Dose Of Amikacin Research Articles

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.

Population pharmacokinetics of amikacin in Korean adult patients

Background To determine demographic and clinical covariates that affect amikacin pharmacokinetic parameters in Korean clinical population Methods For 200 Korean adult patients (115 men and 85 women), blood samples were drawn at the trough and peak steady-state plasma concentrations after multiple infusions of the drug. Amikacin concentration was analyzed by Fluorescence Polarization Immunoassay. Using one-compartment model, the clearance and volume of distribution of amikacin and their relevance to various covariates (creatinine clearance, sex, ward (intensive care unit vs general), disease diagnosed) were estimated by a nonlinear mixed effect model using the NONMEM software, with a stepwise addition method for covariate selection. Results Creatinine clearance had the most significant influence on amikacin pharmacokinetics (p << 0.0001 for clearance, p <0.0001 for volume of distribution). In particular, amikacin clearance was significantly influenced by ward (1.37 (1.18–1.56) for intensive care unit, 2.24 (2.09–2.39) for general) and urinary tract infection (UTI) (1.44 (0.85–2.03) for UTI, 2.13 (1.97–2.29) for no UTI), with numbers denoting mean values (95% confidence interval) (L/hr). Conclusions Our results suggest that a pharmacokinetic model incorporating clinically important covariates would be necessary for a nonbiased amikacin dosage individualization in Korean clinical population. Further study would be needed to verify the appropriateness of the model proposed here. Clinical Pharmacology & Therapeutics (2005) 77, P86–P86; doi: 10.1016/j.clpt.2004.12.220

Single daily amikacin versus cefotaxime in the short-course treatment of spontaneous bacterial peritonitis in cirrhotics

To compare the efficacy and safety of single daily amikacin vs. cefotaxime in the 5-d treatment of spontaneous bacterial peritonitis (SBP). Thirty-seven cirrhotic patients with SBP, 19 in group A and 18 in group B, were studied. Group A received 1 g of cefotaxime every 6 h, and group B received 500 mg of amikacin qd. Both antibiotics were administered up to 5 d and the responses were compared. Infection was cured in 15 of 19 patients (78.9%) treated with cefotaxime and in 11 of 18 (61.1%) treated with amikacin. Four patients of the Cefotaxime group (21.1%) and five patients of the Amikacin group (27.8%) died. Two in each group (10.5% vs 11.1%) had renal impairment during study period. One in each group (5.3% vs 5.6%) may be considered to suffer from nephrotoxicity due to increased urinary beta(2)-microglobulin concentration. In this study, single daily doses of amikacin in the treatment of SBP in cirrhotics were not associated with an increased incidence of renal impairment or nephrotoxicity. However, a 5-d regimen of amikacin is less effective than a 5-d regimen of cefotaxime in the SBP treatment.

Self-protection against aminoglycoside ototoxicity in guinea pigs

Background Amikacin is a semisynthetic aminoglycoside. It acts against most of the microbial species. Amikacin limitation of the therapeutic application is the ototoxicity which promotes permanent lesions in the cochlear system. Aminoglycoside antibiotics have ototoxic potential. The target cells are preferentially the outer hair cells in the cochlear basal turns. Amynoglicoside antibiotics can quelate iron forming a complex with oxidate properties and promotes the formation of free radicals. Responsible for production of lesions in the hair cells. Objective The objective of the present investigation was to determine whether the use of the aminoglycoside amikacin at small doses may lead to the occurrence of some types of resistance to or protection against ototoxicity of the drug by analyzing lesions to the organ of Corti by scanning electron microscopy. Methods The study was conducted on 31 guinea pigs that were divided into 4 groups, amikacin was administered intramuscularly. The groups consisted of: group A = control group: 5 animals (10 cochleae); group B = 5 animals (10 cochleae), amikacin 20 mg/kg/day for 30 days; group c = 7 animals (13 cochleae), amikacin 400 mg/kg/day for 12 days; group d = 14 animals (26 cochleae) amikacin 20 mg/kg/day for 30 days, followed by 400 mg/kg/day for 12 days. Histological studies were performed by scanning electron microscopy. Three cochleae were excluded. Results In groups A and B, the cells were normal in all cochleae, in group C there were extensive lesions of the 2 more basal turns, and in group D there was a significant reduction of lesions in the 2 more basal turns compared with group C, which had received the ototoxic dose of amikacin alone. Conclusion We conclude that the non-ototoxic dose of amikacin administered before the ototoxic dose of the same antibiotic had a statistically significant protective effect on the 2 more basal turns of the guinea pig cochlea.

