Clin Pharmacokinet 2011; 50 (8): 493-503

REVIEW ARTICLE 0312-5963/11/0008-0493/$49.95/0

ª 2011 Adis Data Information BV. All rights reserved.

A Reappraisal of Current Dosing Strategies for

Intravenous Fosfomycin in Children and Neonates
Friederike Traunmüller,1 Martin Popovic,1,2 Karl-Heinz Konz,3 Patrick Vavken,4,5 Andreas Leithner6
and Christian Joukhadar1,5,7
1 J&P Medical Research Ltd, Vienna, Austria
2 Department of Radiology, Division of Interventional and Cardiovascular Radiology, Medical University of Vienna, Vienna, Austria
3 Department of Angiology and Diabetology, Hospital St Kamillus der Kliniken Maria Hilf, Mönchengladbach, Germany
4 Department of Orthopedic Surgery, Children’s Hospital, Boston, MA, USA
5 Harvard Medical School, Boston, MA, USA
6 Department of Orthopedic Surgery, Medical University of Graz, Graz, Austria
7 Beth Israel Deaconess Medical Center, Boston, MA, USA

Contents

Abstract. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 493
1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 494
2. Methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 495
2.1 Study Collectives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 495
2.2 Pharmacokinetic Modelling. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 495
3. Simulation of Multiple Dosing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 495
3.1 Pharmacokinetic-Pharmacodynamic Calculations. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 495
4. Results . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 495
4.1 Children . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 495
4.2 Healthy Pre-Term and Full-Term Neonates . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 496
4.3 Pre-Term Neonates Aged 1–3 Days. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 496
4.4 Pre-Term Neonates Aged 3–5 Weeks . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 496
5. Discussion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 496
5.1 Pharmacokinetics of Fosfomycin in Children and Neonates. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 497
5.2 Current Dosage Recommendations in Light of Pharmacokinetic-Pharmacodynamic Theories . . . . . . . . . . . . . . . . . . . . . . . . . . 497
6. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 502

Abstract The rising incidence of multi-drug resistant bacterial pathogens has renewed interest in the long-known
antibacterial fosfomycin. Not least because of its low toxicological potential, there is good clinical experience
with intravenous fosfomycin for various Gram-positive and Gram-negative infections in the treatment of
children and neonates. However, the current dosing recommendations for intravenous fosfomycin vary
widely in paediatric patients.
In the present review, we summarized available plasma pharmacokinetic data derived from neonates or
children following intravenous administration of fosfomycin. Subsequently, we used this information for
recalculation of different dosing strategies and simulated a variety of clinically applied dosing regimens. The
percentage of time above the minimal inhibitory concentration (T>MIC) was calculated for each dosing
strategy, as this pharmacokinetic-pharmacodynamic parameter was shown to be most predictive of anti-
microbial and clinical success of fosfomycin treatment.
Our data corroborate the current practice of selecting the dosage of intravenous fosfomycin primarily on
the basis of bodyweight and age in paediatric patients. As with other ‘time-dependent’ antibacterials, a
494 Traunmüller et al.

dosing interval of 6–8 hours should be preferred over 12 hours except for immature neonates. Given a
T>MIC target of 40–70%, currently recommended dosing strategies appear to be insufficient in children
aged 1–12 years, if pathogens with MICs of ‡32 mg/L are suspected and subjects are presenting with nor-
mal renal function. Likewise, the lowest recommended daily dose for neonates and infants (aged up to
12 months) of 100 mg/kg bodyweight of fosfomycin should be considered only for pre-term neonates with a
postmenstrual age below 40 weeks.

1. Introduction as a valuable alternative agent in the armamentarium against

Infection due to multi-drug resistant bacteria is a world-wide
health problem and is associated with high mortality. While
pathogens conferring resistance to ‘standard’ antimicrobials
were initially isolated solely from hospitalized patients, they are
nowadays increasingly found in community-acquired infec-
tions.[1,2] The search for antimicrobial agents that can effec-
tively combat these problem pathogens has led to renewed
interest in the long-known antibacterial fosfomycin. Fosfo-
mycin inhibits uridine diphosphate-N-acetylglucosamine en-
olpyruvyl transferase, which is a key enzyme in early bacterial
cell-wall synthesis steps.[3] At therapeutically relevant con-
centrations, fosfomycin exerts excellent in vitro bactericidal
activity against a wide spectrum of Gram-positive and Gram-
negative bacterial pathogens. This specifically applies to me-
thicillin (meticillin)-resistant Staphylococcus aureus and meti-
cillin-resistant Staphylococcus epidermidis, penicillin-resistant
pneumococci, vancomycin-resistant enterococci, extended-
b-lactamase-producing Gram-negative species and the majority
of Pseudomonas aeruginosa strains.[4,5] Even in regions where
fosfomycin is frequently prescribed, the emergence of resistance
to fosfomycin is a minor problem.[6-10] This is probably due to
the fact that this antibacterial is currently not utilized in bio-
industry and animal husbandry.
Intravenous fosfomycin is generally well tolerated and its
adverse effects mostly do not necessitate treatment discontinua-
tion. The most relevant adverse effects, reported to occur at
a frequency of 1–10%, are gastrointestinal symptoms and
phlebitis at the site of drug administration.[5] In neonates and
children, no significant adverse events attributable to fosfo-
mycin have been observed, even after up to 4 weeks of intra-
venous administration.[11,12]
Furthermore, fosfomycin exerts favourable chemical char-
acteristics that are responsible for negligible protein binding[13]
and allow for good penetration ability into the interstitial space
fluid of tissues.[14-17] Thus, in the fosfomycin disodium for-
mulation for intravenous use, this drug preparation has been
trusted for nearly four decades by clinicians in Japan and in
different countries in the European Union and South America
multi-drug-resistant infections.[4]
As summarized in a review by Barbour et al.,[18] antibacterials
that act on bacterial cell-wall synthesis display time-dependent
killing of bacteria. The pharmacokinetic-pharmacodynamic
parameter most predictive of bacterial eradication is the time
above the minimum inhibitory concentration (T>MIC), usually
expressed as a percentage of the dosing interval.[19] Accord-
ingly, several authors have provided convincing evidence for
predominantly time-dependent killing by fosfomycin.[19-22]
However, at present there is limited information about the
breakpoint value for the T>MIC that should be targeted in
therapy with fosfomycin. The T>MIC thresholds reported for
b-lactam antibacterials may be taken as a benchmark, as these
compounds share with fosfomycin the ability to inhibit bac-
terial murein synthesis.[3,23] Clinical success may be expected
when the free plasma concentration of a b-lactam antibacterial
exceeds the pathogen’s MIC for at least 40-50% of the dosing
interval in immunocompetent subjects.[24] However, a value of
70-100% is required in difficult-to-treat infections and/or in
cases of neutropenia.[24,25]
On the other hand, there is a broad consensus that effective
target site concentrations, rather than plasma concentrations of
an antibacterial, are essential for eradication of the pathogen
and a successful clinical outcome. The derivation of dosage
recommendations for fosfomycin from plasma pharmacokinet-
ics and T>MIC estimates seems to meet both points of view,
because fosfomycin is almost entirely unbound to proteins, and
several investigations in vivo have confirmed the achievement of
a complete concentration equilibrium between plasma and in-
terstitial space fluid shortly after administration.[14-16]
Not least because of its low toxic potential, there is good
clinical experience with fosfomycin in the treatment of children
and neonates for various indications.[11,12,26,27] Table I shows
currently approved dosing schemes for children, neonates and
infants quoted in summaries of product characteristics for in-
travenous fosfomycin, which are in part influenced by locally
available formulation strengths. The daily dosage most fre-
quently chosen in clinical practice for children across a broad
age range is 200 mg/kg/day divided into two to three doses.

