MEDLINE Abstracts: Once-Daily Aminoglycoside Dosing in Pediatric Patients
MEDLINE Abstracts: Once-Daily Aminoglycoside Dosing in Pediatric Patients
What's the latest in once-daily aminoglycoside dosing and administration in pediatric patients? Find out in this easy-to-navigate collection of recent MEDLINE abstracts compiled by the editors at Medscape Pharmacotherapy.
Bass KD, Larkin SE, Paap C, Haase GM
J Pediatr Surg. 1998;33(7):1104-7
Background/Purpose: To achieve cost-effective health care in adults, once-daily aminoglycosides administration has been used and judged to be safe and efficacious. A similar strategy in children requires the characterization of pharmacokinetic parameters and the development of a therapeutic monitoring protocol for this antibiotic regimen.
Methods: A prospective, controlled, randomized (2:1) study was undertaken in 50 pediatric patients between June 1995 and September 1997. Children between 6 months and 18 years who required gentamicin therapy based on independent clinical assessment were eligible if they had normal renal function, no aminoglycoside allergies, were not neutropenic, or did not have cystic fibrosis. Measurements included a peak, 4-hour, 8-hour, and trough gentamicin levels to determine volume of distribution (Vd) and elimination constant (Ke). Ototoxicity and nephrotoxicity were monitored by pre- and postaudiology examinations and serial calculated creatinine clearance determinations, respectively.
Results: Thirty-three patients received 7.5 mg/kg every 24 hours, and 17 patients received 2.5 mg/kg every 8 hours. Most frequent indications for treatment were ruptured appendicitis (n = 19) followed by wound infections caused by trauma (n = 4), but the spectrum of treatment was broad including enteric, genitourinary, central nervous system, biliary, ophthalmologic, and orthopedic infections. Pharmacokinetic data indicated that 24-hour dosing resulted in higher peak levels compared with 8-hour dosing (20.4 +/- 45.4 v 7.2 +/- 6.2 mg/L, P < .0001) and lower trough levels (0.29 +/- .02 v 0.69 +/- 0.13, P < .0001), whereas rate of elimination constant and volume of distribution were not significantly different. No nephrotoxicity or ototoxicity has been noted in either group.
Conclusions: These data confirm that once-daily dosing of gentamicin is a safe method of treatment that provides equivalent pharmacokinetics compared with traditional dosing and enhances bactericidal effect based on higher peak levels, avoids toxicity, and allows cost savings.
Vervelde ML, Rademaker CM, Krediet TG, et al
Ther Drug Monit. 1999;21(5):514-9
Population pharmacokinetic parameters of gentamicin in preterm neonates on a once-daily dosage regimen of 3.0 mg/kg given intravenously every 24 hours were established prospectively. In 34 preterm neonates with a mean gestational age of 32 +/- 4 (SD), 182 serum gentamicin levels (91 peak/trough pairs) were determined. Individual adjustments of dose or dosage interval were calculated by computer-aided Bayesian forecasting. The parameters Vd, ke, and CL for each patient were obtained by the nonparametric estimation of maximization method. The predictive power of the model was calculated and the pharmacokinetic estimates were statistically analyzed with SPSS/PC. Cluster analysis showed a division into 2 subpopulations (designated 1 and 2) on the basis of postnatal age. The mean +/- SD postnatal age of subpopulation 1 (n = 29) was 6 +/- 2 days (range 1-7) and of subpopulation 2 (n = 5) 15 +/- 4 days (range 12-24). The mean +/- SD gentamicin relative clearances of subpopulation 1 and subpopulation 2 were 0.0515 +/- 0.0128 and 0.1026 +/- 0.0102 L kg(-1) hr(-1), respectively (p < 0.05). The mean +/- SD values for Vd (Lkg(-1)) in both populations 1 and 2 were 0.6916 +/- 0.1670 and 0.7509 +/- 0.1961, respectively (not significantly different). For ke these data were 0.0744 +/- 0.0200 and 0.1366 +/- 0.0522 (p < 0.05). Statistics showed that the data for Vd and ke of subpopulation 1 were normally distributed (Vd and ke skewness 1.61 and 1.46; kurtosis 3.09 and 3.10 respectively). The model yielded a bias of -0.11 mg/L and a precision of 0.36 mg/L. It is recommended that gentamicin be started in a dosage of 3.5 mg/kg intravenously once-daily under close monitoring.
