Sixteen CCTs (n=823) were included.: 11 randomised controlled trials (RCTs), 4 CCTs with a historical control group and one cohort study. Data for 5 trials were derived from subgroups.
The studies seldom completely reported study design and methodology. The most common sources of bias were different daily doses and different times of assessing SDCs. All but 6 studies had potential sources of bias.
SDCs (12 CCTs, n=698).
EDI was associated with a significantly lower risk of peak (RR 0.50, 95% CI: 0.26, 0.94; P=0.033) and trough (RR 0.36, 95% CI: 0.25, 0.56; P<0.001) SDC outside the therapeutic range than TID.
There was no clear evidence of publication bias for peak or trough RR (P>0.10).
There were statistically significant differences between studies accepting lower versus higher peak SDC (P=0.013), for RCTs versus non-randomised CCTs (P<0.01) but not for trials with bias versus trials without bias (P>0.1).
For the 4 studies accepting lower peak SDC with TID, there was no significant difference between EID and TID. For the 8 studies using higher peak SDC, EID was associated with a significantly lower risk of peak SDC outside the therapeutic range (RR 0.38, 95% CI: 0.24, 0.61, P<0.001). There was no significant difference in the risk of peak SDCs outside the therapeutic range between EID and TID for all RCTs and for RCTs using higher therapeutic peak range (the results were reported); EID was associated with a significantly lower risk of troughs outside the therapeutic range than TID (RR 0.42, 95% CI: 0.26, 0.66, P<0.001). The 5 non-randomised trials showed a significantly lower risk of both peak and trough SDC outside the therapeutic range for EID in comparison with TID (the results were reported).
Efficacy and toxicity.
Treatment failure (9 CCTs, n=555): one trial reported treatment failure in two neonates, both in the TID arm. No deaths were reported.
Nephrotoxicity (12 CCTs, n=589): one trial found urinary alanine aminopeptidase in all participants, while another found raised creatinine concentration in 30 of the 40 participants (13 in the TID arm and 17 in the EID).
Ototoxicity (4 CCTs, n=210): one event was found in the EID group.