Serum Gentamicin Concentrations Research Articles

Two-versus three-sample method for estimating gentamicin pharmacokinetic values

The performances of two-sample and three-sample methods for estimating gentamicin pharmacokinetic values were studied. The medical records of patients who had received a gentamicin dosage consultation at a Veterans Affairs medical center between June 1989 and May 1991 were reviewed. For each patient, the pharmacokinetics service had prospectively used three serum gentamicin concentrations (SGCs) determined from three blood samples taken during an initial gentamicin regimen to estimate gentamicin pharmacokinetic values and determine the alternative would achieve the desired SGCs. In the two-sample method, the authors retrospectively used the initial peak and trough SGCs determined from two blood samples to estimate pharmacokinetic values and establish an alternative regimen. The two methods were evaluated by comparing their results with each other and with the actual pharmacokinetic values determined from SGCs measured during the subsequent gentamicin regimen. A total of 27 patients (all men; mean age, 62 years) were included in the study. The two-sample and three-sample methods differed significantly in their estimates of elimination rate constant and half-life but not clearance, volume of distribution, or the daily dose needed to achieve the intended SGCs. Neither method produced estimates that differed significantly from the actual pharmacokinetic values. The three-sample method was less biased than the two-sample method in the prediction of trough SGCs. In middle-aged and elderly men, a two-sample method and a three-sample method of estimating gentamicin pharmacokinetics differed significantly only in the prediction of trough SGCs. The difference was probably not clinically important.

The pharmacokinetics of once daily gentamicin in neutropenic adults with haematological malignancy.

Seven febrile neutropenic adults with normal renal function were treated with intravenous gentamicin 4.5 mg/kg once a day in combination with azlocillin. Gentamicin serum concentrations 1, 2, 4, 8, and 24 h after a 30 min infusion were 10.9 +/- 0.6, 7.1 +/- 0.4, 4.2 +/- 0.2, 1.8 +/- 0.1 and 0.16 +/- 0.003 mg/L respectively. The pharmacokinetics were best described by a triphasic plot including a distribution phase (about 1/2 h) and two elimination phases, an early and late.

Effects of dietary protein conditioning on gentamicin-induced nephrotoxicosis in healthy male dogs

Summary Eighteen 6-month-old male Beagles with normal renal function were allotted at random to 3 groups of 6 dogs each. For 21 days, each group was fed a diet that was similar except for protein content (high protein, 27.3%; medium protein, 13.7%; and low protein, 9.4%). After the conditioning period, gentamicin was administered at a dosage of 10 mg/kg of body weight, IM, every 8 hours for 8 days, and the respective diet was continued. Clearance of endogenous creatinine, 24-hour urinary excretion of protein and enzymes (γ-glutamyltransferase, and N-acetyl- β-d-glucosaminidase, and fractional clearance of sodium and potassium (%) were determined before and after dietary protein conditioning and on days 2, 4, 6, and 8 of gentamicin administration. Additionally, trough serum gentamicin concentration was determined on days 2, 4, 6, and 8 of gentamicin administration. At the end of the study, all dogs were euthanatized; renal histologic features were graded, using a continuous ranking scale, and renal cortical gentamicin concentrations were measured. Data were ranked and analyzed, using a nonparametric equivalent of a two-way anova; P < 0.05 was considered significant. After the dietary conditioning period (prior to gentamicin), dogs fed the high-protein diet had higher endogenous creatinine clearance and urinary excretion of protein, compared with dogs fed the low-protein diet. Differences existed among groups after 8 days of gentamicin administration. Dogs fed the high-protein diet had higher creatinine clearance, lower serum creatinine concentration, lower fractional clearance of sodium, lower urinary excretion of N-acetyl-β-d-glucosaminidase and lower trough serum gentamicin concentration, compared with dogs fed the medium- and low-protein diets. Dogs fed the high-protein diet also had lower urinary excretion of protein and lower fractional clearance of potassium, compared with dogs fed the low-protein diet. There was no difference in urinary excretion of γ-gluta-myltransferase among groups on day 8 of the study. Proximal tubular necrosis was more severe in dogs fed the medium-protein diet, compared with dogs fed the high-protein diet; however, there were no differences in renal cortical gentamicin concentrations among groups. In conclusion, feeding the high-protein diet prior to and during gentamicin administration reduced nephrotoxicosis in these dogs.

