Dosing regime antibiotics, Differences Ceftazidim vs. Piperacillin/Tazobactam

Question

My son has CF . For the past 32 years he was successfully treated by i.v. antibiotics on a yearly basis. During i.v. courses, his CF outpatient clinic prescribed ceftazidim (Fortum) every 8h and amikacin once per day.
My questions:
1. Would it be adventageous if he could receive his antibiotics by continuous infusion therapy over 24h?
2. Given that his Pseudomonas aeruginosa is sensitive to both ceftazidim and piperacillin/tazobactam, which antibiotic agent should be preferred as combination partner with amikacin?

Answer

Hello Mrs. Schoening,
Answer to question 1:
Question 1: Over the past decade, the recommended dosage intervals for aminoglycosides (such as amikacin) increased, with one to two dosages/d being increasingly recommended. 12-24 hourly high peak aminoglycoside dosing has been shown to be less toxic but equally efficacious as 8 hourly dosing. There is a direct correlation between increased trough levels and toxic side effects of the drug. In contrast, high peak levels seem to be substantially harmless related to the side effects. When compared to other antibiotics, aminoglycosides (and here in particular amikacin) are characterised by a long post-antibiotic effect (PAE), i.e. the bactericidal effect lasts several hours over the exposition with the antibiotic. Therefore, once daily high peak aminoglycoside dosing has become the standard in CF care, at least in Germany.
Although ceftazidim (Fortum) is characterized by a relatively long half-life time compared with other Cephalosporines (approx. 2h), a continuous infusion therapy seems an appropriate therapeutic alternative. Therefore, the European Guidelines (Doering et al. Antibiotic therapy against Pseudomonas aeruginosa in cystic fibrosis. A European consensus. Eur Respir J 2000; 16:749 767) list both an 8-hourly dosing regime or continuous dosing over 24h. The latter recommendation is based on a study of continuous dosing of ceftazidim over 21d that reported clinically favorable results. However, the study did not compare with alternative dosing regimes (Vinks et al. Continuous infusion of ceftazidime in CF patients during home treatment. J Antimicrob Chemother 1997; 40:125 33). From our experience, however, the acceptance of the 8-hourly dosing regime is clearly higher with our patients.
Question 2:
There are few comparative studies. Nevertheless, the combination of aminoglycosides with ceftazidim seems best examined and is considered standard therapy of Pseudomonas aeruginosa infection in CF patients, at least in Germany. Compared with ceftazidim, piperacillin has a markedly higher formation of resistance towards Pseudomonas aeruginosa (hazard ratio Ceftazidim 0,8; Piperacillin 5,2; Carmeli et al. Emergence of antibiotic resistant Pseudomonas aeruginosa: Comparisson of risk associated with different antipseudomonal agents. Antimicrob Agents Chemother 1999; 43:1379 82), comparative data for tazobac seem not availiable. Furthermore, allergies against ß-lactam antibiotics were frequently reported for CF patients, with the greatest incidence for acylaminopenicillins (piperacillin). The European consensus (Doering et al. Antibiotic therapy against Pseudomonas aeruginosa in cystic fibrosis. A European consensus. Eur Respir J 2000; 16:749 767) summarizes: "combination of aminoglycosides with a cephalosporin such as ceftazidime seem to be superior in their effect on pulmonary function, clinical situation and drug resistance compared to combination with penicillin".
Taken together, it seems justifiable to continue the ceftazidim treatment of your son, particularly as his tolerance to this drug is well proven and ceftazidim remains in vitro active against his specific P. aeurginosa strain.

Yours sincerely,
Dr. Tim O. Hirche

23.04.2008