[Concentration of tazobactam/piperacillin in the cerebrospinal fluid of patients with Haemophilus influenzae type B meningitis].

While the incidence of Haemophilus influenzae type b (Hib) meningitis is expected to decrease with the widespread use of the Hib vaccine, the resistance of Hib has actually increased. Therefore, selection of the initial antibiotics used for treatment must be performed with resistant bacteria, including beta-lactamase negative ampicillin resistant H. influenzae (BLNAR), in mind. Tazobactam/piperacillin (TAZ/PIPC) has a satisfactory minimum inhibitory concentration (MIC) against BLNAR and is a beta-lactamase inhibitor. Although there is no insurance coverage for its use in patients with meningitis, the penetration of TAZ/PIPC into cerebrospinal fluid (CSF) in animal experiments promises a satisfactory result, and we have been using a combination of ceftriaxone (CTRX) and TAZ/PIPC as an initial treatment and a resistant bacteria countermeasure in patients with Hib meningitis at our hospital since 2008. We examined the concentration of TAZ/PIPC in CSF to further investigate the possibility of using TAZ/PIPC as an antibiotic treatment against bacterial meningitis. In cases treated with a 1: 8 drug formulation of TAZ/PIPC against Hib meningitis at our hospital, we used the remaining portion of a CSF sample collected after the initiation of TAZ/PIPC administration and then measured the concentrations of TAZ and PIPC in the CSF. Six specimens from 5 patients between the ages of 6 and 59 months were examined. The dosage of TAZ/PIPC was 95.7-113.6 mg/kg/dose x 3 times/day, and the CSF concentrations at 0-105 minutes after the completion of the administration were 0.319-1.32 microg/mL for TAZ and 2.54-7.74 microg/mL for PIPC. With the approved dosage, the peak concentration level during the acute period indicated a sufficient CSF concentration level for the antibacterial and beta-lactamase inhibition effects against Hib. As an antibiotic treatment for H. influenzae meningitis, the combined usage of TAZ/PIPC is likely to be effective as a resistant bacteria countermeasure, in addition to third-generation cephem drugs and meropenem.

[Transferability of tazobactam/piperacillin (TAZ/PIPC) to cerebrospinal fluid of rabbit with meningitis caused by Staphylococcus aureus].

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.

Kinetics of piperacillin and tazobactam in ventricular cerebrospinal fluid of hydrocephalic patients.

Its broad antibacterial spectrum qualifies the combination of piperacillin and tazobactam for therapy of nosocomial bacterial central nervous system (CNS) infections. Since these infections sometimes are accompanied by only minor dysfunction of the blood-cerebrospinal fluid (CSF) barrier, patients with noninflammatory occlusive hydrocephalus who had undergone external ventriculostomy were studied (n = 9; age range, 48 to 75 years). After administration of the first dose of piperacillin (6 g)-tazobactam (0.5 g) over 30 min intravenously, serum and CSF were drawn repeatedly and analyzed by high-performance liquid chromatography. Pharmacokinetics were determined by noncompartmental analysis. Maximum concentrations of piperacillin in CSF ranged from 8.67 to <0.37 mg/liter (median, 3.42 mg/liter), and those of tazobactam ranged from 1.37 to 0.11 mg/liter (median, 0.45 mg/liter). CSF maxima were observed, in median, 1.5 and 2 h after the end of the infusion. Elimination in CSF was considerably slower than in serum (median half-life at beta phase for piperacillin, 5.9 h in CSF versus 1.47 h in serum; for tazobactam, 6.1 h versus 1.34 h). For tazobactam, the ratio of the area under the concentration-time curve (AUC) in CSF to the AUC in serum was approximately three times as high as that for piperacillin (medians, 0.106 versus 0.034). In view of the tazobactam concentrations in CSF observed in this study, the practice of using a constant concentration of 4 mg of tazobactam per liter for MIC determination is inadequate for intracranial infections. Larger amounts of tazobactam than the standard dose of 0.5 g three times daily may be necessary for CNS infections.

Different ratios of the piperacillin-tazobactam combination for treatment of experimental meningitis due to Klebsiella pneumoniae producing the TEM-3 extended-spectrum beta-lactamase.

