Clinical evaluation of piperacillin with observations on penetrability into cerebrospinal fluid

We evaluated the pharmacokinetics and therapeutic efficacy of piperacillin combined with tazobactam, a novel P-lactamase inhibitor, in experimental meningitis due to a I-lactamase-producing strain of Kl-positive Escherichia coli. Different doses of piperacillin and tazobactam, as single agents and combined (8:1 ratio; dosage range, 40/5 to 200/25 mg/kg per h), and of ceftriaxone were given to experimentally infected rabbits by intravenous bolus injection followed by a 5-h constant infusion. The mean (+ standard deviation) rates for penetration into the cerebrospinal fluid of infected animals after coadministration of both drugs were 16.6 _ 8.4% for piperacillin and 32.5 ± 12.6% for tazobactam. Compared with either agent alone, combination treatment resulted in significantly better bactericidal activity in the cerebrospinal fluid. The bactericidal activity of piperacillin-tazobactam was dose dependent: cerebrospinal fluid bacterial titers were reduced by 0.37 ± 0.19 log1o CFU/ml per h with the lowest dose versus 0.96 ± 0.25 log1o CFU/ml per h with the highest dose (P < 0.001). At the relatively high doses of 160/20 and 200/25 mg of piperacillin-tazobactam per kg per h, the bactericidal activity of the combination was comparable to that of 10 and 25 mg of ceftriaxone per kg per h, respectively.

Section: Methodsmentioning

confidence: 70%

Evaluation of piperacillin-tazobactam in experimental meningitis caused by a beta-lactamase-producing strain of K1-positive Escherichia coli

Kern

Kennedy

Sachdeva

et al. 1990

“…Since oxacillin is Ͼ90% protein bound, it is unlikely that trough-free drug levels of 32 g/ml (as used in this study) could be achieved in a clinical setting. However, depending on renal clearance, levels of ampicillin and piperacillin in blood of 75 to 80 g/ml (with proportional concentrations of sulbactam and tazobactam) are achievable with high-dose continuous infusions (4,6,9), and levels of ampicillin as high as 103 to 130 g/ml have been reported (11). Protein binding levels are reported to be 18% for both ampicillin and amoxicillin (7), 16% for piperacillin (2), 38% for sulbactam (3), and 20 to 23% for tazobactam (2).…”

Section: Discussionmentioning

confidence: 99%

Synergy of Daptomycin with Oxacillin and Other β-Lactams against Methicillin-Resistant Staphylococcus aureus

Rand

Houck

2004

134

We previously observed marked synergy between daptomycin and both rifampin and ampicillin against vancomycin-resistant enterococci (VRE). Because the synergy between daptomycin and ampicillin was observed for 100% of VRE strains with high-level ampicillin resistance (ampicillin MIC of >128 g/ml), we looked for synergy between daptomycin and other ␤-lactams against 18 strains of methicillin-resistant Staphylococcus aureus (MRSA) by employing a time-kill method using Mueller-Hinton broth supplemented to 50 mg of Ca 2؉ /liter. All strains were resistant to oxacillin (16 of 18 strains were resistant at drug concentrations of >256 g/ml), and all strains were susceptible to daptomycin (the MIC at which 90% of the tested isolates were inhibited was 1 g/ml). Daptomycin was tested at concentrations of 2, 1, 0.5, 0.25, 0.125, and 0.0625 g/ml alone or in combination with oxacillin at a fixed concentration of 32 g/ml. Synergy was found for all 18 strains with daptomycin at one-half the MIC in combination with 32 g of oxacillin/ml, and synergy was found for 11 of 18 strains (61%) with daptomycin at one-fourth the MIC or less in combination with oxacillin. At 24 h, the daptomycin-oxacillin combination with daptomycin at one-half the MIC showed bactericidal activity against all 18 strains, and the combination with one-fourth the daptomycin MIC showed bactericidal activity against 9 of 18 strains. We also used a novel screening method to look for synergy between daptomycin and other ␤-lactams. In this approach, daptomycin was incorporated into Ca Daptomycin is a novel lipopeptide antibiotic with bactericidal activity against a wide range of clinically important grampositive bacteria, including vancomycin-resistant enterococci (VRE) and methicillin-resistant Staphylococcus aureus (MRSA). In a recent study, we found synergy between daptomycin and both rifampin and ampicillin against VRE (12a). In that work, a screening technique was used to test daptomycin with 18 other antibiotics, and promising combinations were further tested by time-kill studies. In brief, daptomycin was added to Ca 2ϩ -supplemented Mueller-Hinton broth at subinhibitory concentrations, and the Etest-determined MIC of individual antibiotics on agar containing daptomycin was compared with the MIC on agar without daptomycin. When MRSA strains were studied with this method, combinations of daptomycin and ␤-lactams were found to warrant further study. In this report, we present comparative results for several daptomycin-␤-lactam combinations by the screening method and confirmative time-kill studies using combinations of daptomycin and oxacillin or ampicillin-sulbactam for 18 strains of MRSA. MATERIALS AND METHODSEighteen randomly selected strains of MRSA were obtained from the clinical microbiology laboratory at Shands Hospital at the University of Florida, Gainesville, between January and March 2002. All isolates were tested for relatedness by pulsed-field gel electrophoresis at the Mayo Medical Laboratories, Rochester, Minn. Five isolates were different from ea...

“…Piperacillin has been shown to be effective in experimental and human Pseudomonas aeruginosa, Escherichia coli, and Streptococcus sp. meningitis (4,25). The combination of piperacillin and tazobactam was as potent as ceftriaxone in meningitis caused by a ␤-lactamase-producing E. coli strain (10).…”

mentioning

confidence: 99%

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

Nau

Kinzig‐Schippers

Sörgel

et al. 1997

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.