Pharmacodynamics of ceftazidime administered as continuous infusion or intermittent bolus alone and in combination with single daily-dose amikacin against Pseudomonas aeruginosa in an in vitro infection model

Abstract

We compared the pharmacodynamics and killing activity of ceftazidime, administered by continuous infusion and intermittent bolus, against Pseudomonas aeruginosa ATCC 27853 and ceftazidime-resistant P. aeruginosa 27853CR with and without a single daily dose of amikacin in an in vitro infection model over a 48-h period. Resistance to ceftazidime was selected for by serial passage of P. aeruginosa onto agar containing increasing concentrations of ceftazidime. Human pharmacokinetics and dosages were simulated as follows: half-life, 2 h; intermittent-bolus ceftazidime, 2 g every 8 h (q8h) and q12h; continuous infusion, 2-g loading dose and maintenance infusions of 5, 10, and 20 g/ml; amikacin, 15 mg/kg q24h. There was no significant difference in time to 99.9% killing between any of the monotherapy regimens or between any combination regimen against ceftazidime-susceptible P. aeruginosa. Continuous infusions of 10 and 20 g/ml killed as effectively as an intermittent bolus of 2 g q12h and q8h, respectively. Continuous infusion of 20 g/ml and an intermittent bolus of 2 g q8h were the only regimens which prevented organism regrowth at 48 h, while a continuous infusion of 5 g/ml resulted in the most regrowth. All of the combination regimens exhibited a synergistic response, with rapid killing of ceftazidime-susceptible P. aeruginosa and no regrowth. Against ceftazidime-resistant P. aeruginosa, none of the ceftazidime monotherapy regimens achieved 99.9% killing. The combination regimens exhibited the same rapid killing of the resistant strain as occurred with the susceptible strain; however, regrowth occurred with all regimens. The combination regimens of continuous infusion of 20 g/ml plus amikacin and intermittent bolus q8h or q12h plus amikacin continued to be synergistic. Overall, continuous infusion monotherapy with ceftazidime at concentrations 4 to 5 and 10 to 15 times the MIC was as effective as an intermittent bolus of 2 g q12h (10 to 15 times the MIC) and q8h (25 to 35 times the MIC), respectively, against ceftazidime-susceptible P. aeruginosa. Combination therapy with amikacin plus ceftazidime, either intermittently q8h or by continuous infusion of 20 g/ml, appeared to be effective and exhibited synergism against ceftazidime-resistant P. aeruginosa.

Pharmacodynamics of Cefepime Alone and in Combination with Various Antimicrobials against Methicillin-Resistant Staphylococcus aureus in an In Vitro Pharmacodynamic Infection Model

“…Although not statistically significant, we observed a greater reduction in bacterial density as a function of dosing interval. This relationship has been previously shown with cefepime against gram-negative organisms (6,9,11,12,41). The observed activity of cefepime against MRSA in this study may be related to some minimal activity against penicillin-binding protein 2a and/or due to a heteroresistance profile for beta-lactams in which some initial activity may be expected against a portion of the bacterial inoculum (40).…”

“…In our study, the most potent activity against MRSA was observed when cefepime was combined with an aminoglycoside. ␤-Lactams plus aminoglycoside have traditionally demonstrated synergy and additivity for a variety of pathogens, including P. aeruginosa, Enterobacteriaceae, and Acinetobacter (12,29,30,33,43,46). We found that combinations of cefepime plus an aminoglycoside administered every 12 h or every 24 h demonstrated the most potent activity.…”

Activities of Trovafloxacin and Ampicillin-Sulbactam Alone or in Combination versus Three Strains of Vancomycin- Intermediate Staphylococcus aureus in an In Vitro Pharmacodynamic Infection Model

“…As noted, we did not observe changes in MICs. We and others previously have observed this regrowth phenomenon (7,22). Regrowth in the in vitro infection models appears to occur most often for antibiotics with time-dependent activity during pharmacokinetic simulations, where concentrations either stay just above the MIC or fall below the MIC during the course of dosing intervals.…”

Antibiotics Against Endocarditis – Past, Present and Future (Experimental Data)

“…The oxazolidinone is a timedependent antibiotic and for these drugs, the time above the MIC (T>MIC) is usually considered a critical parameter in the assessment of therapeutic efficacy (Carbon, 1990). In general, the maximal activity of continuous infusion was obtained at a steady-state concentration in serum equal to a multiple of the MIC, as previously demonstrated for ceftazidime (Cappelletty et al, 1995). To confirm this, continuous infusion of linezolid was used by Jacqueline et al to investigate whether it improves in vivo activity.…”