An evaluation of three new immunoassays for determination of serum gentamicin concentrations.

Three new immunoassays for determination of serum gentamicin concentration were assessed: a latex agglutination assay (Technicon), an enzyme immunoassay (EMIT 2000) and a multi-layer thin-film immunoassay (Opus). All three were easy to use, had good within- and between-assay reproducibility, good reliability and acceptable linearity. The standard curve stability was shortest with the latex agglutination assay and longest with the thin-film. The thin-film assay calibrators gave approximately double the expected concentration when assayed by polarisation fluoroimmunoassay but this did not effect the assay's performance. When compared with the polarisation fluoroimmunoassay results of patient samples, all three methods gave an excellent correlation. The technical aspects of these three methods make them acceptable for clinical use.

Bayesian forecasting of gentamicin pharmacokinetics in pediatric intensive care unit patients.

The predictive performance of a one compartment Bayesian forecasting program was evaluated in pediatric intensive care unit patients with normal renal function. Gentamicin pharmacokinetic parameters were determined in 44 PICU patients (0.8 month to 14 years old) from all available serum concentrations and doses by nonlinear least squares regression. Population pharmacokinetic parameter estimates were established from 27 of the PICU patients. Mean prediction error (ME) and mean absolute error (MAE) for 2 future sets of peak and trough gentamicin serum concentrations with the use of the population parameter estimates with and without feedback were evaluated in the remaining 17 patients. Mean clearance (+/- SD) and volume of distribution for all 44 patients were 0.123 +/- 0.041 liter/hour/kg and 0.424 +/- 0.116 liter/kg, respectively. Bayesian forecasting of the second set of peak and trough concentrations with feedback from the first set of peak and trough concentrations resulted in smaller bias (peak ME, -0.15 mg/liter; trough ME, 0.13 mg/liter) and better accuracy (peak MAE, 0.91 mg/liter; trough MAE, 0.28 mg/liter) compared with the population parameter estimates alone (peak ME, 0.4 mg/liter; trough ME, 0.28 mg/liter; peak MAE, 1.21 mg/liter; trough MAE, 0.57 mg/liter). This study indicates that gentamicin volume of distribution in PICU patients is larger than non-PICU literature values. The Bayesian program, with specific population parameter estimates for PICU patients, provides accurate initial and subsequent predictions of gentamicin serum concentrations.

Determination of gentamicin pharmacokinetics by bioelectrical impedance in critically ill adults.

This investigation compares the accuracy of calculating gentamicin pharmacokinetic parameters by a noninvasive body composition technique (bioelectrical impedance analysis; BIA) with an empiric method, against the two-point method as the criterion standard. A prospective concurrent open label design was used. The 32 medical and surgical intensive care unit beds at Henry Ford Hospital, a not-for-profit, university-affiliated teaching hospital, served as the setting. Twenty critical ill adults, Therapeutic Index Scoring System (TISS) = 4, who required gentamicin as part of their normal course of therapy for gram-negative bacillary infections, were evaluated. Gentamicin Vd and k were calculated by three methods. After measurement of body composition parameters by BIA, previously derived gentamicin dosing equations were used to predict gentamicin volume of distribution (Vd) and elimination rate constant (k) (BIA method). Empiric estimates of these parameters (Vd = 0.3L/kg and k derived from creatinine clearance) were compared with the BIA parameters against a criterion standard Vd and k determined from a two-point sampling of gentamicin serum concentrations. Measurements of BIA parameters and gentamicin serum concentrations were made in duplicate with coefficients of variation, < or = 2% and < or = 3%, respectively. The BIA and empiric methods produced resultant pharmacokinetic parameters (Vd and k) not different than those measured by the two-point method. There were no statistically significant differences in mean error (bias), or mean squared error (precision) for both Vd and k assessed by the empiric or BIA methods.(ABSTRACT TRUNCATED AT 250 WORDS)

Assessment of bioelectrical impedance for individualizing gentamicin therapy in neonates.

