus was demonstrated by comparing the uptake of E(2)17betaG into the isolated choroid plexus and oatp-1 transfected COS-7 cells; in addition, reverse transcription-polymerase chain reaction and Western blot analysis indicated the presence of MRP in the choroid plexus. Together with the direction of transcellular transport, the basolateral localization of MRP on the choroid plexus was suggested. By regulating the activity of these efflux transporters, it is possible to improve the brain entry of certain substrates.

Determination of cefotaxime and desacetylcefotaxime in cerebrospinal fluid by solid-phase extraction and high-performance liquid chromatography.

A high-performance liquid chromatographic procedure has been developed for the measurement of cefotaxime and desacetylcefotaxime in cerebrospinal fluid. Both compounds were isolated from cerebrospinal fluid samples using solid-phase extraction (SPE). LiChrolut RP-18 (200 mg; 3 ml) columns and a mixture of methanol-phosphate buffer pH 7 (1:1) were applied to elute cefotaxime and its desacetyl metabolite. The separation was performed on a LiChrospher 100RP-18 (5 microm; 250 x 4 mm I.D.) column. The mobile phase consisted of 0.01 M acetate buffer pH 4.8-methanol (85:15), flow-rate was 1.5 ml/min. Cefotaxime and desacetylcefotaxime were detected at a wavelength of 254 nm by UV-Vis detector. The range of concentrations for method calibration and for analytical studies was 1.56-100 microg/ml. The quantitation limit in cerebrospinal fluid was 0.39 microg/ml for cefotaxime and 0.78 microg/ml for desacetylcefotaxime. The extraction recovery from cerebrospinal fluid spiked with cefotaxime and desacetylcefotaxime was 90.4-100.1% and 97.4-102.9%, respectively. The RSDs were below 10.7% for cefotaxime and 6.8% for desacetylcefotaxime. The developed SPE-HPLC method was applied for cefotaxime and desacetylcefotaxime determination in cerebrospinal fluid of children with hydrocephalus after intraventricular administration.

Comparative perilymph permeability of cephalosporins and its significance in the treatment and prevention of suppurative labyrinthitis.

Cephalosporins are nonototoxic antibiotics that provide excellent coverage for almost all bacteria that can cause suppurative labyrinthitis. In this study we performed comparative perilymph permeability determinations of the three cephalosporins that we deemed to have the most clinical potential in these varied situations. Perilymph pharmacokinetic profiles were established for ceftazidime, cefuroxime, and cefotaxime and its metabolite desacetylcefotaxime in 36 guinea pigs by using the technique of high-performance liquid chromatography. At 1, 2, 3, 4, and 6 hours after intravenous administration of the three cephalosporins at a dose of 100 mg/kg of body weight, ceftazidime consistently exhibited the highest perilymph concentration. Desacetylcefotaxime showed the next highest capacity for penetration into perilymph. Keeping in mind that the choice of drug for the treatment of suppurative labyrinthitis should be based foremost on culture and sensitivity studies, we consider ceftazidime to be the first-line agent for treatment and prevention of both meningogenic labyrinthitis and labyrinthitis complicating acute or chronic otitis media.

Pharmacokinetics of cefotaxime and its desacetyl metabolite in plasma and in cerebrospinal fluid.

The aim of the study was to investigate the pharmacokinetic modelling of Cefotaxime (CTX) and its main metabolite Desacetyl Cefotaxime (DCTX) which has a less antibacterial activity than the CTX. After intravenous administration of 1g of CTX to 26 patients, the plasma concentrations determined by HPLC showed that the pharmacokinetics of CTX and transformation to DCTX can be described with an open five-compartment model. The implications of this are discussed from the clinical point of view.

[Treatment with a cefotaxime-fosfomycin combination of staphylococcal or enterobacterial meningitis in adults]. / Traitement par l'association céfotaxime-fosfomycine des méningites de l'adulte à staphylocoques ou à entérobactéries.