Pharmacokinetics of Once‐Daily Amikacin in Healthy Foals and Therapeutic Drug Monitoring in Hospitalized Equine Neonates

The objectives of this study were to investigate the pharmacokinetics of once‐daily amikacin in healthy neonates, to determine amikacin concentrations in hospitalized foals, and to determine the minimum inhibitory concentrations (MICs) of amikacin against gram‐negative isolates from blood cultures in septic foals. Median half‐life, clearance, and volume of distribution of amikacin in healthy 2‐ to 3‐day‐old foals after administration of an intravenous bolus of amikacin (25 mg/kg) were 5.07 hours (4.86‐5.45 hours), 1.82 mL/min/kg (1.35‐1.97 mL/min/kg), and 0.785 L/kg (0.638‐0.862 L/kg), respectively. Statistically significant (P&lt;.05) decreases in area under the curve (14% decrease), mean residence time (19% decrease), and C24hplasma amikacin concentrations (29% decrease) occurred between days 2–3 and 10–11. Plasma amikacin concentrations in healthy foals at 0.5 hours (C05h) were significantly higher (P= .02) than those of hospitalized foals. Sepsis, prematurity, and hypoxemia did not alter amikacin concentrations. The MIC at which 90% of all gram‐negative isolates from equine neonatal blood cultures were inhibited by amikacin was 4 |xg/mL, suggesting that amikacin C05hof 40 μg/mL should be targeted to achieve a maximum serum concentration to MIC ratio of 10:1. The proportion of foals with C05h&gt;40 μg/mL was significantly higher(P&lt;.0001) in hospitalized foals receiving a dose of amikacin at 25 mg/kg (22/24 or 92%) than in foals receiving a dose at 21 mg/kg (9/25 or 36%), whereas no difference was found in the proportion of foals with C24hconcentrations ≥3 μg/mL between the 2 groups. An initial dose at 25 mg/kg is recommended for once‐daily amikacin in equine neonates.

Pharmacokinetics of a high dose of amikacin administered at extended intervals to neonatal foals

To determine disposition kinetics of amikacin in neonatal foals administered high doses at extended intervals. 7 neonatal foals. Amikacin was administered (21 mg/kg, i.v., q 24 h) for 10 days. On days 1, 5, and 10, serial plasma samples were obtained for measurement of amikacin concentrations and determination of pharmacokinetics. Mean +/- SD peak plasma concentrations of amikacin extrapolated to time 0 were 103.1 +/- 23.4, 102.9 +/- 9.8, and 120.7 +/- 17.9 microg/mL on days 1, 5, and 10, respectively. Plasma concentrations at 1 hour were 37.5 +/- 6.7, 32.9 +/- 2.6, and 30.6 +/- 3.5 microg/mL; area under the curve (AUC) was 293.0 +/- 61.0, 202.3 +/- 40.4, and 180.9 +/- 31.2 (microg x h)/mL; elimination half-life (t(1/2)beta) was 5.33, 4.08, and 3.85 hours; and clearance was 1.3 +/- 0.3, 1.8 +/- 0.4, and 2.0 +/- 0.3 mL/(min x kg), respectively. There were significant increases in clearance and decreases in t(1/2)beta, AUC, mean residence time, and plasma concentrations of amikacin at 1, 4, 8, 12, and 24 hours as foals matured. Once-daily administration of high doses of amikacin to foals resulted in high peak plasma amikacin concentrations, high 1-hour peak concentrations, and large values for AUC, consistent with potentially enhanced bactericidal activity. Age-related findings suggested maturation of renal function during the first 10 days after birth, reflected in enhanced clearance of amikacin. High-dose, extended-interval dosing regimens of amikacin in neonatal foals appear rational, although clinical use remains to be confirmed.

