Indian Pediatrics 1999; 36:133-137 

Randomized Controlled Trial of Once vs Twice Daily Gentamicin Therapy in Newborn

Gentamicin is often used in combination with β-Iactam antibiotics as a first line drug in nurseries for treating infants with suspected or documented bacterial infection. With an elimination half life of 6.25 hours in preterms and 4.5 hours in term neonates( 1), gentamicin has conventionally been given at 12 hourly intervals in the first week of life. However, extended dosage intervals are being advocated for better antibacterial killing and reduced toxicity(2,3). Further, it avoids the development of adaptive resistance(4).

The aim of this study was to determine whether gentamicin administered once daily is as good as the standard twice daily regimen by estimation of peak and trough gentamicin levels in newborn babies.

Seventy three neonates born at gestational ages of 32 weeks or more in the Christian Medical College and Hospital, Vellore, between November 1996 and October 1997 with suspected or confirmed infection in early neonatal life for which gentamicin therapy was indicated were included in this study. All the babies studied were hemodynamically stable and had normal urine output. Serum electrolytes and. blood urea were within normal limits. None of the mothers received gentamicin prior to delivery.

The subjects were divided into preterm (32-36 weeks) and term (≥37 weeks) groups. Babies in each of these groups were randomly assigned to receive injection gentamicin at a dose 'of either 2.5 mg/kg twice a day or 4 mg/kg once daily. The drug was taken from a stock solution of 4 mg/ml and administered intravenously over Y2 hour followed by a 0.5 ml of normal saline flush.

Blood for serum gentamicin concentration (SGC) estimation was drawn from, a peripheral vein using .a sterile needle in a plastic , sample collection tube with no anticoagulants. The blood samples for trough and peak levels were collected half an hour before and 1 hour after administration of the second dose of gentamicin.

Blood was allowed to clot and the serum separated. SGC was estimated in the laboratory within 12 hours using the EMIT- Gentamicin kit (Behring Diagnostic Inc., California, USA) with Hitachi 704 selective discrete analyzer. Along with every batch of patient samples, quality control serum at two levels (Bio-Rad Laboratories, California, USA) were also analyzed. Samples with gentamicin concentration >6 µg/ml were suitably diluted and reassessed. This method has a sensitivity of 0.2 µg/ml and a day-to-day co-efficient of variation of <3%. .

Trough levels of <2 µg/ml and peak levels of 4-10 µg/ml were considered as normal(5). When any baby was found to have levels outside the therapeutic range, the dosage schedule was changed as per the nursery protocol.

Statistical Analysis

This trial was an "equivalence trial" using the alternative hypothesis that the treatment effects are similar or the difference between the two arms is within the difference 8*=10%. Statistical methods for equivalence trials such as 95% confidence intervals (CI) and test of significance incorporating a clinically meaningful difference (8*=10%) were used(6).

The sample size was calculated with α and β errors at 5% and 20% respectively and 8*=10% using the formula meant for equivalence trials(6).

Results

Forty eight term and 25 preterm babies were included in the study. Among preterms, the mean birth weight and gestational age were comparable in the once and twice daily groups: 1919 ± 255 g vs 1830 ± 184 g, and 34.2 ± 1.1 weeks vs 33.0 ± 0.7 weeks, respectively. Similarly, the mean birth weight and gestational age of term neonates in the once and twice daily groups were comparable,: 2935 + 552 g vs 2968 ± 613g and 39.2 ± 1.4 weeks vs 39 ± 1.3 weeks, respectively. AU the preterm infants were appropriate for gestational age, whereas the five term small for gestational age babies were equally distributed: 2 in the twice daily and 3 in the twice daily group.

The results of peak and trough SGC estimation are depicted in Table 1. In the preterm group, 30.8% and 58.3% of babies had trough levels >2µg/ml in the once daily and twice daily arms, respectively. The lower limit of the 95% CI (-11 %) suggests that toxic trough levels would be as low as 11% in the once daily regimen. There is also significant evidence (p = 0.06) to show that the effects are similar. In this sub-group, the two regimens are also similar in terms of peak values outside the therapeutic range.
 

TABLE I 

Serum Gentamicin Concentration by Gestational Age Subset After 4mg/kg Once Daily and 2.5 mg/kg Twice Daily Dosage.

Among babies of ≥37 weeks' gestation, 8.3% of babies once daily gentamicin had trough values >2 µg/ml, as compared to 12.5%  of babies given twice daily gentamicin. The lower limit of the 95% CI of -12.8% implies that the effect of once daily gentamicin could be as low as 12.8%. There is also marginally significant evidence (p=0.10) to show that the effects are similar. There is also evidence to show that the two regimens are similar in the occurrence of toxic and sub-therapeutic peak levels of SGC in terms babies.

Thus, it is evident that gentamicin administered intravenously at 4 mg/kg once daily is as effective as 2.5 mg/kg given twice daily, both in term and preterm neonates.

Discussion

In early neonatal life many infants receive prophylactic and therapeutic gentamicin for the management of sepsis. In treating these babies it is important to minimize the toxic effects of the drug. It is just as important not to treat these infants inadequately if they have a life threatening infection. To attain optimum therapeutic levels and minimize toxic side effects, many dosage schedules of gentamicin have been recommended such as at 12 hourly, 18 hourly and 24 hourly intervals(7,8).

Five half-lives of gentamicin are necessary to achieve a steady state level(9), but stress is given to estimate SGC early in the course of therapy so that any necessary modification may be made immediately to achieve the optimal concentration(10). Thus we have estimated SGC with the second dose of the drug, similar to other trials(8, 11).

In this study adequate therapeutic levels of gentamicin were achieved in term babies on once daily (92.4%) as well as twice daily (83.4%) regimens. Similar results were also obtained in preterm babies on either regimen: once daily (87.5%) and twice daily (83.4%). This is in accordance with other studies(12- 14).

Trough SGC above 2 µg/ml and 4 µg/ml increase the likelihood of nephrotoxicity and ototoxicity, respectively(15- 18). In the present study, both in term and preterm neonates, the percentage of babies with trough levels beyond the therapeutic range was com- parable in the two regimens. Some authors have reported significantly greater incidence of toxic trough levels with twice daily gentamicin administration, although we did not find this(7, 11, I 3). The percentage of babies with elevated peak SGCs was also comparable in both regimens.

Thus our study shows that a once daily regimen of gentamicin therapy is as good as the twice daily regimen in terms of trough and peak SGC in early neonatal life.

A once daily regimen has several advantages over the twice daily regimen. Despite its relatively short half life, gentamicin has a prolonged post antibiotic effect; antibacterial activity persists beyond the time that measurable drug is present in the blood(19). Moreover, once daily administration allows less contact time between the organism and the drug and thus has less opportunity for adaptive post- exposure resistance to develop(4).

Further, in health care centers with limited resources in terms of disposables, medications and manpower, a once daily schedule. of gentamicin therapy would be both economical as well as convenient.