a Department of Paediatrics, Neonatal Intensive Care Unit, Christchurch Womens Hospital, Christchurch; b Department of Clinical Pharmacology, Christchurch Hospital, PO Box 4710, Christchurch, New Zealand; c School of Pharmacy, University of Queensland, Australia
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Abstract |
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Introduction |
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We are not aware of any evidence to suggest that aminoglycoside pharmacodynamics in neonates will differ from those in adults. Aminoglycosides display concentration-dependent killing11 and a post-antibiotic effect (the length of which is proportional to the peak concentration),12 and pathogens develop adaptive resistance.13 Therefore, to maximize clinical efficacy, higher peak concentrations should result in improved bacterial kill and a longer post-antibiotic effect, while a drug-free' period should occur in each dosing interval to allow the reversal of adaptive resistance.
Aminoglycoside-induced nephrotoxicity may be reduced by limiting the total exposure per dosing interval to acceptable levels (for example AUC024 < 100 mgh/L),14 and by ensuring a low concentration or drug-free period in each dosing interval to allow redistribution of the aminoglycoside out of the proximal renal tubules where it is known to concentrate.15
There have been two main approaches to aminoglycoside dosing in neonates. The first aims for traditional peak (Cmax; 610 mg/L) and trough (Cmin; <2 mg/L) values based on the same goals as for multiple daily dosing in adults, with a regimen of 2.5 mg/kg every 824 h, and perhaps as long as 36 h in pre-term infants. However, 2.5 mg/kg may not produce a therapeutic Cmax after the first dose, and, at these dosing intervals, may produce Cmin > 2 mg/L after the third and subsequent doses.8,16
The second approach aims for higher Cmax and lower Cmin values, with varying doses per kg, in an attempt to simulate adult once-daily dosing.17 Studies using this approach in neonates have generally adopted q24 h dosing intervals with or without loading doses.1823 Therapeutic monitoring is often not initiated until the third dose. Although the mean Cmax achieved is significantly higher in all groups when receiving q24 h regimens, only one study reported values >10 mg/L.20 The Cmin observed with q24 h dosing in neonates is generally lower than with traditional dosing, but higher than that seen in adults, as a result of decreased CL. This is particularly so in low birth weight infants, in whom trough concentrations similar to those after traditional dosing are observed.
Both these approaches have pitfalls. The 1224 h dosing of 2.5 mg/kg falls between the adult traditional and once-daily approaches, and may achieve the best of neither. The once-daily method often fails to achieve the adult once-daily dosing principles (i.e. Cmax > 10 mg/L, Cmin below the limit of detection <0.25 mg/L).14 Therefore, the adult once-daily model is not being replicated in neonates.
More recently, there have been other approaches that do not utilize set dosing intervals or set doses for all infants.24,25 Langhendries et al.24 used amikacin 15.520 mg/kg at dosing intervals from 24 to 42 h. Cmax values were 2530 mg/L and trough concentrations were 17 mg/L and assessment of the acceptability of these was based on traditional goals (25 mg/L). In no infants did there appear to be a drug-free period, which is important for the reversal of adaptive resistance. Ohler et al.25 gave gentamicin or tobramycin 5 mg/kg at intervals of 2448 h, the interval being longer for infants <35 weeks of age, and if there were any risk factors e.g. birth depression, decreased renal function, etc. Only in the >35 week post-conception age group did >50% of patients achieve a Cmax > 10 mg/L; Cmin values ranged from 0.11.5 mg/L.
Any new dosing method must be sufficiently flexible to allow for inter-patient variability and the changes in renal function seen in the first 2 weeks ex utero.26 Total aminoglycoside exposure (i.e. AUC024), should be no greater than that acceptable in adults, simply because no better basis is available as a starting point. Target Cmax and Cmin concentrations should approach those based on the adult once-daily concept. Early (after the first dose) and regular pharmacokinetic monitoring would also seem warranted to achieve these goals rapidly24 at least until it is shown that such monitoring is unnecessary.27
In adults, a suggested approach to once-daily aminoglycoside dosing is to use a target AUC based on an AUC024 of 101 mgh/L, which is the AUC024 associated with traditional dosing when aiming for a Cmax of 8 mg/L and a Cmin of 2 mg/L.14 The once-daily dose to achieve this AUC024 should ensure that Cmax is >10 mg/L and Cmin is <1 mg/L even at renal function as low as 0.35 mL/s. This method, based on a target AUC024, is the preferred method of individualizing aminoglycoside dosage in Australasia,28 and its use has been described in several studies.6,29,30 Monitoring for this method occurs during the first dose, so subsequent doses are individualized for the patient's individual pharmacokinetics.