Lundergan FS, Glasscock GF, Kim EH, Cohen RS
Pediatrics. 1999;103(6 Pt 1):1228-34
Objective: We developed a simplified gentamicin dosing protocol for all neonates using a loading dose and once-daily dosing that would have an equal or lower incidence of toxicity and an equal or improved effectiveness compared with a regimen with no loading dose that included use of divided daily dosing.
Methods: All neonatal intensive care unit patients with a postnatal age ≤7 days and started on gentamicin therapy at the discretion of the attending neonatologist were evaluated in this comparative cohort study. All peak and trough serum drug levels (SDL), pertinent demographic data, and markers of potential nephrotoxicity, ototoxicity, and cure were tracked prospectively during 132 consecutive, nonrandomized courses of therapy on a new gentamicin protocol. These were compared with data retrieved retrospectively throughout 103 consecutive, nonrandomized courses of therapy in a control group.
Results: Initial measured peak SDL were higher (7.8 +/- 1.1 microgram/mL vs 6.1 +/- 1.0 microgram/mL) and trough SDL were lower (0.9 +/- 0.2 microgram/mL vs 2.7 +/- 0.6 microgram/mL) in the protocol term subset, compared with the control term subset (gestational age, ≥37 weeks; weight, ≥2500 g). One hundred percent of the initial and maintenance peak SDL in term protocol neonates were 5 to 12 micrograms/mL; compared with 84% of the initial and 61% of maintenance peak SDL in the term control group. One hundred percent of the initial and maintenance trough SDL were in the desired range of <2 micrograms/mL in term protocol neonates; compared with 70% of the initial and 94% of maintenance trough SDL in the term control group. No significant differences were found in any SDL in low birth weight neonates (gestational age <37 weeks or weight <2500 g and >1500 g) in the protocol compared with the control group. The very low birth weight (weight <1500 g) protocol neonates had a significantly higher mean initial trough SDL (2.3 +/- 0.7 micrograms/mL vs 1.5 +/- 0.6 micrograms/mL) and a lower incidence of initial trough SDL <2.0 micrograms/mL (30% vs 95%) than very low birth weight neonates in the control group. No differences were seen between groups in incidence of significant rise in serum creatinine or failure of hearing screen.
Conclusion: A loading dose followed by once-daily dosing was shown to result in SDL in the safe and therapeutic range in all term neonates in this study. In low birth weight neonates, this regimen resulted in peak and trough SDL throughout therapy that were similar to those observed in the control group. Delaying the initiation of maintenance once-daily dosing until 36 to 48 hours after the loading dose would be expected to result in a higher incidence of initial trough SDL in target range for very low birth weight neonates.
Thureen PJ, Reiter PD, Gresores A, et al
Pediatrics. 1999;103(3):594-8
Objectives: To compare performance and cost analysis of two gentamicin regimens in infants ≥34 weeks' gestation requiring antibiotics for a 72-hour rule-out sepsis evaluation. A once-daily dosing (ODD) regimen of 4 mg/kg was compared with a standard twice-daily dosing (TDD) regimen of 2.5 mg/kg every 12 hours.
Setting and Design: Infants at two university-affiliated Level III nurseries were prospectively temporally allocated to receive ODD (n = 27) or TDD (n = 28) as part of their 72-hour empirical antibiotic regimen. Performance of dosing regimens was based on target serum gentamicin concentrations (SGC) established prospectively as a peak of 5 to 10 microgram/mL and a trough of ≤2 microgram/mL. SGC were determined by fluorescence polarization immunoassay on day 3 of therapy. Cost data were obtained by distributing a questionnaire to 15 pediatric pharmacy practice sites. Inquiries were made regarding hospital cost of drug acquisition, drug supplies, drug preparation and administration, and serum concentration analysis. Performance and cost data were then used to do a cost-effectiveness analysis.
Results: Mean peak concentrations were higher with ODD (7.9 +/- 0.2 microgram/mL) than TDD (6.7 +/- 0.3 microgram/mL). Half of the patients in the TDD group had trough concentrations >2 microgram/mL, compared with none in the ODD group. Overall, 57% of the SGCs in the TDD group were outside the target concentration range versus 7% in the ODD group. Based on questionnaire results, a total 72-hour process cost of ODD versus TDD was compared for regimens with and without use of SGC analysis. If SGCs are obtained, more than 75% of the cost associated with gentamicin therapy is attributable to SGC analysis. Based on a cost-effectiveness analysis, ODD was the dominant dosing strategy in all categories analyzed.
