Peak Gentamicin Concentrations Research Articles

External Validation of Model-Based Dosing Guidelines for Vancomycin, Gentamicin, and Tobramycin in Critically Ill Neonates and Children: A Pragmatic Two-Center Study.

BackgroundThe Dutch Pediatric Formulary (DPF) increasingly bases its guidelines on model-based dosing simulations from pharmacokinetic studies. This resulted in nationwide dose changes for vancomycin, gentamicin, and tobramycin in 2015.ObjectiveWe aimed to evaluate target attainment of these altered, model-based doses in critically ill neonates and children.MethodsThis was a retrospective cohort study in neonatal intensive care unit (NICU) and pediatric ICU (PICU) patients receiving vancomycin, gentamicin, or tobramycin between January 2015 and March 2017 in two university hospitals. The first therapeutic drug monitoring concentration for each patient was collected, as was clinical and dosing information. Vancomycin and tobramycin target trough concentrations were 10–15 and ≤ 1 mg/L, respectively. Target gentamicin trough and peak concentrations were < 1 and 8–12 mg/L, respectively.ResultsIn total, 482 patients were included (vancomycin [PICU] n = 62, [NICU] n = 102; gentamicin [NICU] n = 97; tobramycin [NICU] n = 221). Overall, median trough concentrations were within the target range for all cohorts but showed large interindividual variability, causing nontarget attainment. Trough concentrations were outside the target range in 66.1%, 60.8%, 14.7%, and 23.1% of patients in these four cohorts, respectively. Gentamicin peak concentrations were outside the range in 69% of NICU patients (term neonates 87.1%, preterm infants 57.1%). Higher creatinine concentrations were associated with higher vancomycin and tobramycin trough concentrations.ConclusionThis study illustrates the need to validate model-based dosing advice in the real-world setting as both sub- and supratherapeutic concentrations of vancomycin, gentamicin, and tobramycin were very prevalent. Our data underline the necessity for further individualization by addressing the high interindividual variability to improve target attainment.Electronic supplementary materialThe online version of this article (10.1007/s40272-020-00400-8) contains supplementary material, which is available to authorized users.

Clinical audit of gentamicin use by Bayesian pharmacokinetic approach in critically ill children

IntroductionCritically ill children tend to have altered gentamicin pharmacokinetics (PK); and so we carried out an audit of gentamicin use using the estimated peak concentrations (Cmax), trough concentrations (Cmin) and area-under-the-concentration-time curve (AUCs) by Bayesian approach. MethodsCritically ill children with at least one serum gentamicin concentrations available were recruited. We used multiple models Bayesian adaptive control to estimate Cmax, and AUC0-t following each dose. Pediatric risk, injury, failure, loss, end stage renal disease (pRIFLE) criteria was used to identify the incidence of acute kidney injury (AKI). ResultsSeventy-three children (961 doses and 143 concentrations) were analysed. AUC0-24 was observed to be higher in earlier age groups with a steady decline in older children. Similar changes were observed in Cmax, Cmin and AUC0-24 at steady state. Significantly higher proportions of children in the other age groups were estimated to have Cmax between 5 and 10 mg/L compared to neonates. Neonates had a higher risk of Cmax above 10 mg/L. Patients with augmented renal clearance exhibited lower AUC0-24 and reduced proportion achieving the target AUC0-24 levels. Nearly one-third of children were observed to meet the pRIFLE criteria for AKI. ConclusionWe observed higher initial doses and peak concentrations of gentamicin in neonates and infants compared to older age groups in critically ill children. Uniformity in the paediatric-specific standard treatment guidelines for gentamicin is the need of the hour.

Local concentrations of gentamicin obtained by microdialysis after a controlled application of a GentaColl sponge in a porcine model.