Thirty-two patients were included in this trial: 22 with staphylococcal meningitis (including 5 methicillin-resistant) and 10 with enterobacterial meningitis. Mean duration of treatment was 14.5 and 15.9 days respectively. The combination was synergistic in vitro against 10 of the 12 strains of Staphylococcus and 5 of the 6 strains of Enterobacteriaceae studied. Bacteriological sterilization occurred in all cases which could be evaluated, and clinical recovery was obtained in 95.2% of patients with staphylococcal meningitis (4 unrelated deaths) and 100% of patients with enterobacterial meningitis (2 deaths). Bactericidal power of the cerebro-spinal fluid, often less than 1/8, was not correlated with effectiveness against Staphylococci. Mean CSF concentrations of cefotaxime, desacetylcefotaxime and fosfomycin on the 2nd and 15th days of treatment were 4, 3.5 and 39.8 mg/l and 2.2, 2.1 and 28.0 mg/l, respectively. Clinical and biological acceptability was satisfactory. There were three cases of superinfection or colonization, by Pseudomonas and Enterobacter.

[The penetration of cefotaxime into the cerebrospinal fluid. Comparison between acute and chronic stages in intracranial diseases].

Two grams of cefotaxime (CTX) were administrated by drip infusion to 10 patients (11 material) with acute or chronic stage of intracranial diseases. Concentrations of CTX in the serum and the cerebrospinal fluid (CSF) were determined at 15, 30, 60, 120, 240 and 300 minutes after injection. The results obtained were summarized as follows: Serum levels: Peak levels of CTX in sera were 66.2 +/- 10.23 (S.E.) micrograms/ml in the acute stage group (ASG), and 75.7 +/- 31.39 (S.E.) micrograms/ml at 15 minutes after injection in the chronic stage group (CSG). There were no significant difference between the 2 groups. CSF levels: Peak levels of the drug in CSF were 1.35-4.32 micrograms/ml in ASG and 0.18-0.7 microgram/ml in CSG. Average concentration at 60 minutes after injection was 1.11 +/- 0.09 (S.E.) micrograms/ml in ASG and 0.30 +/- 0.08 (S.E.) micrograms/ml in CSG. The value in ASG was significantly higher than the value in CSG by t-test. The ratio between CSF and serum levels: The levels increased as time passed in both groups and the values in ASG were higher than those in CSG at all time points. Average ratios at 60 minutes after injection were 3.85 +/- 0.29 (S.E.)% in ASG and 1.12 +/- 0.50 (S.E.)% in CSG. The value in ASG was significantly higher than that in CSG by t-test. From the above results, it is considered that CTX is useful for the prophylaxis of postoperative infections in intracranial diseases.

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

Cefotiam (CTM) is a new cephem antibiotic which has potent activities against Gram-positive and Gram-negative bacteria. We investigated the prophylactic treatment of CTM in orthopedic surgery and the concentrations of CTM Gram-negative in cerebrospinal fluid. The mean serum concentration at 2 hours after the drip infusion of CTM (3 g) was 28.28 +/- 5.48 micrograms/ml, and the mean concentration of CTM in cerebrospinal fluid was 0.58 +/- 0.07 micrograms/ml. From the result of multi-regression analysis in group I (12 cases, over 40 years old) and group II (10 cases, below 39 years old), it was suggested that the factor of age had a marked effect on cerebrospinal fluid concentrations of CTM. (Group I greater than Group II) High concentrations of CTM in cerebrospinal fluid after the 3 g-administration, exceeding the MIC80 for most causative organisms, suggested very useful prophylactic treatment of CTM in orthopedic surgery.

[The migration of cefotiam to cerebrospinal fluid].

