Search

Studies have shown that administration of the β-lactam antibiotic ceftriaxone (CEF) attenuates ethanol consumption and cocaine seeking behavior as well as prevents ethanol-induced downregulation of glutamate transporter 1 (GLT-1) expression in central reward brain regions. However, it is not known if these effects are compound-specific. Therefore, the present study examined the effects of two other β-lactam antibiotics, amoxicillin (AMOX) and amoxicillin/clavulanate (Augmentin, AUG), on ethanol drinking, as well as GLT-1 and phosphorylated-AKT (pAKT) levels in the nucleus accumbens (Acb) and medial prefrontal cortex (mPFC) of alcohol-preferring (P) rats. P rats were exposed to free-choice of ethanol (15% and 30%) for five weeks and were given five consecutive daily i.p. injections of saline vehicle, 100 mg/kg AMOX or 100mg/kg AUG. Both compounds significantly decreased ethanol intake and significantly increased GLT-1 expression in the Acb. AUG also increased GLT-1 expression in the mPFC. Results for changes in pAKT levels matched those for GLT-1, indicating that β-lactam antibiotic-induced reductions in ethanol intake are negatively associated with increases in GLT-1 and pAKT levels within two critical brains regions mediating drug reward and reinforcement. These findings add to a growing literature that pharmacological increases in GLT-1 expression are associated with decreases in ethanol intake and suggest that one mechanism mediating this effect may be increased phosphorylation of AKT. Thus, GLT-1 and pAKT may serve as molecular targets for the treatment of alcohol and drug abuse/dependence., (Copyright © 2015 Elsevier B.V. All rights reserved.)

In the management of cerebrospinal fluid (csf) fistulae, associated with head and facial injury, prophylactic antimicrobial drugs are employed commonly to prevent the occurrence of bacterial meningitis. Under normal circumstances, penicillins achieve a low csf/plasma concentration ratio, but trauma may reduce the efficacy of the blood-brain barrier and permit increased amounts of penicillins to enter the csf. To test this hypothesis, with respect to Augmentin (amoxycillin and clavulanic acid), an animal study was undertaken. Under general anaesthesia, the brains and meninges of a group of 10 rabbits were traumatised to produce csf fistulae. Following the administration of an intravenous bolus of Augmentin, the blood and csf concentrations of Augmentin were measured over a period of 6 h and compared with those measurements from an untraumatised control group of 10 rabbits. No difference in the csf/plasma ratio was apparent between the two groups. The results of this study, therefore, suggest that trauma to the brain and meninges does not increase the permeability of the blood-brain barrier to Augmentin.

Penetration of aspoxicillin (ASPC), a new semisynthetic penicillin, to cerebrospinal fluid (CSF) and clinical studies against bacterial infections were carried out and the following results were obtained. The concentration of ASPC in CSF was below 1 microgram/ml at 1 hour after intravenous administration of about 50 mg/kg dose to 2 cases of aseptic meningitis on the acute stage. The concentration of ASPC in CSF was above 10 micrograms/ml at 1 hour after intravenous administration of about 80 mg/kg dose to 3 cases of purulent meningitis on the acute stage, and was above 2 micrograms/ml even on the recovering stage. On each stage, its concentration was more than minimum inhibitory concentration of H. influenzae (less than or equal to 0.05 microgram/ml; at inoculum size of 10(6) cells/ml). Clinical efficacy of ASPC was good in all 3 cases of purulent meningitis, excellent in 3 cases, good in 3 cases and poor in 1 case out of 7 cases of septicemia, good in 2 cases and poor in 1 case out of 3 cases of gastroenteritis, respectively. And clinical efficacy of other diseases were excellent or good, that were 2 cases of tonsillitis, 2 cases of soft tissue abscess, 1 case of purulent lymphadenitis and 1 case of urinary tract infection, respectively. Side effects were mild eosinophilia in only 2 cases out of 22 cases.

A serum amoxycillin concentration of 0.11 g/l was established as being treponemicidal in a rabbit model with orchitis. Seventeen patients treated with amoxycillin 2 g by mouth three times a day plus 500 mg probenecid twice a day attained treponemicidal CSF amoxycillin concentrations. Thus amoxycillin by mouth offers an effective alternative method for treating patients with neurosyphilis.

A single intravenous dose of 2.0 g of amoxicillin and 0.2 g of potassium clavulanate was given to patients with bacterial meningitis, and the pharmacokinetics of both drugs in the cerebrospinal fluid (CSF) and plasma were evaluated. Twenty-one patients aged 14 to 76 years were studied. Both amoxicillin and potassium clavulanate were detectable in the CSF as early as 1 h and reached peak concentrations by approximately 2 h. The highest mean CSF concentrations were 2.25 micrograms/ml for amoxicillin and 0.25 micrograms/ml for potassium clavulanate and were found in patients with moderately or severely inflamed meninges. The CSF penetration relative to plasma for amoxicillin and potassium clavulanate was 5.8 and 8.4%, respectively. These levels suggest that the amoxicillin-potassium clavulanate combination may be effective for the treatment of bacterial meningitis caused by beta-lactamase-producing pathogens.

