Serum Gentamicin Concentrations Research Articles

Pharmacokinetics of Gentamicin and its Interaction with Paracetamol after i.v. Administration in Buffalo Calves (Bubalus bubalis)

The disposition kinetics was conducted in fi ve healthy female buffalo calves following single i.v dose (5mg/kg) of gentamicin alone and with paracetamol (40mg/kg,i.v.). The study revealed that the plasma concentrations of gentamicin were signi fi cantly higher when it was given with paracetamol as compared to alone between 0.042 to 0.333 hrs and at 24 hrs. Serum concentrations of gentamicin was detected for longer period (48 hrs) in urine in both groups of experimental animals. In case of urine drug attained its peak level at the same time interval (1.5 hrs) in both groups with the concentration of 83.42±3.14 i­ g/ml after alone and 545.1±25.85 i­ g/ml with paracetamol administration. The extrapolated zero time plasma concentrations during distribution phase (A) and theoretical zero time plasma concentrations (Cop) were signi fi cantly (p< 0.01) higher 34.48±2.35 and 39.03±2.40 i­ g/ml respectively. Also signi fi cantly higher distribution rate constant ( ii ) of 1.935±0.1119 h -1 and lower distribution half life (t 1/2 ii ) of 0.36±0.02 hrs were observed, when gentamicin was given with paracetamol. Elimination half life (t 1/2 i¢ ) of 6.67±0.11 hrs was not signi fi cantly higher when gentamicin was given with paracetamol. AUC (62.16±2.82 mg/L.hrs) was signi fi cantly (p< 0.05) higher while MRT (6.93±0.36hrs) was not signi fi cantly higher when gentamicin was given with paracetamol. The values of K 12 , K 21 and Kel were calculated to be 1.088±0.111 h -1 , 0.323±0.028 h -1 and 0.628±0.024 h -1 respectively when gentamicin was given concurrently with paracetamol. T~P (5.04±0.16) was signi fi cantly (p< 0.01) higher, while Vd area (0.78±0.03L/Kg) and ClB (1.35±0.06 ml/Kg/min) were not signi fi cantly higher when gentamicin was given with paracetamol. The present investigation established that both gentamicin and paracetamol interacted with altered their kinetic behaviour. The combination with paracetamol may be beni fi cial because paracetamol reduced the maintenance doses of gentamicin which may be much advantageous in the fi eld of veterinary practice in the dose of 5 mg/kg daily by systemic route and 36 hourly when given with paracetamol in urinary tract infection.

Accuracy of Empiric Gentamicin Dosing Guidelines in Neonates

To evaluate the accuracy of a neonatal gentamicin nomogram to achieve therapeutic gentamicin serum concentrations without further adjustment, allowing for decreased serum drug monitoring Retrospective single center review of all gentamicin pharmacokinetic evaluations in patients ≤ 30 days of life from July 2005 - June 2007. Patients were evaluated for postnatal age, gestational age, weight, serum creatinine, dose/interval, serum drug peaks and troughs, results of discharge hearing test and recent use of indomethacin. Logistic regression was utilized to determine potential factors impacting overall dosing accuracy, potentially allowing for decreased therapeutic drug monitoring. Factors found to be significant were incorporated into new guidelines which were evaluated through pharmacokinetic modeling. Overall accuracy rate was 84% when empiric dosing guidelines were utilized; 16% of all doses were changed due to supratherapeutic troughs and 1% were changed due to subtherapeutic peaks. Variables found to impact the necessity for dose changes incuded gestational age (p≤0.001), weight (p≤0.001), indomethacin use (p≤0.001), number of indomethacin doses used (p≤0.001 and p=0.009 for 1-3 and 4-6 doses, respectively), and SCr in patients ≥ 7 days old (p=0.028); however, only gestational age remained a significant predictor when all other factors were considered (p=0.008). The current guidelines were changed to account for increased troughs in patients ≤ 28 weeks gestation and examined through pharmacokinetic modeling. Pharmacokinetic modeling of the new guidelines predicted an overall accuracy of 94%. From the data gathered regarding the accuracy in patients ≥ 35 weeks gestation, we recommend to decrease therapeutic drug monitoring within this cohort. Utilizing the results of regression analysis, the current guidelines have been adjusted to allow for increased clearance in patients ≤ 28 weeks gestation, although they still need to be prospectively evaluated.