The use of bioelectrical impedance (BI) analysis as a non-invasive approach for individualizing gentamicin therapy in newborn infants has been investigated in a two phase study. In Phase I, 1/impedance and length were identified as statistically significant predictors of the distribution volume of gentamicin (Adj R2 = 0.78, CV = 12.42%), and length/impedance and post-conceptual age were predictors of total systemic clearance (Adj R2 = 0.83, CV = 14.5%), following the administration of 2.5 mg.kg-1 gentamicin to 17 neonates (gestational age (GA) 27 to 36 weeks). In a prospective validation of these relationships in an independent (Phase II) group of 27 infants (GA 26 to 41 weeks), predicted serum gentamicin concentrations were close to those achieved. Several instances of high prediction errors (predicted minus achieved levels) were observed in infants with known or suspected renal impairment and they caused significant (P < 0.05) perturbation in the bias and accuracy of the models. Daily BI measures over a four to five day period were able to detect individual changes in the fat-free body compartments, which were translated into alterations in gentamicin regimens. This simple, non-invasive and relatively inexpensive bedside technique provides a potentially valuable means to individualize gentamicin therapy without relying on the measurement of serum gentamicin concentration.

Pharmacokinetics and potential use of gentamicin in budgerigars (Melopsittacus undulatus).

The pharmacokinetics of gentamicin were evaluated in budgerigars. Intramuscular (i.m.) administration of 5 and 10 mg/kg dosages produced serum gentamicin concentrations of 17.3 and 37.0 micrograms/ml respectively, at 0.25 hr following injection, but concentrations declined with a terminal half-life of 0.53 h. Based on these results, a dosage regimen of 5 to 10 mg/kg of gentamicin, intramuscularly, every 8 hours for up to 3 days, was considered to be safe and could be used against many of the common bacterial infections in budgerigars. Serum AST, ALT, LDH, CK, creatinine and uric acid values were determined after i.m. injection of either gentamicin or physiological saline every 8 hours for up to 3 days, and tissue samples of various organs were examined histologically. The most prominent adverse effect found was muscular damage at the injection site. Measurement of AST, ALT and CK activity seemed to be a sensitive method to determine pathological changes at the injection site in the budgerigars.

Prediction of Gentamicin Concentrations in Neonates and Infants Using a Bayesian Pharmacokinetic Model

This study retrospectively characterized population-based pharmacokinetic parameters for gentamicin in neonates and young infants, and evaluated the predictive performance of these parameters in a Bayesian forecasting program. Population parameter estimates were determined from the serum concentration-time data of 19 neonates and infants using a one-compartment open infusion model and nonlinear least-squares regression analysis. Univariate and multiple stepwise linear regression analyses were used to determine significant relationships between demographic characteristics and gentamicin pharmacokinetic parameters. Creatinine clearance and postnatal age were the most significant predictors of weight-standardized gentamicin clearance (model r2 = 0.86). The relationships between patient characteristics and population-based parameters were incorporated into the one-compartment Bayesian forecasting model. A second group of 17 neonates and infants receiving 35 courses of gentamicin therapy were used to evaluate the predictive performance of the population-based parameters and a Bayesian forecasting model. The population parameters provided accurate prediction of steady state gentamicin concentrations throughout multiple courses of therapy within the same patient. Bayesian forecasting further minimized the mean prediction error (bias) once a set of steady state peak and trough serum gentamicin concentrations became available (peak concentrations: -0.062 vs. -0.273 mg/l; trough concentrations: -0.006 vs. -0.161 mg/l). The mean absolute error (accuracy) was similar for the two sets of parameters. The observed accuracy of both the population parameters and Bayesian forecasting suggests that monitoring of serum gentamicin concentrations can be kept to minimum in neonates and infants.

