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In a rabbit model of meningitis caused by a pneumococcus highly resistant to penicillin (MIC, 4 microg/ml), meropenem, a broad-spectrum carbapenem, was bactericidal (-0.48+/-0.14 deltalog10 cfu/ml h) and slightly superior to ceftriaxone (-0.34+/-0.23 deltalog10 cfu/ml x h) and vancomycin (-0.39+/-0.19 deltalog10 cfu/ml x h). Although the combination of vancomycin with ceftriaxone was significantly more active than ceftriaxone alone (-0.55+/-0.19 deltalog10 cfu/ml x h), only an insignificant gain was observed by the addition of vancomycin to meropenem (-0.55+/-0.28 deltalog10 cfu/ml x h).

Major epidemiological changes have altered the empiric therapy of patients with bacterial meningitis, a disease with significant morbidity and mortality. We offer recommendations for empiric management decisions and specific antibiotic choices for patients with bacterial meningitis.

Cefazolin, an antibiotic commonly used for surgical prophylaxis, may not adequately penetrate the intervertebral disk or cerebrospinal fluid. The combination of gentamicin and cefuroxime has been found to penetrate both structures in adequate levels and was used in 40 consecutive elective spine cases without a postoperative infection or antibiotic-related complications.

The transferability of tazobactam/piperacillin (TAZ/PIPC) to cerebrospinal fluid (CSF) was studied employing rabbits with experimental meningitis caused by Staphylococcus aureus. 125 or 250 mg/kg of TAZ/PIPC was intravenously administered to rabbits with experimental meningitis then concentrations of TAZ and PIPC in CSF and serum were measured. In the group to which 125 mg/kg of TAZ/PIPC was administered, mean concentration of TAZ in CSF was 7.3 and 2.4 micrograms/ml at 30 and 60 min after administration, respectively, and concerning PIPC, it was 10.1 and 3.5 micrograms/ml, respectively. CSF/serum ratio of TAZ was 29.4% and 31.4%, respectively, and that of PIPC was 24.3 and 35.6%, respectively. In the group to which 250 mg/kg of TAZ/PIPC was administered, mean concentration of TAZ in CSF was 16.5 and 12.6% micrograms/ml, respectively, and concerning PIPC, it was 25.6 and 18.2 micrograms/ml, respectively. CSF/serum ratio of TAZ was 22.1 and 56.1%, respectively, and that of PIPC was 12.2 and 51.9%, respectively. Addition of TAZ did not make significant change of transferability of PIPC to CSF. Considering the antibacterial effect of TAZ/PIPC against main causative organism of meningitis, this agent was thought to be effective for the treatment of purulent meningitis.

The activities of meropenem, imipenem, ceftriaxone, and vancomycin were evaluated against 80 penicillin-susceptible and -resistant Streptococcus pneumoniae strains. Meropenem, imipenem, ceftriaxone, and vancomycin MICs at which 90% of the isolates are inhibited were 0.5, 0.25, 1, and 0.25 microg/ml, respectively. Against penicillin-resistant strains, the best killing activity at cerebrospinal fluid concentrations was obtained with imipenem and ceftriaxone-vancomycin. However, while the killing activity of imipenem was significantly greater than that of meropenem, no significant difference was observed between the activities of meropenem and ceftriaxone-vancomycin.

We evaluated the in vitro killing activities of ceftriaxone, imipenem, vancomycin, gentamicin, fosfomycin, and rifampin, alone and in combination, against 26 Streptococcus pneumoniae strains (penicillin G MICs, > 0.125 to 2 micrograms/ml) isolated from the cerebrospinal fluid of children with meningitis. The antibiotics were tested at clinically achievable concentrations in cerebrospinal fluid. After 5 h of incubation, imipenem was the most effective drug. None of the combinations had synergistic activity. Killing by beta-lactam antibiotics or vancomycin was enhanced by the addition of gentamicin, reduced by the addition of rifampin, and unaffected by the addition of fosfomycin.

Access to the cerebrospinal fluid, which is the only objective reflection of the essential parametres, is very limited. Investigators have long tried to design an animal model. Presently, the experimental model of the newborn rat is most often used for studying pathogenic factors in haematogenous meningitis. In contrast, the rabbit model is more adapted to therapeutic investigation The main advances have been therapeutic and pathophysiologic. Good examples are the identification of optimum antibiotic levels in the cerebrospinal fluid, and the demonstration of the responsibility of mediators produced by the host in triggering the inflammation. The principle of corticosteroid treatment before induction of bacterial lysis by antibiotics in Haemophilus meningitis is a result of such work.