Conclusions: ODD of gentamicin at 4 mg/kg in neonates ≥34 weeks' gestation is the preferable treatment strategy based on: 1) significantly improved SGC performance compared with TDD; 2) elimination of the need for routine SGC collection in infants on short courses of therapy; and 3) significant antibiotic-associated hospital cost savings when compared with conventional therapy of TDD and SGC analysis.
Bragonier R, Brown NM
J Antimicrob Chemother. 1998;42(1):103-6
The pharmacokinetics and toxicity of once-daily intravenous tobramycin were studied prospectively in seven children with cystic fibrosis. Mean 1 h post-dose concentrations of 21.9 mg/L (S.D. 3.0) and 40.2 mg/L (S.D. 8.1) were achieved following tobramycin doses of 8 mg/kg and 15 mg/kg, respectively. The half-life (mean 2.3 h) was unchanged at the two doses, as were the total clearance and volume of distribution. All patients responded well to therapy. No nephrotoxicity occurred, but one patient showed transient ototoxicity.
Krivoy N, Postovsky S, Elhasid R, Ben Arush MW
Infection. 1998;26(6):396-8
Ten children received amikacin twice daily and 13 were treated using the single daily protocol. All had fever and neutropenia on admission, and received a total daily dose of 20 mg/kg when included in the study. Individual pharmacokinetic parameters were calculated using a one-compartment model for two blood amikacin samples. The mean (+/- SD) of elimination half-life (h), amikacin clearance (l/h/kg), volume of distribution (l/kg), peak concentration (microgram/ml) and trough concentration (microgram/ml) were: 2.51 (0.74) and 2.85 (0.32) h; 0.26 (0.16) and 0.115 (0.02) l/h/kg; 0.74 (0.44) and 0.47 (0.11) l/kg; 19.1 (12.3) and 42.6 (12.6) micrograms/ml; 0.85 (0.74) and 0.18 (0.24) microgram/ml with twice and single daily dosage schedules, respectively. A single daily dose of amikacin had a significantly longer elimination half-life, lower clearance, higher peak concentration and lower trough concentration in comparison to the twice-daily schedule. The use of amikacin 20 mg/kg daily delivered in a single daily dose is recommended for immunocompromised pediatric patients with fever and neutropenia, in spite of the measured pharmacokinetic differences.
What's the latest in once-daily aminoglycoside dosing and administration in pediatric patients? Find out in this easy-to-navigate collection of recent MEDLINE abstracts compiled by the editors at Medscape Pharmacotherapy.
Bass KD, Larkin SE, Paap C, Haase GM
J Pediatr Surg. 1998;33(7):1104-7
Background/Purpose: To achieve cost-effective health care in adults, once-daily aminoglycosides administration has been used and judged to be safe and efficacious. A similar strategy in children requires the characterization of pharmacokinetic parameters and the development of a therapeutic monitoring protocol for this antibiotic regimen.
Methods: A prospective, controlled, randomized (2:1) study was undertaken in 50 pediatric patients between June 1995 and September 1997. Children between 6 months and 18 years who required gentamicin therapy based on independent clinical assessment were eligible if they had normal renal function, no aminoglycoside allergies, were not neutropenic, or did not have cystic fibrosis. Measurements included a peak, 4-hour, 8-hour, and trough gentamicin levels to determine volume of distribution (Vd) and elimination constant (Ke). Ototoxicity and nephrotoxicity were monitored by pre- and postaudiology examinations and serial calculated creatinine clearance determinations, respectively.
Results: Thirty-three patients received 7.5 mg/kg every 24 hours, and 17 patients received 2.5 mg/kg every 8 hours. Most frequent indications for treatment were ruptured appendicitis (n = 19) followed by wound infections caused by trauma (n = 4), but the spectrum of treatment was broad including enteric, genitourinary, central nervous system, biliary, ophthalmologic, and orthopedic infections. Pharmacokinetic data indicated that 24-hour dosing resulted in higher peak levels compared with 8-hour dosing (20.4 +/- 45.4 v 7.2 +/- 6.2 mg/L, P < .0001) and lower trough levels (0.29 +/- .02 v 0.69 +/- 0.13, P < .0001), whereas rate of elimination constant and volume of distribution were not significantly different. No nephrotoxicity or ototoxicity has been noted in either group.
Conclusions: These data confirm that once-daily dosing of gentamicin is a safe method of treatment that provides equivalent pharmacokinetics compared with traditional dosing and enhances bactericidal effect based on higher peak levels, avoids toxicity, and allows cost savings.
