JAC Advance Access originally published online on March 13, 2006
Journal of Antimicrobial Chemotherapy 2006 57(5):1017-1019; doi:10.1093/jac/dkl053
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Correspondence |
Pilot study of continuous infusion cefepime in adult patients with cystic fibrosis
1 University of Southern California School of Pharmacy, Los Angeles, CA 90089 2 Adult Cystic Fibrosis Center 1520 San Pablo Suite #1000, Los Angeles, CA 90033; 3 Keck School of Medicine, 1975 Zonal Avenue KAM500, Los Angeles, CA 90089, USA; 4 University of Oslo School of Pharmacy, Farmasøytisk Institutt, UiO Postboks 1068 Blindern, 0316 Oslo, Norway
* Correspondence address. University of California, School of Pharmacy, 1985 Zonal Avenue, Los Angeles, CA 90089, USA. Tel: +1-323-442-1402; Fax: +1-626-6283024; E-mail: beringer{at}usc.edu
Keywords: pharmacokinetics , ß-lactams , time above MIC , t > MIC , Pseudomonas aeruginosa
Sir,
A combination therapy with aminoglycoside and an antipseudomonal ß-lactam agent is the recommended treatment for acute pulmonary exacerbations caused by Pseudomonas aeruginosa in cystic fibrosis (CF) patients. The activity of ß-lactams depends on the duration that the drug concentrations exceed the MIC for the organism. Rapid regrowth of the organisms is seen once the drug concentration falls below the MIC.1 Since the half-lives of many antibiotics are relatively short in CF patients and since patients frequently harbour isolates of P. aeruginosa with reduced susceptibility to multiple antibiotics, the current practice of intermittent administration of ß-lactam agents may not be the optimal administration technique in this population. Therefore, we conducted a pilot study to compare the pharmacokinetics and preliminary efficacy of cefepime administered as an intermittent infusion (II) or continuous infusion (CI) in CF patients.
CF patients were prospectively randomized to receive either II or CI cefepime once the study was approved by the local Institutional Review Board. Dosing regimens were as follows: cefepime (Elan Pharmaceuticals, San Diego, CA, USA) 50 mg/kg over 30 min every 8 h (maximum 6 g/day) in the II group; a loading dose of 15 mg/kg over 30 min, followed by a CI of 100 mg/kg/24 h (maximum 6 g/day) via a portable infusion pump (Microject 30, Sorensen Medical, West Jordan, UT, USA) in the CI group. Tobramycin was initiated in all patients.
Seven serial blood samples were taken from both groups over the first 6 h of cefepime therapy, with three additional samples in the CI group on days 5, 9 and 14. Cefepime concentrations were assayed using HPLC as described previously,2 and analysed with ADAPT II software using a two-compartment model (Biomedical Simulations Resource, University of Southern California, Los Angeles, CA, USA). Sputum samples were collected by expectoration or by induction of sputum with hypertonic saline (3%).3 IL-8 was measured using an ELISA kit (Biosource, Belgium) available commercially. The duration of treatment was 14 days with a follow-up at 2 weeks.
Nine patients completed the study. The demographics and baseline clinical characteristics of patients in the II and CI groups were comparable. All patients were chronically infected with P. aeruginosa, and the majority of the strains were susceptible to cefepime (MIC50 of 6 mg/L in both groups). Significant airway inflammation as indicated by the presence of sputum IL-8 was seen in the II and CI groups at baseline (49.3 and 48.1 pg/mL, respectively). A pulmonary function test demonstrated moderate pulmonary dysfunction in the II group and severe pulmonary dysfunction in the CI group (FEV1 49.0 and 35.5% of the predicted value, respectively).
The pharmacokinetics of cefepime did not differ when given as an II or CI (Table 1) and was well described by a two-compartment model. Significant differences between the two groups were noted in Cmax, Cmin and Css values as expected. Importantly, all patients receiving CI maintained drug concentrations above the MIC (range 4–12 mg/L) throughout the dosing period. In contrast, in patients receiving II, the serum concentrations dropped below the MIC for 25% of the dosing interval. Notably, the dose of cefepime administered by CI was also 20% lower than in the II regimen (5 versus 6 g).
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Response to cefepime therapy was assessed based on changes in bacterial density, inflammatory mediators and improvement in pulmonary function (Table 1). P. aeruginosa density declined from baseline at the end of the antibiotic therapy as expected, but it returned to baseline concentrations by 2 weeks post-therapy. The changes in bacterial density between follow-up and baseline were similar between the two groups. Changes in IL-8 concentrations and ESR between the groups were not significantly different during the treatment phase or at follow-up. Inconsistent results on changes in levels of inflammatory mediators as a result of antibiotic therapy have been reported previously which are probably related to the ongoing chronic inflammation present within the airways of patients with CF. Pulmonary function (FEV1) improved in both groups during the treatment period. The improvement appeared slightly greater in the CI group; however, the difference was not statistically significant. At follow-up, values for bacterial density, IL-8, ESR and FEV1 did not differ significantly from the baseline values in both groups (data not shown).
Maximal activity of ß-lactams is observed when serum concentrations remain above the MIC for 70% of the dosing interval; however, this may not be feasible against P. aeruginosa or other Gram-negative organisms with increasing resistance.4,5 We have demonstrated that CI provides a more efficient means of attaining the pharmacodynamic target (concentrations 4–5 times the MIC), resulting in an overall reduction in the daily dosage.
The limitation of our study is that it was a pilot study with a small sample size. Thus, outcome differences between the cefepime II group and the cefepime CI group did not reach statistical significance. Larger studies are needed to confirm the positive trends in clinical outcomes with CI cefepime in CF patients noted in this pilot study.
Transparency declarations
We have no conflicts of interest to declare.
Acknowledgements
We would like to thank the pharmacy, nursing and laboratory staff at the University Hospital, and Microbial Research Lab at LAC Medical Center for their assistance with the study. This work was supported in part by a grant from Elan Pharmaceuticals.
References
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Craig WA, Ebert SC. Continuous infusion of ß-lactam antibiotics. Antimicrob Agents Chemother 1992; 36: 2577–83.
2.
Sprauten PF, Beinger PM, Louie SG et al. Stability and antibacterial activity of cefepime during continuous infusion. Antimicrob Agents Chemother 2003; 47: 1991–4.
3.
Wong HH, Fahy JV. Safety of one method of sputum induction in asthmatic subjects. Am J Respir Crit Care Med 1997; 156: 299–303.
4. Burgess DS, Hastings RW, Hardin TC. Pharmacokinetics and pharmacodynamics of cefepime administered by intermittent and continuous infusion. Clin Ther 2000; 22: 66–75.[CrossRef][Web of Science][Medline]
5.
Tam VH, McKinnon PS, Akins RL et al. Pharmacodynamics of cefepime in patients with gram-negative infections. J Antimicrob Chemother 2002; 50: 425–8.
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