Local treatment with gentamicin may be an important tool in the prevention and treatment of surgical site infections in high-risk procedures and patients. The aim of this study was to evaluate the pharmacokinetic profile of gentamicin in bone and surrounding tissue, released from a controlled application of a GentaColl sponge in a porcine model. In eight female pigs, a GentaColl sponge of 10 × 10 cm (1.3 mg gentamicin/cm2 ) was placed in a cancellous bone cavity in the proximal tibia. Microdialysis was used for sampling of gentamicin concentrations over 48 hours from the cavity with the implanted GentaColl sponge, cancellous bone parallel to the cavity over and under the epiphyseal plate, cortical bone, the intramedullary canal, subcutaneous tissue, and the joint cavity of the knee. Venous blood samples were obtained as reference. The main finding was a mean peak drug concentration (95% CI) of gentamicin in the cancellous bone cavity containing the implanted GentaColl sponge of 11 315 (9049-13 581) μg/mL, persisting above 1000 μg/mL until approximately 40 hours after application. Moreover, the concentrations were low (<1 μg/mL) in the surrounding tissues as well as in plasma. The mean peak gentamicin concentration from the cancellous bone cavity after a controlled application of a GentaColl sponge was high and may be adequate for the prevention of biofilm formation. However, high MIC strains and uncontrolled application of the GentaColl sponge may jeopardize this conclusion.

Improving peak concentrations of a single dose regime of gentamicin in patients with sepsis in the emergency department

ObjectiveTo achieve an optimal effect in patients with sepsis at the emergency department (ED), the gentamicin peak-concentration should be sufficiently high (i.e. peak-concentration/MIC ≥8–10). ICU patients with sepsis often need higher gentamicin doses to achieve sufficiently high peak-concentrations. The aim of this study is to investigate which dose is needed to reach adequate peak-concentrations in patients presenting with sepsis at the ED.MethodsPatients with sepsis at the ED were included from August 2015 until February 2017. Peak-concentrations were measured in blood 30 minutes after the first gentamicin dose. The study consisted of three phases. In the first phase, peak-concentrations were measured after a standard dose of 5mg/kg. In the second phase, a simulation ((peak-concentration/actual dose) × simulated dose) was performed to determine which dose was needed to reach adequate gentamicin peak-concentrations of ≥16mg/L. In the third phase, peak-concentrations were measured for the best simulated dose.ResultsIn phase one, of 86 patients who received a dose of 5mg/kg, 34 (39.5%) patients did not reach the target peak-concentration of ≥16mg/L, and 73 (84.9%) did not reach ≥20mg/L. In phase two, the simulation showed that with a dose of 7mg/kg 83 (96.5%) patients would reach peak-concentrations ≥16mg/L, and 67 (77.9%) of ≥20mg/L. In phase three, 53 patients received a dose of 7mg/kg, of whom 45 (84.9%) reached peak-concentrations of ≥16mg/L, and 31 (58.5%) of ≥20mg/L.ConclusionPatients with sepsis at the ED need higher doses of gentamicin. A dose of 7mg/kg is needed to achieve adequate peak-concentrations in the majority of patients.

Influences of age and disease on peak and trough plasma gentamicin concentrations in horses

Influences of age and disease on peak and trough plasma gentamicin concentrations in horses

Quantitative Analysis of Gentamicin Exposure in Neonates and Infants Calls into Question Its Current Dosing Recommendations.

Optimal dosing of gentamicin in neonates is still a matter of debate despite its common use. We identified gentamicin dosing regimens from eight international guidelines and seven Swiss neonatal intensive care units. The dose per administration, the dosing interval, the total daily dose, and the demographic characteristics between guidelines were compared. There was considerable variability with respect to dose (4 to 6 mg/kg), dosing interval (24 h to 48 h), total daily dose (2.5 to 6 mg/kg/day), and patient demographic characteristics that were used to calculate individualized dosing regimens. A model-based simulation study in 1071 neonates was performed to determine the achievement of efficacious peak gentamicin concentrations according to predefined MICs (Cmax/MIC ≥ 10) and safe trough concentrations (Cmin ≤ 2 mg/liter) with recommended dosing regimens. MIC targets of 0.5 and 1 mg/liter were used. Dosing optimization was performed giving priority to the first day of treatment and with the goal of simplifying dosing. Current gentamicin neonatal guidelines allow to achieve effective peak concentrations for MICs ≤ 0.5 mg/liter but not higher. Model-based simulations indicate that to attain peak gentamicin concentrations of ≥10 mg/liter, a dose of 7.5 mg/kg should be administered using an extended dosing interval regimen. Trough concentrations of ≤2 mg/liter can be maintained with a dosing interval of 36 to 48 h in neonates according to gestational and postnatal age. For treatment beyond 3 days, therapeutic drug monitoring is advised to maintain adequate serum concentrations.

