Community-aquired pneumonia caused by atypical bacteria or viruses was studied in a double-blind trial comparing fleroxacin 400 mg od and doxycycline 100 mg bd for 10 days. The aetiology was confirmed in 258 of 411 cases (66%), of which 133 were caused by Mycoplasma spp., Chlamydia spp. or Legionella spp.; 30 patients had viral infection, nine had pneumococcal or Haemophilus influenzae infection and 93 had mixed aetiology. In intention-to-treat analyses clinical response rates in fleroxacin-treated patients were 86% (157/182) and 75% (137/182) 2-8 days and 3-5 weeks after therapy, respectively. Corresponding results with doxycycline were 93% (177/191) and 85% (162/190), respectively. Differences between treatments seemed to be due to the lower activity of fleroxacin compared with doxycycline against mycoplasma and pneumococci. Drug-related adverse events were reported in 39% of 204 fleroxacin patients and in 34% of 207 doxycycline patients. The null hypothesis that fleroxacin was <15% inferior to doxycycline was accepted at early follow-up but rejected at later review.

The effect of intravenous ciprofloxacin (CPX) pretreatment on the kinetics and brain sensitivity for thiopental was studied in male rats using a previously developed electroencephalographic (EEG) threshold method. Thiopental was administered intravenously with constant infusion rate. Immediately after the appearance of the first burst suppression of 1 sec. or more (the "silent-second") in the EEG the infusion was stopped and the rats were killed by decapitation. The dose of thiopental needed to reach the criterion of silent-second was slightly reduced in ciprofloxacin pretreated rats when compared with saline pretreated controls. One rat that developed seizures after CPX pretreatment needed a considerably reduced dose of thiopental to induce the silent-second. The serum concentrations of thiopental were markedly reduced in the experimental group while no significant differences were found in the concentrations of thiopental in the different parts of the central nervous system (CNS), fat or muscle tissue. The kinetics of CPX were also affected. The experimental group (CPX + thiopental treated) had significant higher brain concentrations of CPX than the corresponding only CPX treated control group while no differences were found in the serum concentrations of CPX between the groups. As previously suggested, the distribution of thiopental in the CNS is not only dependent on its lipid solubility, but also as a weak organic acid, on the transport system for organic acids out of the CNS which both thiopental and ciprofloxacin seem to use and mutually compete for it.

Neurotoxic reactions caused by beta-lactam antibiotics occur frequently following direct application of antibiotic to the brain surface or into the cerebral cisterns. Epileptogenic reactions have also been observed after administration of very high systemic doses. There seem to be considerable differences in the neurotoxic potential of the various beta-lactams; benzylpenicillin, cefazolin and, lately, imipenem/cilastatin appear to be drugs with higher neurotoxic potential than other compounds. There is now strong evidence that the concentration of beta-lactam in the brain, and not that in the cerebrospinal fluid, is the decisive factor for the risk of neurotoxic reactions. Factors known to increase the risk of neurotoxicity are excessive doses, decreased renal function, damage to the blood-brain barrier, preexisting diseases of the central nervous system, old age and concurrent use of drugs that are nephrotoxic or that may lower the seizure threshold. Another factor that may be of importance is blockage of the transport system that is responsible for transport of beta-lactams out of the central nervous system.

The effect of benzylpenicillin (BPC) pretreatment on the kinetics and brain sensitivity for thiopental was studied in male rats using a previously developed electroencephalgrafic (EEG) threshold method. Thiopental was infused intravenously with constant infusion rate. The rats were killed by decapitation immediately after the first burst suppression of 1 sec. or more (the silent second) which was observed in the EEG-record during the infusion. Thiopental concentration in serum and in different brain regions was determined by a high pressure liquid chromatografic method. After pretreatment with 0.9 g/kg of BPC the dose of thiopental needed to induce the silent second was significantly reduced (-20 per cent) when compared with saline treated controls. The serum concentration was also reduced (-30 per cent) after this BPC pretreatment but the concentrations in the different brain regions were the same in both groups. After pretreatment with 1.2 g/kg of BPC almost all animals had convulsions, the dose needed to obtain the silent second was very much reduced and there were reduced concentrations of thiopental in the different brain regions. After both doses of BPC high negative correlations were found between BPC concentrations in brain tissue and thiopental concentrations in hippocampus and brainstem indicating an interaction between the drugs. The most probable site of this interaction is the organic acid transport system out of the CNS which could be used by both substances. Lipid solubility is not the only factor involved in the distribution of thiopental in the rat brain.