Serum Gentamicin Concentrations in Encephalopathic Infants are Not Affected by Therapeutic Hypothermia

Mild hypothermia for 72 hours is neuroprotective in newborns with moderate or severe hypoxic-ischemic encephalopathy. A core temperature of 33.5 degrees C might reduce drug clearance leading to potential toxicity. Gentamicin is nephrotoxic and ototoxic at high serum concentrations. No study has investigated the influence of 72 hours of hypothermia on serum gentamicin concentrations (SGCs) in children of any age. We aimed to compare the SGCs in encephalopathic infants who underwent intensive care with therapeutic hypothermia or normothermia. Data were collected retrospectively from 2 NICUs in Bristol, United Kingdom, that offered cooling therapy within clinical trials since 1998. Eligible infants (n = 55) developed grade 2/3 encephalopathy after birth and fulfilled the entry criteria defined in the CoolCap trial. Encephalopathic infants with similar demographic values were either nursed under normothermia or 72 h-hypothermia. Once-daily gentamicin dosage (4-5 mg/kg) was administered, and trough SGC was recorded with corresponding creatinine concentrations. The time and number of omitted drug doses were noted. Mean trough SGC (pre-second dose) and mean plasma creatinine concentrations for both treatment groups were similar (gentamicin: 2.19 +/- 1.7 [hypothermia] and 2.30 +/- 2.0 [normothermia] mg/L; creatinine: 115.6 +/- 42.8 [hypothermia] and 121.0 +/- 45.1 [normothermia] mumol/L). Forty percent of the trough SGCs in both groups were above the recommended trough concentration of 2.0 mg/L. A significant correlation (r(2) = 0.36) was found between high SGCs and impaired renal function assessed by raised plasma creatinine levels regardless of treatment options. Our data confirm that impaired renal function is strongly associated with high SGCs. Reduced body temperatures do not affect the clearance of gentamicin.

Evaluation of the effect of intravenous volume expanders upon the volume of distribution of gentamicin in septic neonates

Sepsis has been reported to increase the volume of distribution of gentamicin in neonates. To determine whether this was caused by the use of intravenous volume expanders a retrospective nested case-control study was performed comparing confirmed septic neonates with non-septic controls. Data were collected on intravenous administration of 0.45% saline/10% dextrose, 0.45% saline/5% dextrose, 0.9% normal saline, red blood cells, platelets, immunoglobulin (Intragam P) and albumin. A population pharmacokinetic analysis was performed using NONMEM for 116 neonates (29 confirmed septic) from which 363 gentamicin serum concentrations were available. The final covariate model was CL=0.097x(current weight/2)(1.3)x(postnatal age/7)(0.29) and V=1.07x(current weight/2)(0.8)+(confirmed sepsis)x0.13. The gentamicin volume of distribution was not significantly influenced by the cumulative intravenous volume expanders. The principal covariates that affected the gentamicin volume of distribution were current body weight and confirmed sepsis.

Once daily dose gentamicin in neonates — is our dosing correct?

The aim of this paper is to study the safety and efficacy (measured by therapeutic level) of once daily gentamicin in neonates >or=32 weeks of gestation and <or=7 days of age. Level II neonatal intensive care unit. Neonates >or=32 weeks of gestation and <or=7 days of age treated with gentamicin for presumed sepsis. Gentamicin was administered by intravenous injection at 4 mg/kg/day once daily. Peak and trough gentamicin levels were measured at the third dose. In neonates with gestational age between 32 and 36 weeks, 14 out of 65 (22%) had trough serum concentration >2 mg/L. Only 39 (60%) had peak and trough levels within the therapeutic range. All babies who had audiometric evaluation (62 out of 65) had normal hearing. Out of the 65 babies, 60 had paired serum creatinine levels estimated and none had evidence of renal dysfunction. Among term neonates, only 2 out of 50 had the trough serum concentration of >2 mg/L. In 38 (76%) of the 50 neonates, the trough serum gentamicin concentration was <2.0 mg/L and the peak level was <10 mg/L. Forty-eight babies had audiometric evaluation which was normal. A dose of 4 mg/kg/day produces serum gentamicin levels outside the therapeutic range in two-fifths of neonates between 32 and 36 +/- 6 weeks. A single dose of 4 mg/kg/day of gentamicin is appropriate for term babies and probably excessive for 32-36 weeks' neonates.