Therapeutic Drug Monitoring of Gentamicin Peak Concentrations in Critically Ill Patients.

Adequate gentamicin peak concentrations (Cmax) are important for optimal clinical efficacy. Within a critically ill patient, substantial variability in Cmax can occur over time, hampering the usefulness of therapeutic drug monitoring (TDM). The aim of this study was to evaluate the effect of gentamicin dosing based on Cmax after the first dose on gentamicin target attainment in critically ill patients. From gentamicin-treated critically ill patients, dosing information, clinical parameters, and serum concentrations were collected prospectively. A population pharmacokinetic model was developed using nonlinear mixed-effects modeling to estimate Cmax after each dose. To evaluate the usefulness of routine TDM, percentages of Cmax within (%Cther, 15-20 mg/L), above (>20 mg/L), and below (%Csubther, <15 mg/L) the therapeutic range after the first and second doses were compared. In addition, simulations were performed to evaluate the impact of TDM. Four hundred sixteen measurements from 59 patients receiving 130 gentamicin doses were included. In the 30 patients who received >1 dose, TDM increased %Cther from 40% after a first median dose of 5.0 mg/kg to 50% after the second dose, and decreased %Csubther from 47% to 30%. Simulations using a 5 mg/kg starting dose revealed %Cther after the second dose of 28.4% without and 36.8% with TDM and %Csubther of 56.9% and 29.3%, respectively. Increasing the simulated starting dose to 6 mg/kg increased %Cther after the first dose from 27.7% to 33.5% and decreased %Csubther from 58.6% to 35.6%. TDM after a first dose of 6 mg/kg had no substantial effect on %Cther or %Csubther after the second dose. Gentamicin dosing based on Cmax after the first dose increased %Cther and decreased %Csubther, but did not result in therapeutic Cmax in half of the patients. When simulating a higher starting dose, %Csubther after the first dose decreased, and TDM showed no additional influence. These data suggest that a starting dose of 6 mg/kg should be considered and that repeated Cmax measurements are not of added value.

Clinical Pharmacokinetics of Gentamicin in Neonates

Gentamicin is a bactericidal aminoglycoside antibiotic, it inhibits the protein synthesis. Gentamicin is active against the majority of aerobic gram-negative bacilli such as Pseudomonas, Klebsiella and Escherichia coli. The gentamicin doses are 3 mg/kg once-daily for preterm newborns 35 weeks of gestation. The monitoring of gentamicin serum concentration is recommended when infants are treated for 48 hours or more. The gentamicin peak concentration must be at least 8 times the minimum inhibitory concentration (MIC) to be bactericidal and the gentamicin trough concentration must be < 2 µg/ml to avoid ototoxicity and nephrotoxicity.Once-daily dosing of gentamicin (4 mg/kg), is preferred than twice-daily dose of 2.5 mg/kg gentamicin. A gentamicin loading dose (4 mg/kg), followed by once-daily dosing of 2.5 mg/kg yields safe and target range in neonates. An extended dosing interval of 48-hour (5 mg/kg gentamicin), was compared with twice-daily dose of 2.5 mg/kg gentamicin. Infants in the 48-hour interval and in the twice-daily achieved peak gentamicin concentrations of 9.43 µg/ml and 6.0 µg/ml, respectively, (p<0.001), and trough gentamicin concentrations were 1.08 µg/ml and 1.54 µg/ml, respectively, (p<0.001). The infants born small for gestational age have a reduced gentamicin clearance, and a more prolonged gentamicin half-life than infants born appropriate for gestational age. Patent ductus arteriosus, extracorporeal membrane oxygenation, therapeutic hypothermia, and asphyxia reduce the gentamicin clearance.

