Continuous versus Intermittent Infusions of Ceftazidime for Treating Exacerbation of Cystic Fibrosis

Abstract

The present multicenter, randomized crossover study compared the safety and efficacy of continuous infusion with those of short infusions of ceftazidime in patients with cystic fibrosis. Patients with chronic Pseudomonas aeruginosa colonization received two successive courses of intravenous tobramycin and ceftazidime (200 mg/kg of body weight/day) for pulmonary exacerbation administered as thrice-daily short infusions or as a continuous infusion. The primary endpoint was the variation in the forced expiratory volume in 1 s (FEV 1 ) during the course of antibiotic treatment. Sixty-nine of the 70 patients enrolled in the study received at least one course of antibiotic treatment. The improvement in FEV 1 at the end of therapy was not statistically different between the two treatment procedures (؉7.6% after continuous infusion and ؉5.5% after short infusions) but was better after continuous ceftazidime treatment in patients harboring resistant isolates (P < 0.05). The interval between the course of antibiotic treatments was longer after the continuous infusion than after the short infusion of ceftazidime (P ‫؍‬ 0.04). The mean serum ceftazidime concentration during the continuous infusion was 56.2 ؎ 23.2 g/ml; the mean peak and trough concentrations during the short infusions were 216.3 ؎ 71.5 and 12.1 ؎ 8.7 g/ml, respectively. The susceptibility profiles of the P. aeruginosa isolates remained unchanged and were similar for both regimens. Quality-of-life scores were similar whatever the treatment procedure, but 82% of the patients preferred the continuous-infusion regimen. Adverse events were not significantly different between the two regimens. In conclusion, the continuous infusion of ceftazidime did not increase its toxicity and appeared to be as efficient as short infusions in patients with cystic fibrosis as a whole, but it gave better results in patients harboring resistant isolates of P. aeruginosa.

Population Pharmacokinetic Comparison and Pharmacodynamic Breakpoints of Ceftazidime in Cystic Fibrosis Patients and Healthy Volunteers

“…Giving the same daily dose as a short-term infusion q6h instead of q8h achieved only a PK-PD MIC breakpoint of 2 mg/liter in CF patients. This prediction is in excellent agreement with the better outcome for CF patients with resistant or intermediate isolates when they received continuous ceftazidime infusion compared to when they received short-term infusion (both coadministered with tobramycin) (36,63) and with results from in vitro PD models (1,20,51).…”

“…Daily doses of up to 12 g ceftazidime split into 3 or 4 intermittent doses have been recommended for CF patients (24), whereas other authors recommend lower daily doses of 6 g in adult CF patients (30). To increase the PK-PD MIC breakpoints and clinical outcome, continuous infusion of ceftazidime has been proposed and studied in CF patients (8,13,23,36,42,59,(74)(75)(76).…”

How To Minimize Toxic Exposure to Pyridine during Continuous Infusion of Ceftazidime in Patients with Cystic Fibrosis?

“…In a multicenter, randomized, crossover study performed in 69 patients with moderate lung disease, we compared intermittent infusion and continuous infusion of CAZ for treating APE (14). The drug was administered at the relatively high dose of 200 mg/kg of body weight per day.…”

“…The recommended dosages administered at Cystic Fibrosis French Reference Centers are historically based on the following European Consensus guideline, i.e., 150 to 250 mg/kg/day divided every 6 to 8 h (maximum of 12 g/day) and on studies performed at higher intermittent or continuous regimens that have demonstrated similar tolerability profiles and improved efficacy in the management of the APE episodes (14,(25)(26)(27)(28). In contrast, it has been demonstrated that compared with an intermittent infusion dosing regimen, continuous-infusion beta-lactam therapy achieves the target serum concentration for susceptible organisms using a 41% to 50% lower total daily dose of CAZ (29,30).…”

“…Throughout the study, we used the recommended dosing regimen commonly used in CF French reference centers and followed the study conducted by Hubert et al, i.e., a continuous infusion of 12 g of CAZ per day of treatment (14). In this work, the drug was administered using a PIP.…”