Suboptimal Aminoglycoside Dosing in Critically Ill Patients

Maximal aminoglycoside (AG) killing requires that the ratio of peak serum concentrations (Cmax) to the minimum inhibitory concentration (MIC) of the pathogen exceeds by > or =10. This has been shown to hasten resolution of infection in the general patient population. It was postulated that critically ill patients, likely to have larger intravascular volumes, are underdosed. The primary aim was to determine Cmax to MIC target attainment rate in medical intensive care unit (MICU) patients. A retrospective review of MICU patients who received at least 1 intravenous dose and serum concentration of either gentamicin or tobramycin was performed. A population pharmacokinetic model was developed, and MIC distributions for AG were used in determining the Cmax/MIC and in calculating the probability of attaining the pharmacodynamic (PD) target. One hundred two unique patients with 211 AG concentrations were analyzed to determine population pharmacokinetic parameters. Mean maximum clearance (CL) was 3.14L/h (95% confidence interval: 1.26-4.54 L/h), and mean volume of distribution (V) was 53 L (95% confidence interval: 38-66.8 L/h). Glomerular filtration rate and standardized body weight were identified as significant covariates for clearance in the final model. Standardized body weight also significantly affected V. There was only a 20% and 40% probability that patients receiving 7 mg/kg of gentamicin and tobramycin, respectively, will achieve PD target over the range of MIC distributions. Based on these data, the majority of critically ill patients would not be predicted to achieve the PD target under current dosing regimens. This may be a result of intensive care unit patients having a larger volume of distribution than reported in the literature. Future recommendations for treating gram-negative infections in the MICU population include using initial doses of 7 mg/kg of either gentamicin or tobramycin, measuring Cmax after the first dose, and determining MIC for the pathogen(s) with adjustment of subsequent doses to achieve the PD target.

Pharmacological differences between once daily and twice daily gentamicin dosage in newborns with suspected sepsis

To evaluate two different regimens for gentamicin administration (once or twice daily) in newborns with suspected sepsis, and the ability of these regimens to achieve recommended serum gentamicin concentrations (SGC) within the therapeutic range. Setting Neonatal intensive care unit. We conducted a retrospective study of newborns > or =34 weeks gestational age (GA) admitted with suspected sepsis to the neonatal unit at Stavanger University Hospital from 1st February 2003 to 31st May 2005. During the first period patients received gentamicin 2.5 mg/kg twice daily (n = 62) and during the last period patients received gentamicin 4 mg/kg once daily (n = 73). In both groups, levels of gentamicin were obtained before and after the third given dose. Mean peak levels were lower and mean trough levels were higher in the twice daily regimen compared to the once daily regimen (P < 0.001 for both). About 16 newborns in the twice daily regimen had trough levels higher than the recommended level (<2 microg/ml) compared to two children in the once daily regimen (P < 0.001). High peak levels (>10 microg/ml) were achieved in one child in the twice daily regimen compared to eight children in the once daily regimen (P = 0.04). The number of children with a low peak level (<5 microg/ml) was only three and one respectively (n.s). In newborns with suspected sepsis, gentamicin 4 mg/kg once daily provided higher peak and lower trough gentamicin levels compared to administering gentamicin 2.5 mg twice daily.

