Evaluation of azlocillin in-vitro and in discriminative animal models of infection

This study examined the penetration of aztreonam into the cerebrospinal fluid (CSF) and brain in noninfected rabbits and rabbits with experimental meningitis caused by Pseudomonas aeruginosa. Animals received either 600 or 1,200 mg of aztreonam administered intravenously over 6 h. Aztreonam did not readily enter the CSF in the absence of meningitis. In noninfected animals, mean concentrations in the CSF ranged from 1.1 to 3.0 micrograms/ml with the 600-mg dose and from 2.3 to 4.7 micrograms/ml with the 1,200-mg dose. In contrast, mean concentrations of aztreonam in the CSF were significantly higher (P less than 0.01) at each sampling time in rabbits with experimental meningitis caused by P. aeruginosa. They ranged from 10.2 to 14.6 micrograms/ml with the 600-mg dose and from 29 to 40 micrograms/ml with the 1,200-mg dose. Although concentrations in the brain measured at 6 h tended to be higher in infected rabbits, this difference was not statistically significant. Aztreonam therapy produced a substantial decline in CSF bacterium counts over 6 h: mean CSF counts decreased 2.4 log10 CFU/ml in the 600-mg dose group and 3.0 log10 CFU/ml in the 1,200-mg dose group. The results of this study suggest that aztreonam may be useful in the therapy of meningitis caused by P. aeruginosa.

Section: Discussionsupporting

confidence: 69%

Penetration of aztreonam into cerebrospinal fluid and brain of noninfected rabbits and rabbits with experimental meningitis caused by Pseudomonas aeruginosa

Strausbaugh¹,

Bodem²,

Laun³

1986

“…Our results clearly demonstrate that serum bactericidal activity adequate for treatment of systemic infections can be attained in rabbits with parenteral administration of ciprofloxacin and that the efficacy of this agent against P. aeruginosa endocarditis in rabbits is comparable to that of azlocillin plus tobramycin, a combination previously shown to be effective (14,15) at dosages which produce serum concentrations analagous to those attained in humans after standard parenteral regimens (6,9,12,14).…”

Section: Methodssupporting

confidence: 62%

“…Endocarditis was induced in 2-to 3-kg New Zealand White rabbits by using modifications of previously described techniques (1, 2, [13][14][15]20). A polyethylene catheter (type PE-90 Intramedic; Clay-Adams, Parsippany, N.J.) was introduced through the right carotid artery and threaded across the aortic valve after adequate anesthesia was induced with intramuscular ketamine (35 mg/kg) and xylazine (5 mg/kg).…”

Section: Methodsmentioning

confidence: 99%

See 1 more Smart Citation

Comparison of ciprofloxacin with azlocillin plus tobramycin in the therapy of experimental Pseudomonas aeruginosa endocarditis

