[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.

Clinical significance of cerebrospinal fluid inhibitory titers of antibiotics, based on pharmacokinetic/pharmacodynamic parameters, in the treatment of bacterial meningitis.

The cerebrospinal fluid (CSF) inhibitory titer (CSF-IT) of an antibiotic, which can be used to estimate the duration of time above the agent's MIC in the CSF, was introduced as one of the indices to evaluate the effectiveness of antibiotic selection in treating bacterial meningitis. The CSF-IT was determined via a microdilution method. A suspension of the causative organism was added to a tube containing twofold diluted CSF and double-concentrated Mueller-Hinton broth with supplement. The CSF-IT was determined by the maximum point without turbidity of medium after overnight incubation at 37 degrees C. Concerning the strain of beta-lactamase-negative ampicillin-resistant Haemophilus influenzae (BLNAR), the killing rates of both meropenem and piperacillin were compared in an in vitro pharmacokinetic (PK) model, in which human pharmacokinetics in CSF were simulated. Organisms recovered from the CSF in 37 treated clinical cases of bacterial meningitis were H. influenzae, Streptococcus agalactiae, Streptococcus pneumoniae, Escherichia coli, and Neisseria meningitidis; in these cases, the CSF-IT ranged from 1: 8 to as high as 1: 4 096. In the in vitro PK model, the concentrations of both drugs were higher than the MICs over a period of 24 h; however, the killing rate of piperacillin was higher than that of meropenem, and bacterial regrowth was observed after the administration of meropenem. A CSF-IT value higher than 1: 32 indicates that the antibiotic concentration in the CSF exceeds the MIC for 24 h. The effect of piperacillin on BLNAR depends not only on the time above MIC of 24 h but also on the maximum concentration in the CSF.

[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.

[Tissue concentrations of piperacillin in humans]. / Concentrations tissulaires de la pipéracilline chez l'homme.

High serum levels and low degree of protein binding are the main factors which confer upon piperacillin a good distribution in tissues and biological fluids. In CSF, interstitial fluid, pleural and peritoneal fluids, piperacillin levels varied depending on the dose and on local inflammatory conditions; they reached high values ranging from 20 to 50 micrograms/ml corresponding to 18 to 25% of simultaneous serum levels. In bile, high and early levels of piperacillin were achieved, reaching about 1.200 to 3.200 micrograms/ml 100 min after i.v. injection of 2 or 4 g of the drug; in gallbladder wall more than 500 micrograms/g were measured. High tissue concentrations were found after 4 g i.v. of the drug in the renal cortex: 23 to 115 micrograms/g; in prostatic tissue: 70 micrograms/g; in bone: 15 micrograms/g; in cardiac tissue, especially myocardial tissue: 113 micrograms/g. In the female genital tract, the penetration of piperacillin was noticeable; levels of 15 to 45 micrograms/g were measured in uterus, ovary and salpinx: in contrast, placental transfer of piperacillin was limited. In the respiratory tract, the distribution of piperacillin was rapid, and concentrations of 12 to 30 micrograms/ml and 25 to 55 micrograms/g were found in bronchial secretions and bronchial mucosa respectively a 4 g i.v. dose. Studies of piperacillin distribution in the human body indicate that the drug reaches therapeutic levels in most tissues and biological fluids.

Continuous sampling for determination of pharmacokinetics in rat cerebrospinal fluid.

A method for determining drug concentration relationships between plasma and cerebrospinal fluid (CSF) in rats is described. Continuous CSF samples were collected directly from the third anterior ventricle with an indwelling cannula inserted through the bregma point, and drug concentrations were determined by high-pressure liquid chromatography and radioimmunoassay micromethods. Three antibiotics with different abilities to cross the blood-CSF barrier (chloramphenicol, piperacillin, and gentamicin) were tested. This method was found to be reproducible for each drug even if the antibiotic levels were low and the sample volumes very small. Peak CSF concentrations occurred between 0.75 and 1.25 h after injection for all three antibiotics. Percent penetration values at 1 h were 50, 1.2, and 5.4% for chloramphenicol, piperacillin, and gentamicin, respectively.

[Penetration of piperacillin into the cerebrospinal fluid of patients with purulent meningitis]. / Pénétration de la pipéracilline dans le liquide céphalo-rachidien des malades atteints de méningite purulente.

Ten patients with purulent meningitis received 3 intravenous injections of 4 g piperacillin at intervals of 8 hours, in addition to the usual antimicrobial treatment. Piperacillin was assayed in serum and CSF by high performance liquid chromatography. The mean CSF concentration of the drug was 9.2 micrograms/ml and its mean percentage of penetration was 22,7%. There were no significant differences in CSF concentrations between days 2 to 4 (inflamed meninges) and days 10 to 20 (patient cured). It is concluded that piperacillin shows good CSF penetration and could be useful to treat selected cases of meningitis due to Gram-negative bacilli.

Piperacillin in early neonatal infection.

Seventy infants with suspected bacterial infection in the first 48 hours of life were treated either with piperacillin and flucloxacillin or with penicillin and gentamicin. Infection was confirmed and successfully eradicated in 6 of the 35 infants receiving piperacillin and flucloxacillin. Four infants treated with penicillin and gentamicin had confirmed infection and one deteriorated initially but then recovered when treated with piperacillin. Serum piperacillin concentrations above 100 mg/l and cerebrospinal fluid piperacillin concentrations of 2.6-6 mg/l were noted for up to four hours and 7 hours respectively, even in the absence of inflamed meninges, after administration of piperacillin 100 mg/kg body weight intravenously. Median half life of piperacillin was 6.5 hours and was prolonged in renal impairment. Piperacillin is considered to be a safe and effective first line single agent treatment for early neonatal infection but because some Escherichia coli are resistant to it we recommend that a second agent be used in critically ill infants with neutropenia or meningitis.