Effect of dietary nitrogen intake on gentamicin disposition in sheep.

The effect on gentamicin pharmacokinetics of a diet high (HP) (120 g/day) or low (LP) (25 g/day) in digestible proteins was studied in sheep. Gentamicin sulphate (4 mg/kg) and inulin (40 mg/kg) were administered by the intravenous route to six ewes of local Moroccan breed. The serum gentamicin concentrations were consistently higher in ewes that received a LP diet. Clearance was 0.93 +/- 0.13 ml/mm/kg in the LP group and 1.64 +/- 0.40 ml/mm/kg in the HP group. The volume of distribution at steady state (Vss) was lower in the LP group (11% of body weight) than in the HP group (21.8% of body weight). These diet-linked variations in pharmacokinetic parameters were also obtained in the disposition of inulin following the intravenous administration of a single dose. This suggests that the protein content of the diet modifies the distribution of body water and kidney function. The therapeutic, toxicological and hygienic implications of these modifications are discussed.

Disagreement with liability for failure to monitor serum gentamicin concentrations

Disagreement with liability for failure to monitor serum gentamicin concentrations

Time course of trough serum gentamicin concentrations in preterm and term neonates.

Trough serum concentrations (Cmin) of gentamicin were followed during up to 96h of treatment in 44 neonates (17 preterm and 27 term), treated with intramuscular gentamicin 2.5 +/- 0.3 mg/kg (mean +/- SD) twice daily, a dosage that was not changed during the follow-up period. Relationships with patients' gestational age, postnatal age, postconceptional age and bodyweight were analysed to identify circumstances in which gentamicin should be monitored. Gentamicin Cmin values after 24h correlated better with neonate's postconceptional age (r = -0.42) or gestational age (r = -0.37) than with postnatal age or bodyweight. Correlations with postconceptional age and gestational age improved after 96h (r = -0.71 and r = -0.67, respectively). From 24 to 96h Cmin increased from 1.5 to 2 mg/L (p < 0.001) in the preterm neonates and from 1.5 to 2.5 mg/L (p < 0.01) in those preterm neonates < or = 32 weeks of gestational age, while differences between neonates < or = 3 days and > 3 days of postnatal age were nonsignificant. The Cmin at 24h was potentially toxic (> 2 mg/L) in 9% of the neonates (12% of preterm and 7% of term neonates). At 96h, the percentage of neonates with toxic Cmin values increased to 25% (65% of all preterm neonates and 100% of preterm neonates < or = 32 weeks of gestational age), whereas in term neonates it decreased to 0%. In conclusion, in preterm neonates < or = 32 weeks of gestational age a dosage of 2.5 mg/kg every 24h should be used, and gentamicin concentrations should be monitored. However, in term neonates > 7 days of postnatal age a dosage of 3.5 mg/kg twice daily should be recommended.

Serum Gentamicin Concentrations in Postpartum Endomyometritis

Gentamicin in combination with other antibiotics is frequently used in the treatment of postpartum endomyometritis. The need to monitor and maintain therapeutic concentrations, however, is controversial. To assess the role of monitoring, serum gentamicin concentrations were prospectively studied in an obstetric population treated for postpartum endomyometritis. Clinical course was correlated to serum gentamicin levels obtained using a 1 mg/kg/dose regimen. No patient demonstrated therapeutic concentrations. Sixteen of 18 obstetric patients (88%) exhibited a clinical response despite subtherapeutic serum gentamicin concentrations. The two failures included one case of septicemia and one wound seroma. Serum gentamicin levels of this obstetric population when compared to those from a gynecologic population treated for benign disease demonstrated no statistical difference. These data suggest that clinical response provides an accurate indication of the efficacy of therapy and that gentamicin doses of 1 mg/kg/dose provide sufficient antibiotic coverage in most cases. These results do not support the use of increased gentamicin dosages and the need to attain therapeutic levels in the obstetric patient, as previously suggested.