36th International Symposium on Intensive Care and Emergency Medicine : Brussels, Belgium. 15-18 March 2016.

36th International Symposium on Intensive Care and Emergency Medicine : Brussels, Belgium. 15-18 March 2016.

Therapeutic monitoring of amikacin and gentamicin in critically and noncritically ill patients.

Objective:Therapeutic drug monitoring (TDM) enables individualization in the treatment to optimize clinical benefit and minimize drugs' side effects. Critically ill septic patients represent a challenge for antimicrobial treatment because of pathophysiological impact of sepsis on pharmacokinetics of drugs. The aim of this study was to assess the appropriateness of gentamicin and amikacin dosing in critically and noncritically ill patients, as well as to estimate the need for its regular therapeutic monitoring.Subjects and Methods:It was a prospective study which included 31 patients on gentamicin and 16 patients on amikacin from four different units who met the inclusion criteria. Trough concentrations of drugs were measured in serum just before third or fourth dose of antibiotic, whereas peak concentrations were measured in serum 1 h after the completion of drug administration (steady state). Relevant data on patients' clinical course of disease, comorbidities, and concomitant medication were collected from medical charts in order to identify their possible influence on drugs' concentrations.Results:Peak concentrations of amikacin were in reference range in 81.8% critically ill and in 80% of noncritically ill patients (P = 0.931). Peak concentrations of gentamicin were in reference range in 88.9% critically ill and in 77.3% of noncritically ill patients (P = 0.457).Conclusion:Serum concentrations of aminoglycosides (amikacin and gentamicin) were in reference range in most of the patients in our study, suggesting that dosing of these drugs in the University Hospital Clinical Center, Banja Luka, was adequate. In patients without kidney or liver disease, regular TDM of aminoglycosides is not necessary.

Extended-Interval Gentamicin Dosing in Achieving Therapeutic Concentrations in Malaysian Neonates

To evaluate the usefulness of extended-interval gentamicin dosing practiced in neonatal intensive care unit (NICU) and special care nursery (SCN) of a Malaysian hospital. Cross-sectional observational study with pharmacokinetic analysis of all patients aged ≤28 days who received gentamicin treatment in NICU/SCN. Subjects received dosing according to a regimen modified from an Australian-based pediatric guideline. During a study period of 3 months, subjects were evaluated for gestational age, body weight, serum creatinine concentration, gentamicin dose/interval, serum peak and trough concentrations, and pharmacokinetic parameters. Descriptive percentages were used to determine the overall dosing accuracy, while analysis of variance (ANOVA) was conducted to compare the accuracy rates among different gestational ages. Pharmacokinetic profile among different gestational age and body weight groups were compared by using ANOVA. Of the 113 subjects included, 82.3% (n = 93) achieved therapeutic concentrations at the first drug-monitoring assessment. There was no significant difference found between the percentage of term neonates who achieved therapeutic concentrations and the premature group (87.1% vs. 74.4%), p = 0.085. A total of 112 subjects (99.1%) achieved desired therapeutic trough concentration of <2 mg/L. Mean gentamicin peak concentration was 8.52 mg/L (95% confidence interval [Cl], 8.13-8.90 mg/L) and trough concentration was 0.54 mg/L (95% CI, 0.48-0.60 mg/L). Mean volume of distribution, half-life, and elimination rate were 0.65 L/kg (95% CI, 0.62-0.68 L/kg), 6.96 hours (95% CI, 6.52-7.40 hours), and 0.11 hour(-1) (95% CI, 0.10-0.11 hour(-1)), respectively. The larger percentage of subjects attaining therapeutic range with extended-interval gentamicin dosing suggests that this regimen is appropriate and can be safely used among Malaysian neonates.