Strunk

Gratz

Maserati

et al. 1985

The efficacy of ciprofloxacin (Bay o 9867), a promising new quiiolone, was compared with the efficacy of azlocillin plus tobramycin in rabbits with experimentally induced Pseudomonas aeruginosa endocarditis. The MBCs of ciprofloxacin, azlocillin, and tobramycin against the test strain were 0.5, 8, and 4 JLg/ml respectively.Ciprofloxacin at a concentration of 50 mg/kg or azlocillin at a concentration of 200 mg/kg in combination with tobramycin at a concentration of 5 mg/kg was administered intramuscularly at 8-h intervals for 4 days. Both regimens produced median peak serum bactericidal titers of 1:8. The concentrations of ciprofloxacin, azlocillin, and tobramycin in serum, 1.8 ± 0.7, 154 ± 48, and 9.1 ± 2.4 ,g/ml (mean ± standard deviation), respectively, closely approximated concentrations found in humans after accepted dosages. At the end of treatment, the titers of P. aeruginosa were 3.0 ± 1.6 log10 CFU/g of vegetation (mean ± standard deviation) for recipients of ciprofloxacin and 3.2 ± 1.3 log10 CFU/g of vegetation for recipients of azlocillin plus tobramycin. These values compared with control titers of 7.3 ± 1.6 CFU/g. These data indicate that at the doses used, ciprofloxacin was as effective as azlocillin plus tobramycin in the treatment of P. aeruginosa endocarditis in rabbits. Since the latter drug combination has proven efficacy, ciprofloxacin deserves further evaluation in the therapy of systemic infections in animal models and in humans.Ciprofloxacin (Bay o 9867) is a new quinolone carboxylic acid derivative currently being developed for oral and parenteral use (19). Like nalidixic acid, to which it is structurally related, it is active against most members of the family Enterobacteriaceae in vitro. However, ciprofloxacin is much more active against these organisms and also has an extended spectrum of activity against Pseudomonas aeruginosa, Neisseria gonorrhoeae, Staphylococcus aureus, Haemophilus influenzae, and a wide variety of other organisms (3,7,8,10,19 851, 1983). Because of its broad spectrum, potency, and oral efficacy, ciprofloxacin could be useful for oral treatment of systemic infections that in the past required parenteral therapy (e.g., osteomyelitis). Because of the remarkable susceptibility of Pseudomonas sp. to ciprofloxacin, parenteral use of this quinolone might offer advantages over currently available therapy for such infections, in which resistance, drug allergy, and drug toxicity are frequent problems.The observations described above on the antimicrobial activity and pharmacology of ciprofloxacin led us to compare the activity of this quinolone with that of azlocillin plus tobramycin, a combination which has previously been * Corresponding author. t Present address: Instituto Di Clinica, Delle Malattie Infettive, Policlinico S. Matteo, Universita Di Pavia, 27100 Pavia, Italy. shown to be an effective regimen in this model (14) of experimentally induced P. aeruginosa endocarditis in rabbits. MATERIALS AND METHODSIn vitro studies. All 149 P. aeruginosa strains studied were ...

“…Since the MIC of ceftazidime at which 90% of the P. aeruginosa isolates are inhibited is approximately 2 mg/liter (5), the daily dose should be increased to 12 g when the blood-CSF barrier disruption is not pronounced. Because of the known synergism of ␤-lactam antibiotics and aminoglycosides in P. aeruginosa meningitis (17,19), an aminoglycoside should be added in these cases of central nervous system infections caused by P. aeruginosa with minor impairment of the blood-CSF barrier.…”

Section: Discussionmentioning

confidence: 99%

Cerebrospinal fluid ceftazidime kinetics in patients with external ventriculostomies

Nau

Prange

Kinzig

et al. 1996

Ceftazidime has proven to be effective for the treatment of bacterial meningitis caused by multiresistant gram-negative bacteria. Since nosocomial central nervous system infections are often accompanied by only a minor dysfunction of the blood-cerebrospinal fluid (CSF) barrier, patients with noninflammatory occlusive hydrocephalus who had undergone external ventriculostomy were studied (n = 8). Serum and CSF were drawn repeatedly after the administration of the first dose of ceftazidime (3 g over 30 min intravenously), and concentrations were determined by high-performance liquid chromatography by using UV detection. The concentrations of ceftazidime in CSF were maximal at 1 to 13 h (median, 5.5 h) after the end of the infusion and ranged from 0.73 to 2.80 mg/liter (median, 1.56 mg/liter). The elimination half-lives were 3.13 to 18.1 h (median, 10.7 h) in CSF compared with 2.02 to 5.24 h (median, 3.74 h) in serum. The ratios of the areas under the concentration-time curves in CSF and serum (AUCCSF/AUCS) ranged from 0.027 to 0.123 (median, 0.054). After the administration of a single dose of 3 g, the maximum concentrations of ceftazidime in CSF were approximately four times higher than those after the administration of 2-g intravenous doses of cefotaxime (median, 0.44 mg/liter) and ceftriaxone (median, 0.43 mg/liter) (R. Nau, H. W. Prange, P. Muth, G. Mahr, S. Menck, H. Kolenda, and F. Sörgel, Antimicrob. Agents Chemother. 37:1518-1524, 1993). The median AUCCSF/AUCS ratio of ceftazidime was slightly below that of cefotaxime (0.12), but it was 1 order of magnitude above the median AUCCSF/AUCS of ceftriaxone (0.007) (Nau et al., Antimicrob. Agents Chemother. 37:1518-1524, 1993). The concentrations of ceftazidime observed in CSF were above the MICs for most Pseudomonas aeruginosa strains. However, they are probably not high enough to be rapidly bactericidal. For this reason, the daily dose should be increased to 12 g in cases of P. aeruginosa infections of the central nervous system when the blood-CSF barrier is minimally impaired.