The concentration of cefotiam (CTM), a newly synthesized cephem derivative antibiotic in serum and cerebrospinal fluid after single intravenous treatment was determined and its utility in the field of cerebral neurosurgery was studied. 1. One gram or 2 g of CTM was intravenously administered for 1 time to 10 patients admitted to our department. Dose dependency was observed in the progress of the mean serum concentration. There was no difference in the specific rate of constant, and the ratio of AUC between the group treated with 1 g and the one with 2 g was 1:1.9. The biological half-lives of the elimination phase for both dose levels were about 1.1 hours. 2. Disparity was recognized in the cerebrospinal fluid concentration in spite of the dose dependency. Although a case with comparatively high value of 1.37 micrograms/ml at 60 minutes after administration were seen in the 1 g treatment group, generally the migration concentration was low. Good cerebrospinal fluid concentration was attained in all of the cases in the 2 g treatment group, and the peak values ranged from 0.59 to 10.16 micrograms/ml. 3. The concentration ratio of cerebrospinal fluid to serum in the 2 g treatment group elevated till 360 minutes after administration, and the maximum values ranged from 15.8 to 89.8%. 4. The migration to the cerebrospinal fluid was faster in cases with slight inflammation than those without inflammation in the 2 g treatment group. 5. It was assumed that the prophylactic effect of CTM 2 g administration against staphylococci, streptococci and Klebsiella pneumoniae which are the major causative organisms can be expected in postoperative infection in the field of cerebral neurosurgery.

[Concentration of cefotiam in the cerebrospinal fluid].

Cefotiam of 1 to 2 g was intravenously given during 15 to 60 minutes in 10 cases, and blood levels and cerebrospinal fluid (CSF) levels were studied. Following the drip infusion of cefotiam, maximum blood levels of 25.2 to 305 micrograms per ml was an average of 101.2 micrograms per ml were achieved at 15 to 60 minutes in 9 cases. Half life of cefotiam in serum was from 20 to 50 minutes, and mean time was 39.4 minutes. In contrast, maximum CSF levels of cefotiam were ranged 1.4 to 17.2 micrograms per ml and mean value was 5.7 micrograms per ml in 8 cases. The ratios of CSF levels to blood levels were calculated from 1.7 to 6.6% with an average of 4.6%. The CSF levels of cefotiam showed long delay and long decay. The period between the drip infusion and peak levels of cefotiam in CSF showed 60 to 420 minutes and mean time was 194 minutes. Half life varied between 45 and 270 minutes with an average of 178 minutes. No side effects were found in all cases.

[Penetration of cefotiam dihydrochloride into cerebrospinal fluid (author's transl)].

It is well recognized that only very low concentration of antibiotics is obtained from cerebrospinal fluid (CSF) despite its high blood concentration. It has been attributed to the blood-brain and blood-CSF barriers. Penetration of CTM into CSF was studied in 7 patients. Two of them were complicated with septic meningitis, and others were not infected. CTM was administered intravenously and samples were obtained from both serum and CSF from 15 minutes to 4 hours for determination of concentration of the antibiotics. In 2 patients with meningitis, the peak level of CTM in CSF after intravenous injection of 2 g and 1 g of CTM was 197 mcg/ml (46% of peak serum concentration), and 17.3 mcg/ml (38% of peak serum level), respectively. In noninfected patients the peak level of CTM in CSF after intravenous injection of 1g of CTM was from 0.3 mcg/ml to 1.9 mcg/ml (0.84% approximately 3.64% of peak serum concentration). We conclude that the percent penetration of CTM into CSF increases in the presence of the inflamed meninges and that prophylactic dosage of CTM for postoperative meningitis will be intravenous administration of 2 g of CTM in adults.

[Transportation of cefotiam from serum to cerebrospinal fluid (author's transl)].

Cefotiam (1 g) was administered by one-shot intravenous injection to the patients proceeding a brain surgery. The cerebrospinal fluid (CSF) and serum were taken as a specimen, and the concentration CTM was assayed by agar-well method using Proteus mirabilis ATCC 21100. The most high concentration of CTM was 2,273 micrograms/ml in serum, and 2.3 micrograms/ml in CSF, respectively. The concentration of CTM in serum, CSF, and CSF/serum ration were determined at the indicated time. It appears likely that CTM can pass into CSF more easily than other cephalosporins.