Government liable for failure to monitor a patient's serum gentamicin concentration in an Army hospital

Government liable for failure to monitor a patient's serum gentamicin concentration in an Army hospital

Intramammary administration of gentamicin as treatment or experimentally induced Escherichia coli mastitis in cows

Summary In 8 Holstein cows, 50 colony-forming units (cfu) of Escherichia coli was administered into 1 mammary gland. Sections were established in all inoculated glands. In 4 of the 8 cows, 500 mg of gentamicin sulfate was administered by intramammary infusion 14 hours after inoculation; the other 4 cows were untreated controls. Infusions of gentamicin also were given after each of the 3 succesive milkings after the initial infusion, so that a total dose of 2 g of gentamicin was given to each of the treated cows. During the 33-hour treatment period and for the first milking after the last infusion of gentamicin, the treated cows had a mean gentamicin concentration of ≥ 31.0 μg/ml in milk samples that were collected from inoculated quarters immediately before each milking. Concentrations of 0.34 and 0.69 μg of gentamicin/ml were detected in milk from 2 cows at 8 days after inoculation with E coli. Mean serum concentrations of gentamicin were ≥ 0.37 μg/ml throughout the treatment period and the first 0.2 hours after the last infusion, with a mean peak concentration of 0.96 μg/ml at 24.4 hours. The range of peak concentration of gentamicin detected in urine from all treated cows was 42 to 74.4 μg/ml. Peak concentration of E coli in milk in the treated cows 6.08 ± 1.02 log10 cfu/ml) did not significantly (P &gt; 0.05) differ from that of the control cows (5.26 ± 1.00 log10 cfu/ml). Similarly, mean duration of infection in the treated cows (54 hours) did not differ significantly from that of the control cows (48 hours). The treatment groups also did not differ significantly in peak concentrations of albumin or IgGl in milk, although mean concentrations of albumin and IgGl at 16 hours after inoculation, and of albumin at 20 hours, was significantly (P &lt; 0.05) higher in the milk from control cows than from the treated cows. Mean values of peak rectal temperature and of mean rectal temperature throughout the trial did not differ between the groups. At the end of the 4-week trial, 1 of 4 inoculated glands in treated cows and 3 of 4 in control cows had somatic cell counts less than or equal to preinoculation concentrations (5.18 log10 cells/ml). Intramammary administration of gentamicin did not affect the duration or severity of experimentally induced E coli mastitis. In addition, substantial concentrations of gentamicin were detected in the serum of treated cows, suggesting that intramammary treatment may result in prolonged drug residues in tissue

The release of gentamicin after total hip replacement using low or high viscosity bone cement

Low viscosity bone cement is expected to give improved long term fixation of prosthetic components by increased intrusion into cancellous bone. Fixation is more difficult to achieve after revision for infection because of the inferior quality of the bone. We have compared the amount of gentamicin released from high viscosity and low viscosity bone cements in 41 patients undergoing total hip replacement. The concentration of gentamicin in serum and the wound secretion, and the amount recovered from the urine, was about three times higher for low viscosity cement. A possible explanation for this is an increase in surface area of the cement body because of improved intrusion of cement into bone. The improved mechanical fixation and the high concentration of gentamicin of the bone cement interface favours the use of low viscosity cement, especially in revision for deep infection.

Individualising Gentamicin Dosage Regimens

The various components required for individualising clinical drug dosage regimens are reviewed, including a study of 3 types of fitting procedures, 2 types of gentamicin pharmacokinetic model and the utility of D-optimal times for obtaining serum gentamicin concentrations. The combination of the current Bayesian fitting procedure, the kslope pharmacokinetic model [in which the elimination rate constant (kel) can change from dose to dose with changing creatinine clearance] and the explicit measurement of the assay error pattern yielded predictions of future serum gentamicin concentrations which were (a) slightly better than those found using weighted nonlinear least squares; (b) somewhat better than those found with Bayesian fitting and a fixed-kel model; (c) better than those found using the traditional linear regression fitting procedure and a fixed kel model. D-Optimally timed pairs of concentrations also predicted future concentrations at least as well, and more cost effectively.

