Continuous infusion of ceftazidime with a portable pump is as effective as thrice-a-day bolus in cystic fibrosis children

Ceftazidime is particularly efficient against Pseudomonas aeruginosa in cystic fibrosis patients. Thus, the spontaneous production of pyridine, which is a toxic product, raises some concern. Our aim was to examine the kinetics of degradation of ceftazidime in portable infusion pumps either at 4°C, 22°C, or 33°C and to propose some recommendations in order to reduce the pyridine exposure. Two administration models were studied in vitro. In model 1, we administered 12 g of ceftazidime infused over 23 h (once-daily infusion) compared to 6 g infused over 11.5 h in model 2 (twice-daily regimen). Samples were collected at 0 h and then every 4 and 2 h after the shaping of portable infusion pumps in models 1 and 2, respectively. Both ceftazidime and pyridine were analyzed using an ultraviolet high-performance liquid chromatograph. Production of pyridine is highly depending on the temperature. The in situ production of pyridine per day of treatment decreases at a ratio close to 1/6 and 1/3 between 33°C and 4°C in models 1 and 2, respectively. Regardless of the conditions, the production of pyridine is significantly lower in model 2, whereas the total delivery amount of ceftazidime is significantly higher at 4°C and 33°C compared to that in model 1. According to a the precautionary principle, these findings lead to three major recommendations: (i) exposing a solution of ceftazidime to over 22°C should be strictly avoided, (ii) a divided dose of 6 g over 11.5 h instead of a once-daily administration is preferred, and (iii) infusion should be administered immediately after reconstitution.

Section: Discussionmentioning

confidence: 98%

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

Bourget¹,

Amin

Dupont³

et al. 2014

“…tobramycin and ceftazidime in patients with CF (25). Nevertheless, because of the high rate of resistance among P. aeruginosa isolates, we decided not to reduce the doses of ceftazidime for delivery by CI in comparison to those used for the SI, contrary to the reductions used in previous studies (4,22,33), because we thought that higher doses might be more effective. We observed considerable variability in serum ceftazidime concentrations during intermittent administration (with very high C max s and very low C trough s, even below the MIC in some cases), whereas the C ss remained permanently above the MIC during CI.…”

Section: Discussionmentioning

confidence: 99%

“…A few clinical studies have considered a 24-h CI of ceftazidime in CF patients (4,22,33). Those studies reported good clinical results and few complications but included only a small number of patients.…”

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confidence: 99%

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

Hubert

Roux

Lavrut

et al. 2009

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.

“…Accordingly, several clinical trials have been initiated over the last half-decade, most notably in difficult-to-treat situations such as suspected gram-negative infections in critically ill patients (3), severe infections in intensive care patients (8,16,21,24,37), septicemia (1), severe sepsis (20), and cystic fibrosis (29,40). Yet, as clearly pointed out by one of the first promoters of the continuous infusion of ␤-lactams (6), this mode of administration, through programmable pumps or other similar devices, requires the drug to remain sufficiently stable in solution over the projected duration of the infusion.…”

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confidence: 99%

“…This reinforces our previous conclusion (30) . We are aware of a recent study (29) in which ceftazidime was infused to cystic fibrosis patients with the aid of portable pumps changed only every 24 h. Presumably, these pumps were carried under clothes, and the drug was therefore exposed to temperatures exceeding 25°C. While no adverse effect was reported, these authors did not address specifically the issue of pyridine toxicity nor did they check for the intactness of ceftazidime and release of pyridine under these conditions of use.…”

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confidence: 99%

Comparative Stability Studies of Antipseudomonal β-Lactams for Potential Administration through Portable Elastomeric Pumps (Home Therapy for Cystic Fibrosis Patients) and Motor-Operated Syringes (Intensive Care Units)

Viaene

Chanteux

Servais

et al. 2002

176

123

The stability of antipseudomonal ␤-lactams in concentrated solutions was examined in view of their potential administration by continuous infusion with external pumps (for intensive care patients) or with portable pumps carried under clothing (for cystic fibrosis patients). Aztreonam (100 g/liter), piperacillin (128 g/liter, with tazobactam), and azlocillin (128 g/liter) remained 90% stable for up to more than 24 h at 37°C (mezlocillin [128 g/liter] was stable at 25°C but not at 37°C). Ceftazidime (120 g/liter), cefpirome (32 g/liter), and cefepime (50 g/liter) remained 90% stable for up to 24, 23.7, and 20.5 h at 25°C but only for 8, 7.25, and 13 h at 37°C, respectively. The control of temperature therefore appears to be critical for all three cephalosporins that cannot be recommended for use in portable pumps carried under clothes for prolonged periods for reasons of stability. Cefpirome and cefepime solutions developed an important color change (from light yellow to dark red) upon exposure when stored at 30°C or higher. Degradation of ceftazidime was accompanied by the liberation of pyridine which, at 37°C, was in excess of what is allowed by the U.S. Pharmacopeia, i.e., 1.1 mg/liter, after 8 and 12 h for drug concentrations of 12 and 8.3%, respectively. Imipenem and meropenem are too unstable (10% degradation at 25°C after 3.5 and 5.15 h, respectively) to be recommended for use by continuous infusion. Faropenem, examined in comparison with imipenem and meropenem, proved as stable as aztreonam or piperacillin.␤-Lactams are one of the most typical antibiotic classes for which the pharmacodynamic data, collected in vitro, as well as in animal studies, clearly indicate a potential advantage of a continuous infusion over the more conventional, discrete mode of administration (see references 6, 22, 23, 38, and 41 for reviews). Accordingly, several clinical trials have been initiated over the last half-decade, most notably in difficult-to-treat situations such as suspected gram-negative infections in critically ill patients (3), severe infections in intensive care patients (8,16,21,24,37), septicemia (1), severe sepsis (20), and cystic fibrosis (29,40). Yet, as clearly pointed out by one of the first promoters of the continuous infusion of ␤-lactams (6), this mode of administration, through programmable pumps or other similar devices, requires the drug to remain sufficiently stable in solution over the projected duration of the infusion. In a previous study (30), we examined the stability of ceftazidime in solution and found it to be critically dependent on the temperature within the 20 to 37°C range (68 to 99°F). This sets clear limitations on the potential use of ceftazidime by continuous infusion if administrations every 24 h are contemplated without periodic changes of the solutions. Chemical considerations suggest that the stability of the main ␤-lactams currently registered for human medicine use may vary to a meaningful extent. Unfortunately, these variations, and their consequences as far as continuous infu...