Estimation of Creatinine Clearance

Estimation of Creatinine Clearance

Influence of Hemodialysis on Gentamicin Pharmacokinetics, Removal During Hemodialysis, and Recommended Dosing

Aminoglycoside antibiotics are commonly used in chronic kidney disease stage 5 patients. The purpose of this study was to characterize gentamicin pharmacokinetics, dialytic clearance, and removal by hemodialysis and to develop appropriate dosing strategies. Design Setting, Participants, and Measurements: Eight subjects receiving chronic, thrice-weekly hemodialysis with no measurable residual renal function received gentamicin after a hemodialysis session. Blood samples were collected serially, and serum concentrations of gentamicin were determined. Median (range) systemic clearance, volume of distribution at steady state, and terminal elimination half-life were 3.89 ml/min (2.69-4.81 ml/min), 13.5 L (8.7-17.9 L), and 39.4 h (32.0-53.6 h), respectively. Median (range) dialytic clearance, estimated amount removed, and percent maximum rebound were 103.5 ml/min (87.2-132.7 ml/min), 39.6 mg (19.7-43.9 mg), and 38.7% (0%-71.8%), respectively. Gentamicin dialytic clearance was statistically significantly related to creatinine dialytic clearance (r(2) = 0.52, P = 0.04), although this relationship is not likely to be strong enough to serve as a surrogate for gentamicin monitoring. The pharmacokinetic model was used to simulate gentamicin serum concentrations over a one-wk period. In clinical situations where gentamicin is used as the primary therapy in a patient receiving hemodialysis with a CAHP hemodialyzer, conventional doses after each dialysis session are not as efficient at achieving treatment targets as predialysis dosing with larger doses.

Determination of Extended-Interval Gentamicin Dosing for Neonatal Patients in Developing Countries

Infectious diseases account for an estimated 36% of neonatal deaths globally. The purpose of this study was to determine safe, effective, simplified dosing regimens of gentamicin for treatment of neonatal sepsis in developing countries. Neonates with suspected sepsis in the neonatal intensive care unit (NICU) at Christian Medical College and Hospital (CMC), Vellore, India (n = 49), and Dhaka Shishu Hospital (DSH), Bangladesh (n = 59), were administered gentamicin intravenously according to the following regimens: (1) 10 mg every 48 hours for neonates <2000 g; (2) 10 mg every 24 hours for neonates 2000-2249 g; and (3) 13.5 mg every 24 hours for neonates > or =2500 g. Serum gentamicin concentration (SGC) at steady state and pharmacokinetic indices were determined. Renal function was followed while under treatment and hearing was examined 6 weeks to 3 months after discharge. All neonates, except 1 weighing 2000-2249 g at DSH, had a peak SGC >4 microg/mL. Overall, 5 (10%) and 17 (29%) infants had a peak SGC level > or =12 microg/mL from CMC and DSH, respectively, and 10 (20%) and 4 (7%) cases from CMC and DSH, respectively, had a trough SGC level > or =2 microg/mL. However, no infant <2000 g had a trough SGC level > or =2 microg/mL. We found no evidence of gentamicin nephrotoxicity or ototoxicity. Safe, therapeutic gentamicin dosing regimens were identified for treatment of neonatal sepsis in developing country settings. Administration of these doses could be simplified through use of Uniject, a prefilled, single injection device designed to make injections safe and easy to deliver in developing country settings.

Subclinical kidney injury incites endotoxin hyperresponsiveness

gentamicin, an aminoglycoside discovered in 1963 from micromonospora, is one of the most commonly used antibiotics against Gram-negative infections. Aminoglycosides achieve bacterial killing by binding to bacterial ribosomes, causing blockade of protein synthesis through failure of initiation and

A pharmacokinetic basis for improving therapeutic outcomes of aminoglycoside therapy during continuous venovenous haemodiafiltration

The objective of this study was to quantify the impact of continuous venovenous haemodiafiltration (CVVHDF) on amino-glycoside pharmacokinetics and to suggest dosing strategies to improve therapeutic outcomes for these drugs in critically ill patients treated with CVVHDF. There has been limited published data on aminoglycoside pharmacokinetics during CRRT. This data deficit had led to subtherapeutic dosing, identified by a retrospective evaluation of amikacin and gentamicin serum concentrations, in patients treated with CVVHDF, undertaken as part of this research.

