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Journal of Antimicrobial Chemotherapy (1996) 38, 499-505
Pharmacokinetics of once-a-day netilmicin (6 mg/kg) in neonates
J. J. Ettiinger*, K. A. Bedford*, A. M. Lovering*, D. S. Reeves', B. D. Speidel* andA. P. MacGowan**
'Department of Neonatal Medicine;bBristol Centre for Antimicrobial Research &Evaluation, Southmead Health Services NHS Trust and the University of Bristol,Department of Medical Microbiology, Southmead Hospital, Westbury-on-Trym,
Bristol, BSW 5NB, UK
The pharmacokinetics of once a day netilmicin (6 mg/kg) was studied in 21 neonates.The babies were divided into three groups according to gestational age: group I aged>36 weeks; group II between 34-36 weeks and group III <34 weeks. Serumconcentrations were variable between patients and the concentration 24 h after thefirst dose ranged from 0.8 to 3.8 mg/L with only two babies having concentrationsof < 1 mg/L while seven had concentrations of > 2 mg/L. There were also largepatient-to-patient variations in serum half-life, volume of distribution, area under thecurve and relative plasma clearance such that these parameters could not becorrelated to gestational age or weight. Absolute plasma clearance was correlatedwith both gestational age and weight. There was evidence of accumulation betweenthe first and second dose for all three patient groups and for patients of gestationalage < 34 weeks (group III) these observations were statistically significant. Anetilmicin dosage of 4.5 mg/kg once a day may be more suitable for all neonatessupported by assay of serum concentrations.
Introduction
The pharmacokinetics of netilmicin in neonates has been examined before and the mainconclusion to be drawn from these studies is the large interpatient variability in observedserum concentrations in this group (Bergan & Michalsen, 1982; Kuhn et al., 1986).Previously serum half-life, volume of distribution, absolute plasma clearance and 'peak'serum concentration have been related to weight and gestational age (Siegel et al., 1979).Others have been able to relate absolute plasma clearance to chronological age (Kuhnet al., 1986). However, such correlations have not always been possible, presumably dueto the variable handling of aminoglycosides by neonates (Bergan & Michalsen, 1986).
Once-daily aminoglycoside therapy has been shown to be clinically effective andpossibly less toxic if compared with multiple doses, not only in a wide variety of mainlyadult patients (Parker & Davey, 1993; MacGowan & Reeves, 1994; MacGowan, 1994;Barza et al., 1996) but also in children (Kafetzis et al., 1991; Viscoli et al., 1991).
However, although aminoglycosides play an important role in the antimicrobial
•Corresponding author.Tel: +44-{117>950-5050; Fax: + 44-(117>959-3154; E-mail: [email protected]
4990305-7453/96/090499 + 07 $12.00/0 © 1996 The British Society for Antimicrobial Chemotherapy
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500 J. J. Ettlinger et al.
therapy of neonatal sepsis, limited data are available concerning the pharmacokinetics,efficacy and toxicity of once daily aminoglycosides in neonates. For example,Langeandnes et al. (1993) confirmed the safety of once daily over twice daily amikacinin 22 male neonates but no data exist on the pharmacokinetics or clinical efficacy. Incommon with other clinical areas where aminoglycosides are used, once-daily therapywould provide an opportunity to simplify dosing, perhaps reduce the number ofaminoglycoside assays and lessen toxicity in neonates. This study was designed toinvestigate the pharmacokinetics of netilmicin (6 mg/kg) given iv once a day to neonatesof varying gestational age who required admission to our Special Care Baby Unit.
Patients and methods
Neonates requiring iv antimicrobials were included in the study. Babies were excludedif they were thought to have renal imparement or had a urine output of less thanl.OmL/kg/h. In addition to netilmicin (6 mg/kg), every 24 h patients also received a/J-lactam, usually penicillin, flucloxacillin or cefotaxime. Netilmicin was administeredby slow iv injection and blood samples taken 4 h and 24 h after the first dose and 2,4, 8, 16 and 24 h after the second dose.
Netilmicin was assayed using a fluorescence polarisation method (TDx, AbbottLaboratories) employing the reverse dilution protocol we previously described forconcentrations of <1.0mg/L (White et al., 1994).