ª 2011 Adis Data Information BV. All rights reserved. Clin Pharmacokinet 2011; 50 (8)
Dosing of IV Fosfomycin in Children and Neonates 495

Table I. Recommended total daily dosages of intravenous fosfomycin in children, infants and neonates with normal renal function
Countrya Product name Dosage (mg/kg/d [no. of partial doses]) Reference

children aged 1–12 y; infants aged 1-12 mo; pre-term and full-term
bodyweight 10–38/40 kg bodyweight up to 10 kg neonates aged 0-1 mo
Austria Fosfomycin Sandoz 4–8 g [2–3] 100–200/400b [2–3] 100–200/400b [2–3] 5
b
Germany Infectofos 100–200/300 [3] 200–250 [3] 100 [2] 28
Spain Solufos 200–400c [2–3] 29
c,d
France Fosfocine 100–200 30
a The values were obtained from summaries of product characteristics for products distributed in these European Union member countries.
b Maximum dosage for severe infections.
c Dosage stated for ‘children’ (no sub-division for age).
d The number of partial doses was not specified.

However, the appropriate dosing of intravenous fosfomycin in 3. Simulation of Multiple Dosing

paediatric patients is still a matter of debate.
Consequently, we fitted an open two-compartment pharm-
acokinetic model to plasma concentration data for fosfomycin
from the medical literature and simulated steady-state condi-
tions for different approved and hypothetical dosing regimens.
On the basis of calculations of the T>MIC for relevant bacterial
pathogens, we herein propose optimized dosing schemata for
different age groups in paediatric patients.
2. Methods
Based on linear pharmacokinetic behaviour of fosfomycin,[35]
concentration-time curves were calculated and plotted for steady-
state conditions, aiming to simulate clinically relevant dosing
regimens. Briefly, these calculations were based on the accu-
mulation factor (Af), which can be estimated by equation 1:
1
Af ¼
1  e  kb  t (Eq. 1)
where kb is the apparent terminal elimination rate constant at
the b phase of the curve, and t is the dosing interval.[36]

2.1 Study Collectives 3.1 Pharmacokinetic-Pharmacodynamic Calculations

The mean observed concentrations from three pharm-
acokinetic studies in children and neonates were analysed.[31-33]
The published demographic characteristics and pharmaco-
kinetic data for the respective study collectives are summarized
in table II.
2.2 Pharmacokinetic Modelling
Commercially available computer software (Kinetica; In-
naphase, Philadelphia, PA, USA) was applied to fit an open
two-compartment pharmacokinetic model for intravascular
administration to each individual plasma concentration-time
profile. Subsequently, a mean model curve was generated and
used for further simulations of single- or multiple-dose regi-
mens. In cases where the individual plasma concentrations were
not available,[32] the model was fitted to the curve generated
from the reported mean values. Goodness of fit was assessed by
visual inspection of the plots and by evaluating the correlation
between observed and predicted concentrations, the random dis-
tribution of the respective residuals and the absence of a signif-
icant correlation between independent model parameters.[34]
The values of the T>MIC were calculated for plasma for
each dosing regimen using equation 2, assuming that the pa-
thogens’ MICs ranged between 8 and 32 mg/L for the vast
majority of clinically relevant bacteria:[9,37-39]
lnðCt =MICÞ
T > MIC ¼ þ Ta
kb (Eq. 2)
where Ct is the concentration at 2 hours[24,25] or 3 hours[26] after the
start of the infusion, and Ta is the duration of time between the
first available concentration exceeding the MIC and Ct.
4. Results
4.1 Children
Figures 1 and 2 show observed and predicted concentration-
time profiles following different doses and intervals in children
aged 3.5-7.9 years (bodyweight ~15-26 kg) with various infec-
tions. The observed data were derived from pharmacokinetic
studies by Iwai et al.[31] and Guggenbichler et al.[32] As shown in
table III, all dosing schedules, except for 70–100 mg/kg every

ª 2011 Adis Data Information BV. All rights reserved. Clin Pharmacokinet 2011; 50 (8)
496 Traunmüller et al.