Extent of Agreement in Gentamicin Concentration Between Serum That Is Drawn Peripherally and From Central Venous Catheters

At our institution, patients who receive once-daily dosing of gentamicin have serum concentrations determined 3 and 6 hours after dose administration. Patients with single-lumen central venous catheters have the 3-hour samples drawn peripherally. The objective of this study was to evaluate the extent of agreement between peripheral and central venous catheter serum gentamicin concentrations drawn 3 hours after dose administration. In this prospective, observational study, patients provided both a peripheral and a central blood sample for determination of serum gentamicin concentration. The order of sampling (central venous catheter versus peripheral first) was randomized. Agreement was assessed by determination of the intraclass correlation coefficient and Bland-Altman analysis. The clinically acceptable targets for the lower limit of the intraclass correlation coefficient and Bland-Altman limits of agreement were defined a priori as >0.80 and +/-6%, respectively. Differences between the theoretical dose adjustments using the central venous catheter versus the peripheral sample result were described. Forty-five pairs of samples were collected: 42 from single-lumen implantable central venous catheters (ports) and 3 from peripherally inserted central venous catheters. The intraclass correlation coefficient was 0.91. However, the Bland-Altman analysis resulted in a mean percentage difference (central venous catheter versus peripheral) of -0.92% and limits of agreement of -27.9% to 26.0%. The gentamicin dose adjustment based on the central venous catheter sample result would have led to clinically significant dose adjustments in 19 (42%) cases, when compared with the peripheral sample result. These results indicate a lack of agreement between peripheral and single-lumen central venous catheter samples. In particular, ports are not appropriate sites for monitoring serum gentamicin concentrations.

Gentamicin concentrations in synovial fluid obtained from the tarsocrural joints of horses after implantation of gentamicin-impregnated collagen sponges

To determine synovial fluid gentamicin concentrations and evaluate adverse effects on the synovial membrane and articular cartilage of tarsocrural joints after implantation of a gentamicin-impregnated collagen sponge. 6 healthy adult mares. A purified bovine type I collagen sponge impregnated with 130 mg of gentamicin was implanted in the plantarolateral pouch of 1 tarsocrural joint of each horse, with the contralateral joint used as a sham-operated control joint. Gentamicin concentrations in synovial fluid and serum were determined for 120 hours after implantation by use of a fluorescence polarization immunoassay. Synovial membrane and cartilage specimens were collected 120 hours after implantation and evaluated histologically. Median peak synovial fluid gentamicin concentration of 168.9 microg/mL (range, 115.6 to 332 microg/mL) was achieved 3 hours after implantation. Synovial fluid gentamicin concentrations were < 4 microg/mL by 48 hours. Major histologic differences were not observed in the synovial membrane between control joints and joints implanted with gentamicin-impregnated sponges. Safranin-O fast green stain was not reduced in cartilage specimens obtained from treated joints, compared with those from control joints. Implantation of a gentamicin-impregnated collagen sponge in the tarsocrural joint of horses resulted in rapid release of gentamicin, with peak concentrations > 20 times the minimum inhibitory concentration reported for common pathogens that infect horses. A rapid decrease in synovial fluid gentamicin concentrations was detected. The purified bovine type I collagen sponges did not elicit substantial inflammation in the synovial membrane or cause mechanical trauma to the articular cartilage.

Population pharmacokinetics of gentamicin in premature newborns

To determine the pharmacokinetic parameters of gentamicin in a population of 200 premature newborns and to investigate the influence of several clinical and physiopathological covariates on the pharmacokinetics of the drug. To validate the pharmacokinetic analysis performed in another population of 50 premature newborns. A total of 200 premature newborns were evaluated at the neonatal intensive care unit of Severo Ochoa Hospital (Madrid, Spain). Four hundred and seventeen serum drug concentrations were included. Mean gestational age (GA) was 32.19+/-2.97 weeks, mean postnatal age (PNA) was 5.49+/-5.41 days and mean body weight (BW) was 1.68+/-0.63 kg. Fifty additional newborns were studied for validation (mean GA 32.62+/-3.07 weeks, mean PNA 5.17+/-3.77 days and mean BW 1.80+/-0.67 kg). Dosing, serum gentamicin concentrations and 15 covariates were collected. Data analysis was performed with NONMEM. One- and two-compartment open models were evaluated. Four parameters were analysed with the two-compartment open model: clearance (CL), central volume (Vc), peripheral volume (Vp) and intercompartmental clearance (Q). The two-compartment open model was found to significantly better describe gentamicin pharmacokinetics in the neonate. More than PNA or GA, creatinine clearance (CLCR) plays an important role in the elimination of gentamicin in premature newborns. Creatinine clearance is also related to GA. The appropriate dosing regimens given in accordance with the characteristics of the patients are 5 mg/kg/48 h and 4 mg/kg/24 or 36 h for neonates<32 weeks and >or=32 weeks of GA, respectively.