Twenty six infants were recruited to the study. Four infants had inadequate numbersof blood samples taken for pharmacokinetic analysis and one was withdrawn becauseof poor urine output. Therefore, twenty-one patients had sufficient data points ontime-serum concentration plots for pharmacokinetic analysis. Pharmacokineticparameters were calculated using a best fit line through the netilmicin concentrationsat 2, 4 and 8 h, 16 and 24 h. The serum half life (Til2f}) was calculated from the bestfit line through the 2, 4 and 8 h time points and the concentration at time zero (Co)derived by extrapolation backwards. Ttny (the serum half life related to the deepcompartment) was calculated from netilmicin concentration at 8, 16 and 24 h. Thevolume of distribution was calculated {VD - Dose/C0) and the area-under-the-curve wasdetermined using a commercially available software package (Siphar, Simed, France).
Absolute plasma clearance was calculated (C/p = Dose/AUCo x) and the relativeplasma clearance was the absolute value corrected for weight. Gestation was assessedby maternal dates and ultrasound scans at 16-18 weeks. The study was approved bythe Research Ethics Committee at Southmead Hospital.
Results
The babies were divided into three groups depending on gestational age. Group I weremore than 36 weeks old (n = 7), group II between 36 and 34 weeks (n = 6) and groupIII less than 34 weeks (n = 8). There were more males than females in each group butthe chronological age in days when therapy started was similar (Table I). Birth weightwas lower in premature babies than those delivered at term and unsurprisinglygestational age was well correlated with weight (r = 0.91, P < 0.01).
The mean netilmicin concentration (range; S.D.) 4 h after the first dose was 6.6(4.9-10.2; 1.7) in group I, 6.2 (5.5-6.7; 0.5) in group II and 5.0 (3.7-5.9; 0.7) in groupIII. Concentrations 24 h after the first dose ranged from 0.8 to 3.8 mg/L with only two
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Netilmicin pharmacokinetics in neonates 501
of 21 babies having netilmicin concentrations of < 1 mg/L but seven havingconcentrations of > 2 mg/L (Table II). The Figure and Table II show the serumnetilmicin concentrations in the 24 h after the second dose. There was considerablevariation in the measured serum netilmicin concentrations with up to five-folddifferences in concentrations 24 h afer the second dose (range 0.9-5.0 mg/L). The meannetilmicin concentration at 4 h was higher on day 2 than day 1 in all three groups. Ofthose patients who had blood taken at 4 h or 24 h on both day 1 and day 2, 17 of 20at 4 h and 15 of 18 at 24 h had higher netilmicin concentrations on day 2 than day 1.However, it was only in group III patients, that the 4 and 24 h concentrations measuredon day 1 (5.0 ± 0.7 mg/L and 2.1 ± 0.4 mg/L, respectively) were significantly lower thanthose measured on day 2 (7.1 + 1.2 mg/L and 2.7 ± 0.6 mg/L, respectively; P < 0.05 forboth 4 and 24 h data). After the second dose of netilmicin only one patient, a term babyin group I, had a 24 h post dose concentration of < 1 mg/L while 11 had concentrationsof > 2 mg/L. Although the mean netilmicin concentration ± s.D. at 2 h post dose onday 2 decreased from 10.6 + 1.2 mg/L in group I, to 9.9 + 1.0 mg/L in group II and9.2 ± 1.1 mg/L in group III, the 2 h post dose netilmicin concentration could not becorrelated with gestational age or weight. Similarly while the mean netilmicinconcentrations at 24 h post dose were higher in groups II and III than group I, 24 hpost dose concentrations could not be correlated to gestational age or weight, either onday 1 or day 2 of therapy.