Table II. Summary of the published demographic characteristics and pharmacokinetic data for the study collectives included in the present analysis
Study n Chronological PMAa (wk) Bodyweight Single bolus Cmax t½b (h) Vd (L/kg) CL CLR or CLCR Reference
group age (kg) dose (mg/kg) (mg/L) (mL/min/ (mL/min/
1.73 m2) 1.73 m2)
Children 5 5.6 – 1.7 y NA 19.6 – 4.5 25b 58 – 15b 0.9 – 0.2 0.32 – 0.09 4.3 – 1.2c 3.1 – 2.2c 31
Children 10 5.3 – 0.8 y NA 18.9 – 3.0 25 102 – 15 1.6 – 0.3 ~0.28 112 – 17 ND 32
Children 10 6.1 – 1.0 y NA 21.3 – 4.5 50 194 – 53 1.7 – 0.2 ~0.31 106 – 25 ND 32
Full-term 5 ND Not 3.4 – 0.3 25 62 – 18d 2.4 – 0.5 ~0.34 47 – 17 ND 32
neonatesd provided
Pre-term 5 ND Not 1.9 – 0.4 25 62 – 18d 2.8 – 0.5 ~0.41 40 – 10 ND 32
neonatesd provided
Pre-term 6 1-3 d 36.3 – 0.7 1.9 – 0.1 50 99 – 11 7.0 ND ND 15.5 – 8.2e 33
neonates
Pre-term 5 20-34 d 38.7 – 2.6 2.2 – 0.2 50 97 – 16 4.9 ND ND 19.2 – 7.3e 33
neonates
a Sum of gestational age plus chronological age.
b Infusion over 1 h.
c The values are expressed in mL/min/kg.
d Pre-term and full-term neonates were merged into a single study group.
e CLCR value.
CL = apparent total body clearance of drug from plasma; CLCR = creatinine clearance; CLR = renal clearance; Cmax = maximum plasma concentration; NA = not
applicable; ND = no data; PMA = postmenstrual age; t½b = apparent terminal elimination half-life; Vd = apparent volume of distribution.

6 hours, produced T>MIC values for MICs of £32 mg/L taken from a pharmacokinetic study by Molina et al.[33] The
(T>MIC32) of £60%. lowest recommended daily dose of fosfomycin 100 mg/kg given
in two partial doses resulted in mean plasma concentrations
4.2 Healthy Pre-Term and Full-Term Neonates higher than 32 mg/L for the entire dosing interval (table III).

Figure 3 shows observed and predicted concentration-time
profiles following different doses and intervals in healthy neo-
nates. The observed data were taken from a pharmacokinetic
study by Guggenbichler et al.[32] The study collective included
five pre-term neonates and five full-term neonates (bodyweight
1.9–3.4 kg; ages not given) in which a prophylactic antibacterial
treatment was indicated for premature rupture of the mem-
branes or primary reanimation, respectively. With an intra-
venous dosage regimen of fosfomycin 50–100 mg/kg every
8 hours or 50–70 mg/kg every 6 hours, plasma T>MIC values
between 70% and 100% for MICs of up to 64 mg/L with peak
concentrations of less than 300 mg/L could be achieved in this
study group (table III).
4.4 Pre-Term Neonates Aged 3–5 Weeks
Figure 5 shows observed and predicted concentration-time
profiles following different doses and intervals in five pre-term
neonates aged 20-34 days. Data were derived from a study by
Molina et al.[33] In this study group, with a daily dose of fos-
fomycin 100 mg/kg, a T>MIC32 of 60–80% may be expected.
In contrast, a daily dose of fosfomycin 150–200 mg/kg given
in 3–4 partial doses resulted in T>MIC32 values of >100%
(table III). The T>MIC32 values for all study groups and dif-
ferent dosing regimens are summarized in table III.
5. Discussion

4.3 Pre-Term Neonates Aged 1–3 Days
Figure 4 shows observed and predicted concentration-time
profiles of fosfomycin following different doses and intervals in
six pre-term neonates aged 1-3 days. The observed data were
The dosing recommendations for fosfomycin in paediatric
patients vary widely throughout Europe (table I). To elucidate
the relationship between age-dependent plasma pharmaco-
kinetics, recommended dosage regimens and the susceptibility
of relevant bacteria, plasma concentration data from published

ª 2011 Adis Data Information BV. All rights reserved. Clin Pharmacokinet 2011; 50 (8)
Dosing of IV Fosfomycin in Children and Neonates 497

studies on children and neonates were subjected to pharm- contribute to this finding, yet clearly the physiologically low
acokinetic modelling and pharmacokinetic-pharmacodynamic glomerular filtration rate (GFR) is the major determinant in
analysis. this particular sub-population. Figure 6 depicts the age-related
changes in GFR and creatinine clearance, a parameter that,
5.1 Pharmacokinetics of Fosfomycin in Children
despite some limitations, is widely used to estimate the GFR in
and Neonates children and neonates.[41-43]
Against this background, clinicians must meticulously con-
In healthy subjects at any age, fosfomycin is eliminated by sider the stage of renal development when compounds (such as
glomerular filtration without tubular secretion.[13,31,35] As fosfomycin) that are principally eliminated by glomerular fil-
shown in figures 1 and 2 and in table II, the plasma pharm- tration are to be used in neonates and small infants.[40,44] A
acokinetics of fosfomycin, in terms of the elimination half-life practical clue is the ‘postmenstrual age’, which represents the
and total clearance for the age group of 3-8 years,[31,32] have sum of the gestational and the chronological (postnatal) ages,
been shown to be similar to those of renally healthy adults.[13,35] and is the preferred term to describe an infant’s age during the
However, a considerable prolongation of the elimination half- neonatal period in clinical paediatrics.[45]
life was shown for the study populations comprising full-term
and pre-term neonates, with the longest value being observed 5.2 Current Dosage Recommendations in Light of
in pre-term neonates within their first postnatal week of life Pharmacokinetic-Pharmacodynamic Theories
(figures 2–5 and table II). The neonates’ larger volume of dis-
tribution, which is due to a higher relative proportion of body Drug dosing in children aged <12 years is mostly a function
water, compared with older children and adults,[40] may also of bodyweight or body surface area. Ideally, dose adjustments

Cpred (100 mg/kg sd) Cpred (200 mg/kg bid)