Evaluation of an amikacin loading dose for nosocomial infections in very low birthweight infants

Aim: To develop a simplified amikacin dosage regimen for nosocomial infections in preterm infants including a loading dose in order to achieve therapeutic Maximum Serum Concentrations early in the course of therapy. Methods: Open, non‐comparative study during November 2000 to April 2001. The modified amikacin dosing and monitoring protocol included a loading dose of 10mg/kg in the first week of life, followed by a maintenance regimen of 7.5 mg/kg every 24 h. After the first week of life the corresponding doses were 17 mg/kg (loading) and 15 mg/kg (maintenance). A peak level was measured 30 min after the second dose, a trough level immediately before the third dose. Results: Twenty‐five very low birthweight infants (median birthweight 739 g, median gestational age 25 wk) who had 34 episodes of amikacin treatment were included in the analysis. Median amikacin peak and trough values were 37.1 μmol/1 and 6.3 μmol/1, respectively. Twenty‐nine of all peak levels (85%) and 30 of all trough levels (88%) were within the targeted range of &gt;35 μmol/1 and &lt;8.5 μmol/1, respectively. All patients with elevated trough levels were of extremely low birthweight and were born in the 24th week of gestation. Hearing evaluations were performed in 17 of 19 surviving infants at discharge home, all of which gave normal results. Conclusion: The new amikacin dosing protocol yielded targeted peak and trough concentrations in a high percentage of very low birthweight infants with nosocomial infection after the first week of life. Our simplified dosage regimen achieved acceptable serum concentrations in all birthweight and gestational age groups, with the exception of extremely low birthweight infants weighing less than 700 g and/or with a gestational age of 24 wk or less. Only limited information can be gained from our data regarding the use of amikacin during the first week of life.

Evaluation of an amikacin loading dose for nosocomial infections in very low birthweight infants.

To develop a simplified amikacin dosage regimen for nosocomial infections in preterm infants including a loading dose in order to achieve therapeutic Maximum Serum Concentrations early in the course of therapy. Open, non-comparative study during November 2000 to April 2001. The modified amikacin dosing and monitoring protocol included a loading dose of 10 mg/kg in the first week of life, followed by a maintenance regimen of 7.5 mg/kg every 24 h. After the first week of life the corresponding doses were 17 mg/kg (loading) and 15 mg/kg (maintenance). A peak level was measured 30 min after the second dose, a trough level immediately before the third dose. Twenty-five very low birthweight infants (median birthweight 739 g, median gestational age 25 wk) who had 34 episodes of amikacin treatment were included in the analysis. Median amikacin peak and trough values were 37.1 micromol/l and 6.3 micromol/l, respectively. Twenty-nine of all peak levels (85%) and 30 of all trough levels (88%) were within the targeted range of >35 micromol/l and <8.5 micromol/l, respectively. All patients with elevated trough levels were of extremely low birthweight and were born in the 24th week of gestation. Hearing evaluations were performed in 17 of 19 surviving infants at discharge home, all of which gave normal results. The new amikacin dosing protocol yielded targeted peak and trough concentrations in a high percentage of very low birthweight infants with nosocomial infection after the first week of life. Our simplified dosage regimen achieved acceptable serum concentrations in all birthweight and gestational age groups, with the exception of extremely low birthweight infants weighing less than 700 g and/or with a gestational age of 24 wk or less. Only limited information can be gained from our data regarding the use of amikacin during the first week of life.

