Cefoselis

Cefoselis is a widely used antibiotic of β-lactam [1].

Cefoselis has a large antibacterial spectrum against gram positive bacterium. It is a 4th generation of cephalosporin. Cefoselis has some side effects, such as inducing seizures and convulsion in elder and renal failure patients. Through testing the dialysate and blood samples by HPLC, it shows that cefoselis appears in the striatal dialysate samples does-dependently and disappears rapidly from the extracellular fluid. In renal failure rats, the elimination half-lives of cefoselis are prolonged. It may be one factor of the seizures caused by cefoselis. In addition, administration of cefoselis into the hippocampus causes highly increase of extracellular glutamate and slightly increase of GABA, suggesting that cefoselis induces seizures through blocking the GABA receptors [1].

References:
[1] Ohtaki K, Matsubara K, Fujimaru S, Shimizu K, Awaya T, Suno M, Chiba K, Hayase N, Shiono H. Cefoselis, a beta-lactam antibiotic, easily penetrates the blood-brain barrier and causes seizure independently by glutamate release. J Neural Transm. 2004 Dec;111(12):1523-35.

Multicenter, double-blind, randomized clinical trial of parenterally administered Cefoselis versus Cefepime for the treatment of acute bacterial infections.[Pubmed:25027339]

Eur Rev Med Pharmacol Sci. 2014;18(14):2006-12.

AIM: This study aims to evaluate the clinical efficacy and safety of intravenous Cefoselis injection for the treatment of acute moderate and severe bacterial infections. PATIENTS AND METHODS: A multicenter, double-blind, randomized clinical trial was carried out using Cefepime as control. Patients received 1.0 g of either Cefoselis or Cefepime for moderate infections or 2.0 g for severe infections at an interval of 12 hours for 7 to 14 days. A total of 276 patients (138 with Cefoselis, 138 with Cefepime) with respiratory or urinary tract infections were enrolled in the study. Up to 137 and 124 patients receiving Cefoselis and 132 and 125 patients receiving Cefepime were eligible for the ITT (intent to treat) and PP (per protocol) analyses, respectively. RESULTS: At the end of the treatment, the cure rates and effective rates were 59.68% (74/124) and 93.55% (116/124) with Cefoselis, and 56.00% (74/124) and 90.40% (116/124) with Cefepime. The bacterial eradication rates of the two groups were 90.32% and 93.85%, respectively. No statistical differences were observed on the above-mentioned parameters between the two groups (all p > 0.05). Adverse events, mainly mild aminotransferase elevation and mild leukopenia, were observed in 11.59% (16/138) and 13.77% (19/138) of patients with Cefoselis and Cefepime, respectively (p > 0.05). CONCLUSIONS: Cefoselis is an effective and safe choice against acute moderate and severe respiratory infections and UTI (urinary tract infection).

Stability studies of cefoselis sulfate in the solid state.[Pubmed:26073113]

J Pharm Biomed Anal. 2015 Oct 10;114:222-6.

The process of degradation was studied by using an HPLC-DAD method. Two degradation products were identified with a hybrid ESI-Q-TOF mass spectrometer. The influence of temperature and relative air humidity (RH) on the stability of Cefoselis sulfate was investigated. In the solid state at increased RH the degradation of Cefoselis sulfate was an autocatalytic reaction of the first order with respect to substrate concentration while in dry air was first-order reaction depending on the substrate concentration. The kinetic and thermodynamic parameters of degradation were calculated.

Intracerebroventricular injection of the antibiotic cefoselis produces convulsion in mice via inhibition of GABA receptors.[Pubmed:12376152]

Pharmacol Biochem Behav. 2002 Dec;74(1):53-9.

A majority of beta-lactam antibiotics (e.g., cephalosporins and penicillins) have convulsive activity to a greater or lesser extent. (6R,7R)-3-[[3-Amino-2-(2-hydroxyethyl)-2H-pyrazol-1-ium-1-yl]methyl]-7-[(Z)-2-(2- aminothiazol-4-yl)-2-methoxyiminoacetylamino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct -2-ene-2-carboxylate monosulfate (Cefoselis), a newly developed injectable beta-lactam antibiotic with activity against methicillin-resistant Staphylococcus aureus (MRSA), might induce convulsions if cerebral concentrations become highly elevated. In the present study, we examined whether or not Cefoselis had convulsive activity after direct brain administration, and we attempted to clarify the pharmacological mechanism of action. When Cefoselis was injected into the lateral ventricle of the mouse brain at doses higher than 20 microg/animal, it produced convulsions dose-dependently. Cefoselis (50 microg/animal)-induced convulsions were prevented by pretreatment with 5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine (MK-801), diazepam and phenobarbital (ED(50) values (mg/kg) of 0.78, 1.59 and 33.0, respectively), but not by carbamazepine or phenytoin. When the effects of these anticonvulsants on the convulsions induced by intracerebral injection of bicuculline methiodide (BMI) or N-methyl-D-aspartate (NMDA) were investigated, the inhibitory profile of anticonvulsants on Cefoselis-induced convulsions was similar to those induced by BMI (125 ng/animal) but differed markedly in their inhibitory activity on NMDA (100 ng/animal)-induced convulsions, which were not inhibited by diazepam. These results suggest that Cefoselis may be convulsive at higher concentrations through a mechanism involving inhibition of gamma-aminobutyric acid (GABA)(A) receptors.

Cefoselis, a beta-lactam antibiotic, easily penetrates the blood-brain barrier and causes seizure independently by glutamate release.[Pubmed:15565489]

J Neural Transm (Vienna). 2004 Dec;111(12):1523-35.

Cefoselis is a widely used beta-lactam antibiotic, but occasionally induces seizures and convulsion in elder and renal failure patients. However, beta-lactams are known not to pass through the blood-brain barrier (BBB). In this study, we examined the BBB penetration of Cefoselis in normal and renal failure rats by means of brain microdialysis. Cefoselis was dose-dependently appeared in brain extracellular fluid in proportion to its blood level. The elimination constant from brain extracellular fluid (apparent) was slightly lower than that from blood. These results indicated that Cefoselis might penetrate the BBB or be discharged by a certain transport system. In contrast to the result of Cefoselis, cefazolin, a leading drug of cephalosporins, could not be detected in the brain extracellular fluid after an intravenous injection. In renal dysfunction rats, the elimination half-lives of Cefoselis from both blood and brain were extensively prolonged. This would be one of responsible factors inducing seizures seen in patients. However, the additional factor, such as decrease in brain function related to aging, would be involved in seizures in patient received Cefoselis, because an extremely high dose was required to induce seizures even in renal failure rats. A local administration of Cefoselis into the hippocampus through the microdialysis probe caused a striking elevation of extracellular glutamate, with a minimum increase in gamma-aminobutyric acid (GABA). However, a systematic Cefoselis administration via the tail vein did not elevate extracellular glutamate and GABA concentrations in the hippocampus of renal failure rats that exhibited marked seizures. These results suggested that not the stimulation of glutamate release, but the blockade of GABA receptors might be responsible for the seizure induced by Cefoselis.