Vervelde ML, Rademaker CM, Krediet TG, et al
Ther Drug Monit. 1999;21(5):514-9
Population pharmacokinetic parameters of gentamicin in preterm neonates on a once-daily dosage regimen of 3.0 mg/kg given intravenously every 24 hours were established prospectively. In 34 preterm neonates with a mean gestational age of 32 +/- 4 (SD), 182 serum gentamicin levels (91 peak/trough pairs) were determined. Individual adjustments of dose or dosage interval were calculated by computer-aided Bayesian forecasting. The parameters Vd, ke, and CL for each patient were obtained by the nonparametric estimation of maximization method. The predictive power of the model was calculated and the pharmacokinetic estimates were statistically analyzed with SPSS/PC. Cluster analysis showed a division into 2 subpopulations (designated 1 and 2) on the basis of postnatal age. The mean +/- SD postnatal age of subpopulation 1 (n = 29) was 6 +/- 2 days (range 1-7) and of subpopulation 2 (n = 5) 15 +/- 4 days (range 12-24). The mean +/- SD gentamicin relative clearances of subpopulation 1 and subpopulation 2 were 0.0515 +/- 0.0128 and 0.1026 +/- 0.0102 L kg(-1) hr(-1), respectively (p < 0.05). The mean +/- SD values for Vd (Lkg(-1)) in both populations 1 and 2 were 0.6916 +/- 0.1670 and 0.7509 +/- 0.1961, respectively (not significantly different). For ke these data were 0.0744 +/- 0.0200 and 0.1366 +/- 0.0522 (p < 0.05). Statistics showed that the data for Vd and ke of subpopulation 1 were normally distributed (Vd and ke skewness 1.61 and 1.46; kurtosis 3.09 and 3.10 respectively). The model yielded a bias of -0.11 mg/L and a precision of 0.36 mg/L. It is recommended that gentamicin be started in a dosage of 3.5 mg/kg intravenously once-daily under close monitoring.
Lundergan FS, Glasscock GF, Kim EH, Cohen RS
Pediatrics. 1999;103(6 Pt 1):1228-34
Objective: We developed a simplified gentamicin dosing protocol for all neonates using a loading dose and once-daily dosing that would have an equal or lower incidence of toxicity and an equal or improved effectiveness compared with a regimen with no loading dose that included use of divided daily dosing.
Methods: All neonatal intensive care unit patients with a postnatal age ≤7 days and started on gentamicin therapy at the discretion of the attending neonatologist were evaluated in this comparative cohort study. All peak and trough serum drug levels (SDL), pertinent demographic data, and markers of potential nephrotoxicity, ototoxicity, and cure were tracked prospectively during 132 consecutive, nonrandomized courses of therapy on a new gentamicin protocol. These were compared with data retrieved retrospectively throughout 103 consecutive, nonrandomized courses of therapy in a control group.
Results: Initial measured peak SDL were higher (7.8 +/- 1.1 microgram/mL vs 6.1 +/- 1.0 microgram/mL) and trough SDL were lower (0.9 +/- 0.2 microgram/mL vs 2.7 +/- 0.6 microgram/mL) in the protocol term subset, compared with the control term subset (gestational age, ≥37 weeks; weight, ≥2500 g). One hundred percent of the initial and maintenance peak SDL in term protocol neonates were 5 to 12 micrograms/mL; compared with 84% of the initial and 61% of maintenance peak SDL in the term control group. One hundred percent of the initial and maintenance trough SDL were in the desired range of <2 micrograms/mL in term protocol neonates; compared with 70% of the initial and 94% of maintenance trough SDL in the term control group. No significant differences were found in any SDL in low birth weight neonates (gestational age <37 weeks or weight <2500 g and >1500 g) in the protocol compared with the control group. The very low birth weight (weight <1500 g) protocol neonates had a significantly higher mean initial trough SDL (2.3 +/- 0.7 micrograms/mL vs 1.5 +/- 0.6 micrograms/mL) and a lower incidence of initial trough SDL <2.0 micrograms/mL (30% vs 95%) than very low birth weight neonates in the control group. No differences were seen between groups in incidence of significant rise in serum creatinine or failure of hearing screen.