Cpred (50 mg/kg sd) Cpred (100 mg/kg bid)
Cpred (25 mg/kg sd) Cpred (50 mg/kg bid)
a Cobs (25 mg/kg sd) b MIC32
1000 1000

100 100

10 10
Fosfomycin plasma concentration (mg/L)

1 1

0.1 0.1
0 4 8 12 16 20 24 0 4 8 12 16 20 24

Cpred (100 mg/kg tid) Cpred (100 mg/kg qid)

Cpred (70 mg/kg tid) Cpred (70 mg/kg qid)
Cpred (50 mg/kg tid) Cpred (50 mg/kg qid)
c MIC32 d MIC32
1000 1000

100 100

10 10

1 1
0 4 8 12 16 20 24 0 4 8 12 16 20 24
Time (h)

Fig. 1. Mean (standard deviation) observed (Cobs) and predicted (Cpred) plasma concentration-time profiles of fosfomycin in children aged 3.5–7.9 y following
intravenous infusions of different doses over 1 h (n = 5):[31] (a) 25, 50 and 100 mg/kg sd; (b) 50, 100 and 200 mg/kg bid; (c) 50, 70 and 100 mg/kg tid; (d) 50, 70
and 100 mg/kg qid. bid = twice daily; MIC32 = minimum inhibitory concentration of 32 mg/L; qid = four times daily; sd = single dose; tid = three times daily.

ª 2011 Adis Data Information BV. All rights reserved. Clin Pharmacokinet 2011; 50 (8)
498 Traunmüller et al.

Cpred (100 mg/kg sd) Cpred (200 mg/kg bid)

Cpred (50 mg/kg sd)
Cpred (25 mg/kg sd)
Cobs (50 mg/kg sd)
a Cobs (25 mg/kg sd)
1000 1000
Cpred (100 mg/kg bid)
Cpred (50 mg/kg bid)
Cpred (25 mg/kg bid)
b MIC32

100 100

10 10
Fosfomycin plasma concentration (mg/L)

1 1

0.1 0.1
0 4 8 12 16 20 24 0 4 8 12 16 20 24

Cpred (100 mg/kg tid) Cpred (100 mg/kg qid)

Cpred (70 mg/kg tid) Cpred (70 mg/kg qid)
Cpred (50 mg/kg tid) Cpred (50 mg/kg qid)
c MIC32 d MIC32
1000 1000

100 100

10 10

1 1
0 4 8 12 16 20 24 0 4 8 12 16 20 24
Time (h)

Fig. 2. Mean (standard deviation) observed (Cobs) and predicted (Cpred) plasma concentration-time profiles of fosfomycin in children aged 5-6 y following
intravenous bolus administration of different doses (n = 10):[32] (a) 25, 50 and 100 mg/kg sd; (b) 25, 50, 100 and 200 mg/kg bid; (c) 50, 70 and 100 mg/kg tid;
(d) 50, 70 and 100 mg/kg qid. bid = twice daily; MIC32 = minimum inhibitory concentration of 32 mg/L; qid = four times daily; sd = single dose; tid = three times daily.

should be based on observed drug concentrations. However, T>MIC was shown to correlate well with in vitro bacterial
this is currently not feasible in clinical practice for most drugs. eradication by fosfomycin and therefore represents a valuable
Thus, in the attempt to predict clinical and antimicrobial determinant for clinical efficacy in animals and humans.[15,19-22]
treatment success of a specific dose or dosing regimen of an According to national authorities in Europe and the US, bac-
antibacterial, well established pharmacokinetic-pharmacody- terial susceptibility to fosfomycin is declared by MIC values of
namic indices are becoming increasingly influential.[18,24] The £32 and £64 mg/L, respectively. However, these susceptibility

Table III. T>MIC32 values for different fosfomycin dosing regimens

Age group T>MIC32 value (%)

50 mg 100 mg 200 mg 50 mg 70 mg 100 mg 25 mg 50 mg 70 mg 100 mg

bid bid bid tid tid tid qid qid qid qid
Children aged 3–12 y[31] 20 30 40 30 37 45 20 40 50 61
Children aged 5-6 y[32] 24 39 54 38 49 60 29 53 67 82
[32]a
Full-term and pre-term neonates 41 67 87 69 85 105 54 102 124 146
Pre-term neonates aged 1-3 d[33] 100 159 219 181 224 271 156 276 334 396
[33]
Pre-term neonates aged 20-34 d 60 101 142 107 137 169 80 163 203 245
a Merged into a single study group.
bid = twice daily; qid = four times daily; tid = three times daily; T>MIC32 = time above a minimum inhibitory concentration of 32 mg/L.

ª 2011 Adis Data Information BV. All rights reserved. Clin Pharmacokinet 2011; 50 (8)
Dosing of IV Fosfomycin in Children and Neonates 499

breakpoints are valid for distinct species only.[46-48] In general, a mended in Europe for patients aged 1–12 years can be regarded
wide spectrum of bacterial pathogens, which are causative of as sufficient only for bacteria with an MIC of not more than
infections in soft tissues, heart valves, lung, bone and joints, 16 mg/L. One way to improve the T>MIC and concomitantly
exert an MIC within the range of 8–32 mg/L.[9,37,38] Thus, to be avoid unnecessarily high peak concentrations of fosfomycin is
on the safer side, we chose an MIC of 32 mg/L as a representa- to shorten the dosing interval, e.g. 70–100 mg/kg every 6 hours.
tive target value for a treatment schedule. The T>MIC results Based on the T>MIC results, a dosing regimen of 100 mg/kg
for fosfomycin dosage regimens in children and neonates for an every 6 hours would be desirable for the treatment of infections
MIC of 32 mg/L are summarized in table III. caused by bacteria with an MIC of up to 32 mg/L, e.g. coagulase-
As shown, with the fosfomycin dosing schemes currently negative staphylococci, enterococci, distinct Enterobacteriaceae
approved in Germany, Spain and France for the age group of and P. aeruginosa. However, this regimen would amount to a
1–12 years, which amount to 100–200 mg/kg twice daily or total daily fosfomycin dose of 16 g in a child with a bodyweight of
30–100 mg/kg three times daily (table I), the minimum re- 40 kg and would thus be higher than the upper limit stated in the
quirement of a T>MIC of 40-50% is barely achieved, if at all, in Austrian regulations. Nevertheless, the proposed regimen of fos-
the study subjects (table III). Furthermore, even less clinical fomycin 100 mg/kg every 6 hours seems justifiable in a case of life-
success may be expected in immunocompromised or neutro- threatening nosocomial infection and/or disturbance of immune
penic patients. Likewise, the less restrictive Austrian recom- function, e.g. in a child with an underlying malignant disease.
mendation (fosfomycin 4–8 g daily divided into 2–3 doses) may Our pharmacokinetic-pharmacodynamic data for 1- to 3-day-
be appropriate only for children below 20 kg of bodyweight. old pre-term neonates (postmenstrual age 36-38 weeks) corrob-
Thus, it appears that the dosage schedules currently recom- orate the German dosing recommendation of 50 mg/kg twice