Pharmacokinetics and clinical evaluations of gentamicin-induced nephrotoxicity in puppies

Background: The study was aimed at investigating the effect of dosing intervals on gentamicin nephrotoxicity in puppies. Methods: Local puppies were assigned to Groups A and B (n=6) and administered gentamicin intramuscularly once (6 mg/kg) or twice (3 mg/kg) daily, respectively, for 5 consecutive days. Biochemical parameters such as urine protein, creatinine, ɤ-glutamyl transferase, as well as serum creatinine (SCR) and urea nitrogen were determined spectrophotometrically using specific kits before and after treatment. Peak and trough serum concentrations of gentamicin were determined by immunoassay on 1st and 5th day treatment. Thereafter, elimination rate constants and corresponding half-lives were calculated. Results: No significant increase in SCR concentrations in both groups was observed, but values on day 7 were slightly above normal. Conversely, there was a significant increase above normal in serum urea nitrogen on days 4 and 7 in Group A, whereas this was observed only on day 7 in Group B. Even though all other biochemical parameters assayed for were within normal, an increasing trend was noticed as the length of treatment days increased in both groups. In both groups, peak serum concentrations of gentamicin did not differ significantly. There was a 4- and 16-fold significant increase in trough levels after the last treatment in Groups A and B, respectively. Although peak and trough concentrations increased with increasing length of treatment, all the values were well below 10 µg/ml and 2 µg/ml, respectively, as required. Conclusion: These suggest the risk of nephrotoxicity following treatment with gentamicin beyond 5 consecutive days irrespective of the dosing interval in puppies.

Predictive performance of gentamicin dosing nomograms

BackgroundSeveral nomograms have been proposed to facilitate the determination of initial gentamicin dosing regimens in clinical settings. This study aimed to assess the predictive performance of these nomograms in Korean patients.MethodsGentamicin concentrations were determined in 84 patients with infective endocarditis (IE) and in 95 patients with other infections. All patients underwent therapeutic drug monitoring in Seoul National University Hospital from 2006 to 2012. Individual pharmacokinetic parameters were estimated using a Bayesian method, which predicted steady state peak and trough serum concentrations. Six nomograms were evaluated in patients with “other” infections: the Thomson guidelines, Hull-Sarubbi table, and Rule of Eights, for multiple daily dosing; and the Hartford nomogram, Barnes-Jewish Hospital nomogram, and Sanford Guide, for extended-interval dosing. In IE patients, synergistic combination dosing nomograms, based on the American Heart Association dosing interval guidelines, were evaluated.ResultsGentamicin dosing nomograms performed poorly in attaining the target peak serum concentrations. Multiple-daily dosing nomograms predicted peak serum gentamicin concentrations better than did the extended-interval dosing nomograms (31.9%–72.3% vs 4.3%–45.7%, respectively). Similarly, in patients with IE, the once-daily dosing nomogram resulted in a significantly lower percentage of patients achieving target peak gentamicin concentrations than that associated with the thrice-daily dosing nomogram (P=0.0015). All of the multiple-daily dosing, extended-interval dosing, and synergistic combination dosing nomograms predicted the nontoxic target trough concentrations in >80% of patients.ConclusionGentamicin dosing nomograms performed poorly in achieving the target peak serum concentrations. New gentamicin nomograms may be required in patients with IE, particularly for once-daily dosing. Therapeutic drug monitoring is highly recommended for gentamicin to ensure that the target concentrations are achieved.