We evaluated the pharmacokinetics and therapeutic efficacies of piperacillin and tazobactam, a beta-lactamase inhibitor, given either alone or in different combinations (80:10, 200:10, and 80:25 mg/kg/h), in experimental meningitis due to a strain of Klebsiella pneumoniae producing the TEM-3 extended-spectrum beta-lactamase. Treatment was administered intravenously as a 7-h constant infusion preceded by a bolus of 20% of the total dose. The mean (+/- standard deviation) rates of penetration into the cerebrospinal fluid (CSF) of infected animals were 6.7 +/- 3.9% for piperacillin given alone and 36.3 +/- 21.9% for tazobactam given alone. Combination treatment significantly magnified the concentration of either drug in CSF. Concentrations of bacteria in CSF increased throughout therapy in animals given either drug alone, even at high dosages. In animals given the combination at dosages of 80:10 and 200/10 mg/kg/h, only a suboptimal reduction of CSF bacterial titers was obtained in vivo, i.e. -0.49 +/- 0.34 and -0.73 +/- 0.49 log CFU/ml/h, respectively. An increase in the tazobactam dosage within the combination (80:25 mg/kg/h) was required in order to obtain a significantly faster elimination of viable organisms from the CSF (-0.97 +/- 0.35 log CFU/ml/h). The study shows that tazobactam is able to provide effective protection against piperacillin hydrolysis by the TEM-3 enzyme within the CSF. Appropriate dosage regimens of various beta-lactam-tazobactam combinations may deserve comparative studies in experimental meningitis caused by organisms producing extended-spectrum beta-lactamases.

Concentrations of potassium clavulanate (CVA) and ticarcillin sodium (TIPC) in the plasma and cerebrospinal fluid (CSF) of patients after neurosurgical intervention were determined at various times after a 1-hour drip infusion (3.2-g dose). Patients whose blood-brain barriers were supposed to be maintained in almost a normal condition were selected. CSF was obtained through a catheter placed in the anterior horn of the lateral ventricle in all the patients. Maximum plasma levels (micrograms/ml) of 57.6 to 384.0 with an average of 169.7 (TIPC) and 0.41 to 26.2 with an average of 6.1 (CVA) were achieved at the termination of infusion. The maximum CSF levels (micrograms/ml) were 0.61 to 18.8 (TIPC) and 0.1 to 6.81 (CVA) with mean values of 4.5 and 1.2, respectively. Plasma half lives (T1/2) (minute) were 24 to 93 (TIPC) and 32 to 227 with mean values of 58 and 127, respectively. The mean values of the CSF half lives (minute) were 237 (TIPC) and 113 (CVA). The ratios (%) of CSF levels to plasma levels in maximum concentration (Cmax), AUC (area under concentration curve) and half life (T1/2) were calculated. Cmax ratios were 0.2 to 29.2 (TIPC) and 1.4 to 69.8 (CVA) with mean values of 4.4 and 22.8, respectively. AUC ratios were 0.3 to 23.5 (TIPC) and 1.1 to 70.2 (CVA) with mean values of 4.3 and 22.4, respectively. T1/2 ratios were 1.3 to 18 (TIPC) and 1.1 to 4.3 (CVA) with mean values of 5.5 and 2.3, respectively. These values indicate that CVA/TIPC may be classified into a group of antibiotics with good penetration into the CSF.

Detailed studies of pharmacodynamic principles relevant to the therapy of bacterial meningitis are difficult to perform in man, while the rabbit model of bacterial meningitis has proved to be extremely valuable and has led to insights that appear relevant for the treatment of humans. Most importantly in the light of the restricted penetration of antibiotics into the CSF, animal studies have shown that in meningitis there is a dose-response curve between the CSF concentrations achieved by antibiotics and their bactericidal activity. This appears to be true for all classes of antibiotics thus far examined, including the beta-lactams, which do not show such a dose-response behaviour in other infections. Only CSF concentrations that exceed the MBC of the infecting organism by at least 10-30-fold achieve consistent and rapid bactericidal activity. Such rapid bactericidal activity is a requirement for successful therapy with beta-lactams and can be impaired with certain antibiotics by the specific conditions in infected CSF (protein content; acidic pH; slow-growing bacteria). However, rapid antibiotic killing of the infecting organisms may not be without adverse effects either. Some antibiotics, particularly beta-lactams lead to the brisk liberation of bacterial cell wall components (e.g. endotoxin, in the case of Gram-negative organisms) which have an inflammatory effect on the host and can lead to a temporary deterioration of the disease. Dexamethasone, when administered with the antibiotic, can prevent some of the adverse effects of rapid bacterial lysis.