Cpred (100 mg/kg sd) Cpred (200 mg/kg bid)

Cpred (50 mg/kg sd) Cpred (100 mg/kg bid)
Cpred (25 mg/kg sd) Cpred (50 mg/kg bid)
a Cobs (25 mg/kg sd) b MIC32
1000 1000

100
100

10

10
Fosfomycin plasma concentration (mg/L)

0.1 1
0 4 8 12 16 20 24 0 4 8 12 16 20 24

Cpred (100 mg/kg tid) Cpred (70 mg/kg qid)

Cpred (70 mg/kg tid) Cpred (50 mg/kg qid)
Cpred (50 mg/kg tid) Cpred (25 mg/kg qid)
c MIC32 d MIC32
1000 1000

100 100

10 10

1 1
0 4 8 12 16 20 24 0 4 8 12 16 20 24
Time (h)

Fig. 3. Mean (standard deviation) observed (Cobs) and predicted (Cpred) plasma concentration-time profiles of fosfomycin in a collective comprising healthy
pre-term (n = 5) and full-term (n = 5) neonates (ages not given) following intravenous bolus administration of different doses:[32] (a) 25, 50 and 100 mg/kg sd;
(b) 50, 100 and 200 mg/kg bid; (c) 50, 70 and 100 mg/kg tid; (d) 25, 50 and 70 mg/kg qid. bid = twice daily; MIC32 = minimum inhibitory concentration of 32 mg/L;
qid = four times daily; sd = single dose; tid = three times daily.

ª 2011 Adis Data Information BV. All rights reserved. Clin Pharmacokinet 2011; 50 (8)
500 Traunmüller et al.

daily. With this regimen, bacteria with an MIC of up to 64 mg/L paired. Actually, a daily dose of fosfomycin 200 mg/kg in
are expected to be covered for 65% to >100% of the dosing 2–3 divided doses, which amounts to 1–2 g/day for a body-
interval, even though a somewhat reduced ability to combat weight of 5–10 kg, is the most frequently utilized dosage for
bacterial infections may be assumed in pre-term neonates. infants in current clinical practice. Plasma concentration data
However, in another group of neonates at a chronological age for intravenous fosfomycin in infants between 1 and 12 months
of 3–5 weeks (postmenstrual age 36–43 weeks), the clearance of of age are currently not available in the medical literature.
fosfomycin was higher, presumably in accordance with the However, as the GFR in children at 44 weeks of postmenstrual
more advanced stage of renal development. Thus, in this par- age rapidly reaches and even exceeds the corresponding values
ticular group, the dosage schedule of fosfomycin 50 mg/kg twice in adults,[40,42] a daily dose of fosfomycin 300 mg/kg may be
daily may be regarded as less advantageous on the grounds of more appropriate in the respective children’s age group.
the postulated requirement for a T>MIC of 40–100%. A dos- Recently, Suzuki et al.[49] published easily comprehensible
age of fosfomycin 25 mg/kg four times daily may be a better equations for estimation of appropriate dosing of antimicrobial
choice when a total daily dose of 100 mg/kg is targeted. The agents undergoing extensive renal excretion. According to
approved dosage schedules of fosfomycin 50–70 mg/kg three these authors, and given the negligible protein binding and the
times daily or ideally 50 mg/kg four times daily (total daily dose lack of significant tubular secretion of fosfomycin, the dose
150–210 mg/kg) may be taken into consideration for severe adjustments may be provided by the GFRinfants/GFRadults
infections, when less susceptible pathogens are suspected or ratio. As the dosing recommendations in this publication were
when the infant’s immune system is underdeveloped or im- established for fosfomycin in an orally administered low-dose

Cpred (100 mg/kg sd) Cpred (200 mg/kg bid)

Cpred (50 mg/kg sd) Cpred (100 mg/kg bid)
Cpred (25 mg/kg sd) Cpred (50 mg/kg bid)
a Cobs (50 mg/kg sd) b MIC32
1000 1000

100
100

10

10
Fosfomycin plasma concentration (mg/L)

0.1 1
0 4 8 12 16 20 24 0 4 8 12 16 20 24

Cpred (100 mg/kg tid) Cpred (70 mg/kg qid)

Cpred (70 mg/kg tid) Cpred (50 mg/kg qid)
Cpred (50 mg/kg tid) Cpred (25 mg/kg qid)
c MIC32 d MIC32
1000 1000

100 100

10 10

1 1
0 4 8 12 16 20 24 0 4 8 12 16 20 24
Time (h)

Fig. 4. Mean (standard deviation) observed (Cobs) and predicted (Cpred) plasma concentration-time profiles of fosfomycin in pre-term neonates aged 1–3 d
(postmenstrual age 36–38 wk) following intravenous bolus administration of different doses (n = 6):[33] (a) 25, 50 and 100 mg/kg sd; (b) 50, 100 and 200 mg/kg
bid; (c) 50, 70 and 100 mg/kg tid; (d) 25, 50 and 70 mg/kg qid. bid = twice daily; MIC32 = minimum inhibitory concentration of 32 mg/L; qid = four times daily;
sd = single dose; tid = three times daily.