The neurotoxic potential of benzylpenicillin administered as a continuous intravenous infusion was studied in rabbits with intact blood-CNS barriers, experimentally established Enterobacter cloacae meningitis and experimental renal failure, secondary to cephaloridine-induced acute tubular necrosis after iv administration. The concentrations of benzylpenicillin in serum, CSF and brain tissue fluid were assayed at the onset of epileptogenic electroencephalographic activity. The brain tissue concentrations of benzylpenicillin were consistently higher than those in CSF in both infected and uninfected animals. The highest brain tissue fluid concentrations of benzylpenicillin were found in rabbits with renal failure after cephaloridine pretreatment. The brain tissue fluid concentrations of benzylpenicillin rather than the CSF concentrations were decisive for neurotoxicity. Cephaloridine-induced uraemia, but not the combination of uraemia and meningitis, resulted in a significantly increased tolerance of high intracerebral concentrations of benzylpenicillin before EEG-changes were precipitated.

Rabbits were given benzylpenicillin, imipenem/cilastatin and a penem beta-lactam, FCE 22101, as constant intravenous infusions with intervals of greater than or equal to 7 days between doses. Neurotoxicity was defined as epileptogenic electroencephalographic (EEG) activity. Mean doses precipitating neurotoxicity were 486 mg/kg of benzylpenicillin, 86 mg/kg of imipenem and 102 mg/kg of FCE 22101 leading to mean serum concentrations of 606, 55 and 30 mg/l, respectively. Doses and serum concentrations of benzylpenicillin were significantly (P less than 0.001) higher than those of imipenem or FCE 22101. Neurotoxicity was seen at significantly (P less than 0.02) higher serum concentrations of imipenem than of FCE 22101. Neurotoxicity seemed to be related to antibiotic concentrations in brain tissue fluid (BTF) rather than to CSF concentrations which were less than 0.2 mg/l in 10 of 11 animals tested after administration of imipenem or FCE 22101. In BTF, significantly (P less than 0.001) higher concentrations of benzylpenicillin than of imipenem or FCE 22101 were found. When related to concurrent serum concentrations, BTF penetration of benzylpenicillin and FCE 22101 did not differ significantly but both these antibiotics penetrated significantly better than imipenem. In conclusion, imipenem/cilastatin and FCE 22101 were more neurotoxic in rabbits than benzylpenicillin but did not show major differences from each other.

A retrospective analysis was performed of 54 consecutive adult patients with intracranial abscesses hospitalized between 1973 and 1985. Clinical signs and symptoms were varying and no single symptom was found in more than 48 % of the patients. Also the laboratory findings were of limited diagnostic value. The etiology of the infections varied with the sources and could be identified in 42 of the patients. In patients with postoperative abscesses or infections after penetrating head injuries Staphylococcus aureus was the most commonly found causative agent. In patients with abscesses originating from sinus, dental or otogenic infections, anaerobic bacteria dominated and most patients had multiple bacterial isolates. A majority of patients (33/47) with diagnosed abscesses were treated with both surgical drainage and systemic antibiotics. 14 patients received antibiotics only, due to inoperable abscesses or spontaneous regression without surgery. 17 of the patients (31.5%) died from their intracranial infections and only 9 survived without sequelae. Important prognostic factors were missed diagnosis and presence of multiple or ruptured abscesses. One patient died of acute brain stem herniation after lumbar puncture, a procedure which was found to be of limited diagnostic value and which seems to be contraindicated in patients with intracranial abscesses.

