Predictors of insufficient amikacin peak concentration in critically ill patients receiving a 25 mg/kg total body weight regimen

The objective of this study was to describe amikacin pharmacokinetics (PK) in critically ill patients receiving equal doses (30 ml/kg of body weight/h) of continuous venovenous hemofiltration (CVVH) and continuous venovenous hemodiafiltration (CV-VHDF). Patients receiving amikacin and undergoing CVVH or CVVHDF were eligible. Population pharmacokinetic analysis and Monte Carlo simulation were undertaken using the Pmetrics software package for R. Sixteen patients (9 undergoing CVVH, 11 undergoing CVVHDF) and 20 sampling intervals were analyzed. A two-compartment linear model best described the data.

Section: Discussionmentioning

confidence: 99%

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

Roger

Wallis

Muller

et al. 2016

“…Two amikacin concentrations are measured, at 1 to 2 h and at 8 to 10 h after the end of infusion of this first dose, to permit dose individualization (6). Recent clinical studies corroborate this approach by suggesting that an initial amikacin dose Ն25 mg/kg is likely needed as empirical therapy of certain Gramnegative infections (7)(8)(9)(10). Herein, we report on the amikacin exposure profile observed in our patients with this higher-thanregulatory-approved amikacin treatment strategy (1).…”

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confidence: 99%

Optimizing the Initial Amikacin Dosage in Adults

White

Lomaestro

Pai

2015

bWe report on the pharmacokinetics (PK) and pharmacodynamics (PD) of high-dose (>15 mg/kg of body weight per day) amikacin. A mean (standard deviation [SD]) maximum drug concentration in the serum (C max ) and 24-h area under the concentration-time curve (AUC 24 ) of 101 (49.4) mg/liter and 600 (387) mg · h/liter, respectively, were observed (n ‫؍‬ 73) with 28.0 (8.47) mg/kg/day doses. An initial amikacin dose of 2,500 mg in adults weighing 40 kg to 200 kg with therapeutic drug monitoring to adjust the maintenance dose will optimize its PK and PD.A mikacin is an important component of an initial empirical antimicrobial treatment strategy against major Gram-negative pathogens associated with serious infections. The regulatory approved dose of this aminoglycoside is 15 mg/kg of body weight per day as 2 to 3 divided doses (1). Aminoglycoside dosing has shifted from divided daily dosing to single daily dosing in order to optimize its concentration-dependent pharmacokinetic-pharmacodynamic (PK-PD) profile (2, 3). This dosing paradigm seeks to achieve a maximum concentration of drug in the serum (C max )/ MIC of 8 to 10 and an area under the concentration-time curve (AUC)/MIC of 75 (3-5). As a consequence, currently accepted standard doses of aminoglycosides, such as tobramycin, are now administered 5 to 10 mg/kg once daily in patients with normal kidney function, that is roughly 2-fold higher than the regulatory approved dose of 3 to 5 mg/kg/day in divided doses (5).The typical 4-fold higher MIC 90 (4 to 8 mg/liter) of amikacin against Pseudomonas aeruginosa compared to tobramycin (1 to 2 mg/liter) coupled with the dose proportionality of aminoglycosides led our institution to adopt an initial empirical amikacin dose of 24 mg/kg in noncritically ill patients and 30 to 40 mg/kg in critically ill patients. Two amikacin concentrations are measured, at 1 to 2 h and at 8 to 10 h after the end of infusion of this first dose, to permit dose individualization (6). Recent clinical studies corroborate this approach by suggesting that an initial amikacin dose Ն25 mg/kg is likely needed as empirical therapy of certain Gramnegative infections (7-10). Herein, we report on the amikacin exposure profile observed in our patients with this higher-thanregulatory-approved amikacin treatment strategy (1). We also provide a clear rationale for the consideration of an alternate empirical fixed amikacin dosing strategy in line with the current clinical adult total body weight (TBW) distribution.After institution review board approval, patients Ն21 years of age who received at least one dose of amikacin from 1 January 2012 to 30 June 2014, who had two serial amikacin measurable concentrations, and who had an estimated creatinine clearance (CL CR ) Ͼ30 ml/min based on the Cockcroft-Gault equation were included (11). Information pertaining to patient demographics, laboratory values, amikacin dose, administration and infusion times, amikacin concentration, and sample collection times were collected. Amikacin concentrations were measured by an a...