Pharmacokinetics of Once-Daily Amikacin in Healthy Foals and Therapeutic Drug Monitoring in Hospitalized Equine Neonates

The objectives of this study were to investigate the pharmacokinetics of once-daily amikacin in healthy neonates, to determine amikacin concentrations in hospitalized foals, and to determine the minimum inhibitory concentrations (MICs) of amikacin against gram-negative isolates from blood cultures in septic foals. Median half-life, clearance, and volume of distribution of amikacin in healthy 2- to 3-day-old foals after administration of an intravenous bolus of amikacin (25 mg/kg) were 5.07 hours (4.86-5.45 hours), 1.82 mL/min/kg (1.35-1.97 mL/min/kg), and 0.785 L/kg (0.638-0.862 L/kg), respectively. Statistically significant (P <.05) decreases in area under the curve (14% decrease), mean residence time (19% decrease), and C24h plasma amikacin concentrations (29% decrease) occurred between days 2-3 and 10-11. Plasma amikacin concentrations in healthy foals at 0.5 hours (C0.5h) were significantly higher (P = .02) than those of hospitalized foals. Sepsis, prematurity, and hypoxemia did not alter amikacin concentrations. The MIC at which 90% of all gram-negative isolates from equine neonatal blood cultures were inhibited by amikacin was 4 microg/mL, suggesting that amikacin C0.5h of 40 microg/mL should be targeted to achieve a maximum serum concentration to MIC ratio of 10:1. The proportion of foals with C0.5h 40 microg/mL was significantly higher (P < .0001) in hospitalized foals receiving a dose of amikacin at 25 mg/kg (22/24 or 92%) than in foals receiving a dose at 21 mg/kg (9/25 or 36%), whereas no difference was found in the proportion of foals with C24h concentrations > or = 3 microg/mL between the 2 groups. An initial dose at 25 mg/kg is recommended for once-daily amikacin in equine neonates.

Immunomodulatory clarithromycin treatment of experimental sepsis and acute pyelonephritis caused by multidrug-resistant Pseudomonas aeruginosa.

Clarithromycin was administered intravenously to 55 rabbits to evaluate its effect on experimental sepsis caused by multidrug-resistant Pseudomonas aeruginosa. Acute pyelonephritis was induced after ligation of the right ureter and injection of 10(8) CFU of the test isolate per kg of body weight into the renal pelvis. The animals were divided into six groups: group A, controls; group B, rabbits that received one intravenous dose of 80 mg of clarithromycin per kg concomitantly with bacterial challenge; group C, rabbits that received two doses of clarithromycin, the second one of which was given 2 h after the first one; group D, rabbits that received 15 mg of amikacin per kg; group E, rabbits that received one dose of clarithromycin and amikacin; and group F, rabbits that received two doses of clarithromycin and amikacin. Serum endotoxin levels were estimated by the QCL-1000 Limulus amoebocyte lysate assay, tumor necrosis factor alpha (TNF-alpha) levels were measured by a bioassay, and malondialdehyde (MDA) levels were measured by the thiobarbiturate assay. Viable bacterial counts in various tissue samples were also assessed. The mean survival times of the animals in groups A, B, C, D, E, and F were 4.50, 7.69, 4.07, 4.55, 11.55, and 11.60 days, respectively (P = 0.033 for group D versus group F, P = 0.006 for group D versus group E, P = not significant for group B versus group E, P = 0.042 for group C versus group F). Serum endotoxin levels were similar between groups at all sampling times; TNF-alpha and MDA levels in groups B, C, E, and F decreased significantly over follow-up. The numbers of viable bacterial cells in the infected kidney were similar among the groups; those in the liver, spleen, lungs, and mesenteral lymph nodes were significantly decreased in groups B, E, and F compared to those in groups A and D. It is concluded that a prolongation of survival in animals with experimental sepsis caused by multidrug-resistant P. aeruginosa was achieved after coadministration of clarithromycin and amikacin and that the increased survival was probably attributable to the immunomodulatory properties of clarithromycin.

