Dried plasma spots for therapeutic monitoring of amikacin: Validation of an UHPLC-MS/MS assay and pharmacokinetic application.

Amikacin (AMI) is an aminoglycoside antibiotic widely used in the treatment of severe infections caused by multi-resistant bacteria, with established exposition targets in therapeutic drug monitoring (TDM). The usual specimen for AMI concentration measurement is plasma or serum. The access to TDM of AMI in Developing Countries is constrained by the limited availability of laboratories performing the quantitation of this drug. In this context, the use of dried microsamples, such as dried plasma spots (DPS) could be an alternative to allow reduced specimen transportation and storage costs in resource-limited settings, increasing the access to TDM of AMI. This study aimed to develop and validate the first report of simultaneous determination of AMI and creatinine (CRE) in DPS, using UHPLC-MS/MS. Precision, accuracy and stability assays showed acceptable results. AMI was stable in DPS for 14 days at 6 °C, 2 days at 22 °C, and one day at 42 °C. CRE was stable during 14 days at all tested temperatures. AMI and CRE concentrations in DPS and plasma were compared by Passing-Bablok regression and Bland and Altmann plots and presented comparable results. Estimates of patient's clearance, volume of distribution and suggested doses of AMI were also similar using DPS or plasma concentrations. The assay provides a useful logistic alternative to allow more widespread access to dose individualization of AMI in limited resources settings.

Population Pharmacokinetics of Amikacin Administered Once Daily in Patients with Different Renal Functions.

The aim of this work was to evaluate the pharmacokinetics of amikacin in Mexican patients with different renal functions receiving once-daily dosing regimens and the influence of clinical and demographical covariates that may influence the optimization of this antibiotic. A prospective study was performed in a total of 63 patients with at least one determination of amikacin plasma concentration. Population pharmacokinetic (PK) parameters were estimated by nonlinear mixed-effects modeling; validations were performed for dosing recommendation purposes based on PK/pharmacodynamic simulations. The concentration-versus-time data were best described by a one-compartment open model with proportional interindividual variability associated with amikacin clearance (CL) and volume of distribution (V); residual error followed a homoscedastic trend. Creatinine clearance (CLCR) and ideal body weight (IBW) demonstrated significant influence on amikacin CL and V, respectively. The final model [CL (liters/h) = 7.1 × (CLCR/130)0.84 and V (liters) = 20.3 × (IBW/68)2.9] showed a mean prediction error of 0.11 mg/liter (95% confidence interval, -3.34, 3.55) in the validation performed in a different group of patients with similar characteristics. There is a wide variability in amikacin PK parameters in Mexican patients. This leads to inadequate dosing regimens, especially in patients with augmented renal clearance (CLCR of >130 ml/min). Optimization based on the final population PK model in Mexican patients may be useful, since reliability and clinical applicability have been demonstrated in this study.

Population pharmacokinetics of amikacin in patients with pediatric cystic fibrosis.

INTRODUCTION: Amikacin is commonly used in patients with pediatric cystic fibrosis (CF) for the treatment of pulmonary exacerbations. Amikacin efficacy is related to maximum plasma concentration/minimum inhibitory concentration (Cmax/MIC) ratio >8. Pharmacokinetic data in patients with pediatric CF are scarce. The aim of this study was to develop a population pharmacokinetic (PopPK) model describing amikacin disposition in patients with pediatric CF. METHODS: CF patients under 18 years of age with pulmonary exacerbation who received amikacin were enrolled. Patients received different amikacin regimens (30 mg-1 kg-1 day-1 every 8, 12, or 24 hours) depending on the patient's status and hospital protocols. Amikacin serum levels were obtained for therapeutic drug monitoring. PopPK model was developed using MONOLIX Suite-2018R1 (Lixoft). RESULTS: A total of 39 patients (114 amikacin concentrations) were included in this study. Population estimates for the elimination rate constant (k) and the volume of distribution (V) were 0.541 hours-1 and 0.451 L/kg, respectively. Between-subject and between-occasion variability were 53% and 16.5% for k and 31% and 22% for V, respectively. Bodyweight was a significant covariate associated with V. Based on simulations, almost 70% of the patients receiving 30 mg-1 kg-1 day-1 every 24 hours would achieve a Cmax/MIC ratio >8 which is an appropriate therapeutic goal while no patient in the other two groups (Q8 and Q12) would achieve that objective. CONCLUSIONS: The regimen of 30 mg-1 kg-1 day-1 every 24 hours more adequately fulfilled the therapeutic target for amikacin. Although all our patients had good clinical results and a good adverse-events profile, further studies are necessary to redefine the optimal treatment strategy.

