Effects of ampicillin, cefazolin and cefoperazone treatments on GLT-1 expressions in the mesocorticolimbic system and ethanol intake in alcohol-preferring rats.

Chronic ethanol consumption is known to downregulate expression of the major glutamate transporter 1 (GLT-1), which increases extracellular glutamate concentrations in subregions of the mesocorticolimbic reward pathway. While ß-lactam antibiotics were initially identified as potent upregulators of GLT-1 expression, only ceftriaxone has been extensively studied in various drug addiction models. Therefore, in this study, adult male alcohol-preferring (P) rats exposed chronically to ethanol were treated with other ß-lactam antibiotics, ampicillin, cefazolin or cefoperazone (100mg/kg) once daily for five consecutive days to assess their effects on ethanol consumption. The results demonstrated that each compound significantly reduced ethanol intake compared to the saline-treated control group. Importantly, each compound significantly upregulated both GLT-1 and pAKT expressions in the nucleus accumbens and prefrontal cortex compared to saline-treated control group. In addition, only cefoperazone significantly inhibited hepatic aldehyde dehydrogenase-2 enzyme activity. Moreover, these ß-lactams exerted only a transient effect on sucrose drinking, suggesting specificity for chronically inhibiting ethanol reward in adult male P rats. Cerebrospinal fluid concentrations of ampicillin, cefazolin or cefoperazone have been confirmed using high-performance liquid chromatography. These findings demonstrate that multiple ß-lactam antibiotics demonstrate efficacy in reducing alcohol consumption and appear to be potential therapeutic compounds for treating alcohol abuse and/or dependence. In addition, these results suggest that pAKT may be an important player in this effect, possibly through increased transcription of GLT-1.

Drug concentrations in the serum and cerebrospinal fluid of patients treated with cefoperazone/sulbactam after craniotomy.

BACKGROUND: To identify changes in cefoperazone/sulbactam penetration into cerebrospinal fluid (CSF) after craniotomy and to investigate preliminarily whether cefoperazone/sulbactam CSF concentration can reach therapeutic level when administered intravenously after neurosurgical operation. METHODS: Neurosurgical patients with an indwelling ventricular drainage pipe who received prophylactic cefoperazone/sulbactam for the treatment of intracranial infection were received a cefoperazone/sulbactam 2:1, 3.0-g infusion for 3 hours every 6 hours for 24 h. Venous blood and CSF specimens were collected to determine cefoperazone/sulbactam concentrations. RESULTS: The cefoperazone and sulbactam concentrations in serum were highest at the second hour (237.54 ± 336.72 mg/L and 66.52 ± 80.38 mg/L, respectively) and then decreased. The cefoperazone and sulbactam concentrations in CSF were highest at the 4th hour (39.22 ± 75.55 mg/L and 6.24 ± 8.35 mg/L, respectively) and then decreased. CSF penetration measured by the ratio of peak concentrations (CSF/serum) was 8.6% ± 7.2% for cefoperazone and 13.5% ± 11.9% for sulbactam, CSF penetration measured by the ratio of trough concentrations (CSF/serum) was 13.4% ± 5.3% for cefoperazone and 106.5% ± 87.5% for sulbactam. CSF penetration represented by the ratio of area under the curve (AUC) of CSF and serum was 14.5% for cefoperazone and 22.6% for sulbactam. Neurosurgical impairment of the blood-brain barrier may improve the CSF penetration of these drugs, but it is difficult to reach the MIC90 of resistant bacteria. If single intravenous administration time was extended to 3 hours, the serum concentrations of drugs were able to meet the PK/PD standard (T> MIC%> 50%) for treating common, highly resistant bacteria. CONCLUSIONS: The CSF penetration of cefoperazone/sulbactam may be enhanced after neurosurgical impairment of the blood-brain barrier. This study is a pilot research of cefoperazone/sulbactam using in neurosurgical individuals, However, it needs to be confirmed by further large-scale studies.

Cefoperazone therapy of bacterial meningitis: a clinical trial.

Sixteen hospitalized patients, aged between 10 and 76 years (mean: 34.3 years), with bacterial meningitis were treated i.v. with cefoperazone at daily doses of 4.5 g to 9 g. In two cases ampicillin was given in combination with cefoperazone during the last four days and the first five days of treatment, respectively. The following organisms were isolated: Neisseria meningitidis (n = 9), Haemophilus influenzae (n = 3), Escherichia coli (n = 2), Streptococcus pneumoniae (n = 2). Fourteen patients completely recovered from infection and the pathogens were eradicated; the treatment failed in only two patients and both were cured with alternative treatment. Furthermore, in 11 patients cefoperazone serum and CSF levels were determined four times during the first week of treatment (1st, 3rd, 5th and 7th days). No important side effects were recorded.

[The penetration of cefoperazone into the cerebrospinal fluid in patients on acute or chronic stage].