The mean Tl/2p was greater in group II (6.7 ± 2.6 h) and group III (6.6 ± 2.9 h) thangroup I (4.6 + 1.3 h) and the mean volume of distribution corrected for weight increasedfrom 0.41 ± 0.05 L/kg in group I to 0.52 ± 0.09 L/kg in group III. The mean AUC alsoincreased from 199.6 ± 123.7 mg/L/h in group I to 226.9 ± 37.8 mg/L/h in group II and237.1 ± 63.1 mg/L/h in group III while the absolute plasma clearance (mL/min)declined from 2.38 ± 0.95 mL/min in group I to 1.07 ± 0.29 mL/min in group II then0.61 ± 0.21 mL/min in group III. However, if the plasma clearance was corrected forweight (mL/min/kg) then clearance only declined from 0.64 ± 0.24 mL/min/kg in groupI to 0.45 ± 0.11 mL/min/kg in group III (Table III). Neither gestational age or weightcould be correlated with TinP, volume of distribution (L/kg) nor relative plasmaclearance corrected for weight (mL/min/kg). Absolute plasma (mL/min) clearance wascorrelated to both gestational age (r = 0.858, P < 0.01) and weight (r = 0.719,P<0.0\).
We attempted to calculate the T^y but this was difficult due to the small number oftime points and complicated by the need to give a further dose every 24 h. It is likelythat the Tl/2y measured here is an under estimate of the true value.
Discussion
The mean serum T\np described in the three groups in this study ranging from 4.6 to6.7 h are similar to that previously described by Siegel et al. (1979) of 3.4-4.7 h andBergan & Michalsen (1982) of 5.8 h. Kuhn et al. (1986) reported a mean T]f2 longer thanours at 8.6 h and also a higher mean volume of distribution (0.63 mL/kg) and meanplasma clearance (0.72 mL/min/kg). The studies before that of Kuhn et al. (1986) hadreported lower mean volumes of distributions more in keeping with our observations.(Siegel et al., 1979; Bergan & Michalsen, 1982). Like others, we were unable to makeany correlations between gestational age or weight and Tmfi, VD, AUC or relativeplasma clearance, (Bergan & Michalsen, 1982; Kuhn et al., 1986). This is related to the
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Tab
le I
. P
atie
nt i
nfor
mat
ion
(mea
n (r
ange
; s.
D.))
on
the
thre
e gr
oups
ana
lyse
d (g
esta
tion
al a
ge i
n pa
rent
hesi
s ag
ains
t gr
oup
num
ber
Gro
upI
(>3
6 w
eeks
) II
(34
-36
wee
ks)
III
(<3
4 w
eeks
)
Num
ber
of p
atie
nts
7 6
8G
esta
tion
(w
eeks
) 40
(38
-42;
1.2
) 35
.5 (
35-3
6; 0
.5)
29.4
(26
-33;
2.8
)F
emal
e/m
ale
2/5
1/5
0/8
Wei
ght
(kg)
3.
67 (
3.07
-4.1
2; 0
.32)
2.
36 (
1.45
-2.8
; 0.
43)
1.39
(0.
90-1
.93;
0.3
6)C
hron
olog
ical
age
at
star
t of
the
rapy
(da
ys)
0.86
± 0
.35
1.0
±2
.2
1.5
±2
.6D
ose
(mg)
21
.7 (
18-2
4; 1
.9)
14.2
(8.
7-16
.8;
2.6)
8.
3 (6
.1-1
1.6;
2.1
)
Tab
le I
I. M
ean
netil
mic
in c
once
ntra
tion
s in
ser
um o
n th
e fi
rst
and
seco
nd d
ays
of t
hera
py
5-
Mea
n (r
ange
; S.
D.)
conc
entr
atio
ns o
f ne
tilm
icin
(m
g/L
) at
the
fol
low
ing
times
pos
t do
se (
h)fi
rst
dose
se
cond
dos
e a
4 24
2
4 8
16
24
g
Gro
up I
6.
6(4.
9-10
.2;
1.7)
1.
6(0.
8-3.
8; 1
.0)
10.6
(9.
1-13
.2;
1.4)
7.
4(5.
2-11
.2;
1.8)
4.
6(3.
4-7.
5;
1.3)
2.
7 (1
.8-6
.6;
1.7)
1.
9(0.
9-5.
0;
1.4)
*
Gro
up I
I 6.
2 (5
.5-6
.7;
0.5)
2.
1 (1
.6-3
.0;
0.5)
9.
9 (8
.9-1
1.6;
1.0
) 7.
8 (5
.6-1
0.0;
1.6
) 6.
0 (5
.2-6
.9;
0.6)
4.