The aims of this study were to audit the use of gentamicin in a Neonatal Intensive Care Unit to determine whether 2.5 mg/kg every 824 h effectively achieved the target Cmax and Cmin values. The data were used to develop and test prospectively an extended interval gentamicin dosing method using the AUC approach, aiming to achieve a concentrationtime profile consistent with adult once-daily dosing (Cmax > 10 mg/L, AUC024 = 100 mgh/L).
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Materials and methods |
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A prospective audit was undertaken of gentamicin concentrations resulting from the traditional gentamicin dosing guidelines at Christchurch Women's Hospital Neonatal Intensive Care Unit. All neonates who were treated with gentamicin during a 5 month period were considered for audit regardless of weight and gestational age. Neonates were excluded if they received less than three doses, did not have both pre- and post-dose serum concentrations results, if there was evidence of laboratory error or insufficient sample volume, or if the time of sampling was not recorded.
Gentamicin 2.5 mg/kg was administered as a 30 min infusion via a Graseby Medical MS I 6A Syringe Driver (Smiths Medical, Auckland, New Zealand) and IVAC Smallbore extension (Alaris, San Diego, CA, USA) set into a peripheral cannula or long line. The dose was given undiluted in enterally fed neonates, and diluted with 5% dextrose in parenterally fed neonates so as to maintain the prescribed hourly rate of fluids. A flush of 5% dextrose was given over a further 30 min post-infusion. The dosing interval was adjusted according to weight and postnatal age (Table 1).
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Population pharmacokinetic analysis
The concentrationtime data for gentamicin in 53 neonates were modelled to derive the Vd and CL for each individual and the population as a whole, using the Bayesian program PKBUGS31,32 ver 1.1 (MRC Biostatistics Unit, Cambridge, UK). A one-compartment model with zero-order infusion and additive residual variance was assumed. The Bayesian iterative process in PKBUGS uses the Markov chain Monte Carlo (MCMC) simulation technique. This process is performed for all individuals and for the population simultaneously.
Estimation of Cmax, Cmin and AUC. Cmax, Cmin, AUC per dose (AUCdose) and AUC per 24 h (AUC024) for the first and third dose in each patient were calculated using their values of Vd and CL using standard one-compartment pharmacokinetic equations described by Begg et al.14
Development of an extended interval AUC dosing method
Covariate analysis. Linear regression analysis was performed to determine the relationships between the estimated value of CL and each of weight, post-menstrual age and serum creatinine for each neonate, using GraphPad Prism ver 3.0 (GraphPad Software, San Diego, CA, USA). The relationships between Vd and each of weight, post-menstrual age and serum creatinine were analysed in a similar manner. Using the results of the regression analysis, models were developed to produce estimates of CL and Vd for neonates of any given weight. Descriptive statistics (mean, s.d. and 95% CI) were used to describe the pharmacokinetic and demographic data, using GraphPad Prism.
Simulation of model. The models for estimation of CL and Vd were used in a series of simulations using Microsoft Excel to develop a new dosing schedule. The aim of the dosing schedule was to maximize efficacy and minimize toxicity by achieving Cmax > 10 mg/L, Cmin close to 0 mg/L, and an AUC024 close to but not exceeding 100 mgh/L. The new dosage schedule was based on a one-compartment model with zero-order, 30 min infusion to produce the desired concentrationtime curves for neonates ranging in weight from 0.5 to 5.0 kg. The dosing interval was increased from 24 to 36 or 48 h if the predicted Cmax was <10 mg/L, while trying to maintain an AUC024 of 100 mgh/L. The dose was based on the equation:
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Prospective audit of the extended interval AUC method
The new extended interval AUC dosing method was tested in a prospective audit of concentrations achieved after the first dose. All neonates treated with gentamicin over a 2 month period were considered for audit regardless of age. Neonates were excluded only if they weighed less than 0.75 kg, or did not have two serum samples taken in the first dosing interval after the gentamicin dose.
