Once-Daily Amikacin Dosing in Burn Patients Treated with Continuous Venovenous Hemofiltration

Abstract

Amikacin clearance can be increased in burn injury, which is often complicated by renal insufficiency. Little is known about the impact of renal replacement therapies, such as continuous venovenous hemofiltration (CVVH), on amikacin pharmacokinetics. We retrospectively examined the clinical pharmacokinetics, bacteriology, and clinical outcomes of 60 burn patients given 15 mg/kg of body weight of amikacin in single daily doses. Twelve were treated with concurrent CVVH therapy, and 48 were not. The pharmacodynamic target of >10 for the maximum concentration of drug in serum divided by the MIC (C max /MIC) was achieved in only 8.5% of patients, with a small reduction of C max in patients receiving CVVH and no difference in amikacin clearance. Mortality and burn size were greater in patients who received CVVH. Overall, 172 Gram-negative isolates were recovered from the blood cultures of 39 patients, with amikacin MIC data available for 82 isolates from 24 patients. A 10,000-patient Monte Carlo simulation was conducted incorporating pharmacokinetic and MIC data from these patients. The cumulative fraction of response (CFR) was similar in CVVH and non-CVVH patients. The CFR rates were not significantly improved by a theoretical 20 mg/kg amikacin dose. Overall, CVVH did not appear to have a major impact on amikacin serum concentrations. The low pharmacodynamic target attainment appears to be primarily due to higher amikacin MICs rather than more rapid clearance of amikacin related to CVVH therapy.

Influence of Renal Replacement Modalities on Amikacin Population Pharmacokinetics in Critically Ill Patients on Continuous Renal Replacement Therapy

“…In previous studies with intensive care unit (ICU) patients undergoing CRRT, amikacin clearance varied from 0.53 to 5.34 liters/h, accounting for 40 to 89% of the total body clearance (10)(11)(12)(13)(14)(15). These studies also reported conflicting results on the correlation between drug clearance and CRRT settings (11,14).…”

How can we ensure effective antibiotic dosing in critically ill patients receiving different types of renal replacement therapy?

“…Amikacin and gentamicin were significantly eliminated by continuous venovenous hemofiltration (CVVH) and continuous venovenous hemodiafiltration (CVVHDF) (effluent flow rates 40-68 mL/min), with CRRT accounting for up to 80% of the total clearance (Akers et al, 2011;D'Arcy et al, 2012;Petejova et al, 2012a;Taccone et al, 2011). Both drugs had a sieving coefficient (Sc) of approximately 0.8, suggesting that they freely cross the semipermeable CRRT filter.…”

“…Both drugs had a sieving coefficient (Sc) of approximately 0.8, suggesting that they freely cross the semipermeable CRRT filter. The V d of aminoglycosides is also likely to increase in the presence of critical illness and RRT due to gross fluid balance alterations (Akers et al, 2011;Tang et al, 1999;Triginer et al, 1989).…”

Improving antibiotic dosing in special situations in the ICU

“…In later phase postburn injury (>48-72 h), the patients can exhibit hyperdynamic states that can cause increased cardiac output, increases in renal and nonrenal clearance, significant decreases in plasma albumin concentrations and liver dysfunction [24]. The recent studies published on antibiotic PK/PD in burns patients are summarized in Table 2 [25][26][27][28][29][30][31][32]. The efficacy of highly protein-bound antibiotics (ertapenem, daptomycin, ceftriaxone, the 'oxacillins') in light of hypoalbuminemia is particularly important as small changes in protein binding result in a disproportionately greater amount of unbound drug available for activity; however, the consequential increase in clearance decreases the time that the unbound concentration of antibiotic remains above the minimum inhibitory concentration of the pathogen (MIC, fT> MIC ) leading to potential therapeutic failure if dosing is not adjusted in line with the altered pharmacokinetics.…”