Ready for TDM: Simultaneous quantification of amikacin, vancomycin and creatinine in human plasma employing ultra-performance liquid chromatography-tandem mass spectrometry.

BACKGROUND: Amikacin (AMI) and vancomycin (VAN) are antibiotics largely used in intensive care in the empiric treatment of severe infections by multi-resistant gram-negative and gram-positive bacteria. AMI and VAN are eliminated untransformed by glomerular filtration, showing depuration ratio highly correlated with creatinine (CRE) clearance. AMI, VAN and CRE are highly polar structures, presenting poor retention in reversed-phase liquid chromatography when using conventional stationary phases. OBJECTIVE: This study aimed to develop and validate a simple UPLC-MS/MS method for simultaneous determination of AMI, VAN, and CRE in human plasma for therapeutic drug monitoring. RESULTS: Samples were prepared by protein precipitation, followed by dilution. Heptafluorobutyric acid (HFBA) was added to the mobile phase at low concentration (0.01%), and separation was performed in an ultra-performance reversed-phase column (particle diameter of 1.8 µm). These conditions allowed retention times of 0.92, 0.93, 2.12, 2.17 and 2.27 min for CRE, CRE-D3, AMI, KAN and VAN, respectively. The assay was linear from 0.5 to 100 mg L-1 for AMI and VAN and 5 to 100 mg L-1. Precision, accuracy and stability assays were acceptable according to bioanalytical validation guidelines. Suitable results. Matrix effects were in the range of +10.5 to +11.6% for AMI, -4.3 to -4.5% for VAN, and - 1.7 to +0.7 for CRE. CONCLUSION: The first assay for the simultaneous determination of AMI, VAN and CRE in plasma by liquid chromatography-tandem mass spectrometry was reported. This assay allows the obtention of the necessary analytical data for the clinical application of population pharmacokinetic methods for therapeutic drug monitoring of AMI and VAN.

A double-blind study of the efficacy and safety of multiple daily doses of amikacin versus one daily dose for children with perforated appendicitis in Costa Rica.

BACKGROUND: There is evidence that aminoglycosides given in a single daily dose (once daily dose, ODD) are as effective and safe as multiple daily doses (MDD). However, the published pharmacokinetic and pharmacodynamic data are overly representative of pediatric populations in Europe and the USA, and not representative of low or middle-income countries such as Costa Rica, in which the patient population might differ from those in higher income settings. METHODS: A double-blind, randomized clinical trial of the efficacy and safety of ODD vs. MDD amikacin therapy was conducted for children aged 2-12 years with an intraoperative diagnosis of perforated appendicitis. One hundred patients were randomized following a one-to-one randomization to receive either amikacin 7.5 mg/kg every 8 h (MDD) or 22.5 mg/kg as a single dose (ODD). Patients in both groups were given clindamycin 10 mg/kg every 6 h. Efficacy was evaluated by the occurrence of intra-abdominal abscesses, documented by abdominal ultrasound, and therapeutic failure. Safety was determined by the presence of renal or cochlear toxicity. RESULTS: Fifty patients were enrolled in each group. There were no statistically significant differences in the incidence of intra-abdominal abscesses or therapeutic failures, or in the occurrence of cochlear or renal toxicity, between the MDD and ODD treatment groups. CONCLUSIONS: In this patient population of Costa Rican children with perforated appendicitis, we found that amikacin ODD is as safe and effective as the MDD regimen. This could have implications for national health systems such as that in Costa Rica, as ODD is presumably a more economic option and may reduce the cost of antibiotic treatment in patients with perforated appendicitis. This would need to be confirmed through an economic analysis, which is outside the purview of this paper.

Pharmacokinetics and renal toxicity of three once-a-day doses of amikacin in cows.

Pharmacokinetic variables of amikacin in cows were determined after administration of amikacin sulphate either intravenously (IV) or intramuscularly (IM) at a dose of 25 mg/kg per day for three days. Amikacin concentrations at time zero and maximum serum concentrations were 240.8 microg/mL and 122.53 microg/mL, respectively. The elimination half-life remained unchanged during the three days of administration (T1/2beta = 1.33 +/- 0.029 h for the IV route and T1/2beta = 2.75 +/- 0.38 h for the IM route). Apparent volumes of distribution suggest limited distribution out of the central compartment (VdAUC = 0.154 +/- 0.005 L/kg; Vdc = 36.50 +/- 2.35 L; Vdss = 0.092 +/- 0.004 L/kg). Bioavailability after IM administration was 95%. Serum profiles of urea, creatinine, albumin, electrolytes and pH after 5-day treatment with amikacin at a dose of 25 mg/kg per day IM revealed no changes. Assessment of diffusion of amikacin to milk by a commercially available screening method to detect antibiotic residues revealed that amikacin could not be detected by the fifth milking period after the last treatment. These results suggest that it would be rational to use a large single-daily dose of amikacin for future clinical trials in cows.