The drug was administered as a 30 min infusion as described for the traditional dosing. Blood was sampled for measurement of serum gentamicin concentrations after the first dose, including a peak sample at c. 1 h after the beginning of the infusion, and a mid-dose sample between 12 and 24 h depending on the dosing interval (Table 2). Cmin concentrations were calculated by extrapolation based on a standard linear one-compartment pharmacokinetic model.
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Results |
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Fifty-three neonates with weights ranging from 0.54 to 5.15 kg (mean 2.40 ± 1.16), with post-menstrual ages from 27 to 42 weeks (mean 34.4 ± 4.7), and mean serum creatinine of 0.07 ± 0.02 mmol/L (range 0.030.10) were studied.
Population pharmacokinetic analysis. Two MCMC runs starting from widely different initial values gave virtually identical results, suggesting that convergence had been reached. In this circumstance no statistical tests were used to assess convergence. The mean ± s.d. population value of CL for the population was 0.11 ± 0.07 L/h and the mean value of Vd was 1.1 ± 0.56 L.
Cmax and Cmin from traditional dosing. The extrapolated Cmax and Cmin values after the first and third dose are presented in Figure 1. After the first dose the Cmax (mean = 5.48 ± 0.73 mg/L) was <6 mg/L and therefore potentially sub-therapeutic in 33 (62%) patients. Trough concentrations after the first dose (mean = 1.50 ± 0.68 mg/L) were in the accepted range (<2 mg/L) in 45 (85%) patients. After the third dose, values for Cmax were within the target range of 610 mg/L in 46 (87%) patients, with a mean value of 7.5 ± 1.5 mg/L (range 4.410.5). Cmin values were <2 mg/L in 27 (51%) patients. The median AUC024 achieved with this dosing method was 102 ± 31 mgh/L (range 50193). Fifteen infants (28%) had an AUC024 > 120 mgh/L, which is the absolute maximum AUC that was considered acceptable with regard to toxicity with traditional dosing in adults.14
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Covariate analysis. When adjusted for total body weight, the mean values of CL and Vd were 0.04 L/h/kg and 0.5 L/kg respectively. The best predictors of CL were post- menstrual age (r2 = 0.79, P < 0.0001) and birth weight (r2 = 0.80, P < 0.0001). The best predictors of Vd were weight (r2 = 0.51, P < 0.0001) and post-menstrual age (r2 = 0.44, P < 0.0001). Because weight can be assessed more accurately than post-menstrual age, weight was the chosen predictor of CL and Vd. There was a strong correlation between post-menstrual age and weight (r2 = 0.85, P < 0.0001), so it was not thought appropriate to use both covariates. There was no correlation between serum creatinine and Vd (r2 = 0.01, P = 0.57), and the correlation between serum creatinine and CL, although significant, was poor (r2 = 0.25, P < 0.0001).
The starting doses for the AUC extended interval dosing method derived from the simulation data are shown in Table 2. The simulations indicated that for infants weighing <0.75 kg it was difficult to achieve a Cmax > 10 mg/L. Because 10 mg/L was chosen as a threshold to distinguish the new method from the traditional method, infants <0.75 kg were excluded from the prospective testing.
Prospective testing of the AUC extended interval dosing method
Fifty-one neonates were included in the audit, the mean weight 3.45 ± 0.86 kg (range 0.844.1), mean post-menstrual age 35.0 ± 3.9 weeks (range 2542) and mean serum creatinine 0.05 ± 0.02 mmol/L (range 0.020.13). These characteristics were similar to those of the first audit, except for the mean weight, which was greater as a result of excluding neonates weighing <0.75 kg.
The majority (78%) of neonates achieved a Cmax > 10 mg/L (mean 13.1 ± 3.6, range 5.629.5) (Figure 2). Importantly, only 11 patients (22%) did not achieve a peak of 10 mg/L, and only one patient had a Cmax < 6 mg/L. The mean weight of the neonates that did not achieve high peaks >10 mg/L was 2.9 kg.
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A residual plot of the achieved AUC024 versus the target AUC024 is shown in Figure 3. Random scatter of residuals either side of the x-axis suggested no systematic error. There was a slight underprediction of the AUC024 of c. 6%.
