Pharmacokinetic‐pharmacodynamic evaluation of ceftazidime continuous infusion vs intermittent bolus injection in septicaemic melioidosis

Abstract

Aims Experimental studies have suggested that constant intravenous infusion would be preferable to conventional intermittent bolus administration of beta‐lactam antibiotics for serious Gram‐negative infections. Severe melioidosis (Burkholderia pseudomallei infection) carries a mortality over 40% despite treatment with high dose ceftazidime. The aim of this study was to measure the pharmacokinetic and pharmacodynamic effects of continuous infusion of ceftazidime vs intermittent bolus dosing in septicaemic melioidosis.Methods Patients with suspected septicaemic melioidosis were randomised to receive ceftazidime 40 mg kg−1 8 hourly by bolus injection or 4 mg kg−1 h−1 by constant infusion following a 12 mg kg−1 priming dose and pharmacokinetic and pharmacodynamic parameters were compared.Results Of the 34 patients studied 16 (59%) died. Twenty patients had cultures positive for B. pseudomallei of whom 12 (60%) died. The median MIC90 of B. pseudomallei was 2 mg l−1, giving a minimum target concentration (4*MIC) of 8 mg l−1. The median (range) estimated total apparent volume of distribution, systemic clearance and terminal elimination half‐lives of ceftazidime were 0.468 (0.241–0.573) l kg−1, 0.058 (0.005–0.159) l kg−1 h−1 and 7.74 (1.95–44.71) h, respectively. Clearance of ceftazidime and creatinine clearance were correlated closely (r = 0.71; P < 0.001) and there was no evidence of significant nonrenal clearance.Conclusions Simulations based on these data and the ceftazidime sensitivity of the B. pseudomallei isolates indicated that administration by constant infusion would allow significant dose reduction and cost saving. With conventional 8 h intermittent dosing to patients with normal renal function, plasma ceftazidime concentrations could fall below the target concentration but this would be unlikely with a constant infusion. Correction for renal failure, which is common in patients with meliodosis is Clearance =k* creatinine clearance where k = 0.72. Calculation of a loading dose gives median (range) values of loading dose, DL of 18.7 mg kg−1 (9.5–23) and infusion rate I = 3.5 mg kg−1 h−1 (0.4–13) (which equals 84 mg kg−1 day−1). A nomogram for adjustment in renal failure is given.

Continuous versus intermittent administration of piperacillin-tazobactam in intensive care unit patients with ventilator-associated pneumonia

“…[6] In addition, several studies have evaluated clinical outcomes including severity of illness, duration of mechanical ventilation, mortality, clinical cure from actual infection, time to normalization of leukocytosis or pyrexia and lengths of ICU stay. [8–22] Similar to other studies,[11202327] no significant differences were found between the CI ( n = 31) and the II ( n = 30) groups in terms of sex, age, APACHE II score at ICU admission, diagnosis and microorganism responsible for VAP in this study. Consequently, mortality is not mainly dissimilar in the continuous and intermittent dosed groups.…”

“…Consequently, mortality is not mainly dissimilar in the continuous and intermittent dosed groups. [8–1113142027] Rapid improvement in PaO 2 /FiO 2 has been granted as the most precise marker for adequate treatment. Duration of treatment was directly associated with the CPIS score at the time of pulmonary infection diagnosis in the Micek et al .…”

“…[57] However, the clinical benefit of CI or II of β-lactam antibiotics is in doubt in humans. Clinical outcomes such as mortality,[8–16] time to normalization of leukocytosis or pyrexia,[10141718] adverse events,[19] microbiological outcome,[1820] duration of mechanical ventilation[11151720] and length of stay are comparable between bolus and continuous dosing of β-lactam antibiotics in seriously ill patients. [11151719] CI of β-lactam antibiotics may not also lead to a significant progression in the clinical cure compared with an intermittent bolus.…”

Does prolonged β-lactam infusions improve clinical outcomes compared to intermittent infusions? A meta-analysis and systematic review of randomized, controlled trials

“…The remaining studies included patients receiving continuous infusion β-lactams [3,4,9,11,15-17,19,20,22,23]. Six studies used the same total daily dose of β-lactams in both study arms [9,15,17-20].…”

Continuous infusion of antibiotics in the critically ill: The new holy grail for beta-lactams and vancomycin?

“…Even when using CI, the combination of pathogens with MICs close to the susceptibility breakpoint and critically ill patients with lower than expected Css (because of increased Vd and increased drug clearance) can lead to critically low Css/MIC ratios below the advised ratio of 2.5 to 4. An overview of studies [11,15,25-33] investigating PK-parameters of continuous infusion of different antimicrobials in critically ill patients is shown in Table 1. In most of these studies, the Css/MIC ratio is well above 2.5.…”