When unknown sepsis occurs in the newborn (0-4 weeks), ampicillin + gentamicin are given irrespecti

Fråga: When unknown sepsis occurs in the newborn (0-4 weeks), ampicillin + gentamicin are given irrespective of intrauterine age.

Is there any documentation about which gentamicin concentrations that are likely to induce kidney damage or ototoxicity? Are these levels the same as for adults?

Sammanfattning: Gentamicin maximum plasma levels above 10-12 ug/ml and predose concentrations higher than 2 ug/ml should be avoided to prevent risk of oto and nephrotoxicity. There are presently no data to support that other treshold concentrations should be valid for term or preterm neonates.

Svar: Gentamicin is a broad spectrum aminoglucoside extensively used for the treatment of neonatal sepsis. The antimicrobial effect is achieved with serum concentrations around 4 ug/ml. The dose recommended to obtain this serum concentration varies depending on gestational age and birth weight.

Concerning gestational age, there is a slow increase in renal function until week 34 when a marked increase in creatinine clearance is evident. Since this drug is eliminated by glomerular filtration, half life as well as predose and postdose serum levels decrease with increasing gestational age (1). Thereby, in term infants the administration of 2.5 mg/kg/12 hr of gentamicin is recommended as starting dose the first week of life and 2.5 mg/kg/18 hr in preterm infants (2,3). After the first few doses the dose/dose interval must be guided by regular serum concentration determinations.

However, there is a big variability and impredictable variations in serum levels after standard dosage can be obtained.

In adults, it has been well established that serum concentrations above 12 ug/ml may produce ototoxicity (4). Few studies have been performed in neonates due to the difficulties on testing the hearing. Colding et al (5) have administered an iv infusion of gentamicin to 88 newborn infants keeping a steady state serum concentration of 4 ug/ml. After 4 years, 48 of these infants have been examined and no hearing loss was found.

Nephrotoxicity in the newborn infant is difficult to evaluate: renal function increases during the first week of life and differs from preterm to on-term infants, clearance determinations are difficult to perform in neonates and serum creatinine elevation is a late manifestation of impaired kidney function not reflecting acute disturbances.

Studies in adults suggest that pre-dose gentamicin concentrations greater than 2 ug/ml are associated with an increasing risk of nephrotoxicity ocurring in 3-10 per cent of adult patients (2). However, impaired renal function per se will lead to higher predose levels.

Several enzymes have been measured trying to find an index of a possible renal damage. N-acetyl-beta-glucosaminidase (NAG), a lysosomal enzyme excreted in the urine after damage to the proximal tubule cell, is excreted in larger amounts in infants treated with gentamicin. This suggests damage to the lysosomes in the proximal tubular cells but does not imply by itself diseased kidneys. Enzymuria did correlate with predose concentrations above 2 ug/ml (6). However, there is another study preformed in 107 neonates receiving gentamicin where the increased excretion of this enzyme did not correlate with through concentrations but did correlate with the peaks (7).

From a recent study on data from 143 infants a nomogram has been constructed for calculation of adequate initial doses for these patients (8). Prospective therapeutic drug monitoring is of course also requested.