Clinical pharmacokinetics in optimal gentamicin dosing regimen in neonates

Abstract Gentamicin is readily used for suspected or proven sepsis in neonates, yet it shows considerable inter-individual pharmacokinetic variability, which limits achievements of therapeutic levels. Hence, the aim of this study was to compare peak and trough gentamicin concentrations according to dosing regimen, to evaluate pharmacokinetic parameters, and to consider adjustments of dosing regimen. Babies with infection were treated with 1 h infusion, and daily dose of 5 or 7.5 mg/kg depending on the age. Patients were randomized into two groups: I — dosing interval 12 h (n=8), II — 24 h (n=11). Two steady-state blood samples were obtained. Pharmacokinetic parameters were calculated using one-compartment model. The results showed a difference (p&lt;0.05) in peak gentamicin concentrations between the groups, and tendency of lower trough levels in the group II. Calculated pharmacokinetic parameters included the volume of distribution (Vd) 0.52±0.47 l/kg, clearance (CL) 0.055±0.036 l/hkg and a half-life (t1/2) of 6.89±3.21 h. Based on the method for dosing regimen adjustments, there was a need to extend dosing interval to 36 h in 6 patients

Pharmacokinetics of Intraperitoneal Gentamicin in Peritoneal Dialysis Patients with Peritonitis (GIPD Study)

Peritonitis is a major infectious complication in peritoneal dialysis patients, and intraperitoneal antibiotic administration is preferred to ensure maximal antibiotic concentrations at the site of infection. This study aimed to describe the plasma and infection site pharmacokinetics of intraperitoneal gentamicin in patients with peritonitis. This prospective pharmacokinetic study of intraperitoneal gentamicin was conducted in peritoneal dialysis patients presenting to hospital with clinically defined signs and symptoms of peritonitis. Twenty-four patients were administered a 0.6-mg/kg dose of intraperitoneal gentamicin, which was allowed to dwell for 6 hours. Serial blood and dialysate samples were collected for 24 hours after the first dose. Gentamicin concentrations in plasma and dialysate were measured using a validated assay. The median percentage of the dose absorbed into the systemic circulation was 76% (interquartile range=69%-82%) and significantly different between patients with low average, high average, and high peritoneal membrane transporter status (P=0.03). The calculated pharmacokinetic parameters were plasma terminal elimination half-life of 24.7 (20.4-29.9) hours, terminal volume of distribution of 0.30 (0.20-0.36) L/kg, observed peak plasma concentration of 3.1 (2.4-3.4) mg/L, and observed trough plasma concentration of 1.9 (1.4-2.2) mg/L. The peak gentamicin concentration in dialysate was at least eight times the minimum inhibitory concentration of the likely pathogens. The high systemic absorption of gentamicin in patients with peritonitis and prolonged plasma elimination half-life may lead to drug accumulation in the systemic circulation, increasing the risk of toxicity.

Simplified Dosing of Gentamicin for Treatment of Sepsis in Bangladeshi Neonates

Extended-interval dosing of gentamicin has several advantages over conventional multiple-daily dosing for the treatment of sepsis. The study was conducted to evaluate the pharmacokinetics of gentamicin for the treatment of neonatal sepsis in predetermined doses at 24- or 48-hour intervals, according to weight category, and to develop a simplified protocol for use in peripheral healthcare settings in developing countries. This prospective observational study was conducted among 59 neonates admitted to the Special Care Nursery at Dhaka Shishu Hospital, Bangladesh, with suspected sepsis and treated with antibiotics, including gentamicin. Intravenous dosing of gentamicin according to weight category was: 10 mg every 48 hours if the infant weighed < 2,000 g (n = 23), 10 mg every 24 hours if the infant weighed 2,000-2,249 g (n = 12), or 13.5 mg every 24 hours if the infant weighed 2,500-3,000 g (n = 24). Peak and trough concentrations of gentamicin and the presence of signs of nephrotoxicity and ototoxicity were determined. The mean +/- standard deviation peak concentration of gentamicin was 12.3 +/- 3.7 microg/mL in infants weighing < 2,000 g, 9.6 +/- 3.1 microg/mL in infants 2,000-2,249 g, and 10.0 +/- 3.4 microg/mL in infants 2,500-3,000 g. Initial peak concentration of gentamicin was > 12 microg/mL in 28.8% and initial trough concentration was > 2 microg/mL in 6.8% of the subjects. No signs of nephrotoxicity or ototoxicity were detected. Favourable pharmacokinetic parameters found with the simplified dosing regimen suggest that it is safe for the treatment of neonatal sepsis.