Cefoperazone (CPZ) was administered to 10 patients with cerebrovascular disturbances at acute and chronic phases to investigate its passage into the cerebrospinal fluid. The antibiotic was administered at dosages of 1 g and 2 g to patients in the acute phase to examine the dose-dependency. The results obtained are summarized as follows: 1. Serum concentrations Peak values of CPZ were 46.9 +/- 4.42 microgram/ml in acute phase patients in 1 g dosage group (acute group 1), 253.1 +/- 63.2 micrograms/ml in acute phase patients in 2 g dosage group (acute group 2), and 197.9 +/- 15.7 micrograms/ml in chronic phase patients in 2 g dosage group (chronic group 2) at 1 hour after CPZ administration. Concentrations of CPZ varied about 5-fold between the 1 g dosage group and the 2 g dosage groups. The acute group 2 showed generally higher values of CPZ concentrations than the chronic group 2. 2. Cerebrospinal fluid concentrations. Peak values were 0.96 +/- 0.30 microgram/ml (at 3 hours) in acute group 1, 4.55 +/- 3.41 micrograms/ml (at 1 hour, except 1 case) in acute group 2, and 1.29 +/- 1.28 micrograms/ml (at 1 hour) in chronic group 2. Acute group 2 showed generally higher values than chronic group 2. 3. CPZ was considered useful for the prevention of postoperative infections in the field of brain surgery.

Cefoperazone therapy of bacterial meningitis: a preliminary report.

Eleven hospitalized patients with bacterial meningitis were treated with cefoperazone at daily dosage ranging between 3 and 8 g intravenously. Seven patients had proven Gram-negative bacterial infections, but in four patients the aetiological agent remained unknown. Eight patients completely recovered from infection and the pathogens were eradicated, in one patient the treatment failed and in two patients only some improvement was registered. Furthermore in five patients cefoperazone serum and cerebrospinal fluid levels were determined four times in the first week of treatment (1st, 3rd, 5th and 7th day). No side-effects were recorded. Cefoperazone can be considered as effective antimicrobial agent in the therapy of bacterial meningitis.

[Clinical studies of cefoperazone in neurosurgery].

A multicenter trial consisting of 164 institutions through out Japan, has been conducted to study the transfer of cefoperazone (CPZ) into the cerebrospinal fluid (CSF), and the clinical effectiveness of CPZ as a therapeutic or prophylactic agent in neurosurgery. The levels of CPZ in serum and CSF were determined in 96 patients. After initial dose of 2 g CPZ (intravenous drip infusion for 30 minutes), the serum level of CPZ after 1 hour was 124.5 +/- 6.6 micrograms/ml (Mean +/- S.E.), and even after 6 hours, it maintained as high as 47.8 +/- 16.6 micrograms/ml. The peak CPZ levels in CSF in patients with normal or minimal impairment in blood-CSF-barrier (BCB) (group I) and in those of localized impairment in BCB (group II) were 1.0 +/- 0.5 micrograms/ml at 2 hours and 3.0 +/- 1.8 micrograms/ml at 3 hours, respectively. The highest CSF level was seen in patients with meningitis (group III) and showed 5.0 +/- 2.4 micrograms/ml at 6 hours. After multiple dose of 2 g CPZ (intravenous drip infusion for 30 minutes), the serum kinetics of CPZ were not significantly different from those obtained after initial dose. However, the CPZ levels in CSF were higher than those observed after initial dose in all 3 groups and were higher than MIC75 against relevant pathogens for meningitis such as Escherichia coli, Klebsiella pneumoniae and Staphylococcus aureus. Moreover, in group III peak level of CPZ in CSF exceeded the MIC75 against Pseudomonas aeruginosa which is also frequently isolated from patients with meningitis in neurosurgery. As a therapeutic agent CPZ administered as sole agent was effective in 42 out of 55 cases (76.4%) in meningitis, in 78 out of 116 cases (67.2%) in pneumonia and in 36 out of 47 cases (76.6%) in urinary tract infection (UTI). Its efficacy rate against all infections treated was 72.2% (184/255). Regarding CPZ's prophylactic use, 39 out of 514 cases (7.6%) were judged as having or possibly having infections as follows; meningitis (13/514, 2.5%), pneumonia (15/514, 2.9%), UTI (2/514, 0.4%). In prophylactic use of CPZ, the incidence rates of postoperative meningitis and other central nervous system (CNS) infection following ventricular drainage and supratentorial craniotomy for aneurysm were higher than those observed in other types of operation, 12.0% (3/25) and 6.2% (8/130), respectively. Also, regarding prophylactic use of CPZ, the organisms isolated by culture from 13 cases of postoperative CNS infections included 2 strains of Staphylococcus sp., 1 strain of Serratia sp. and 3 strains of other Gram-negative bacteria (GNB).(ABSTRACT TRUNCATED AT 400 WORDS)

[A study of cefoperazone levels in the cerebrospinal fluid of patients with hydrocephalus].

