Send letter to journal:
Re: Single daily dose aminoglycosides in the neonatal period appear to be effective: but are they safe?

Dear Editor,

A recent article by Nestaas et al.[1] deserves comment. This meta- analysis attempts to evaluate the relative efficacy and toxicity of “extended interval dosing” (EID), compared to “traditional dosing” (TD), of aminoglycosides administered to newborn infants. The conclusion of the analysis was that “extended interval dosing of aminoglycosides in neonates is safe and effective, with a reduced risk of serum drug concentrations outside the therapeutic range”.

This interpretation of the data presented can be questioned on several grounds. Even with meta-analysis, the number of reported treatment failures (2 in the TD group, none in the EID group from a total of 555 patients) was too small to establish a statistically significant difference between the two regimes in relation to efficacy.[1]

There were certainly more serum drug concentrations, both peak and trough, which were outside the defined therapeutic range using TD, compared to EID. However, this difference was only seen in trials which were aiming for a higher (usually 5-12 mg/L) peak serum drug concentration.[1] This observation is a self-fulfilling prophecy. With EID, the drug is given at the same maintenance dose rate (mg/kg/day), but with higher single doses and longer dosage intervals than with TD. Basic pharmacokinetic principles indicate that during EID, peak serum drug concentrations will be higher and trough concentrations lower, than when smaller drug doses are given at shorter dosage intervals (TD).[2]

The finding of increased numbers of serum drug concentrations outside the desired therapeutic range seems compelling, but is per se not necessarily a strong argument in favour of EID. The efficacy of aminoglycosides should not be based on this observation alone, even though there are theoretical and in vitro data to support the concept of ‘post antibiotic effect’.[1,3] Because treatment failures with TD are extremely rare,[1] the possible benefit in efficacy of EID becomes less important than establishing with confidence that this regime has similar or less toxicity than TD.

Clinically significant renal impairment in neonates receiving aminoglycosides is extremely rare,[3,4] and is nearly always transient.[4] Of greater significance is the potential for ototoxicity which can occur with excessively high serum drug concentrations.[3] In 1979, Finitzo- Hieber et al,[5] published a comprehensive evaluation of ototoxicity in newborns receiving TD aminoglycosides (gentamicin or kanamycin). More than one hundred infants in each of 3 groups (gentamicin-treated, kanamycin- treated and controls) were followed annually for up to 4 years. Detailed audiological testing, together with measures of vestibular function and psychometric assessment were performed. There were no significant differences between the 3 groups in any of these measures.

By contrast, only 4 of the 16 studies included in this meta-analysis provided any data regarding ototoxicity. Brain stem evoked responses were only measured during, or shortly after, a course of an aminoglycoside (gentamicin or amikacin).[3,4,6,7] No adequate long term assessment of the incidence of hearing impairment has yet been reported in studies using EID. Until conclusive ototoxicity data are available in infants treated with EID, we will continue to use traditional dose aminoglycoside therapy.

References

1. Nestaas E, Bangstad H-J, SandviK L et al. Aminoglycoside extended interval dosing in neonates is safe and effective: a meta-analysis. Arch Dis Child Fetal Neonatal Ed 2005;90:F294-300.

2. Benet LZ, Kroetz DL, Sheiner LB Pharmacokinetics In Hardman JG, Limbird LE, Eds. Goodman & Gilman’s The pharmacological basis of therapeutics 9th ed, McGraw-Hill, New York, 1996:17-27.

3. Lundergan FS, Glasscock GF, Kim EH et al. Once-daily gentamicin dosing in newborn infants. Pediatrics 1999;103:1228-34.

4. Kotze A, Bartel PR, Sommers De K. Once versus twice daily amikacin in neonates: prospective study on toxicity. J Paediatr Child Health 1999;35:283-6.

5. Finitzo-Hieber T, McCracken GH Jr, Roeser RJ et al. Ototoxicity in neonates treated with gentamicin and Kanamicin: Results of a four-year controlled follow-up study. Pediatrics 1979;63:443-50.

6. Landhendries JP, Battisi O, Bertrand JM et al. Once-a-day administration of amikacin in neonates: assessment of nephrotoxicity and ototoxicity. Dev Pharmacol Ther 1993;20:220-30.

Send letter to journal:
Re: Aminoglycoside extended interval dosing in neonates is safe and effective.

Dear Editor,

The meta-analysis “Aminoglycoside extended interval dosing in neonates is safe and effective: a meta-analysis”[1], has been commented on by Emmerson and Edi-Osagie[2] and by Lounghnan[3]. In the meta-analysis, extended interval dosing (EID) were found to provide fewer unfavourable serum drug concentrations (SDC) than traditional dosing (TD), treatment failure to be rare (2 failure were reported in 555 neonates, both treated with TD) and no significant differences in toxicity between the dosing regimens. The two dosing regimens were therefore regarded equally safe and effective, with theoretical and economic advantages in favour of EID.

