Pharmacokinetics and bacteriological effect of ceftazidime in experimental Streptococcus pneumoniae, Haemophilus influenzae, and Escherichia coli meningitis

The penetration into cerebrospinal fluid (CSF) and efficacy of ticarcillin-clavulanic acid, ticarcillin alone, and ceftazidime were compared in rabbits with experimentally induced Klebsiella pneumoniae meningitis. The compounds were administered to simulate in rabbit plasma the concentration-versus-time curves observed in humans after 30-min infusions of Timentin (3 g of ticarcillin plus 100 mg of clavulanic acid), ticarcillin (3 g), and ceftazidime (2 g). Single-and multiple-dosing schedules were used. The penetrations of clavulanic acid into CSF (expressed as [area under the concentration-time curve for CSF/area under the curve for plasma] x 100) after the two dosing schedules were 28 and 24.5%, similar to that for ceftazidime (21%; multiple-dosing only) and greater than those for ticarcillin (8.4 and 9.3%). Ticarcillin was ineffective in reducing viable counts in CSF but, in the presence of clavulanic acid, reduced bacterial numbers by approximately 99% at 4 h after a single dose and by 99.99% at 12 h after three doses given at 4-h intervals. Two doses of ceftazidime given 8 h apart were more effective than the three doses of ticarcillin-clavulanic acid, in keeping with the in vitro activities of these compounds against the infecting organism. These results illustrate the ability of clavulanic acid to penetrate the blood-CSF barrier such that concentrations of the inhibitor in CSF potentiate the activity of ticarcillin against the ticarcillin-resistant, ,-lactamase-producing strain of K. pneumoniae.In the presence of clavulanic acid the antibacterial spectrum of ticarcillin is extended to include ticarcillin-resistant, P-lactamase-producing strains of members of the family Enterobacteriaceae, Pseudomonas aeruginosa, Bacteroides spp., Haemophilus influenzae, and staphylococci (6,8,20). For clavulanic acid to inhibit ,B-lactamases produced in vivo and allow ticarcillin to exert its bactericidal effect, both compounds should display similar distribution characteristics. This has been demonstrated both in animals (4, 5, 24) and in humans (1,3,22). In the study reported here, the penetration into cerebrospinal fluid (CSF) and the efficacy of ticarcillin-clavulanic acid were investigated in a rabbit model of meningitis (18) in which the infecting organism was a strain of Klebsiella pneumoniae.To compensate for the more rapid elimination of ticarcillin (elimination half-life, 0.4 to 0.6 h), clavulanic acid (0.3 to 0.6 h), and ceftazidime (0.75 to 0.88 h) from serum in the rabbit (16, 21, 23; unpublished data) than from serum in humans (half-life, 1.1 ± 0.5, 1.0 + 0.06, and 1.8 ± 0.21, respectively) (7, 9), the antibiotics were administered to infected rabbits by using a procedure designed to simulate in rabbit plasma the concentration-versus-time curves observed in human serum after therapeutic doses. The efficacy of ticarcillinclavulanic acid was compared with results for ticarcillin alone and with those for ceftazidime, a broad-spectrum cephalosporin considered useful for the treatment of gramnegative-bacilliary m...

Section: Discussionsupporting

confidence: 76%

Simulation of human serum pharmacokinetics of ticarcillin-clavulanic acid and ceftazidime in rabbits, and efficacy against experimental Klebsiella pneumoniae meningitis

Mizen

Woodnutt

Kernutt

et al. 1989

“…These data are consistent with results from our previous studies in this animal model (8,(12)(13)(14) and suggest that a minimum bactericidal titer in CSF of 1:8 must be attained to achieve a maximum bacteriological effect. Although continuous-infusion experiments with 100 mg of mezlocillin per kg were not performed in animals infected with mezlocillin-resistant E. coli, the successful results of single-dose studies with this larger dosage are indicative of bacteriological efficacy after continuous infusion therapy as well.…”

supporting

confidence: 82%

“…The results of this study indicate that the bacteriological effect of mezlocillin in experimental meningitis due to susceptible E. coli is comparable to that of moxalactam (14) or ceftazidime (12) in this animal model, despite the substantially lower bactericidal titers in CSF produced by mezlocillin (Table 4). These data are consistent with results from our previous studies in this animal model (8,(12)(13)(14) and suggest that a minimum bactericidal titer in CSF of 1:8 must be attained to achieve a maximum bacteriological effect.…”

mentioning

confidence: 81%

Pharmacokinetics and bacteriological efficacy of mezlocillin in experimental Escherichia coli and Listeria monocytogenes meningitis