A study of once-daily amikacin with low peak target concentrations in intensive care unit patients: Pharmacokinetics and associated outcomes

Purpose: The aim of this study was to assess the pharmacokinetics of individualized amikacin single-dosage regimens targeting low peak serum concentrations in a population of intensive care unit (ICU) patients, and to describe the outcomes associated with this dosing strategy. Materials and Methods: In this prospective, noncomparative, pharmacokinetic study, 36 ICU patients with adequate renal function were treated with amikacin (intravenous infusion), in combination with other antibiotics, for hospital-acquired infections. The initial doses of amikacin were calculated based on individual creatinine clearance values whereas subsequent doses were calculated by using the amikacin pharmacokinetic parameters estimated from the serum concentration-time data of each individual patient (samples were drawn postinfusion, 1 h, 3 h, 6 h, and 10 h after the onset of the infusion and just before the next dose on days 2, 4, and 7 of therapy). Results: Results showed moderate only interpatient and lack of intrapatient (except for the volume of distribution) variability in amikacin pharmacokinetic parameters. There were no significant differences between achieved and target peak levels. Clinical response was noted in 94% and bacteriologic response was noted in 86% of patients. Nephrotoxicity did not occur during or after treatment. Conclusions: Amikacin dosage individualization with low peak target concentrations was successful for the 36 ICU patients. This dosing strategy was not associated with nephrotoxicity, but conclusions on clinical efficacy cannot be drawn from this limited study. © 2003 Elsevier Inc. All rights reserved.

Outpatient, sequential, parenteral‐oral antibiotic therapy for lower risk febrile neutropenia in children with malignant disease

Recent reports and previous randomized trials conducted at the authors' institution suggested that children with lower risk febrile neutropenic (LRFN) may benefit from substitution of oral antibiotic therapy for parenteral therapy. The objective of this study was to determine the efficacy of parenteral-oral outpatient therapy in the management of children with LRFN who were receiving treatment for malignant disease. From August 2000 to April 2002, 135 children with a median age of 7.5 years (range, 1.6-15.8 years) who had a total of 177 episodes of LRFN were included in a prospective, randomized, single-institution trial. Children with LRFN received a single dose of ceftriaxone and amikacin and completed a risk-assessment work-up. All patients were discharged immediately and, at 24 hours, were allocated randomly to two groups: Group A (89 episodes) received oral ciprofloxacin, and Group B (88 episodes) received intravenous ceftriaxone. Most patients (61% in Group A and 51% in Group B) were receiving treatment for leukemia (P value not significant [NS]). Twenty-eight children (31%) in Group A and 22 children (25%) in Group B displayed unexplained fever (P value NS). No significant differences in sites of initial infection were found between the two groups. The median duration of neutropenia was 4.2 days and 4.7 days for Group A and Group B, respectively (P value NS); the median duration of fever was 2.3 days and 2.6 days, respectively (P value NS); and the median duration of antibiotic treatment was 4.5 days and 4.8 days, respectively (P value NS). The overall results of the study were excellent. Only four treatment failures in Group A (5%) and 6 treatment failures in Group B (7%) were observed. These patients were readmitted to the hospital and did well with appropriate treatment. In children with LRFN who are receiving treatment for malignant disease, outpatient oral ciprofloxacin after 24 hours of a single dose of intravenous ceftriaxone and amikacin was as safe and efficacious as parenteral ceftriaxone. Outpatient management and early antibiotic withdrawal were safe for both groups.