Amikacin alters auditory brainstem conduction time in newborns.

The purpose of this paper was to describe whether there are some relationships between amikacin serum levels and central conduction time in brainstem auditory evoked potentials (BAEP) within therapeutic range levels in newborns as index of drug toxicity in brainstem auditory centers in neonatally exposed infants. We performed a cross-sectional study to compare BAEP from 35 infants under amikacin administration and 24 control infants; both examinations were blinded to investigators. Bivariate and partial correlations were calculated between amikacin and BAEP measurements in treated infants. Amikacin determinations were within therapeutic levels. No clinical alterations in BAEP were found and no differences between amikacin-treated and control infants were found. Significant positive Pearson correlation between latency of I-III interwaves interval and amikacin Cmin serum levels was found and was present when calculations were controlled by partial correlations for gestational age at birth and Apgar score at 5 min. The findings suggest that increased amikacin levels in newborns are related to increased latencies in I-III interwave interval in infants, which may be an early index of brainstem effects of subclinical neurotoxicity of amikacin.

Concentraciones sanguíneas de amikacina durante la primera semana de vida en neonatos pretérmino / Blood amikacin concentration during the first week of life in preterm neonates

Objetivo. Informar sobre las concentraciones sanguíneas de amikacina en un grupo de 10 niños durante la primera semana de vida posnatal, con peso promedio de 1.640 ñ .330 Kg, edad gestacional de 34 ñ 2 semanas y con diagnóstico de septicemia, internados en la Unidad de Cuidados Intensivos Neonatales del Instituto Nacional de Perinatología. Material y método. Todos los niños recibieron 7.5 mg/Kg de amikacina por vía endovenosa durante 30 min, dosis que se continuó cada 12 horas en 6 niños y se modificó en 4. El primero y quinto día de tratamiento se determinaron a los 30 min. posdosis de Cpmax y a las 12 horas posdosis la Cpmin, así como la vida media de eliminación (t½el), el volumen de distribución (Vd) y la depuración (Cl). Se consideraron valores terapéuticos entre 15 y 30 µg/mL para la Cpmax y menores de 8 µg/mL para la Cpmin. Resultados. En 6 niños la Cpmax durante la primera dosis fue menor de 15 µg/mL y Cpmin en otros 4 niños fue mayor de 8 µg/mL. Debido a lo anterior, a un niño se le administró la dosis cada 24 horas y a los otros 3 la dosis se disminuyó a 5 mg/Kg cada 24 horas. Para el quinto día de tratamiento en sólo 3 de los 6 niños el grupo en que se mantuvo el esquema de dosis inicial se obtuvieron Cpmax y Cpmin dentro de los valores terapéuticos. Conclusiones. En este grupo de pacientes la administración de amikacina a 7.5 mg/Kg/12 horas no es adecuado por tener un alto riesgo de producir concentraciones tóxicas cuando se alcanza el estado de equilibrio. Se recomienda establecer un esquema de dosificación más óptimo con una dosis de mantenimiento menor, aumentar su intervalo de administración o ambos

Low serum albumin and the increased risk of amikacin nephrotoxicity.

AIM: The purpose of the present study was to know the incidence and risk factors associated with amikacin nephrotoxicity in a cohort of patients form a general medial center. STUDY DESIGN: Prospective follow-up of a cohort of 104 patients treated with intravenous amikacin for at least 36 hours. We assessed serum creatinine every other day and amikacin plasma levels at 48 and 96 hours after treatment was begun. Patients with other risk factors to develop acute renal failure were excluded. The study was conducted at the Hospital de Especialidades, Centro Médico de Occidente, Instituto Mexicano del Seguro Social. RESULTS: Ten patients developed nephrotoxicity (9.6%). According to the logistic regression model, the most powerful predictor of high nephrotoxicity probability was the serum albumin concentration. The lower the serum albumin concentration, the higher the risk of toxicity. The mean serum albumin in the group of patients with nephrotoxicity was 2.6 +/- 0.55 g/dL, while in the group of patients without toxicity it was 3.5 +/- 0.55 g/dL. No differences were observed in the age, sex, diagnosis, renal function and amikacin doses between both groups. Furthermore, low serum albumin concentration was also associated with amikacin accumulation in plasma. The group of patients with hypoalbuminemia (< or = 3.0 g/dL) had a significantly higher trough amikacin plasma level (assessed at 48 and 96 hours of the initiation of treatment) than those with normal serum albumin, with no differences among the age, sex, baseline renal function and received amikacin doses. CONCLUSIONS: We conclude that serum albumin concentration is the most powerful predictor of amikacin nephrotoxicity. The risk factors observed in the present study are similar to those previously observed by us at the Instituto Nacional de la Nutrición Salvador Zubirán.