Odio¹,

Thomas²,

McCracken³

1984

Self Cite

The purpose of this study was to determine the pharmacokinetics and bacteriological effect of mezlocillin in experimental meningitis caused by Listeria monocytogenes and two Escherichia coli strains. The half-life of mezlocillin in cerebrospinal fluid (CSF) was approximately twice that in serum of experimentally infected animals, and the penetration of drug into CSF was 5 to 15% after a single dose and 5 to 20% after continuous-infusion experiments. The bactericidal titer in CSF for both susceptible E. coli and L. monocytogenes was 1:8, whereas for the resistant E. coli strain, titers were <1:2 after single doses of 50 or 100 mg of mezlocillin per kg and 1:4 with continuous infusion. After single-dose and continuous-infusion experiments, the bacteriological effect of mezlocillin in experimental L. monocytogenes infections was similar to that of ampicillin. Mezlocillin reduced the colony counts of susceptible E. coli in CSF by 90% or more after a single dose or continuous infusion but had no appreciable effect on resistant E. coli after a single dose of 50 mg/kg. In contrast, a single dose of 100 mg of mezlocillin per kg eradicated the resistant strain from CSF, despite a bactericidal titer in CSF of <1:2. This unexpected finding prompted us to evaluate the effect of serum on the in vitro susceptibilities of selected coliforms to mezlocillin. The activity of mezlocillin against one susceptible and four resistant strains of gram-negative, enteric bacilli was enhanced manyfold by the addition of fresh rabbit serum; this effect was abolished by heating the serum at 56°C for 30 min. This interaction of mezlocillin and serum against coliform bacteria should be examined in a larger number of experimentally infected animals and in specimens obtained from mezlocillin-treated infants.Currently, initial antimicrobial therapy for neonatal sepsis consists of two drugs, usually ampicillin and an aminoglycoside (19). Although this combination is efficacious in neonates, the potential nephrotoxicity and ototoxicity of the aminoglycosides in premature infants with very low birth weights and the increasing percentages of gram-negative enteric bacilli that are resistant to one or both of these antibiotics limits their usefulness (6, 9). The new broadspectrum cephalosporins, of which only moxalactam and cefotaxime have been approved by the Food and Drug Administration for use in newborn and young infants, are not active against Listeria monocytogenes and enterococci, and there are insufficient efficacy and safety data in neonates to warrant their routine use.Mezlocillin, an ampicillin derivative, has excellent in vitro activity against gram-negative, enteric bacilli, Pseudomonas aeruginosa, Bacteroides fragilis, L. monocytogenes, group B streptococci, and enterococci (4, 19). Because there are no controlled studies of the safety or efficacy of this antibiotic for therapy of neonatal sepsis and meningitis, mezlocillin was evaluated in rabbits with experimental meningitis caused by L. monocytogenes and two Escherichia coli strains. A...

“…When CSF penetration was expressed as the ratio of the simultaneously measured concentrations of the drugs in CSF and plasma, the entry of either drug into the CSF appeared considerably more extensive (Table 5). DISCUSSION Most authors agree that 1-lactam penetration into CSF varies proportionally with protein content and degree of pleocytosis (2,3,8,16,(18)(19)(20). Netland et al (12) classified meningeal inflammation into three very general categories.…”

Section: Resultsmentioning

confidence: 99%

“…,B-Lactam compounds that attain high concentrations in CSF, like moxalactam, ceftazidime, and ceftriaxone, share the common property of not having their renal (and probably choroid plexus) clearance mechanisms influenced by probenecid (16,17). The renal excretion of potassium clavulanate occurs primarily by glomerular filtration (21).…”

Section: Resultsmentioning

confidence: 99%

Penetration of amoxicillin and potassium clavulanate into the cerebrospinal fluid of patients with inflamed meninges

Bakken¹,

Bruun²,

Gaustad³

et al. 1986

A single intravenous dose of 2.0 g of amoxicillin and 0.2 g of potassium clavulanate was given to patients with bacterial meningitis, and the pharmacokinetics of both drugs in the cerebrospinal fluid (CSF) and plasma were evaluated. Twenty-one patients aged 14 to 76 years were studied. Both amoxicillin and potassium clavulanate were detectable in the CSF as early as 1 h and reached peak concentrations by approximately 2 h. The highest mean CSF concentrations were 2.25 ,ug/ml for amoxicillin and 0.25 ,ug/ml for potassium clavulanate and were found in patients with moderately or severely inflamed meninges. The CSF penetration relative to plasma for amoxicillin and potassium clavulanate was 5.8 and 8.4%, respectively. These levels suggest that the amoxicillin-potassium clavulanate combination may be effective for the treatment of bacterial meningitis caused by ,-lactamase-producing pathogens.