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.

Penetration of sulbactam into the cerebrospinal fluid of patients with bacterial meningitis receiving ampicillin therapy.

Concentrations of sulbactam in the CSF of 18 patients with bacterial meningitis who were undergoing treatment with intravenous (iv) ampicillin were determined. Six patients received single doses of sulbactam (1 g) and 12 patients received multiple doses (four times daily) by the iv route at various intervals before lumbar punctures were performed to monitor their condition. Concentrations of sulbactam up to 12 micrograms/ml were detected in the CSF between 1 and 4 hr after dosing, the higher levels being present in the CSF of patients with the most severe meningeal inflammation. There were no significant differences in the concentrations achieved after single or multiple doses of sulbactam, and the concentrations were generally similar to the concurrent concentrations of ampicillin. It is concluded that these results as well as the antibacterial properties of sulbactam plus ampicillin support the evaluation of this combination as an alternative in the treatment of bacterial meningitis.

Penetration of sulbactam into cerebrospinal fluid of patients with viral meningitis or without meningitis.

In a study designed to determine the penetration of sulbactam into the central nervous system, a single intramuscular dose of 0.5-1.0 g was given to 19 patients: nine with viral meningitis and 10 with normal cerebrospinal fluid (CSF). Drug levels in CSF were first detectable 2 hr after administration in patients with viral meningitis and 4 hr after administration in patients with normal CSF. The sulbactam levels were low (0-3.7 mg/ml), and no significant differences were found between levels in the two groups of patients. For the achievement of therapeutic concentrations of sulbactam in CSF, doses larger than those administered in this study should be used in conjunction with a beta-lactam antibiotic.

Sulbactam/ampicillin vs. chloramphenicol/ampicillin for the treatment of meningitis in infants and children.

Eighty-one patients ages one month to 14 years with meningitis were randomized to receive either sulbactam (50 mg/kg per day) and ampicillin (400 mg/kg per day; 41 patients) or chloramphenicol and ampicillin (40 patients). The groups were comparable in terms of sex and degree of illness; however, more patients treated with chloramphenicol/ampicillin than patients treated with sulbactam/ampicillin were younger than 12 months of age (78% vs. 56%). Pathogens were isolated from the cerebrospinal fluid (CSF) of 65 (80%) of the 81 patients. In the sulbactam/ampicillin group, there were 18 Haemophilus influenzae isolates (one resistant to ampicillin), five Streptococcus pneumoniae, five Neisseria meningitidis, one Klebsiella pneumoniae, one Pseudomonas aeruginosa, and one Listeria. In the chloramphenicol/ampicillin group, there were 19 H. influenzae isolates, 10 S. pneumoniae, three N. meningitidis, one Haemophilus parainfluenzae, and one Citrobacter. Of 63 patients with assessable CSF pathogens, one (3%) of 29 treated with sulbactam/ampicillin died (S. pneumoniae) and six (18%) of 34 treated with chloramphenicol/ampicillin died (two, H. influenzae; three, S. pneumoniae; and one, Citrobacter). Twelve percent in the sulbactam/ampicillin group and 18% in the chloramphenicol/ampicillin group had neurologic sequelae. No clinically significant reactions or toxicities were noted. Sulbactam/ampicillin was as effective as chloramphenicol/ampicillin in the treatment of meningitis.

[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.

Mecillinam in cerebrospinal fluid in children.

The penetration of mecillinam, a new beta-lactam penicillin-like antibiotic, into cerebrospinal fluid (CSF) was investigated in 11 children in whom all but 1 was presumed to have non-inflamed meninges. 30 minutes after a single intravenous dose of 30mg/kg, a concentration of approximately 0.30 micrograms/ml was achieved in the CSF (corresponding mean serum concentration 75 micrograms/ml), and this level was maintained during the next 4 hours in spite of rapidly declining serum concentrations, indicating a slow equilibration of mecillinam over the blood-liquor barrier. 1 child with suspected inflamed meninges showed a much higher CSF level of 12.1 micrograms/ml. It is concluded that mecillinam, as is the case for other penicillins, apparently crosses non-inflamed meninges poorly.