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Discussion |
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In contrast, by the third dose the Cmax was mostly therapeutic' (610 mg/L), but the Cmin was >2 mg/L in up to 50% of infants. The high Cmin indicates that significant accumulation had occurred and the neonates were exposed to potentially excessive amounts of aminoglycoside according to adult criteria. The wide range in the AUC024 was of equal concern, with one patient receiving almost double the accepted daily maximum, at 193 mgh/L. These results indicated that it was difficult to achieve adequate peak concentrations without exposing infants to excessive trough concentrations using this dosing regimen and monitoring.
The pharmacokinetic results from our population analysis were similar to those published previously, with the mean CL being about half that of a normal adult on a weight-adjusted basis. Our reported Vd of 0.5 L/kg was similar to those quoted previously18,19 and is approximately double that observed in adult patients receiving aminoglycosides once daily.6 This difference is thought to relate to the greater percentage of body water in infants compared with adults. The larger Vd is likely to be the major reason why traditional dosing failed to achieve the desired therapeutic Cmax in this age group.
The poor correlation (r2 = 0.25, P < 0.0001) between serum creatinine and gentamicin clearance is an interesting observation, as many centres adjust the dosing interval based on the neonatal serum creatinine concentration. In the first few days of life, the neonatal serum creatinine concentration will largely reflect the maternal rather than the neonatal renal function and therefore is not ideal to guide the choice of dose or dosing interval in this group. This is supported further by the relatively poor correlation between serum creatinine and gentamicin clearance. We did not attempt to calculate creatinine clearance by collecting total daily urine output, as this is almost impossible to achieve in normal clinical practice.
The extended interval AUC dosing method developed was applicable to neonates weighing >0.75 kg, with dosing intervals of 24, 36 or 48 h. For infants <0.75 kg, our simulations suggested that it was difficult to achieve a peak concentration of >10 mg/L, and the concentrationtime profile approached that of a constant infusion, therefore not conforming to the ideals of extended interval dosing. Further, at no stage in the dosing interval of these neonates was there a relatively drug-free period. This is not the desired profile to optimize bacterial killing with an aminoglycoside, and is likely to induce a state of constant adaptive resistance while increasing the risk of oto- and nephrotoxicity. Therefore, dosing with aminoglycoside using the extended interval AUC method is not recommended for infants weighing <0.75 kg. It is likely that infants in this weight category at other institutions will have similar pharmacokinetics to those we have observed. On this basis none of the described dosing schedules is likely to work well in this group, as aminoglycoside clearance is insufficient to handle aminoglycoside therapy without a high risk of toxicity.
In contrast to the traditional dosing method, the extended interval AUC dosing method enables concentrations to approach the desired profile of high Cmax, and low Cmin. This should be associated with increased antibacterial killing and reduced toxicity, as has been suggested in meta-analyses of once-daily dosing.33 In addition, monitoring during the first dose interval allows early adjustments in interval or dosage to be made, thus allowing individualization before the next dose is due. This should ensure that clinical effect can be maximized, while minimizing the risk of toxicity. The extended interval method described is similar to that proposed for amikacin by Langhendries et al.,24 except that it used the infant weight to determine dose and interval rather than gestational age.
Because the dosage regimen is adjusted to the individual's pharmacokinetics by either changing the dose, or the dosing interval or both, accumulation following the first dose will be minimal. This is because the dosing interval is always four to five times longer than the individual's half-life in this model. This means that 97% or more of the gentamicin is eliminated within the dosing interval, and therefore accumulation will be negligible.
Therapeutic monitoring, however, is still important in this population as a result of unpredictable inter-patient variability.24 It also enables dose individualization to be made early in therapy.
This study did not attempt to evaluate efficacy or toxicity because of the small numbers of patients involved. It would be useful in the future to compare outcomes of the dosing method using sensitive indices of nephro- and ototoxicity and clinical outcome.
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Acknowledgements |
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Notes |
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Dr Mark Stickland died in an accident during the final stages of this project and was thus unable to approve the final version of the manuscript. A decision was made in discussion between the other authors and the Editorial staff that Dr Stickland would remain as senior author, in view of the tragic and highly unusual circumstances.
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References |
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Received 18 April 2001; returned 9 July 2001; revised 14 August 2001; accepted 26 August 2001