Extended-Interval Gentamicin Administration in Malnourished Children

Malnourished children have several physiologic abnormalities that can affect drug distribution and elimination. The aim of this study was to determine the efficacy, safety and pharmacokinetics of a once-daily dose of gentamicin compared with conventional thrice-daily dosing in malnourished children. To our knowledge, it has not been investigated in this population so far. A total of 310 malnourished children of either gender aged 6 months to 5 years with diarrhea and pneumonia were randomized to receive intramuscular gentamicin 5 mg/kg/day once-daily (OD) (n=148) or the same total daily amount given in three divided doses (TD) (n=162) in addition to ceftriaxone 75 mg/kg/day. After 48 h at steady state, gentamicin pharmacokinetics was assessed by fluorescence polarization immunoassay in a subgroup of 59 children and 43 children in the OD and TD groups, respectively. The groups were equivalent in baseline demographic, clinical and laboratory characteristics. Good and partial clinical responses occurred in 64 per cent vs. 54 per cent and 25 per cent vs. 27 per cent in the OD and the TD children, respectively (p=NS for both comparisons). Five patients in each treatment group died. Renal toxicity defined by change in serum creatinine was not observed in any patient from either group. In the OD group, mean+/-SD serum gentamicin concentrations at 1 (peak), 3, 5, 8, 23, and 24 (trough value) hours after the dose were 11.7+/-4.1, 4.4+/-1.2, 2.08+/-0.9, 1.01+/-0.6, 0.31+/-0.09 and 0.29+/-0.07 mg/l respectively. In the TD group, mean +/-SD serum gentamicin concentration at 1 hour (peak) was 4.7+/-1.8 mg/l and the trough concentration was 0.48+/-0.21 mg/l. In OD group, the gentamicin trough concentration was significantly lower (p<0.001) and the peak concentration was significantly higher (p<0.001) compared to TD group. The results of this study indicate that once-daily gentamicin is effective and safe in malnourished children. Widespread implementation of once-daily dosing in malnourished children is appropriate and will reduce number of intramuscular injections and hospital costs.

Penetration of Gentamicin Into the Alveolar Lining Fluid of Critically Ill Patients With Ventilator-Associated Pneumonia

To estimate the penetration of gentamicin into lung tissue by measuring its concentrations in alveolar lining fluid (ALF) and blood in critically ill patients with ventilator-associated pneumonia (VAP). The study population consisted of 24 patients who were admitted to an ICU for respiratory failure and developed VAP. Patients were scheduled to undergo bronchoscopy with BAL after IV administration of a once-daily, 240-mg schedule of gentamicin for the treatment of VAP. Patients were assigned at random to one of four groups of six patients each according to the scheduled time for bronchoscopy (1, 2, 4, or 6 h, respectively). A serum sample was obtained at 0.5 h (n = 24), and both serum and ALF samples (n = 6) were collected at each of the above specified times for measurement of antibiotic concentrations. Mean +/- SEM gentamicin concentrations in the ALF were 2.95 +/- 0.37, 4.24 +/- 0.42, 3.10 +/- 0.39, and 2.65 +/- 0.35 microg/mL at 1, 2, 4, and 6 h, respectively, after the start of antibiotic infusion. Maximum gentamicin concentrations in serum (13.39 +/- 0.91 mug/mL, n = 24) and ALF (4.24 +/- 0.42 microg/mL, n = 6) were achieved at 0.5 h and 2 h, respectively, giving a penetration ratio of 0.32. The mean ratios of ALF/serum concentrations between 1 h and 6 h ranged from 0.30 to 1.14. After completion of the distribution phase, a significant positive correlation (p = 0.02) was found between gentamicin concentrations in the serum and ALF. Once-daily IV administration of 240-mg gentamicin achieved average peak antibiotic concentrations of 4.24 microg/mL in the ALF 2 h after administration, and an ALF/serum penetration ratio of 32%. Higher gentamicin doses to produce higher peak blood levels than those found with the study dose are necessary to obtain active alveolar concentrations against less sensitive microorganisms in the treatment of VAP in ICU patients.