ª 2011 Adis Data Information BV. All rights reserved. Clin Pharmacokinet 2011; 50 (8)
Dosing of IV Fosfomycin in Children and Neonates 501

Cpred (100 mg/kg sd) Cpred (200 mg/kg bid)

Cpred (50 mg/kg sd) Cpred (100 mg/kg bid)
Cpred (25 mg/kg sd) Cpred (50 mg/kg bid)
a Cobs (50 mg/kg sd) b MIC32
1000 1000

100
100

10

10
Fosfomycin plasma concentration (mg/L)

0.1 1
0 4 8 12 16 20 24 0 4 8 12 16 20 24

Cpred (100 mg/kg tid) Cpred (70 mg/kg qid)

Cpred (70 mg/kg tid) Cpred (50 mg/kg qid)
Cpred (50 mg/kg tid) Cpred (25 mg/kg qid)
c MIC32 d MIC32
1000 1000

100 100

10 10

1 1
0 4 8 12 16 20 24 0 4 8 12 16 20 24
Time (h)

Fig. 5. Mean (standard deviation) observed (Cobs) and predicted (Cpred) plasma concentration-time profiles of fosfomycin in pre-term neonates aged 20-34 d
(postmenstrual age 36–43 wk) following intravenous bolus administration of different doses (n = 5):[33] (a) 25, 50 and 100 mg/kg sd; (b) 50, 100 and 200 mg/kg
bid; (c) 50, 70 and 100 mg/kg tid; (d) 25, 50 and 70 mg/kg qid. bid = twice daily; MIC32 = minimum inhibitory concentration of 32 mg/L; qid = four times daily;
sd = single dose; tid = three times daily.

preparation, they cannot be adopted for intravenous fosfo- CLCR (Galaske et al.)
GFR (Atiyeh et al.)
mycin without taking the oral bioavailability of approximately GFR (Rhodin et al.)
30%[35] into account. However, the concept that appropriate Sigmoid hyperbolic model
dosing of fosfomycin in neonates and small infants is a function 120
GFR or CLCR (mL/min/1.73 m2)

of the natural progression in renal development is confirmed by 100

this study.
80
It should be emphasized that in the present analysis, plasma
concentration data from renally healthy children were pro- 60
cessed. To date, fosfomycin plasma pharmacokinetic profiles
40
derived from children or neonates presenting with different
degrees of renal insufficiency have not been published in the 20

medical literature. However, Fernandez Lastra et al.[50] found a 0

strong positive correlation between creatinine clearance and the 0 20 40 60 80 100 120

elimination rate constant of fosfomycin at the b phase in adults Postmenstrual age (wk)

with different degrees of renal impairment. Thus, a significant Fig. 6. Increase in mean GFR or CLCR with postmenstrual age (gestational
reduction of total clearance and a prolongation of the plasma age plus chronological age) according to Galaske et al.,[41] Atiyeh et al.[42] and
Rhodin et al.[43] The sigmoid hyperbolic model was established from pooled
elimination half-life, compared with children with normal renal
GFR data.[43] GFR values of 120 mL/min/1.73 m2 (comparable to values in
function, can be assumed. This concept, however, remains to be adults) are approached within 1 y of chronological age (92 wk of post-
confirmed in paediatric patients. menstrual age). CLCR = creatinine clearance; GFR = glomerular filtration rate.