The neurotoxic potential of panipenem/betamipron (PAPM/BP), a new carbapenem antibiotic, was compared with that of imipenem/cilastatin (IPM/CS). The drug concentration in cerebrospinal fluid (CSF) at the onset of epileptogenic electroencephalographic (EEG)-activity and the drug distribution into the central nervous system (CNS) were evaluated. Epileptogenic reactions correlated well with drug levels in CSF, but not with drug levels in circulating plasma. The concentration of PAPM in CSF at the onset of epileptogenic EEG-activity was almost twice that of IPM, suggesting that neurotoxic activity of PAPM is about half that of IPM. In addition, in terms of incidence percent for the epileptogenic EEG-activity, PAPM/BP was found to be less toxic than IPM/CS within the dose of 1.0-1.2 g/kg. Concentrations of PAPM in CSF and brain extracellular fluid after PAPM/BP i.v. infusion were comparable with those of IPM after IPM/CS infusion, indicating the similar characteristics of distribution into the CNS for the two antibiotics. From these results of pharmacologic effects and drug distributions, it is suggested that the neurotoxicity of PAPM/BP is less than half that of IPM/CS.

The efficacy and the safety of panipenem/betamipron (PAPM/BP), a new carbapenem antibiotic against infections in pediatrics were studied. The obtain results are summarized as follows. 1. The transfer of PAPM/BP to cerebrospinal fluid (CSF) was studied in 2 cases of purulent meningitis. The PAPM/BP levels in CSF in a dose 26.1 mg/kg peaked at 3.21 micrograms/ml on sampling 30 minutes after administration, followed by decreasing gradually with the improvement in clinical symptoms and came to 0.86 micrograms/ml on the 12th day (30 minutes after administration). 2. PAPM/BP at dose levels of 50 mg/kg to 69 mg/kg a day (daily doses of 104 mg/kg, 175 mg/kg 4 times a day for 2 cases of purulent meningitis) was administered by intravenous drip infusion 3 times daily for 4 to 15 days to 2 cases of purulent meningitis (including 1 case of penicillin-resistant Streptococcus penumoniae meningitis), 3 cases of pneumonia, 2 cases of phlegmon, 2 cases of periproctal abscess and 2 cases of urinary tract infections for a total of 11 cases. As results, all the cases showed good responses including 5 excellent and 6 good responses. Bacteriological efficacies in all of the 9 eligible cases were assessed as "eradicated". 3. As for the safety, an increase in the platelet count and slight evaluation of GOT and GPT were seen in 1 case as abnormal changes in the laboratory findings, although no side-effect was observed. 4. The results above show that PAPM/BP is useful for the treatment of general infections in pediatrics and that a daily dose of about 60 mg/kg given in 3 divided doses in effective enough.(ABSTRACT TRUNCATED AT 250 WORDS)

Studies were carried out on the clinical efficacy of panipenem/betamipron (PAPM/BP) against bacterial infections. The results are summarized as follows: 1. PAPM/BP were administered to total 21 patients (7 cases of pneumonia, 1 case of bronchitis, 3 cases of cellulitis, 2 cases of purulent lymphadenitis, 2 cases of otitis media, 1 case of purulent parotitis, 1 case of sinusitis, 1 case of mastoiditis, 2 cases of urinary tract infection and 1 case of purulent meningitis) by drip intravenous injection. 2. Clinical responses of PAPM/BP were excellent in 12 cases, good in 7, poor in 1 and unknown in 1 case. The overall efficacy rate was 95.0%. 3. Concentration of PAPM in cerebrospinal fluid after 1 hour drip intravenous administration in 1 case of purulent meningitis were 6.84 micrograms/ml at the acute stage and 3.28 micrograms/ml at the recovering stage. 4. Neither side effects nor abnormal laboratory findings were observed except 1 case of increase of thrombocytosis out of 19 cases. 5. From the results, PAPM/BP was determined to be an efficacious and safe drug for the therapy of pediatric infection.

Panipenem/betamipron (PAPM/BP), a new parenteral carbapenem antibiotic, was investigated with regard to their levels in sera and various tissues collected from patients under orthopedic surgery. The subjects were 17 patients, complaining low back pain and hospitalized for surgical operations. PAPM/BP was administered by intravenous drip infusion for 30 minutes of a dose of 500 mg/500 mg. Serum and cerebrospinal fluid (CSF) specimens were taken from 8 patients at 15-70 minutes after administration and assayed for PAPM and BP levels. Serum, bone, and joint capsule samples where taken from the other 9 cases at 25-127 minutes after administration and assayed. PAPM levels in CSF were considerably lower than those in serum. They were 23.74-1.11 micrograms/ml in sera, 0.31-0.05 micrograms/ml in CSF's during 15 to 70 minutes after administration. PAPM levels were 27.85-2.97 micrograms/ml in sera, 2.54-0.20 micrograms/g in bones, 5.63 and 1.67 micrograms/g in joint capsules during 25 to 127 minutes after administration. BP levels in sera and various tissues were low compared to those of PAPM. These results showed that PAPM was detected at higher levels than 0.2 microgram/g in various tissues, except CSF during 20 to 120 minutes after drip infusion of PAPM/BP 500 mg/500 mg for 30 minutes.