The neurotoxic potential of benzylpenicillin, administered as continuous intravenous infusion, was studied in rabbits. Thirteen animals were killed at the onset of epileptogenic EEG activity (seven) or convulsions (six). Benzylpenicillin levels were determined in serum, cerebrospinal fluid (CSF) and brain tissue fluid. High doses of benzylpenicillin were required to induce neurotoxicity; epileptogenic (EEG) changes were seen at serum levels of 510-960 mg/l and convulsions at 920-1902 mg/l. Neurotoxicity correlated well with levels of benzylpenicillin in brain tissue fluid, calculated as 10 x the concentration in whole brain tissue. The correlation of neurotoxic reactions to levels of benzylpenicillin in CSF was poor and the CSF levels were consistently lower than those in brain tissue fluid. The technique used was found to be a satisfactory, though laborious, way to study neurotoxicity of drugs.

The neurotoxic potential of intravenous administered benzylpenicillin (BPC) was studied in rabbits with intact blood-CNS barriers and rabbits with experimental E. coli meningitis. At onset of epileptogenic EEG activity or seizures, serum, CSF and brain tissue were collected for assay of BPC. Based on the fact that, in tissues, BPC seems to remain extracellularly, brain concentrations of BPC were expressed as brain tissue fluid (BTF) levels, calculated as 10x the concentration in whole brain tissue. Neurotoxicity could be precipitated in all rabbits. In normal rabbits BTF levels of BPC were considerably higher than those in CSF indicating a better penetration across the blood-brain barrier (BBB). BPC penetrated better to CSF and BTF in meningitic rabbits than in normal controls, suggesting some degree of damage of the BBB concomitant with meningeal inflammation. E. coli meningitis did not increase the neurotoxicity of BPC. In control rabbits the intracisternal injection of saline resulted in some degree of pleocytosis. Unmanipulated animals are therefore preferable as controls. Epileptogenic EEG-changes was the most precise of the two variables used for demonstration of neurotoxicity. EEG-changes were therefore used as neurotoxicity criterion in the following rabbit experiments. To evaluate the effect of uraemia alone and uraemia plus meningitis on the neurotoxity of BPC in rabbits, cephaloridine was used to induce uraemia. Meningitis was induced by intracisternal inoculation of a cephalosporin resistant strain of E. cloacae. Untreated rabbits were used as controls. Uraemia resulted in increased BTF penetration of BPC, possibly explained by permeability changes in the BBB and/or decreased binding of BPC to albumin. Uraemia did not result in increased penetration of BPC into the CSF of non-meningitic rabbits. Uraemic non-meningitic rabbits had the highest BTF levels of BPC at the criterion, indicating that cephaloridine-induced renal failure increased the epileptogenic threshold in these rabbits. The combination of uraemia and meningitis increased the neurotoxicity of BPC since the criterion was reached at considerably lower BTF levels of BPC. Meningitis, either alone or together with uraemia, did not increase the neurotoxicity in comparison to control rabbits. Higher BTF levels of BPC were found in meningitic rabbits than in controls with intact blood-CNS barriers at onset of EEG-changes. In all groups of rabbits there was a pronounced variability of BPC levels in the CSF while the intra-group variations in BTF levels were much smaller. Thus, BTF and not CSF levels were decisive for the neurotoxicity of BPC.(ABSTRACT TRUNCATED AT 400 WORDS)

The neurotoxic potential of benzylpenicillin administered intravenously as a continuous infusion was studied in rabbits with experimental Escherichia coli meningitis. As controls a group of rabbits was injected with saline into the cisterna magna. The concentrations of benzylpenicillin in serum, CSF and brain tissue fluid were studied at onset of epileptogenic electroencephalographic activity (thirteen rabbits) or convulsions (ten rabbits), with a previously developed method for neurotoxicity studies. E. coli meningitis did not increase the neurotoxicity of benzylpenicillin, despite high concentrations of the drug in both CSF and brain tissue fluid. The intracisternal injection of saline in the control group produced slight pleocytosis in some rabbits indicating some degree of damage of the blood-CSF barrier.