0 (2
.8-4
.7;
0.6)
2.
8 (1
.9-4
.1;
0.8)
a
Gro
up
III
5.0
(3.7
-5.9
; 0.
7)
2.1
(1.6
-2.7
; 0.
4)
9.2
(7.4
-10.
6; 1
.1)
7.1
(5.7
-8.4
; 1.
2)
5.6
(3.6
-7.6
; I.
I)
3.5
(2.5
-4.6
; 0.
6)
2.7
(1.5
-3.5
; 0.
6)
P-
Tab
le I
II.
Pha
rmac
okin
etic
s of
onc
e a
day
netil
mic
in (
6 m
g/kg
/day
) in
neo
nate
s of
var
ying
age
s
Mea
n (r
ange
; s.D
.)P
aram
eter
gr
oup
I gr
oup
II
grou
p II
I
T,p
p (h
) 4.
6 (2
.8-7
.5;
1.3)
6.
7 (2
.5-1
1.4;
2.6
) 6.
6 (3
.5-1
3.0;
2.9
)T
my
(h)
15.4
(8.
0-24
.0;
5.5)
15
.6 (
11.0
-20.
0; 3
.0)
19.0
(10
.5-3
1.0;
5.9
)V
o (L
/kg)
0.
41 (
0.36
-0.4
8; 0
.05)
0.
46 (
0.33
-0.5
4; 0
.08)
0.
52 (
0.43
-0.6
7; 0
.09)
AU
C-»
(m
g/L
/h)
199.
6 (1
07.4
-469
.8;
123.
7)
226.
9 (1
23.7
-286
.0;
37.8
) 23
7.1
(170
.4-3
64.3
; 63
.1)
C/ p
(mL
/min
) 2.
38 (
0.64
-3.2
6; 0
.95)
1.
07 (
0.56
-1.4
; 0.
29)
0.61
(0.
37-1
.06;
0.2
1)C
/ p (
mL
/min
/kg)
0.
64 (
0.35
-0.9
2; 0
.24)
0.
45 (
0.39
-0.5
6; 0
.08)
0.
45 (
0.27
-0.6
1; 0
.11)
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Netihnicin pharmacokinetics in neonates 503
25
Figure . Serum concentrations of netilmicin in neonates following administration of 6 mg/kg IV. • , Patientgroup I data point; O . patient group II data point; A , patient group III data point; — • — , patient groupmean point; •••••••, patient group II mean point; — A — , patient group III mean point.
large patient to patient variation in pharmacokinetic parameters we observed whichwere five-to-six-fold for T\a$, two-fold for VD, four-to-five-fold for AUC and three-to-four-fold for weight-corrected plasma clearance. The reasons for this marked variationis unknown and was not observed in a similar study we performed in febrile adultneutropenic patients (MacGowan et al., 1994). Presumably, new born neonates haveunpredictable changes in renal function and proportion of body water which accountfor these variations. The confirmation of such variations in patients who receive singledaily doses of netilmicin is important as it indicates that gestational age is not a reliablepredictor of pharmacokinetic parameters and that a single dose corrected for weightsupported by serum netilmicin determination will be the best clinical approach to oncedaily therapy—as it is for thrice or twice a day dosing. Our data do, however, showa trend to increasing Ti., VD and AUC and reducing relative plasma clearance withdecreasing gestational age or weight, and others have been able to show Ti and VD wereinversely related to gestational age or weight (Siegel et al., 1979). This is not surprisingas glomerular filtration rate is directly related to gestational age, hence the half-life ofrenally excreted drugs is likely to be longer in premature infants. Such babies also havea higher relative extracellular fluid volume, and hence aminoglycoside volumes ofdistribution will be larger in premature infants compared to older or term neonates(Edwards, 1986). The more surprising observation is that such changes are not trans-lated into predictable changes in pharmacokinetic parameters. A deep aminoglycosidecompartment has been previously described in neonates with an elimination half life of62.4 h and our data supports the presence of a deep compartment but is insufficient tomake an accurate assessment of the Tipy. However, it is likely to be longer than themean Tll2y in the range 15.4-19 h we were able to estimate (Siegel et al., 1979).