Conclusion: A loading dose followed by once-daily dosing was shown to result in SDL in the safe and therapeutic range in all term neonates in this study. In low birth weight neonates, this regimen resulted in peak and trough SDL throughout therapy that were similar to those observed in the control group. Delaying the initiation of maintenance once-daily dosing until 36 to 48 hours after the loading dose would be expected to result in a higher incidence of initial trough SDL in target range for very low birth weight neonates.
Thureen PJ, Reiter PD, Gresores A, et al
Pediatrics. 1999;103(3):594-8
Objectives: To compare performance and cost analysis of two gentamicin regimens in infants ≥34 weeks' gestation requiring antibiotics for a 72-hour rule-out sepsis evaluation. A once-daily dosing (ODD) regimen of 4 mg/kg was compared with a standard twice-daily dosing (TDD) regimen of 2.5 mg/kg every 12 hours.
Setting and Design: Infants at two university-affiliated Level III nurseries were prospectively temporally allocated to receive ODD (n = 27) or TDD (n = 28) as part of their 72-hour empirical antibiotic regimen. Performance of dosing regimens was based on target serum gentamicin concentrations (SGC) established prospectively as a peak of 5 to 10 microgram/mL and a trough of ≤2 microgram/mL. SGC were determined by fluorescence polarization immunoassay on day 3 of therapy. Cost data were obtained by distributing a questionnaire to 15 pediatric pharmacy practice sites. Inquiries were made regarding hospital cost of drug acquisition, drug supplies, drug preparation and administration, and serum concentration analysis. Performance and cost data were then used to do a cost-effectiveness analysis.
Results: Mean peak concentrations were higher with ODD (7.9 +/- 0.2 microgram/mL) than TDD (6.7 +/- 0.3 microgram/mL). Half of the patients in the TDD group had trough concentrations >2 microgram/mL, compared with none in the ODD group. Overall, 57% of the SGCs in the TDD group were outside the target concentration range versus 7% in the ODD group. Based on questionnaire results, a total 72-hour process cost of ODD versus TDD was compared for regimens with and without use of SGC analysis. If SGCs are obtained, more than 75% of the cost associated with gentamicin therapy is attributable to SGC analysis. Based on a cost-effectiveness analysis, ODD was the dominant dosing strategy in all categories analyzed.
Conclusions: ODD of gentamicin at 4 mg/kg in neonates ≥34 weeks' gestation is the preferable treatment strategy based on: 1) significantly improved SGC performance compared with TDD; 2) elimination of the need for routine SGC collection in infants on short courses of therapy; and 3) significant antibiotic-associated hospital cost savings when compared with conventional therapy of TDD and SGC analysis.
Bragonier R, Brown NM
J Antimicrob Chemother. 1998;42(1):103-6
The pharmacokinetics and toxicity of once-daily intravenous tobramycin were studied prospectively in seven children with cystic fibrosis. Mean 1 h post-dose concentrations of 21.9 mg/L (S.D. 3.0) and 40.2 mg/L (S.D. 8.1) were achieved following tobramycin doses of 8 mg/kg and 15 mg/kg, respectively. The half-life (mean 2.3 h) was unchanged at the two doses, as were the total clearance and volume of distribution. All patients responded well to therapy. No nephrotoxicity occurred, but one patient showed transient ototoxicity.
Krivoy N, Postovsky S, Elhasid R, Ben Arush MW
Infection. 1998;26(6):396-8
Ten children received amikacin twice daily and 13 were treated using the single daily protocol. All had fever and neutropenia on admission, and received a total daily dose of 20 mg/kg when included in the study. Individual pharmacokinetic parameters were calculated using a one-compartment model for two blood amikacin samples. The mean (+/- SD) of elimination half-life (h), amikacin clearance (l/h/kg), volume of distribution (l/kg), peak concentration (microgram/ml) and trough concentration (microgram/ml) were: 2.51 (0.74) and 2.85 (0.32) h; 0.26 (0.16) and 0.115 (0.02) l/h/kg; 0.74 (0.44) and 0.47 (0.11) l/kg; 19.1 (12.3) and 42.6 (12.6) micrograms/ml; 0.85 (0.74) and 0.18 (0.24) microgram/ml with twice and single daily dosage schedules, respectively. A single daily dose of amikacin had a significantly longer elimination half-life, lower clearance, higher peak concentration and lower trough concentration in comparison to the twice-daily schedule. The use of amikacin 20 mg/kg daily delivered in a single daily dose is recommended for immunocompromised pediatric patients with fever and neutropenia, in spite of the measured pharmacokinetic differences.
