Is there a pharmacodynamic need for the use of continuous versus intermittent infusion with ceftazidime against Pseudomonas aeruginosa? An in vitro pharmacodynamic model

Despite the promising activity of ceftazidime against Pseudomonas aeruginosa and Burkholderia cepacia, there has not yet been a study that directly compared the pharmacokinetics (PK) of ceftazidime in cystic fibrosis (CF) patients and healthy volunteers by population PK methodology. We assessed the population PK and PK/pharmacodynamic (PD) breakpoints of ceftazidime in CF patients and healthy volunteers.

Section: Discussionsupporting

confidence: 66%

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

Bulitta

Landersdorfer

Hüttner

et al. 2010

“…Intermittent ceftazidime administration might result in undesirably high C max s and low, potentially sub-MIC C trough s, whereas the administration of ceftazidime by CI should avoid these fluctuations and keep the percentage of the time that the concentration is greater than the MIC above 100% for the entire duration of treatment (1,16,29). Moreover, Alou et al have stressed the importance of optimizing the time that the concentration of ceftazidime is greater than the MIC for resistant strains (1): they found no difference in the activities against susceptible and intermediate strains achieved by intermittent infusion and CI regimens, whereas only the CI achieved comparable activity over the same time period, minimizing the differences between the activities of the regimens against resistant and susceptible strains.…”

Section: Discussionmentioning

confidence: 99%

“…We estimated an SD for the change in FEV 1 between the start and the end of each treatment of 12% (31). The regimens were regarded as equivalent if the difference in the change in FEV 1 (by use of the 90% confidence interval) between treatments was less than 5% of the predicted normal FEV 1 . We estimated that with 120 patients randomized, the study would have an 82% power to deem the regimens equivalent if they were truly identical.…”

Section: Methodsmentioning

confidence: 99%

See 1 more Smart Citation

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.

“…For beta-lactams, it has been demonstrated that the stationary concentration (concentration at which killing equals growth) is close to the MIC and that regrowth occurs when the concentration falls below the MIC (9). Bactericidal activity against resistant strains and a higher probability of in vivo microbiological success have been reported with tϾMICs of 90 to 100% (1,2,14). Such pharmacodynamic observations provide a rationale for using continuous antibiotic infusions (10,12,13).…”

mentioning

confidence: 95%

Reassessment of Recommended Imipenem Doses in Febrile Neutropenic Patients with Hematological Malignancies

Lamoth

Buclin

Csajka

et al. 2009

Imipenem plasma concentrations were analyzed in 57 febrile neutropenic patients using the NONMEM program. The recommended 2-g/day regimen achieved coverage of the most common bacteria (MIC 90 ‫؍‬ 1 mg/liter) during the whole dosing interval in only 53% of patients. This goal was achieved in 90% of patients with 3 g/day.Imipenem dosing recommendations (2 g/day) are based on studies in healthy volunteers (8). Pharmacokinetic parameters differ significantly in critically ill patients, and information in febrile neutropenic cancer patients is lacking (4,7,15). The pharmacodynamic parameter best predicting the in vivo antibacterial activity of beta-lactam antibiotics is the time during which plasma concentrations are above the MIC of the causative pathogen (tϾMIC). For imipenem, a tϾMIC during variable proportions of the dosing interval is required to achieve bactericidal activity in neutropenic animal models (3,8). In vitro/in vivo analyses have suggested that an optimal bactericidal activity of beta-lactams is obtained at concentrations exceeding the MIC throughout the dosing interval (2, 9). In potentially life-threatening infections, such as febrile neutropenia, some experts thus recommend to maintain antibiotic concentrations above the MIC over 66 to 100% of the dosing interval (8, 16).The aim of this study was to assess the population pharmacokinetics of imipenem in febrile neutropenic cancer patients in order to optimize dosing recommendations.Consecutive imipenem plasma concentrations (159; 86 troughs and 73 peaks) in 57 febrile neutropenic patients with hematological malignancies (median, 2 samples per patient; range, 1 to 10) were retrospectively analyzed. Imipenem was prescribed according to the recommended dosing schedules for febrile neutropenia (500 mg infused over 30 min every 6 h) and adjusted to the calculated glomerular filtration rate (GFR; derived from age, sex, total body weight, and serum creatinine according to the Cockroft-Gault formula).Blood samples were drawn for trough and peak imipenem measurements around the same dose, 10 min before and at a median of 2 h (range, 0.5 to 4 h) after the start of the infusion. Blood was drawn, processed, and frozen within 1 h after sampling. Free-circulating imipenem plasma concentrations were measured by a high-performance liquid chromatography (HPLC) method validated according to international guidelines: analytical range, 0.25 to 200 mg/liter; intra-/interassay accuracy and precision, Ͻ5% (6).The NONMEM computer program (version VI; GloboMax, Hanover, MD) was used for the pharmacokinetic analysis. Several models were applied and compared for their ability to describe the observations. Simulations were obtained from NONMEM based on the final population model for groups of 1,000 virtual patients, with given covariates receiving different imipenem dosing regimens. The therapeutic objective was to maintain imipenem blood concentrations over the MIC during the whole dosing interval (i.e., troughϾMIC). The targeted MIC was 1 mg/liter (MIC 90 of the most frequ...