Pharmacokinetic dosing of aminoglycosides: a controlled trial

Purpose To evaluate whether individualized pharmacokinetic dosing of aminoglycosides can reduce nephrotoxicity and improve the outcome of patients with gram-negative sepsis. Methods We conducted a prospective controlled trial at a tertiary care university hospital. Eighty-one patients with suspected or documented gram-negative infections were enrolled. All were treated with either gentamicin or amikacin, according to clinical judgement. Patients were allocated to one of two groups based on the last digit (odd/even) of their identification number. In the study group (pharmacokinetic dosing) of 43 patients, plasma aminoglycoside levels were determined 1 hour after initiation of drug infusion and 8 to 16 hours later to estimate the elimination half-life and volume of distribution, from which the subsequent dosage schedule was calculated. Target peak plasma levels were 20 μg/mL for gentamicin and 60 μg/mL for amikacin. Target trough levels were <1 μg/mL for both drugs. The control group (fixed once-daily dosing) consisted of 38 patients who were prescribed single daily doses of gentamicin or amikacin. The primary endpoints were renal toxicity (≥25% increase in serum creatinine level or a serum creatinine level ≥1.4 mg/dL) and 28-day mortality. Results The two study groups were similar in age, sex, indications for therapy, Acute Physiology and Chronic Health Evaluation (APACHE) II score, and clinical assessment at baseline. Although the pharmacokinetic group received significantly greater doses of aminoglycosides than did the once-daily group, the incidence of nephrotoxicity was significantly lower in the pharmacokinetic group (5% [2/43] vs. 21% [8/38], P = 0.03). There was no statistically significant difference in 28-day mortality (27% [12/43] vs. 22% [8/38], P = 0.3). Conclusion These results suggest that individualized pharmacokinetic dosing of aminoglycosides reduces the incidence of nephrotoxicity and allows the use of greater doses of aminoglycosides.

Otoproteção das células ciliadas auditivas contra a ototoxicidade da amicacina

Objetivo: Este estudo teve por objetivo verificar a ocorrência de otoproteção contra a ototoxicidade da amicacina em cobaias. Forma de estudo: experimental. Material e método: Foram estudadas as células ciliadas externas do órgão de Corti de 31 animais por meio de microscopia eletrônica de varredura (JEOL-JMS 5200). Foram estudados 4 grupos: A, controle; B, amicacina 20 mg/kg/dia por 30 dias; C, amicacina 400 mg/Kg/ dia 12 dias; grupo D, amicacina 20 mg/kg/dia por 30 dias seguido de 400 mg/kg/dia por 12 dias. Resultados: Nos grupos A e B, as células estavam normais em todas as cócleas; no grupo C houve lesões extensas nas duas espiras mais basais; no grupo D houve redução significante das lesões nas duas mais basais em comparação com o grupo C que recebeu a dose ototóxica de amicacina isoladamente. Conclusão: Conclui-se que a dose não ototóxica de amicacina administrada previamente à dose ototóxica do mesmo antibiótico tem efeito protetor, estatisticamente significante, nas duas espiras mais basais das cócleas de cobaias.

Antimicrobial agents in extender and their effect on semen preservation and pregnancy rate of inseminated mares

