In vivo efficacy of continuous infusion versus intermittent dosing of ceftazidime alone or in combination with amikacin relative to human kinetic profiles in a Pseudomonas aeruginosa rabbit endocarditis model

Abstract

Ceftazidime and amikacin were administered in a Pseudomonas aeruginosa rabbit endocarditis model using computer-controlled intravenous (iv) infusion pumps to simulate human serum concentrations for the following regimens: continuous (constant rate) infusion of 4, 6 or 8 g of ceftazidime over 24 h or intermittent dosing of 2 g every 8 h either alone or in combination with amikacin (15 mg/kg once daily). The in vivo activities of these regimens were tested on four Pseudomonas aeruginosa strains. Animals were killed 24 h after the beginning of treatment. Efficacy was assessed by comparing the effects of the different groups on bacterial counts in vegetations for each strain tested. For a susceptible reference strain (ATCC 27853; MICs of ceftazidime and amikacin 1 and 2 mg/L, respectively), continuous infusion of 4 g alone or with amikacin was as effective as intermittent dosing with amikacin. For a clinical isolate producing an oxacillinase (MICs of ceftazidime and amikacin 8 and 32 mg/L, respectively), continuous infusion of 6 g was equivalent to intermittent dosing. For a clinical isolate producing a TEM-2 penicillinase (MIC of ceftazidime and amikacin 4 mg/L), continuous infusion of 6 g, but not intermittent dosing, had a significant in vivo effect. For a clinical isolate producing an inducible, chromosomally encoded cephalosporinase (MIC of ceftazidime and amikacin 8 and 4 mg/L, respectively), neither continuous infusion nor intermittent dosing proved effective. Determination of ceftazidime concentrations in vegetations showed that continuous infusion produced tissue concentrations at the infection site far greater than the MIC throughout the treatment. It is concluded that continuous infusion of the same total daily dose provides significant activity as compared with fractionated infusion. This study confirms that a concentration of 4-5 x MIC is a reasonable therapeutic target in most clinical settings of severe P. aeruginosa infection.

Immunomodulatory Clarithromycin Treatment of Experimental Sepsis and Acute Pyelonephritis Caused by Multidrug-Resistant Pseudomonas aeruginosa

“…The animals were then divided into six study groups, as follows: group A (n ϭ 10), control animals that received 30 ml of normal saline intravenously; group B (n ϭ 8), animals that received the clarithromycin regimen concomitantly with the inoculation of P. aeruginosa; group C (n ϭ 7), animals that received clarithromycin, as for animals in group B, and a second dose of clarithromycin exactly 2 h after bacterial challenge; group D (n ϭ 10), animals that received amikacin (Bristol) 30 min after bacterial challenge at a single intravenous bolus dose of 15 mg/kg, as proposed by others (19); group E (n ϭ 10); animals that received the clarithromycin regimen concomitantly with the inoculation of P. aeruginosa and amikacin 30 min after bacterial challenge; and group F (n ϭ 10), animals that received clarithromycin and amikacin, as for the animals in group E, and a second dose of clarithromycin exactly 2 h after bacterial challenge.…”

In vivo impact of the MexAB-OprM efflux system on β-lactam efficacy in an experimental model of Pseudomonas aeruginosa infection

“…15 times the MIC). It has been shown that against severe infections due to P. aeruginosa, for penicillins and cephalosporins not only the time that the antibiotic concentration remains above the MIC (T > MIC) but also the antibiotic concentration/MIC ratio are important criteria for improving survival [12]. In our work, only a high dosage (6 g/day) of CFZ was able to achieve bactericidal activity, and the best regimen was by CI.…”

In Vivo Efficacy of Continuous Infusion versus Intermittent Dosing of Linezolid Compared to Vancomycin in a Methicillin-Resistant Staphylococcus aureus Rabbit Endocarditis Model

“…In particular, continuous infusion of ␤-lactams has been studied. In vivo and in vitro studies have shown that, for the same daily dose, continuous infusion of ceftazidime improves the T Ͼ MIC compared to that obtained by intermittent dosing (9,17,22). The maximal activity of continuous infusion was obtained at a steady-state concentration in serum equal to a multiple of the MIC.…”