“…Nevertheless, achieving the corresponding serum concentrations of AMK in patients is unlikely with conventional dosing of 15 mg/kg body weight/day. AMK doses exceeding 25 mg/kg/day may achieve serum drug levels of Ն60 g/ml, which approaches concentrations of 4ϫ the MIC for strains with MICs of 16 but not 32 g/ml (12)(13)(14).…”

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confidence: 99%

KPC-Producing Klebsiella pneumoniae Strains That Harbor AAC(6′)-Ib Exhibit Intermediate Resistance to Amikacin

Bremmer

Clancy

Press

et al. 2014

The aminoglycoside-modifying enzyme AAC(6=)-Ib is common among carbapenem-resistant Klebsiella pneumoniae (CR-Kp) strains. We investigated amikacin (AMK) activity against 20 AAC(6=)-Ib-producing CR-Kp strains. MICs clustered at 16 to 32 g/ml. By the time-kill study, AMK (1؋ and 4؋ the MIC) was bactericidal against 30% and 85% of the strains, respectively. At achievable human serum concentrations, however, the majority of strains showed regrowth, suggesting that AAC(6=)-Ib confers intermediate AMK resistance. AMK and trimethoprim-sulfamethoxazole (TMP-SMX) were synergistic against 90% of the strains, indicating that the combination may overcome resistance.A minoglycosides are important options for the treatment of infections caused by carbapenem-resistant Klebsiella pneumoniae (CR-Kp) strains. These agents retain potent bactericidal activity against some but not all CR-Kp strains (1). Inactivation by enzymatic modification is the most prevalent mechanism of resistance to the class (2). Indeed, 98% of CR-Kp strains studied at our center possessed at least one aminoglycoside-modifying enzyme (AME), which resulted in variable susceptibility among the aminoglycosides (3).Amikacin (AMK) is uniquely stable against most AMEs. Of the AMEs known to affect AMK, APH(3=)-VI and ANT(4=) confer high-level resistance and are infrequently encountered (4, 5). On the other hand, AAC(6=)-Ib is common among Enterobacteriaceae (2), but the clinical relevance is largely unknown. AAC(6=)-Ib encodes an N-acetyltransferase that catalyzes acetyl coenzyme A (acetyl-CoA)-dependent acetylation of the 6= amino group of AMK. The impact of AAC(6=)-Ib modification on the susceptibility of Gram-negative bacteria to AMK is uncertain. Published reports have identified AMK MICs above (6, 7) and below (7-9) susceptibility breakpoints. Time-kill studies of AMK against CR-Kp strains or other Enterobacteriaceae that produce AAC(6=)-Ib have not been published. The objective of this study was to characterize AMK MICs, time-kill responses, and interactions with other antimicrobials among AAC(6=)-Ib-producing CR-Kp strains at our center.We selected 20 CR-Kp strains from unique patients for analysis. All strains were sequence type (ST) 258, Klebsiella pneumoniae carbapenemase (KPC) producers (18 producers of KPC-2 and 2 of KPC-3), and harbored the aac(6=)-Ib gene by PCR (3). Each strain also harbored SHV-12 and TEM-1 ␤-lactamase genes, but none carried NDM, IMP, VIM, or OXA-48 genes. All carried mutant ompK35 porin genes (AA89 STOP), and 60% (12/20) had mutant ompK36 genes. Sequence analysis revealed three ompK36 mutant genotypes, the most common of which were an insertion at amino acid 134 to 135GD (n ϭ 6) and IS5 promoter insertions (n ϭ 5). The remaining ompK36 mutant isolate had a frameshift at nucleotide position 382. MICs were determined by standard broth microdilution methods. Median MICs of AMK, gentamicin (GEN), and tobramycin (TOB) were 32 (range, 4 to 32 g/ml), 2 (range, 0.5 to Ͼ64 g/ml), and 32 (range, 8 to Ͼ64 g/ml) g/ml, respectively. Susceptib...