The results of a study of the CSF concentration of i.v. amoxicillin in control subjects free of meningeal inflammation are presented. The drug proved capable of passing the blood-brain barrier when employed in sufficiently high doses, even in the absence of meningeal inflammation. The CSF level of the antibiotic was higher than the MIC required for most of the meningeal pathogens.

Forty-three infants and children with bacterial meningitis were treated intravenously with 200 mg of amoxicillin sodium per kg per day for 10 days. (Patients were initially treated with ampicillin and chloramphenicol until the bacterial etiology was defined.) Patients were randomly treated with amoxicillin only or with amoxicillin and four doses of probenecid (10 mg/kg per dose) orally every 6 h for 24 h before the lumbar puncture at day 10. Serum and cerebrospinal fluid (CSF) were obtained on days 1, 5, and 10 of therapy for antibiotic assay. The mean peak serum concentration of amoxicillin of 49.2 micrograms/ml was increased to 61.4 micrograms/ml in patients who received probenecid. The half-life in serum (1.5 h) and area under the curve with probenecid (112.5 micrograms/ml-h) were increased compared with those of amoxicillin alone (1.3 h and 82.2 micrograms/ml-h). The mean peak CSF concentrations on days 1 and 5 were similar, but day 1 concentrations remained between 2.0 micrograms/ml and 5.0 micrograms/ml throughout the 4 h after a dose, whereas the day 5 values decreased at the same decay rate as that in serum. All CSF concentrations were lower on day 10, but patients receiving probenecid had peak values occurring at 1 hr rather than at 0.5 h, and levels were significantly greater at 1 and 2 h after a dose. There were no deaths and patients responded well to treatment.

Hundred and fifteen children suffering of purulent meningitis (S.pneumoniae: 19; H.influenzae: 44; N.meningitidis; 23; others: 29) were treated by amoxicillin 200 mg/kg/day in four intramuscular injections. Spinal taps for assay of antibiotic levels in the CSF were taken 1 or 3 or 6 hours after the injection. The levels were respectively for this samples of 6.9 -1.7-1.4 micrograms/ml during the first 48 hours of treatment and 4.4-1.7-1.9 after one week. The concentrations CSF/serum were from 5 to 9.8 per cent at the beginning of treatment.

The pharmacokinetics of amoxycillin in the CSF following intravenous and oral administration at a 150 mg/kg per day or 250 mg/kg per day dosage in the treatment of purulent meningitis is described. A significant correlation between meningeal inflammation and CSF levels of amoxycillin were observed, including a correlation between the initial neurological state and the outcome of the illness. Despite the early introduction of oral therapy and the reduction in dosage following meningeal and pneumococcal meningitis, no treatment failures could be attributed to this therapeutic regime. Such a treatment schedule, moreover, reduces the risk of superinfection in hospital as well as the cost of treatment and aids the comfort to the patient.

Amoxicillin and ampicillin levels were comparatively studied in blood and CSF of children with purulent meningitis. Thirty one children aged 2 months to 11 years were treated by one of two beta lactams by monotherapy in a daily dose of 200 mg/kg (Group 1: amoxicillin, n = 17; group 2: ampicillin, n = 14). Samples were collected on day 2 one hour after administration of 50 mg/kg IV of the chosen antibiotic. The mean levels observed in serum (69.5 and 53.4 micrograms/ml) and in CSF (7.74 and 7.96) were not significantly different. Beyond these levels we studied different biologic parameters in CSF: leucocytes, polymorphonuclears, protein, glucose and lactic acid. Multiple linear correlations were found, for the two groups and for the whole population between the CSF antibiotic level and the 6 other parameters (group 1: R1 = 0.82; group 2: R2 = 0.88; group 1 + 2: R3 = 0.78). The best correlated parameters with antibiotic CSF level are serum antibiotic level and CSF lactic acid. With these two parameters we can also estimate antibiotic level in CSF with good correlations (R1 = 0.78; R2 = 0.72 and R3 = 0.72).