Efficacy and safety of a single daily dose of gentamicin in hospitalized Indian children: a quasi-randomized trial

To compare the clinical efficacy, pharmacokinetic profiles and safety of once-daily dosing (ODD) and multiple daily dosing (MDD) of gentamicin in hospitalized Indian children. Four hundred children admitted to our hospital were studied prospectively. The patients were randomized to ODD or MDD groups alternately. The primary outcomes were: (i) a good clinical outcome, as defined; and (ii) occurrence of side effects, if any. Clinical efficacy was determined by comparing the proportion of patients with a favourable response between the two groups, while pharmacokinetic profile was assessed by comparing the peak and trough concentrations of the drug in a subgroup of patients. Safety of the two regimens was compared, besides recording any symptoms due to side effects of the drug, with the help of serum creatinine and brainstem-evoked response audiometry (in a subgroup of the patients). We found ODD of gentamicin in hospitalized Indian children to be efficacious and safe. A favourable clinical response was achieved in 167 of the 188 patients (89%) in the ODD group and in 161 of the 212 patients (76%) in the MDD group. Similarly, a higher number of patients in the ODD group showed favourable gentamicin peak concentrations as compared with the MDD group (100% versus 87%). The MDD group showed a higher number of trough concentrations in the undesirable range as compared with the ODD group (17% versus 0%). The study supports extended-interval (single daily) dosing in hospitalized Indian children due to its efficacy and safety with the added advantage of needing fewer injections.

Peak and Trough Concentrations of Gentamicin in the Neonate: A Review of the Literature

Background: Sepsis is common in neonates and is a major cause of morbidity and mortality. 60% of preterm neonates receive at least one antibiotic and 43% of the antibiotics administered to these neonates are aminoglycosides. Gentamicin is an aminoglycoside which is largely used. Dosing of gentamicin gives rise to two concentrations, the peak concentration which is measured soon after dosing, and the trough concentration which is measured before the next administration. There has been a long debate about the appropriate dose of gentamicin to administer to neonates and the interval between doses. The ideal dosing of gentamicin should yield a peak concentration of 10μg/ml and a trough concentration of 1μg/ml. Objectives: The aim of this work is to compare the peak and trough concentrations of gentamicin in the neonate after twice-daily dosing, once-daily dosing and extended interval dosing to establish the safest one for neonates. Another aim of this note is to provide a critical analysis of the literature that can be a useful tool in the hands of physicians. Methods: The bibliographic search was performed electronically using PubMed, as the search engine, until January 14th 2008. Medline searches were performed with the following keywords “twice-daily dosing of gentamicin in neonates” with the limit of “human”; “once-daily dosing of gentamicin in neonates”; “extended interval dosing of gentamicin in neonates”; “pharmacokinetics of gentamicin in neonates”. In addition, the book Neofax: a Manual of Drugs Used in the Neonatal Care by Young and Mangum [2007] was consulted. Results: The peak and trough concentrations were compared after the following dosing schedules of gentamicin 2.5 mg/kg twice-daily dosing, 4 mg/kg once-daily dosing and 5 mg/kg every 48 h defined “extended interval dosing”. Twice-daily dosing was associated with the lowest peak gentamicin concentration and with the highest trough concentration. The lowest trough concentration was associated with the extended interval dosing of gentamicin. Gentamicin is mainly eliminated through glomerular filtration whose rate increases with the growth of the infant. The trough concentration was negatively correlated with the body weight indicating that in better developed neonates gentamicin was more rapidly eliminated. Conclusions: The dosing schedule contributes to determining the peak and trough concentrations of gentamicin in the neonate. There are numerous articles comparing the peak and trough concentrations after twice-daily dosing and oncedaily dosing of gentamicin. In contrast, little is known about the peak and trough concentration of extended interval dosing of gentamicin. More studies are required to better highlight the peak and trough concentrations of extended interval dosing of gentamicin at different gestational age. Keywords: Gentamicin, peak-concentration, trough-concentration, pharmacokinetics, neonate