Emmerson and dr Edi-Osagie [2] addresses the important issue that dosing errors might increase when changing the dosing regimen. If dosing errors occurs, they will probably become less frequent when the new dosage regimen comes into routine practice. Hence, when deciding between the dosing regimens they should be compared after good routines have been established. The change from TD to EID in clinical practice might be more closely resembled in the trials using historical control groups or cohorts than in the randomised trials. If a dose intended for EID is given at TD dosage intervals, both the peak and the trough SDC will be higher and hence more often outside the therapeutic range. A significant increase in dosing errors might therefore be seen as more unfavourable SDC in the EID group in non-randomised than in the randomised trials. However, in the trials included, there opposite was found; there were fewer unfavourable peak and trough SDC within the EID group in the non-randomised trials than in the randomised trials. In the randomised trials, 16 (10.1%) peak and 16 (10.1%) trough out of 158 samples were outside the therapeutic range, compared to 12 (6.5%) peak and 5 (2.7%) trough SDC out of 185 samples in the non-randomised trials.

Lounghnan will continue to use aminoglycoside TD “until conclusive ototoxicity data are available” for EID[3]. To support the safety of TD reference is made to the study by Finitzo-Hieber et al.[4] that found no significant differences in ototoxicity comparing newborns treated with gentamicin, kanamycin and untreated controls. From this study, only the results from the 116 gentamicin treated newborns are relevant, as kanamycin is rarely used today. The average peak SDC was 3.6 mg/l, lower than has been associated with improved clinical outcome[5] and also lower than the peak SDC range in all studies using gentamicin included in the meta-analysis[1]. There were significant loss during follow up in the study; detailed hearing tests for substantial sensoneural hearing impairment were performed in 59 (51%) infants, 14 (12%) were only tested for profound binaural impairment and 43 (37%) were not tested at all. No brainstem response audiometry test was performed. Failure in brainstem response audiometry screening at term has been reported to predict hearing loss at 18 months postconceptional age with a sensitivity of 100% and a specificity of 98% [6]. The meta-analysis reports tests of 210 neonates using brainstem audiometry with no significant differences between the dosing regimens. If 59 clinical courses, often with a sub therapeutic peak gentamicin SDC, should be regarded as “conclusive ototoxicity data”[3] for the safety of TD of the aminoglycosides used today, then the brainstem response audiometry screening in the 210 infants in the trials included in the meta-analysis should probably be regarded as sufficient evidence for the safety of EID. If not, then further evaluation of ototoxicity during and after aminoglycoside treatment is urgently needed, both for the EID and the TD regimens.

Eirik Nestaas

References:

(1) Nestaas E, Bangstad HJ, Sandvik L, Wathne KO. Aminoglycoside extended interval dosing in neonates is safe and effective: a meta- analysis. Arch Dis Child Fetal Neonatal Ed 2005; 90(4):F294-F300.

(2) Emmerson AJB, Edi-Osagie NE. Reducing the dosing frequency of aminoglycosides can increase errors. Arch Dis Child Fetal Neonatal Ed 2006; 91(2):F155-F15a.

(3) Loughnan PM. Single daily dose aminoglycosides in the neonatal period appear to be effective: but are they safe? Arch Dis Child Fetal Neonatal Ed 2006; 91(2):F156.

(4) Finitzo-Hieber T, McCracken GH, Jr., Roeser RJ, Allen DA, Chrane DF, Morrow J. Ototoxicity in neonates treated with gentamicin and kanamycin: results of a four-year controlled follow-up study. Pediatrics 1979; 63(3):443-450.

(5) Moore RD, Smith CR, Lietman PS. The association of aminoglycoside plasma levels with mortality in patients with gram-negative bacteremia. J Infect Dis 1984; 149(3):443-448.

Send letter to journal:
Re: Gentamicin and Amikacin: extended interval dosing in neonates.

Dear Editor,

Recently it has been published a meta-analysis of Cochrane which, specifically for gentamicin, compares daily dose versus multiple dose scheme, and it concludes that, although daily dose could be better, the evidence is even insufficient to confirm it. (1) Additionally, paper of Nestaas included gentamicin and amikacin, although it had got only two papers with amikacin in its references, in according to its Table 1 (one of Langhendries et al and other of Kotze et al, with 22 and 40 newborns respectively). Those two drugs haven't had a differentiated analysis, which seriously is impossible, mainly due to the few data for amikacin. Studies about effective peaks and troughs, and mainly about if they can be safe for newborn in short and long term, have not been been established even. This point could be explained due to several difficulties to get neonate patients for clinical studies and besides the possibility to extract useful blood samples in this type of patients. Probably these are reasons to find so little amount of pharmacokinetics publications of amikacin in newborns. So this point is in investigation stage. Independently of the case of gentamicin that already has been detailed in first paragraph, we should not conclude yet that the daily dose of amikacin is effective and safe. There is important lack of scientific evidence, so we suggest, also partially supported in our clinical experience, until more evidence appears, to continue with traditional schemes that, except for a particular fit, do not include the daily dose for amikacin in newborn.(3)

References:

1 - Rao SC, Ahmed M, Hagan R. One dose per day compared to multiple doses per day of gentamicin for treatment of suspected or proven sepsis in neonates (Cochrane Review) The Cochrane Library, Issue 2, 2006. Chichester, UK

2 - E Nestaas, H-J Bangstad, L Sandvik et al. Aminoglycoside extended interval dosing in neonates is safe and effective: a meta-analysis. Arch. Dis. Child. Fetal Neonatal Ed. 2005; 90: F294-F300