Optimization of therapy against Pseudomonas aeruginosa with ceftazidime and meropenem using chemostats as model for infections

Abstract

Pseudomonas aeruginosa is an opportunistic pathogen that can cause life-threatening infections in patients admitted to intensive care units. Resistance rapidly develops against two drugs of choice: ceftazidime and meropenem. Several therapeutic protocols were compared for reduction in viable cells and limiting development of resistance. Chemostat cultures were exposed to antibiotic concentrations measured in the blood of patients at low (5th percentile), medium (50th percentile) or high (95th percentile) levels in several therapy protocols to simulate therapy. Cultures exposed to ceftazidime recovered after 1 day at low, 2 days at medium and 3 days at high concentrations and developed corresponding levels of resistance. Patterns were very similar for meropenem except that recovery was delayed. Fluctuating levels and intermittent treatment achieved similar reduction of cell numbers at lower resistance costs. Treatment alternating ceftazidime and meropenem reduced cell numbers more than monotherapy, while strongly limiting resistance. Combination therapy was even more effective in both respects. Therapeutic goals are best reached with least risk of resistance when ceftazidime and meropenem are used in combination or alternating, at the highest concentrations the patient can endure. Monotherapy should also apply the highest concentration that is safe for the shortest time that achieves treatment objectives.

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