ª 2011 Adis Data Information BV. All rights reserved. Clin Pharmacokinet 2011; 50 (8)
502
As fosfomycin is administered intravenously in the form of a
sodium salt, precautionary monitoring of the plasma electrolytes
during therapy is advisable. A reduced ability to excrete large
amounts of sodium has been described for full-term neonates as
compared with older infants.[42] In contrast, for pre-term neo-
nates, low tubular reabsorption of sodium and diminished re-
sponsiveness of the distal tubules to aldosterone, leading to an
increased risk of negative sodium balance, was reported.[42,51]
With a partial dose of fosfomycin 50–100 mg/kg in neonates
and infants up to 12 kg of bodyweight, 2.2-17.4 mmoL of so-
dium enters the blood stream, which is supposed to be easily
tolerated.[42,51] To date, there have been no published reports of
cases of fosfomycin-induced hypernatraemia in paediatric
patients that would have required therapeutic measures.
6. Conclusions
Our data corroborate the current practice of selecting the
dosage of intravenous fosfomycin for paediatric patients on the
basis of bodyweight and age. Neonates should be distinguished
by their postmenstrual age rather than by their chronological
age. As with other ‘time-dependent’ antibacterials, a dosing
interval of 6–8 hours should be preferred over 12 hours, except
in pre-term neonates. From a pharmacokinetic-pharmacody-
namic point of view, the currently recommended dosing stra-
tegies for renally healthy children aged 1–12 years appear to be
insufficient when pathogens with an MIC of ‡32 mg/L are
suspected.
Based on T>MIC calculations and current knowledge of
renal clearance of fosfomycin, we provide circumstantial evi-
dence that currently applied and used fosfomycin dosing strategies
require substantial modifications and appear to be suboptimal
for many age groups in children and neonates. However, fur-
ther work is necessary to determine appropriate T>MIC thresh-
olds for therapy with intravenous fosfomycin, to investigate the
pharmacokinetics of fosfomycin in children of any age pre-
senting with different degrees of renal impairment and, finally,
to study the safety and efficacy of the herein recalculated dosing
schemata in well designed clinical trials.
Acknowledgements
We very much appreciate Dieter Steinort’s personal input and signif-
icant dedication to make this interdisciplinary article possible. He is a
consultant for J&P Medical Research Ltd (Vienna, Austria).
Transparency declarations: J&P Medical Research Ltd is an interna-
tional independent life-science research institute, basically operating ac-
cording to the public-private-partnership concept. C. Joukhadar is the
managing director of J&P Medical Research Ltd, owns 100% options, and
ª 2011 Adis Data Information BV. All rights reserved.
Traunmüller et al.
is also a consultant for pharmaceutical companies, including Sandoz and
InfectoPharm, two manufacturers of fosfomycin. F. Traunmüller is an
employee of J&P Medical Research Ltd. All other authors declare that
they have no relationship with companies that make products relevant to
the manuscript, and that they have no conflicts of interest with the present
work. No funding was received for the present article.
List of authors and contributions: Friederike Traunmüller – primary
author of the manuscript; Martin Popovic – pharmacokinetic modelling of
data; Karl-Heinz Konz – substantive suggestions for revision; Patrick
Vavken – co-author of the manuscript and figures; Andreas Leithner –
proofreading and substantial revision of the manuscript; Christian Jou-
khadar – planning of the article, interpretation of data, approval of the
final version of the manuscript and corresponding author.
References
1. Klevens RM, Morrisson MA, Nadle J, et al. Invasive methicillin-resistant
Staphylococcus aureus infections in the United States. JAMA 2007; 298 (15):
1763-71
2. Jones RN, Jacobs MR, Sader HS. Evolving trends in Streptococcus pneumo-
niae resistance: implications for therapy of community-acquired bacterial
pneumonia. Int J Antimicrob Agents 2010 Sep; 36 (3): 197-204
3. Kahan FM, Kahan JS, Cassidy PJ, et al. The mechanism of action of fosfo-
mycin (phosphonomycin). Ann N Y Acad Sci 1974; 235: 364-86
4. Popovic M, Steinort D, Pillai S, et al. Fosfomycin: an old, new friend? Eur
J Clin Microbiol Infect Dis 2010; 29: 127-42
5. Sandoz GmbH. Fosfomycin ‘‘Sandoz’’ 1g i.v.-Trockensubstanz zur In-
fusionsbereitung: summary of product characteristics [in German; online].
Available from URL: http://www.pharmazie.com/graphic/A/07/0-17307.pdf
[Accessed 2011 May 5]
6. Daza R, Gutierrez J, Piedrola G, et al. Antibiotic susceptibility of bacterial
strain isolated from patients with community-acquired urinary tract infec-
tions. Int J Antimicrob Agents 2001; 18: 211-5
7. Bert F, Bruneau B, Lambert-Zechovsky N, et al. Epidemiological studies of the
susceptibility of Pseudomonas aeruginosa to antibiotics [in French]. Pathol
Biol (Paris) 1994; 42: 491-7
8. Witte W. Zur MRSA-Situation in Deutschland 2005 und 2006: Situa-
tionsbericht aus dem Nationalen Referenzzentrum für Staphylokokken.
Epidemiologisches Bulletin 2007 Feb 9; (6): 41-6 [online]. Available from
URL: http://www.rki.de/cln_109/nn_264978/DE/Content/Infekt/EpidBull/
Archiv/2007/06__07,templateId=raw,property=publicationFile.pdf/06_07.pdf
[Accessed 2011 May 31]
9. Falagas ME, Maraki S, Karageorgopoulos DE, et al. Antimicrobial suscepti-
bility of Gram-positive non-urinary isolates to fosfomycin. Int J Antimicrob
Agents 2010; 35: 497-9
10. Falagas ME, Kastoris AC, Kapaskelis AM, et al. Fosfomycin for the treatment
of multidrug-resistant, including extended-spectrum b-lactamase producing,
Enterobacteriaceae infections: a systematic review. Lancet Infect Dis 2010;
10: 43-50
11. Corti N, Sennhauser FH, Stauffer UG, et al. Fosfomycin in the initial treat-
ment of acute haematogenous osteomyelitis. Arch Dis Child 2003; 88: 512-6
12. Baquero F, Hortelano JG, Navarro M, et al. Antibiotherapy of Serratia
marcescens septicemia in children. Chemotherapy 1977; 23 (Suppl. 1): 416-22
13. Kirby WMM. Pharmacokinetics of fosfomycin. Chemotherapy 1977; 23:
141-51
14. Frossard M, Joukhadar C, Erovic B, et al. Distribution and antimicrobial
activity of fosfomycin in the interstitial fluid of human soft tissues. Anti-
microb Agents Chemother 2000; 44 (10): 2728-32
15. Joukhadar C, Klein N, Dittrich P, et al. Target site penetration of fosfomycin in
critically ill patients. J Antimicrob Chemother 2003; 51: 1247-52