No studies have addressed the netihnicin serum concentrations associated withefficacy or toxicity in neonates. However, by extrapolation from adult pharmacokineticdata and clinical trials performed in adults with other aminoglycosides (Noone, Pattison& Garfield, 1974; Moore, Smith & Lietman, 1984) peak levels of >6mg/L may be
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504 J. J. Ertfinger et al.
optimal in patients receiving twice or thrice daily dosing. Serum concentrationsassociated with either nephrotoxicity or ototoxicity have also been difficult to establishbut trough levels of <2 mg/L may minimise risks (MacGowan & Reeves, 1994). It isalso unknown if such a concentration also applies to neonates.
The serum netilmicin concentrations obverved in our patients are very different tothose observed with once-daily netilmicin therapy in adults. In particular the vastmajority of adult patients with normal renal function have concentrations of < 1 mg/Lat 24 h post dose. In this study only two babies had 24 h post dose levels of < 1 mg/Lafter the first dose. In addition and also unlike adults, neonatal patients showed amarked trend towards drug accumulation between the first and second doses and thiswas statistically significant with the youngest group of infants (group III). The 24 hpost-dose netilmicin remains above the MIGw of most likely pathogens, but this is notrequired for aminoglycoside efficacy. It is unknown how long it would take for serumconcentrations to drop below 1 mg/L as it was difficult for us to assess the eliminationTi from the deep compartment. To produce serum-time curves similar to adults whoreceive once daily aminoglycoside therapy, that is high post-dose (> 10 mg/L) and low( < 1 mg/L) 24 h post-dose concentrations is impossible in the neonate, due to theirlonger serum half-life and lower plasma clearance. If a 6 mg/kg dose is used in neonatesa longer dosing interval such as 48 h would be possible, alternatively a smaller dose suchas 3 mg/kg could be employed every 24 h, but then the peak concentration may be toolow. However, as there are no established correlations between serum concentrationsand efficacy or toxicity it may be reasonable to propose keeping 24 h troughconcentration below 2 mg/L, the equivalent of a sustained trough level of 2 mg/L intwice or thrice daily dosing, and, perhaps use a daily dose of 4.5 mg/kg. Clearly sucha dosing schedule would have to be validated pharmacokinetically and in terms of itsclinical efficacy and potential toxicity in a neonatal population.
AcknowledgementWe wish to thank the medical and nursing staff of Southmead Special Care Unit forhelping to perform this study.
References
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Edwards, C. (1986). Pharmacokinetics in the neonate 3. Gentamicin Pharmaceutical Journal 25,518-9.
Kafetzis, D. A., Signidou, L., Vlachos, E., Davros, J., Balramis, Y., Papandreou, E. et al. (1991).Clinical and pharmacokinetic study of single daily dose amikacin in paediatric patient withsevere gram-negative infections. Journal of Antimicrobial Chemotherapy 27, Suppl. C, 105-12.
Kuhn, R. J., Nahata, M. C , Powell, D. A. & Bickers, R. G. (1986). Pharmacokinetics ofnetilmicin in premature infants. European Journal of Clinical Pharmacology 29, 635-7.
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MacGowan, A. P. (1994). Once-daily aminoglycoside therapy: serum monitoring and clinicalindication. Syra Drug Monitor 1, 1-6.
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Parker, S. E. & Davey, P. G. (1993). Practicalities of once-daily aminoglycoside dosing. Journalof Antimicrobial Chemotherapy 31, 4-8.
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Viscoli, C , Dudley, M., Ferrea, G., Boni, L., Castagnola, E., Barretta, M. A. et al. (1991). Serumconcentration and safety of single daily dosing of amikacin in children undergoing bonemarrow transplantation. Journal of Antimicrobial Chemotherapy 27, Suppl. C, 113-20.
White, L. O., MacGowan, A. P., Lovering, A. M., Holt, H. A., Reeves, D. S. & Ryder, D. (1994).Assay of low trough serum gentamicin concentrations by fluorescence polarisationimmunoassay. Journal of Antimicrobial Chemotherapy 33, 1068—70.
(Received 3 January 1995; returned 18 February 1995; revised 8 March 1996; accepted 2 May 1996)
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