The influence of weight with assay error on gentamicin pharmacokinetics using the Bayesian and nonlinear least square regression analysis in appendicitis patients

The purpose of this study was to determine the influence of weight with gentamicin assay error on the Bayesian and nonlinear least squares regression analysis in 12 Korean appendicitis patients. Gentamicin was administered intravenously over 0.5 h every 8 h. Three specimens were collected 48 h after the first dose from all patients at the following times, just before the regularly scheduled infusion, at 0.5 h and 2 h after the end of the 0.5 h infusion. Serum gentamicin levels were analysed by fluorescence polarization immunoassay technique with TDxFLx. The standard deviation (SD) of the assay over its working range had been determined at the serum gentamicin concentrations of 0, 2, 4, 8, 12 and 16 microg/ml in quadruplicate. The polynominal equation of gentamicin assay error was found to be SD (microg/ml) = 0.0246-(0.0495C) + (0.00203C(2)). There were differences in the influence of weight with gentamicin assay error on pharmacokinetic parameters of gentamicin using the nonlinear least squares regression analysis but there were no differences on the Bayesian analysis. This polynominal equation can be used to improve the precision of fitting of pharmacokinetic models to optimize the process of model simulation both for population and for individualized pharmacokinetic models. The result would be improved dosage regimens and the better, safer care of patients receiving gentamicin.

The influence of assay error weight on gentamicin pharmacokinetics using the bayesian and nonlinear least square regression analysis in appendicitis patients

The purpose of this study was to determine the influence of weight with gentamicin assay error on the Bayesian and nonlinear least squares regression analysis in 12 Korean appendicitis patients. Gentamicin was administered intravenously over 0.5 h every 8 h. Three specimens were collected at 48 h after the first dose from all patients at the following times, just before regularly scheduled infusion, at 0.5 h and 2 h after the end of 0.5 h infusion. Serum gentamicin levels were analyzed by fluorescence polarization immunoassay technique with TDxFLx. The standard deviation (SD) of the assay over its working range had been determined at the serum gentamicin concentrations of 0, 2, 4, 8, 12, and 16 microg/mL in quadruplicate. The polynominal equation of gentamicin assay error was found to be SD (microg/mL) = 0.0246 - (0.0495C) + (0.00203C2). There were differences in the influence of weight with gentamicin assay error on pharmacokinetic parameters of gentamicin using the nonlinear least squares regression analysis but there were no differences on the Bayesian analysis. This polynominal equation can be used to improve the precision of fitting of pharmacokinetic models to optimize the process of model simulation both for population and for individualized pharmacokinetic models. The result would be improved dosage regimens and better, safer care of patients receiving gentamicin.

Prediction of gentamicin peak and trough concentrations from six extended-interval dosing protocols for neonates

The ability of six extended-interval gentamicin dosing protocols to achieve desired peak and trough concentrations in neonates was evaluated using simulated calculations based on pooled patient data. The demographic and pharmacokinetic data of 293 neonates age one week or less from three previously published studies were pooled and applied in each of six published protocols. The data collected, including weight, dosage, dosing interval, and measured serum or plasma gentamicin concentrations, were used to determine gentamicin clearance, elimination-rate constant, and distribution volume. Peak and trough gentamicin concentrations were calculated and compared with several therapeutic ranges that aim to achieve high peak concentrations for maximum efficacy and low trough concentrations for minimum toxicity. All protocols resulted in more than 95% of peak concentrations exceeding 5 mg/L. Peaks exceeded 10 mg/L in 26-42% of the simulations. Most of the protocols resulted in high trough concentrations (0.5-1.5 mg/L). Trough concentrations were below 1 mg/L in 51-83% of the simulations. Simulated calculations based on pooled patient data found that six gentamicin dosing protocols for neonates would likely yield acceptable peak concentrations and a trough concentration of < or = 1 mg/L for at least 50% of patients. It may be sufficient to monitor only the trough concentrations when applying these protocols.