Gentamicin Pharmacokinetics in Postpartum Women with Endomyometritis

The pharmacokinetics of gentamicin in postpartum women with endomyometritis were characterized and models for predicting patient pharmacokinetic parameters were developed using multiple regression analysis. Fifty-one women 13-34 years of age received gentamicin in combination with either ampicillin or clindamycin to treat endomyometritis. Forty-three women delivered by cesarean section and 8 women had vaginal deliveries. Gentamicin serum concentrations were determined at steady-state to compute the elimination rate constant (Kc), half-life (t1/2), apparent volume of distribution (Vd), and total body clearance (Cl). Gentamicin dosages were individualized using a one-compartment intermittent infusion model to achieve steady-state peak and trough concentrations of 6.5 and less than 2 micrograms/mL, respectively. The mean gentamicin t1/2 was 2.8 +/- 0.9 h; the mean apparent Vd was 21 +/- 8 L; and the mean total body Cl was 89.5 +/- 31.7 mL/min. Multiple regression analysis revealed that total body weight (TBW) was the best predictor for the apparent Vd, described by the equation Vd = 0.146 TBW + 8.153 (r = 0.56, p = 0.00005). Total body weight and creatinine clearance (Clcr) were included as predictors for total body Cl, described by the equation Cl = 0.264 TBW + 0.337 Clcr + 3.416 (r = 0.68, p = 0.00005). Age and serum creatinine (SCr) were included in the models for the Ke, described by the equation Ke = -3.770 x 10(-3) age -0.115 SCr + 0.449 (r = 0.42, p less than 0.004). Additional patient factors need to be identified to explain the variance in these pharmacokinetic parameters.

SERUM CONCENTRATIONS OF GENTAMICIN IN PATIENTS WITH MYELOMENINGOCELE

Gentamicin serum concentrations were studied in 18 paediatric and adult patients. The doses of gentamicin had to be adjusted for 6 of 18 patients to keep peak and trough serum concentrations below 8 and 2 micrograms/ml, respectively. Thus, serum concentrations monitoring of gentamicin may be useful to individualize doses in patients with myelomeningocele. Additional studies are needed to define specific dosage guidelines in patients of varying ages and disease severity for optimal therapy.

Kinetic study of serum gentamicin concentrations in baboons after single-dose administration

Summary This study establishes preliminary pharmacokinetic data on the use of gentamicin sulfate administered im to baboons. Serum concentrations ≥ 12 μg/ml are generally agreed to cause toxicosis in human beings. On the basis of preliminary test results suggesting that the manufacturer's recommended dosage for dogs of 4.4 mg/kg of body weight caused potentially toxic serum concentrations, a dosage of 3 mg/kg was chosen to conduct a single-dose kinetic study in 6 baboons. Using a single-compartment model, the gentamicin serum half-life for im administration of 3 mg of gentamicin/kg was 1.58 hours, and serum concentrations remained below the potentially toxic concentrations reported for human beings. We suggest that a dosage of 3 mg/kg is safer than a dosage of 4.4 mg/kg administered im to baboons. Minimal inhibitory concentrations for 2 Pseudomonas aeruginosa isolates were ≤ 1 μg/ml. On the basis of our measured elimination half-life of 1.58 hours, it is reasonable to suppose that dosing q 24 h will be inadequate to maintain therapeutic serum concentrations. We calculate that serum concentrations will remain at or above our measured minimal inhibitory concentration for P aeruginosa (1 μg/ml) for 100% of the treatment time if the animal is dosed q 6 h, 78% for dosing q 8 h, and 52% for dosing q 12 h. Therefore, we suggest 3 mg/kg, q 8 h or q 6 h as appropriate dosing schedules for the use of gentamicin sulfate administered im to baboons.