P97
CONCURRENT FRUSEMIDE-THEOPHYLLINE
PHARMACOKINETICS IN PRETERM INFANTS
DOSING
INFLUENCES
VANCOMYCIN
Yeung MY, Smyth JP*, Tracy MB*

Department of Pharmacy *Dept of Neonatal Intensive Care, Nepean Hospital, Sydney, NSW
Background: We have observed an acute decrease in vancomycin serum levels to subtherapeutic range and
failure to achieve anticipated therapeutic levels in babies after receiving theophylline and frusemide
concurrently when usual dosage of vancomycin were given. An increase in glomerular filtration rate (GFR) by
20% in preterm infants after a dose of 5mg/kg of theophylline for apnoea of prematurity was first reported 20
years ago.(1) Huet et al reported dramatic improvement in crea- tinine clearance and urine output in babies
failing to respond to frusemide alone when a stat dose of theophylline (1mg/kg) was added to the treatment of 5
ventilated neonates with respiratory distress syndrome and oliguria. (2) Intravenously administered vancomycin is
80-90% and gentamicin is 100% excreted by glomerular filtration.(3)(4) As gentamicin elimination rate, hence
elimination half-life (te½), has been shown to parallel GFR in preterm neonates,(5 ) changes in vancomycin
serum level, which reflect changes in its pharmacokinetics, should be an equally sensitive marker of GFR
variation. Frusemide treatment is known to induce renal renin release. (6) whereas the intrarenal adenosine,
acting synergistically with angiotensin II, a renin metabolite, mediates the tubuloglomerular feedback, (7) which
is blocked by theophylline, an adenosine receptor antagonist. (8)
Aim: To report the effect of concurrent theophylline-frusemide treatment on vancomycin pharmacokinetics in preterm infants by prospective observation.
Method: All preterm infants who had received vancomycin and had its serum levels measured while being
concurrently treated with theophylline or frusemide alone, or the combination of these two agents were included
so that each infant served as his/her own control. Data on serial serum creatinine levels were also gathered to
detect any significant change in this parameter in relation to the medications given.
Results: Of the 6 preterm infants (GA=27-32 wks, birth wt = 620-1600g) who fulfilled study criteria, none
experienced significant hypoxia and/or acute weight gain during the observation periods of 24 hours each.
Concurrent dosing of theophylline and frusemide coincided with a mean of 20% decrease in serum creatinine
levels, at the same time, there was a drop in vancomycin serum levels to subtherapeutic ranges from previously
attained therapeutic levels, or failure of vancomycin to achieve the anticipated therapeutic levels when initiating
treatment. Theophylline or frusemide administered alone had no effect on these parameters.
Discussion: The intrarenal adenosine-mediated tubuloglomerular feedback would counteract the increase in
glomerular filtration fraction & tubular reabsorptive workload brought about by frusemide-induced increase in
renal renin release. (6)(7) When this tubuloglomerular feedback is eliminated by theophylline(8), the increased
renal renin would increase glomerular filtration fraction, therefore, GFR, as a result of enhanced efferent
vasoconstriction. Since the absence of acute weight gain makes an expansion in volume of distribution unlikely
as a contributing factor, the acute drop in serum creatinine levels and vancomycin serum levels, or lower serum
vancomycin levels attained could be the manifestation of an increase in GFR consequent to the effect of this
theophylline-frusemide pharmacodynamic interaction on the tubuloglomerular system.
1
Zakauddine S, Leake RD and Trygstad CW. Renal effects of theophylline in the premature infant. [Abstract] Clin Res
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USPDI
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