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 of 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 to perform estimation of pharmacokinetic and pharmacodynamic parameters. 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 target concentration CT, 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 these patients is Clearance =k* creatinine clearance where k = 0.072. Calculation of a loading dose gives median (range) values of loading dose, DL of 3.7 mg kg−1 (1.9–4.6) and infusion rate I = 0.46 mg kg h−1 (0.04–1.3) (which equals 14.8 mg kg−1 day−1). A nomogram for adjustment in renal failure is given.

Melioidosis: Epidemiology, Pathophysiology, and Management

“…In that study a bolus dose of 12 mg/kg intravenously followed by a constant infusion of 4 mg/kg/h was found to provide an adequate dose while allowing for a total lower dose to be delivered than with traditional 8-h bolus dosing (7). These data support the use of elastomeric infusion devices (Baxter, Sydney, Australia) through a peripherally inserted central catheter to complete intensive-phase antibiotic therapy for melioidosis in Australia (111,206).…”

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)

“…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.…”

Optimizing beta-lactam antibiotic dosing in critically ill patients: Prolonged infusion versus intermittent bolus administration

“…Thus, it has been suggested that maintaining concentrations above the MIC for 90-100% of the dosing interval is an appropriate PD target for critically ill patients and may prevent antibiotic resistance [5,148,149]. It has also been demonstrated that maximal bactericidal activity occurs when drug concentrations are maintained at four-to five-times the MIC, with higher concentrations providing little added benefit [23,25,26,147,[150][151][152]. Thus, it has been suggested that beta-lactam concentrations should be maintained at least four-to five-times the MIC for extended periods during each dosing interval [5,7,153].…”

“…Research has shown that improved antibiotic exposure can be obtained via three general approaches: (1) increasing the antibiotic dose; (2) increasing the frequency of antibiotic dosing or; (3) by utilizing EI or CI [67,85,86,106,151,[164][165][166][167][168][169][170][171][172][173][174][175]. However, increasing the antibiotic dose has been shown to be less effective to adequately maintain effective drug concentration during a dosing period.…”

“…Numerous clinical comparative studies have been conducted with beta-lactams testing various dosing strategies in various patient populations including critically ill patients [85,86,151,166,169,171,172,[241][242][243][246][247][248][249][250][251][252], patients receiving extracorporeal renal circuit [244,245,253], trauma patients [254], patients with malignant diseases [255], patients with intra-abdominal infections [256], patients with chronic obstructive pulmonary disease (COPD) [257,258] and nonspecific hospitalized patients [173,[259][260][261][262] (Table 1-2). These studies have not shown whether alternative dosing approaches (i.e., CI and EI) are advantageous nor which patient groups may benefit.…”