In this study, the effectiveness of supplementing INRA-96® extender (INRA-Control; original antibiotic formulation: potassium penicillin G = 38 μg/mL; gentamicin sulfate = 105 μg/mL; amphotericin B = 0.315 μg/mL) with amikacin sulfate and potassium penicillin G (AP) was determined. In Exp. 1, two sources of amikacin (INRA-AP-Sigma or INRA-AP-GoldBio) in combination with penicillin G were compared with ticarcillin/clavulanate (INRA-Tim) or no-supplemental antibiotics (INRA-Control) to examine effects on sperm quality and commensal bacterial growth. No differences were detected in semen quality among treatments after 30 min of exposure (Time 30min) or 24 h of cooled storage (Time 24 h; P > 0.05). At both time periods, commensal bacterial growth was significantly lower in Groups INRA-AP-GoldBio and INRA-AP-Sigma than in INRA-Tim or INRA-Control (P < 0.05). In Exp. 2, increasing doses of amikacin sulfate (GoldBio) plus potassium penicillin G (Sigma) - AP (AP-1000, 2000, 3000, 4000 or 5000 μg-IU/mL, respectively) were added to INRA-96® extender and their effects on sperm quality and commensal bacterial growth were evaluated at Time 30min and Time 24 h. Slight reductions in progressive motility and viability were observed at Time 30min in Groups AP-4000 and AP-5000 as compared to other treatment groups (P < 0.05); however, no differences in sperm quality were detected among treatment groups at Time 24 h (P > 0.05). At both time periods, commensal bacterial growth was significantly lower in Groups AP-3000, AP-4000 and AP-5000 than in AP-1000 and AP-2000 (P < 0.05). In Exp. 3, a breeding trial was conducted to determine the effect of adding a high dose of AP (AP-5000) to INRA-96® extender on resulting pregnancy rates of mares bred with cool-stored semen (Time 24 h). Numerical, but not statistical differences, were observed in pregnancy rates between the mares bred with INRA-Control (6/11; 55%) or INRA-AP-5000 (9/11; 82%; P > 0.05). Supplementation of INRA-96® extender with two different concentrations of AP (AP-1000 or AP-5000) was tested in two clinical cases of stallions where semen was moderately to heavily contaminated with Pseudomonas aeruginosa, or both Klebsiella pneumoniae and Pseudomonas aeruginosa. In both cases, addition of AP resulted in a considerable decrease on bacterial growth in cool-stored semen when compared to the use of the original INRA-96® extender without supplemental antibiotics. In conclusion, the addition of amikacin sulfate and potassium penicillin G to INRA-96® extender allowed for effective control of commensal bacteria without affecting sperm quality. Higher doses of amikacin and penicillin can be safely added to INRA-96® extender to improve the antibacterial activity of this extender against commensal, and potentially pathogenic bacteria, while sperm quality and fertility of cooled semen remains unaffected. Based on the results of the present study, we currently recommend that INRA-96® extender can be safely supplemented with amikacin/penicillin by using a conventional dose of 1000 μg/mL – 1000 IU/mL as a prophylactic measure in cases where contamination of the ejaculates with commensal bacteria is evident. Alternatively, a high dose (5000 μg/mL – 5000 IU/mL) can be used as a control method for potentially pathogenic bacteria.

Potentiation of noise-induced hearing loss by amikacin in guinea pigs

Noise and aminoglycosides initially attack cochlear outer hair cells (OHCs). Distortion product otoacoustic emissions (DPOAEs) are used for the early diagnosis of damage to OHCs. The effects of sub-damaging doses of amikacin, an aminoglycoside antibiotic agent, on noise-induced hearing loss (NIHL) were examined in guinea pigs. Animals were grouped by gender and exposed to broadband noise at 105 dB SPL for 12 h and/or injected i.m. with either amikacin (100 mg/kg/day) or saline for 10 days. Auditory brainstem response (ABR) thresholds, along with DPOAE amplitudes, were measured serially before and after noise exposure. DPOAE amplitudes decreased and ABR thresholds elevated immediately after noise exposure and then gradually recovered. At all frequencies, the emission amplitudes recovered completely to pre-exposure baseline values by 4 days after noise exposure. There was no effect of amikacin on either the ABR threshold or DPOAE amplitudes, in animals treated with amikacin only. However, amikacin significantly prolonged the effect of noise exposure on DPOAE amplitude but not on the noise-induced temporary threshold shift (TTS) of the ABR. In animals treated with a combination of noise and amikacin, significant changes in DPOAE amplitudes were still observed at 4 weeks after cessation of noise exposure. No gender difference in the responses to noise and/or amikacin could be demonstrated. The present findings indicate that even sub-damaging dosages of amikacin might impair recovery from NIHL in guinea pigs.

Once-a-Day Individualized Amikacin Dosing for Suspected Infection at Birth Based on Population Pharmacokinetic Models

Amikacin is widely used in the treatment of suspected or confirmed neonatal infections. However, dosage regimens are not well defined in this group of patients because of a wide inter-individual pharmacokinetic variability. An individualized goal-oriented amikacin dosage design was applied using population pharmacokinetic data. A dosing chart was developed for neonates during the first 2 days of life, by using population pharmacokinetic parameter values and USCPACK software. This dosing chart based on gestational age (GA) and body weight gives a once-a-day amikacin dosage regimen involving an injection every 24 h. Validation was performed in 57 neonates less than 2 days old, divided into three GA groups and prospectively treated using the dosing chart. Target peak serum levels of amikacin were obtained in 62–80% of patients after the first dose and in 80–100% after the second dose, and trough concentrations were obtained in 100%. This study has confirmed the need for individualization of amikacin dosage regimens in neonates.