[Transferability of cefodizime to cerebrospinal fluid of rabbits with meningitis caused by Staphylococcus aureus].

The transferability of cefodizime (THR-221, CDZM) to cerebrospinal fluid (CSF) was studied employing rabbits with experimental meningitis caused by Staphylococcus aureus. The mean blood concentration was 195 +/- 18.3 micrograms/ml using phosphate buffer solution (PBS) standard and 474 +/- 22.0 micrograms/ml using rabbit serum standard, respectively, at 15 minutes after intravenous administration of the drug at a dose level of 100 mg/kg. The mean concentration in CSF vs. PBS standard was maximum at 60 minutes after administration, and the mean maximum concentration was 8.74 +/- 2.16 micrograms/ml. Pharmacokinetic parameters calculated from those values were as follows, respectively, for PBS standard and rabbit serum standard; Cmax (CSF/serum): 4.48% and 1.84%. AUC (CSF/serum): 6.15% and 2.02% between 15 and 60 minutes, 10.6% and 3.00% between 15 and 120 minutes and 13.4% and 3.48% between 15 and 180 minutes. T 1/2 for CDZM in CSF: 141 minutes in both cases. T 1/2 (CSF/serum): 3.27 and 2.11. Concentrations in CSF determined using an high performance liquid chromatography method in another rabbits were similar to those determined using the bioassay vs. rabbit serum standard. The bioassayed concentration of this drug (AUC (CSF/serum] vs. PBS standard ranked 9th among 23 other beta-lactam antibiotics tested. That is, the drug distributed favorably as compared to other antibiotics, and it may be worthwhile of running clinical trials on this drug in meningitis when antimicrobial potential against main pathogens of meningitis are considered.

[A study on transference of cefmenoxime into the cerebrospinal fluid].

Two grams of cefmenoxime (CMX) was administered by one-shot intravenous injection to the patients in normal pressure hydrocephalus without meningitis, and the transference of CMX into the cerebrospinal fluid (CSF) from blood was investigated. After the injection of CMX, CSF and serum were serially taken, and the concentrations of CMX were measured by agar-well method using E. coli. The conclusions drawn from this study are summarized as follows: The concentrations of CMX in CSF were more slowly decreased than those in serum. The mean ratio of transference of CMX into CSF from the serum was 1.4%. After the intravenous injection of 2 g CMX, the mean maximum concentration of CMX in CSF was 0.36 microgram/ml, which exceeded 80% MIC (minimal inhibitory concentration) against several Gram-positive cocci and Gram-negative rods, and higher concentrations than the 80% MIC were kept over 4 hours in CSF. The efficacy of CMX may be kept by its injections less than 4 times a day.

[Experimental study on transferability to cerebrospinal fluid of cefodizime in combination with ampicillin].

A study was done on cefodizime (THR-221, CDZM) in combination with ampicillin (ABPC) for its transferability to cerebrospinal fluid (CSF) of rabbits with experimental meningitis caused by Staphylococcus aureus. Blood and CSF were collected at 15, 30, 45, 60, 90, 120 and 180 minutes after intravenous administration of CDZM at 100 mg/kg to 6 rabbits, ABPC at 100 mg/kg to 4 rabbits and simultaneous administration of both drugs at 100 mg/kg each to 5 rabbits. Drug concentrations were assayed with an high performance liquid chromatography method, and pharmacokinetic parameters were calculated. The comparison revealed no significant difference in concentrations achieved among different groups. Therefore, the mutual transferability of these drugs to CSF was not considered to interact adversely due to the simultaneous administration of both drugs. Accordingly, CDZM may be a candidate of chemotherapeutics in the therapy of purulent meningitis, and it is worthy of further investigations.