[A form for soliciting the measurement of drug plasma level and its use in a university hospital]. / Evaluacion de un formulario para solicitud de medicion de niveles plasmaticos de medicamentos y uso de ellos en un hospital universitario.

The correct clinical use of drug plasma levels is frequently jeopardized by neglecting to consider pharmacokinetic parameters at the time of sample drawing. A form to be filled at this time revealed that inadequate information concerning the drug was present in 28% and sampling time in 50% of cases. Accordingly, a new form is proposed to help avoid this information inadequacies and thus lead to better clinical use of drug plasma levels.

Single daily dose amikacin in paediatric patients with severe gram-negative infections.

Twenty-five children with serious Gram-negative infections were treated in a prospective study with amikacin 20 mg/kg administered in a single daily dose as a 30 min iv infusion for 4 to 12 days. In nine cases the amikacin was combined with beta-lactam antibiotics. Escherichia coli were the most frequent bacteria isolated followed by K. pneumoniae, Providencia and Enterobacter spp. and Pseudomonas aeruginosa with MICs ranging from 1 to 16 mg/l. Mean (+/- S.D.) peak and trough concentrations of days 1 and 4 of therapy ranged from 49 +/- 13.5 to 53.6 +/- 13.4 mg/l and 6 + 1.4 to 7.7 +/- 4.1 mg/l respectively. All patients were clinically and bacteriologically cured. No significant adverse reactions were observed. The results suggest that administration of a single daily dose of 20 mg/kg amikacin should be considered practical and safe in children. Further studies are needed.

[Gentamicin and amikacin nephrotoxicity: comparative study in patients with initially normal renal function]. / Nefrotoxicidad de gentamicina y amikacina: estudio comparativo en pacientes con función renal inicial normal.

The purpose of this study was to compare the nephrotoxic potential of amikacin (AK) and gentamicin (GM) in patients (pts) with normal renal function at the beginning of the treatment (Tx) in an open comparative and prospective trial. Nephrotoxicity (NFTX) was defined as a blood creatinine (Cr) increase of at least 50% from the basal (normal) level, or an increase to higher than normal level during, at the end or after Tx. Peak and trough blood GM and AK levels were determined at 72 h of Tx to make proper adjustments in dosing. The two groups (GM, n = 27 and AK, n = 38) were similar in population composition, underlying pathology and infectious process requiring antimicrobials. Patients in the GM group tended to be older (mean age, 56 years) than the AK (mean age, 48 years) p NS; the latter had received more frequently aminoglycoside Tx (69 vs 11%) p less than 0.0005. The GM group received a comparatively lower dose than the AK (x = 2.87 mg/k/d and 16 mg/k/d respectively) but duration of Tx was similar. Fifteen of 27 pts receiving GM (56%) and 7 of 38 receiving AK (18.2%) developed NFTX, p less than 0.004. Five pts in the GM group (18.5%) and 2 in the AK (5.2%) had clinical NFTX. The difference in NFTX persisted after age adjustment. There were no intra or inter group significant differences between pts with or without NFTX. In conclusion, in pts with initial normal renal function gentamicin was significantly more nephrotoxic than amikacin.

Amikacin nephrotoxicity: incidence, clinical course and risk factors: a prospective study in a teaching hospital

Con el fin de conocer la incidencia, curso clínico y factores predisponentes de la toxicidad renal por amikacina, se siguieron durante cinco meses, todos los enfermos hospitalizados que recibieron este aminoglucósido por vía endovenosa. Se escluyeron a los enfermos con: insuficiencia renal aguda, insuficiencia renal crónica en fase sustitutiva; a los que recibieron ciclosporina y/o que desarrollaron durante el seguimiento síndrome hepatorrenal o estado de choque. En todos los casos se obtuvo creatinina sérica al ingreso y posteriormente cada 72 horas y niveles de amikacina en sangre cada 7 días. Se estudiaron 249 pacientes, 123 hombres y 126 mujeres, con edad media ñ DE de 47 ñ 8.5 años, creatinina sérica de 1.08 ñ 0.48 mg/dl y depuración calculada de creatinina de 99 ñ 45 ml/min. Siete pacientes recibieron amikacina como único antibiótico, 194 asociado a otro y 48 como parte de triple esquema