Sensorineural Hearing Loss in Children After Liver Transplantation

DEUTSCH, ELLEN S.; BARTLING, VICTORIA; LAWENDA, BRIAN; SCHWEGLER, JOHN; FALKENSTEIN, KATHLEEN; DUNN, STEPHEN Author Information

Significantly improved oral uptake of amikacin in FVB mice in the presence of CRL-1605 copolymer

Amikacin is an aminoglycoside which is used in the treatment of infection from gram negative bacteria. Amikacin is also used synergistically with penicillin against gram positive cocci. Amikacin cannot be delivered orally probably due to efflux of drug by P-glycoprotein pump in the brush border of intestine. We studied the possibility of delivering amikacin orally in mice using a copolymer (CRL-1605) as a vehicle. This copolymer inhibits P—glycoprotein pump. Two different doses of amikacin were used (500 mg/kg and 100 mg/kg). The concentration of polymer used was 132 mg/kg. The liquid formulation was fed to mice by gavage and serum amikacin concentrations were estimated after one hour and two hours using flourescence polarization immunoassay. We observed a two fold increase in serum amikacin concentration when amikacin was orally delivered in the presence of CRL-1605 compared to controls (amikacin alone). We conclude that gastrointestinal absorption of amikacin is significantly increased in the presence of CRL-1605 in mice.

Pharmacokinetics and urinary excretion of amikacin in low-clearance unilamellar liposomes after a single or repeated intravenous administration in the rhesus monkey.

Liposomal aminoglycosides have been shown to have activity against intracellular infections, such as those caused by Mycobacterium avium. Amikacin in small, low-clearance liposomes (MiKasome) also has curative and prophylactic efficacies against Pseudomonas aeruginosa and Klebsiella pneumoniae. To develop appropriate dosing regimens for low-clearance liposomal amikacin, we studied the pharmacokinetics of liposomal amikacin in plasma, the level of exposure of plasma to free amikacin, and urinary excretion of amikacin after the administration of single-dose (20 mg/kg of body weight) and repeated-dose (20 mg/kg eight times at 48-h intervals) regimens in rhesus monkeys. The clearance of liposomal amikacin (single-dose regimen, 0.023 +/- 0.003 ml min-1 kg-1; repeated-dose regimen, 0.014 +/- 0.001 ml min-1 kg-1) was over 100-fold lower than the creatinine clearance (an estimate of conventional amikacin clearance). Half-lives in plasma were longer than those reported for other amikacin formulations and declined during the elimination phase following administration of the last dose (from 81.7 +/- 27 to 30.5 +/- 5 h). Peak and trough (48 h) levels after repeated dosing reached 728 +/- 72 and 418 +/- 60 micrograms/ml, respectively. The levels in plasma remained > 180 micrograms/ml for 6 days after the administration of the last dose. The free amikacin concentration in plasma never exceeded 17.4 +/- 1 micrograms/ml and fell rapidly (half-life, 1.47 to 1.85 h) after the administration of each dose of liposomal amikacin. This and the low volume of distribution (45 ml/kg) indicate that the amikacin in plasma largely remained sequestered in long-circulating liposomes. Less than half the amikacin was recovered in the urine, suggesting that the level of renal exposure to filtered free amikacin was reduced, possibly as a result of intracellular uptake or the metabolism of liposomal amikacin. Thus, low-clearance liposomal amikacin could be administered at prolonged (2- to 7-day) intervals to achieve high levels of exposure to liposomal amikacin with minimal exposure to free amikacin.