Clin Pharmacokinet 2011; 50 (8)
Dosing of IV Fosfomycin in Children and Neonates
16. Legat FJ, Maier A, Dittrich P, et al. Penetration of fosfomycin into in-
flammatory lesions in patients with cellulitis and diabetic foot syndrome.
Antimicrob Agents Chemother 2003 Jan; 47 (1): 371-4
17. Matzi V, Lindenmann J, Porubsky C, et al. Extracellular concentrations of
fosfomycin in lung tissue of septic patients. J Antimicrob Chemother 2010; 65:
995-8
18. Barbour A, Scaglione F, Derendorf H. Class-dependent relevance of tissue
distribution in the interpretation of anti-infective pharmacokinetic-pharma-
codynamic indices. Int J Antimicrob Agents 2010; 35: 431-8
19. Kumon H, Ono N, Iida M, et al. Combination effect of fosfomycin and
ofloxacin against Pseudomonas aeruginosa growing in a biofilm. Antimicrob
Agents Chemother 1995; 39 (5): 1038-44
20. Grif K, Dierich MP, Pfaller K, et al. In vitro activity of fosfomycin in combi-
nation with various antistaphylococcal substances. J Antimicrob Chemother
2001; 48: 209-17
21. Pfausler B, Spiss H, Dittrich P, et al. Concentrations of fosfomycin in the
cerebrospinal fluid of neurointensive care patients with ventriculostomy-
associated ventriculitis. J Antimicrob Chemother 2004; 53: 848-52
22. Zeitlinger MA, Marsik C, Georgopoulos A, et al. Target site bacterial killing of
cefpirome and fosfomycin in critically ill patients. Int J Antimicrob Agents
2003; 21: 562-7
23. Frère JM. Proceedings: the molecular mechanism of action of beta-lactam
antibacterials: the solution of an apparent paradox. Arch Int Physiol Biochim
1975; 83: 184-6
24. Craig WA. Interrelationship between pharmacokinetics and pharmaco-
dynamics in determining dosage regimens for broad-spectrum cephalospor-
ins. Diagn Microbiol Infect Dis 1995; 22: 89-96
25. Scaglione F, Paraboni L. Pharmacokinetics/pharmacodynamics of antibac-
terials in the intensive care unit: setting appropriate dosage regimens. Int J
Antimicrob Agents 2008; 32: 294-301
26. LLorens J, Ley G, Forés A, et al. Acute infantile pneumonopathies treated with
fosfomycin. Chemotherapy 1977; 23 (Suppl. 1): 315-23
27. Aoyagi S, Kawara T, Mizoguchi T, et al. Methicillin-resistant Staphylococcus
aureus endocarditis following patch closure of a ventricular septal defect:
report of a case. Jpn J Surg 1994; 24: 644-7
28. Infectopharm Arzneimittel und Consilium GmbH. Infectofos 2g/3g/5g/8g:
summary of product characteristics [in German]. Heppenheim: Infectopharm
Arzneimittel und Consilium GmbH, 2009 Jun
29. Laboratorios Busto. Solufos intravenoso 4g 1 inyectable: summary of pro-
duct characteristics [in Spanish; online]. Available from URL: http://prospec
tos.org/prospectos/solufos-intravenoso-4g-1-inyectable/ [Accessed 2011 May 5]
30. Sanofi-Aventis France. Fosfocine 4g IV, poudre et solution préparation in-
jectable pour perfusion: summary of product characteristics [in French; on-
line]. Available from URL: http://www.therapeutique.info/rcp.php?code=
4342 [Accessed 2011 May 5]
31. Iwai N, Nakamura H, Miyazu M, et al. A study of the absorption and excretion
of fosfomycin in children. Jpn J Antibiot 1991 Mar; 44 (3): 345-56
32. Guggenbichler JP, Kienel G, Frisch H. Fosfomycin, ein neues Antibiotikum.
Padiatr Padol 1978; 13: 429-36
33. Molina MA, Olay T, Quero J. Pharmacodynamic data on fosfomycin in under-
weight infants during the neonatal period. Chemotherapy 1977; 23 (Suppl. 1):
217-22
ª 2011 Adis Data Information BV. All rights reserved.
503
34. Gabrielsson J, Weiner D. Pharmacokinetic and pharmacodynamic data anal-
ysis: concepts and applications. 3rd ed. Stockholm: Apotekarsocieteten, 2000
35. Goto S. Fosfomycin, antimicrobial activity in vitro and in vivo. Chemotherapy
1977; 23 Suppl. 1: 63-74
36. Toutain PL, Bousquet-Mélou A. Plasma terminal half-life. J Vet Pharmacol
Ther 2004; 27: 427-39
37. Bogdanovich T, Ednie LM, Shapiro S, et al. Antistaphylococcal activity of
ceftobiprole, a new broad-spectrum cephalosporin. Antimicrob Agents
Chemother 2005 Oct; 49 (10): 4210-9
38. Allerberger F, Klare I. In-vitro activity of fosfomycin against vancomycin-
resistant enterococci. J Antimicrob Chemother 1999; 43: 211-7
39. Schito GC, Naber KG, Botto H, et al. The ARESC study: an international
survey on the antimicrobial resistance of pathogens involved in uncom-
plicated urinary tract infections. Int J Antimicrob Agents 2009; 34: 497-513
40. Alcorn J, McNamara PJ. Pharmacokinetics in the newborn. Adv Drug Del Rev
2003; 55: 667-86
41. Galaske RG. Renal functional maturation: renal handling of proteins by ma-
ture and immature newborns. Eur J Pediatr 1986; 145: 368-71
42. Atiyeh BA, Dabbagh SS, Gruskin AB. Evaluation of renal function during
childhood. Pediatr Rev 1996; 17: 175-80
43. Rhodin MM, Anderson BJ, Peters AM, et al. Human renal function matura-
tion: a quantitative description using weight and postmenstrual age. Pediatr
Nephrol 2009; 24: 67-76
44. Olavarrı́a F, Dölz H, Krause S, et al. Influence of gestational age and postnatal
kidney maturation on the kinetics of gentamicin. Rev Chil Pediatr 1990 Mar-
Apr; 61 (2): 86-90
45. American Academy of Pediatrics. Policy statement: age terminology during the
neonatal period. Pediatrics 2004; 114: 1362-4
46. European Committee on Antimicrobial Susceptibility Testing. Clinical
breakpoints [online]. Available from URL: http://www.eucast.org/clinical_
breakpoints/ [Accessed 2011 May 4]
47. Members of the SFM Antibiogram Committee. Comité de l’Antibiogramme de
la Société Franc¸aise de Microbiologie report 2003. Int J Antimicrob Agents
2003; 21: 364-91
48. Clinical and Laboratory Standards Institute. Performance standards for
antimicrobial susceptibility testing: eighteenth informational supplement
[document reference M100-S18; online]. Available from URL: http://www.
clsi.org [Accessed 2011 Apr 4]
49. Suzuki S, Murayama Y, Sugiyama E, et al. Dose estimation for renal-excretion
drugs in neonates and infants based on physiological development of renal
function. Yakugaku Zhassi 2009; 129 (7): 829-42
50. Fernandez Lastra C, Mariño EL, Dominguez-Gil A, et al. The influence of
uremia on the accessibility of phosphomycin into interstitial tissue fluid. Eur J
Clin Pharmacol 1983; 25: 333-8
51. Al-Dahhan J, Haycock GB, Chantler C, et al. Sodium homeostasis in term and
preterm neonates. Arch Dis Child 1983; 58: 335-42
Correspondence: Dr Christian Joukhadar, J&P Medical Research Ltd,
AuhofstraXe 15/8-9, 1130 Vienna, Austria.
E-mail: christian.joukhadar@jp-medical-research.com or cjoukhad@bidmc.
harvard.edu
Clin Pharmacokinet 2011; 50 (8)