Eleven neurosurgical patients without intracranial infection were given 4 g cefoperazone (CPZ) intravenously for 30 minutes. Ventricular drainage was performed in 10 cases, and 1 case with cisternal drainage. Eight of 11 cases showed moderate to severe ventricular dilatation. Serum and ventricular cerebrospinal fluid (CSF) concentrations of CPZ were measured for 8 hours after injection. Average peak serum concentration of CPZ was 476 micrograms/ml and the half-life was 150 minutes. Patients with obstructive hydrocephalus showed relative good penetration of CPZ in CSF (2.74 approximately 5.29 micrograms/ml). Especially, those who had severe dilatation of ventricles demonstrated sequential increased concentration (5.48 approximately 6.25 micrograms/ml at 8 hours). In poor risk patient and intracerebral hemorrhage with ventricular hemorrhage cases, who had normal range of CSF cell counts and protein, CPZ level was low, less than 2 micrograms/ml. In cases with severe subarachnoid hemorrhage, sufficient concentration (11 micrograms/ml) of CPZ was observed in cisternal CSF. The CPZ concentrations in CSF after 4 g administration did not seem to exceed comparing to 2 g dosing.

[Basic and clinical studies of sulbactam/cefoperazone in pediatric field].

We conducted several studies using a combination of sulbactam (SBT) and cefoperazone (CPZ) in a ratio of 1:1 with the following results. Serum and cerebrospinal fluid (CSF) concentrations of the drugs were determined in 2 rabbits with meningitis caused by S. aureus. Following intravenous injection, serum concentrations of CPZ were higher than those of SBT in both rabbits whereas CSF concentrations were much higher with sulbactam than with CPZ indicating good penetrability of SBT into CSF. The serum concentration of SBT at 1/2, 1, 2 and 4 hours after an intravenous administration of 9.8 mg/kg of the combination to a child were 3.5, 1.4, 0.3 and 0.1 microgram/ml and those of CPZ 19.0, 13.0, 6.7 and 2.9 micrograms/ml, respectively. The half-lives were 0.705 hours for SBT and 1.31 hours for CPZ. An intravenous dose of this combination (19.6 mg/kg) was given 3 times a day to 13-year-old girl with decreased neutrophil chemotaxis due to periblepharal abscess caused by S. aureus. The therapeutic effect was excellent. Though very slight transient eosinophilia was noted, no adverse reaction was found. The susceptibility of the isolated organism to this drug was not determined, but it was found to be resistant to the CTX using the disc method.

[Concentration of antibiotics (cefoperazone) in human brain, brain tumor tissue and cerebrospinal fluid].

The transfer of cefoperazone (CPZ) into cerebrospinal fluid (CSF), brain or brain tumor tissue was studied in 13 cases with brain tumor, chronic subdural hematoma and benign intracranial hypertension in 1982. The peak values of CPZ in serum came up immediately after its rapid intravenous administration and then decreased exponentially. The concentration of CPZ in CSF started to increase with a long delay of about 60 min. The average peak level in CSF remained 21.6 micrograms/ml and corresponded to 10.3% of the peak level in serum. The best transfer of chloramphenicol into CSF has been reported, while that of CPZ would be one of the next. The CPZ levels in CSF showed a slower decay than in serum. The concentration of CPZ in brain reached the peak level in less than 30 min and the average peak level was 36.5 micrograms/g cerebral tissue. The brain to blood rate of the CPZ concentration was 11.1%. The CPZ levels in the brain showed a rapid decrease like the transition of antibiotic levels in serum. The antibiotic levels in brain tumors were divided into two groups. The one showed sharp peak about one tenth of the values in serum. The other was of a slowly increasing type.

Cefoperazone pharmacokinetics in acute childhood meningitis.

We studied the serum pharmacokinetics and cerebrospinal fluid concentrations of cefoperazone in 15 children with acute meningitis. Mean cefoperazone concentrations of 117 micrograms/ml in the serum and 3.8 micrograms/ml in the cerebrospinal fluid were noted 2 hours after a single 100 mg/kg dose. Following multiple 50 or 100 mg/kg doses, the mean peak serum cefoperazone concentrations were 232 and 498 micrograms/ml, respectively, with an overall mean elimination phase half-life of 2.12 hours. The data best fit a linear, two-compartment model. Cerebrospinal fluid concentrations 1.5 to 2.5 hours after the end of cefoperazone infusions ranged from 1.4 to 19.2 micrograms/ml for all doses and states of illness. This represented 1.2% to 6.4% of simultaneous serum values. The cerebrospinal fluid inhibitory titer was greater than or equal to 1:16 in 17 of 18 specimens tested against a strain of Haemophilus influenzae type b resistant to both chloramphenicol and ampicillin. In the doses given, cefoperazone produces adequate cerebrospinal fluid concentrations and bioactivity to treat the common bacterial forms of acute meningitis in infants and children.