Rapid eradication of bacteria from the CSF is critical for the outcome of Haemophilus influenzae meningitis in children. In 15 patients studied, the mean H. influenzae colony counts in CSF were 10(5) CFU/ml (range: 10(2) to 10(9) CFU/ml). Time-kill curves were determined for amoxicillin and cefotaxime alone and in combination with gentamicin or amikacin, against 60 clinical isolates of H. influenzae at concentrations equivalent to those found in CSF following systemic administration. Against beta-lactamase-negative strains (n = 44) a bactericidal effect was observed at 18 h for amoxicillin alone, at 5 h for amoxicillin plus aminoglycosides and at 2.5 h for cefotaxime with or without aminoglycosides. Against beta-lactamase-positive strains a bactericidal effect was observed at 18 h for cefotaxime, at 5 h for amoxicillin plus aminoglycosides and at 2.5 h for cefotaxime plus aminoglycosides. It appears that despite low concentrations of gentamicin or amikacin in the CSF, the accelerated killing of H. influenzae provides a rationale for the initial use of the combination of cefotaxime and aminoglycosides in the initial treatment of H. influenzae meningitis.

Patients with purulent meningitis received amoxicillin-clavulanic acid (200/20 mg/kg [body weight] per day). Clavulanic acid levels in cerebrospinal fluid were less than or equal to 0.05 micrograms/ml in 5 of 18 samples and ranged from 0.1 to 0.8 micrograms/ml in the others. Of 12 cerebrospinal fluid samples tested, 10 lacked bactericidal activity in vitro against a beta-lactamase-producing strain of Haemophilus influenzae.

Eleven children with bacterial meningitis were treated intravenously with amoxicillin sodium to evaluate the efficacy of the parenteral form of amoxicillin for this serious infection and to measure the penetration of the drug into cerebrospinal fluid (CSF). The infecting organisms were Haemophilus influenzae in nine cases and Streptococcus pneumoniae in two. Nine patients had optimal responses to amoxicillin sodium, 200 mg/kg per day for 14 days. Bacteria were also eradicated from CSF of the other two, but one experienced fever and culture-negative CSF pleocytosis after cessation of amoxicillin, and the other developed H. influenzae empyema 2 weeks after termination of therapy. By comparison, 7 of 10 children with meningitis responded optimally to ampicillin (nonrandomized design) during the period of study. The mean peak CSF concentration of amoxicillin was 3.14 mug/ml (ca. 7% of the concomitant mean peak serum level) early during therapy. However, meningeal penetration of the drug declined to a mean peak of 0.63 mug/ml on the final day of therapy. Mild transient neutropenia, noted in five patients, was the most common side effect of amoxicillin sodium therapy; five patients treated with ampicillin also experienced reversible neutropenia. Thus, intravenous amoxicillin sodium provided therapy for bacterial meningitis comparable to that of ampicillin in this limited case-control study.

The entry of amoxicillin and ampicillin into cerebrospinal fluid (CSF) of humans was studied in the absence of meningeal inflammation. Twelve volunteers received 33 mg of amoxicillin per kg intravenously over 30 min and nine volunteers received 33 mg of ampicillin per kg. The CSF specimens were sampled at 1, 2, and 4 h after the beginning of the infusion. Blood samples were obtained at the end of the infusion and at 45, 60, 90, 120, 180, and 240 min after the beginning of the infusion. Amoxicillin and ampicillin were both detected in the CSF. Ampicillin tended to give higher CSF levels than amoxicillin, although the difference was small. Serum concentrations of ampicillin equaled those of amoxicillin.

An experimental meningitis model was produced in rats with Streptococcus pneumoniae Type III and used to evaluate the therapeutic effect of aspoxicillin in comparison with piperacillin, mezlocillin and ampicillin. At the same time, their bactericidal activities and pharmacokinetics in cerebrospinal fluid (CSF) were determined. The experimental meningitis model was prepared by intracisternal inoculation of the organism. The rats in this model began to die 2 days after the infection and all died within 5 days. Histological examination also revealed that this model was a fatal pneumococcal meningitis model in rats. The concentrations of these penicillins in CSF of the infected rats determined by the high performance liquid chromatography method were significantly increased by bacterial infection. Of these drugs, ASPC gave the highest penetration into the infected CSF and the longest persistency in CSF. In a comparison of the bactericidal activity of these penicillins in this model, aspoxicillin at a dose of 20 mg/kg inhibited the regrowth of bacteria in CSF 24 h after administration, but the other three penicillins did not. To conclude, in this new experimental meningitis model in rats, aspoxicillin showed an excellent therapeutic effect due to its stronger bactericidal action and favourable pharmacokinetic properties.

The penetration of amoxicillin into cerebrospinal fluid (CFS) in the presence of meningeal inflammation was evaluated in patients with tuberculous meningitis. Serum and CSF concentrations of amoxicillin were measured at 2 h in nine patients who received a 1-g oral dose and at 1.5 and 4 h in ten patients who received a 2-g intravenous injection of sodium amoxicillin. After the oral dose, CSF concentrations ranged from 0.1 to 1.5 mug/ml. After the intravenous injection, CSF concentrations ranged from 2.9 to 40.0 mug/ml at 1.5 h and from 2.6 to 27.0 mug/ml at 4 h. These data on penetration suggest that parenterally administered sodium amoxicillin may be of value in the therapy of acute bacterial meningitis.