Continuous monitoring of penicillin G and gentamicin in allantoic fluid of pregnant pony mares by in vivo microdialysis

Most current treatments for placentitis in mares are empirical with few control studies to evaluate their effectiveness. To monitor drug concentrations in allantoic fluid of pregnant pony mares using in vivo microdialysis and establish if this method would be useful for determining allantoic concentrations of drugs in normal mares and those with placentitis. Five late gestational pony mares had microdialysis probes inserted into the allantoic fluid using transabdominal ultrasound-guided allantocentesis. Single injections of penicillin G (22,000 u/kg), gentamicin (6.6 mg/kg bwt) and flunixin meglumine (1 mg/kg bwt) were administered i.v. and dialysate samples collected continuously for 24 h. In a separate study, drug concentrations were monitored in allantoic fluid of 2 mares with experimental placentitis induced by intracervical inoculation with Streptococcus equi ssp. zooepidemicus. Drug concentrations were measured by high performance liquid chromatography (penicillin G, flunixin meglumine) or enzyme-linked immunosorbent assay (gentamicin). Penicillin G and gentamicin achieved average peak concentrations of 9.8+/-2.2 and 8.5+/-3.1 microg/ml, respectively, in allantoic fluid of noninfected mares. Pharmacokinetic comparisons indicate that penicillin G persists much longer in allantoic fluid than blood, whereas gentamicin exhibited similar profiles in the 2 compartments. Flunixin meglumine was not detected in allantoic fluid. In infected mares, penicillin G achieved a similar peak concentration in allantoic fluid (11.2 microg/ml) whereas peak gentamicin concentration (3.9 microg/ml) appeared to be reduced relative to drug concentrations in noninfected mares. Microdialysis is a useful technique for continuous in vivo monitoring of drugs in equine allantoic fluid. Our results indicate that penicillin G and gentamicin undergo effective placental transfer in pregnant mares and in 2 mares that transplacental drug transfer may be altered selectively if active placental infection is present. Further studies are needed to evaluate the feasibility of using increased dose intervals for penicillin G and an increased dose rate of gentamicin to effectively combat placental infections in mares.

Nebulised gentamicin—suitable for childhood bronchiectasis

Nebulised antibiotic therapy is an established, safe and effective therapy for cystic fibrosis with chronic pseudomonas infection resulting in improved pulmonary function and reduced hospitalisation. Despite similar respiratory disease, this therapy has not been evaluated in children with non cystic fibrosis bronchiectasis. This study evaluates the suitability of a gentamicin solution and nebuliser combination for use in this population. Materials and methods: Four millilitres of gentamicin (80 mg) in saline delivered by a PARI LC plus ® nebuliser and PARI Turboboy N ® compressor was used. The pH, osmolarity, chloride concentration and aerosol particle size was determined. Ten children with non cystic fibrosis bronchiectasis received nebulised antibiotic and had peak gentamicin concentrations measured in sputum and serum. Pulmonary function was measured pre and post nebulisation. Results: The solution had an osmolarity of 199 mOsm/l, pH of 4.1, chloride concentration of 75 mmol/l and the aerosol a mass median aerodynamic diameter of 3.3 μm. Nebulisation was well tolerated, with no significant change in FEV1. Peak serum levels were at the threshold of detectability (0.3 mg/l). Sputum concentrations had a mean of 624 mg/g and lower 95th confidence interval 25 times the minimum inhibitory concentration for the predominant infecting organism, Haemophilus influenzae. Conclusion: Nebulisation of 80 mg of gentamicin in saline achieved bactericidal concentrations in sputum, was well tolerated and had negligible systemic absorption making it a suitable choice for this population.