We evaluated the pharmacokinetics and therapeutic efficacy of ampicillin combined with sulbactam in a rabbit model of meningitis due to a beta-lactamase-producing strain of Escherichia coli K-1. Ceftriaxone was used as a comparison drug. The MIC and MBC were 32 and greater than 64 micrograms/ml (ampicillin), greater than 256 and greater than 256 micrograms/ml (sulbactam), 2.0 and 4.0 micrograms/ml (ampicillin-sulbactam [2:1 ratio, ampicillin concentration]) and 0.125 and 0.25 micrograms/ml (ceftriaxone). All antibiotics were given by intravenous bolus injection in a number of dosing regimens. Ampicillin and sulbactam achieved high concentrations in cerebrospinal fluid (CSF) with higher dose regimens, but only moderate bactericidal activity compared with that of ceftriaxone was obtained. CSF bacterial titers were reduced by 0.6 +/- 0.3 log10 CFU/ml/h with the highest ampicillin-sulbactam dose used (500 and 500 mg/kg of body weight, two doses). This was similar to the bactericidal activity achieved by low-dose ceftriaxone (10 mg/kg), while a higher ceftriaxone dose (100 mg/kg) produced a significant increase in bactericidal activity (1.1 +/- 0.4 log10 CFU/ml/h). It appears that ampicillin-sulbactam, despite favorable CSF pharmacokinetics in animals with meningitis, may be of limited value in the treatment of difficult-to-treat beta-lactamase-producing bacteria, against which the combination shows only moderate in vitro activity.

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 ticarcillin and clavulanate into the cerebrospinal fluid was studied in ten patients with varying degrees of impairment of the blood-brain barrier. In general, penetration of both drugs was relatively low and variable (5.4 +/- 5.8% for clavulanate and 2.0 +/- 4.0% for ticarcillin) but markedly better in those patients with impaired blood/brain barrier.

Meningitis was induced in white rabbits with a non beta-lactamase producing strain of Staphylococcus aureus. There was no significant difference in the CSF level of ceftazidime after simultaneous administration of ceftazidime with ampicillin or after ceftazidime alone. In contrast the percentage CSF penetration of ampicillin decreased from 8.81% after administration of ampicillin alone to 2.77% after the simultaneous administration of ampicillin with ceftazidime. The ratio of AUC in CSF and serum was 19.4% after ampicillin alone and 7.71% after simultaneous administration with ceftazidime. When ceftriaxone was combined with ampicillin there was no effect on the CSF penetration of either drug. Cephalosporins have unpredictable effects on the CSF concentration of ampicillin, probably due to variable effects on the penetration of ampicillin from blood to CSF.

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.

Concentrations of sulbactam (SBT) and ampicillin (ABPC) in the blood and cerebrospinal fluid (CSF) following an intravenous administration of SBT/ABPC at a dose of 150 mg/kg (SBT/ABPC = 1:2) were determined in 12 rabbits with staphylococcal meningitis. Drug concentrations were measured 9 times, 6 times each with intervals of 15 minutes and thereafter with intervals of 30 minutes. The results were compared with those of a group of 9 rabbits given 100 mg/kg of ABPC alone. 1. The maximum concentration of SBT in the CSF and the percentages of both the maximum concentration and the area under the concentration-time curve (AUC) of SBT in CSF vs. those in serum of the SBT/ABPC group were higher than those of ABPC and the half-life of SBT in the CSF was also longer than that of ABPC, all with significant difference. When these parameters for SBT of SBT/ABPC groups were compared with those of ABPC of the ABPC group, not much differences existed between the 2 groups except that the CSF half-life of SBT was much longer than that of ABPC. 2. The percentages of both the maximum concentration and AUC of ABPC in CSF vs. those in serum of the SBT/ABPC group were significantly lower than those of ABPC of the ABPC group. The CSF half-life of ABPC of the former group was longer than that of the latter. 3. The above results suggest that when SBT and ABPC are administered simultaneously, the penetration of ABPC into the CSF is inhibited.