an estimated 20% of all children born in developing countries acquire an infection during the neonatal period , and infectious diseases account for approximately one - third of all neonatal deaths ( 1,2 ) . many neonatal deaths can be averted if the signs of infection could be recognized early by caregivers and first - line health workers and the disease is treated promptly ( 38 ) . gentamicin is a potent aminoglycoside antibiotic with bactericidal activity against gram - negative bacteria . among the causative agents of neonatal sepsis , gram - negative pathogens play a crucial role , and gentamicin is the drug of choice for first - line management . on the basis of the large volumes of distribution and slow renal clearance of aminoglycosides in neonates , larger doses based on body - weight , administered at longer intervals , are advantageous ( 912 ) . to treat neonatal sepsis more effectively in low - resource settings , it is necessary to develop a strategy for extended - interval dosing of gentamicin , i.e. 24 hours or more in between doses since more frequent contact with a health worker is often not feasible . based on the evidence that extended - interval dosing of gentamicin has many advantages over more frequent - interval dosing regimens , we aimed at evaluating extended - interval dosing regimens for gentamcin , which were developed based on issues of pharmacokinetics , safety , frequency of dosing , body - weight of the patient , and acceptability as described previously ( 13,14 ) . here , we report pharmacokinetic and safety evaluation results from the bangladesh site of a two - site study reported elsewhere ( 13 ) . the study was conducted in dhaka shishu ( children 's ) hospital , a major medical centre for children in south asia , in the neonatal special care nursery where out - born neonates are admitted . we initially aimed at enrolling 20 patients weighing < 2,000 g , 10 patients weighing 2,0002,240 g , and 20 patients weighing 2,5003,000 g with guidance on total enrollment from the study 's data safety monitoring board , which regularly reviewed progress of the trial , with an aim to ensure safety of patients . neonates up to 28 days of age , who were admitted from 15 february to 15 june 2003 for the treatment of suspected or culture - proven neonatal sepsis , were included in the study ( fig . ) . neonates with major congenital anomalies , haemodynamic instability , or compromised renal function were excluded . once a potential participant was identified , a parent was counselled in the presence of a senior staff nurse , and informed written consent was obtained . the ethical review committee at the bangladesh institute of child health , the committee on human research at the johns hopkins bloomberg school of public health , and the path human subjects protection committee approved the protocol . all patients received standard clinical management of sepsis , which included use of additional antibio - tics in combination with gentamicin to provide broad - spectrum coverage as indicated based on available clinical and laboratory data . neonates were enrolled into different weight categories and received a fixed dose and frequency of administration of gentamicin specific for each weight category ( fig . and table ) . the rationale for selection of these dosing - interval regimens has been reported previously ( 13,14 ) . patients weighing 2,2502,499 g were not included in the study because extended - interval dosing regimens of gentamicin , which reliably produce favourable pharmacokinetics , are already available , and further testing was , thus , not warranted . pharmacokinetics of gentamicin by neonatal weight category sd = standard deviation the dose was pushed intravenously over a 30-second period , followed by a flush with 0.5 ml of normal saline . for monitoring trough concentrations of gentamicin , blood was obtained 30 minutes prior to the administration of the third dose , and the peak level was monitored in serum separated from blood collected one hour after the administration of the third dose . since renal excretion of gentamicin is slower in low - birthweight ( lbw ) babies , the safety of administration in patients with very lbw , weighing < 2,000 g was further ensured by giving the doses only at 48-hour intervals . the monitoring strategy for these babies was modified so that the serum level of drug was available as early as possible . thus , serum levels were obtained 2 and 24 hours after the first dose of gentamicin rather than the trough and peak levels around the third dose as for patients weighing > 2,000 g. serum levels of gentamicin were measured by chemiluminescent assay with immulite 2000 ( diagnostic products corporation , los angeles , ca ) . pharmacokinetic indices , including peak and trough levels of genatmicin , were determined as described previously ( 13 ) . for infants weighing > 2,000 g , whenever abnormal gentamicin trough levels were detected , i.e. > 2 g / ml , the dosing - interval was extended from 24 to 48 hours . if the peak concentration was > 12 g / ml , the dose was decreased by 1015% , and if the peak was < 4 g / ml , the dose was increased by 1015% . blood samples were collected from 23 , 12 , and 24 patients in the three weight categories : < 2,000 g , 2,0002,249 g , and 2,5003,000 g respectively . haemoglobin concentration , serum electrolytes , plasma creatinine , and urine output were monitored during the study period . all the enrolled patients were followed up once for hearing assessment between 6 and 12 weeks of age . the study was conducted in dhaka shishu ( children 's ) hospital , a major medical centre for children in south asia , in the neonatal special care nursery where out - born neonates are admitted . we initially aimed at enrolling 20 patients weighing < 2,000 g , 10 patients weighing 2,0002,240 g , and 20 patients weighing 2,5003,000 g with guidance on total enrollment from the study 's data safety monitoring board , which regularly reviewed progress of the trial , with an aim to ensure safety of patients . neonates up to 28 days of age , who were admitted from 15 february to 15 june 2003 for the treatment of suspected or culture - proven neonatal sepsis , were included in the study ( fig . ) . neonates with major congenital anomalies , haemodynamic instability , or compromised renal function were excluded . once a potential participant was identified , a parent was counselled in the presence of a senior staff nurse , and informed written consent was obtained . the ethical review committee at the bangladesh institute of child health , the committee on human research at the johns hopkins bloomberg school of public health , and the path human subjects protection committee approved the protocol . all patients received standard clinical management of sepsis , which included use of additional antibio - tics in combination with gentamicin to provide broad - spectrum coverage as indicated based on available clinical and laboratory data . neonates were enrolled into different weight categories and received a fixed dose and frequency of administration of gentamicin specific for each weight category ( fig . and table ) . the rationale for selection of these dosing - interval regimens has been reported previously ( 13,14 ) . patients weighing 2,2502,499 g were not included in the study because extended - interval dosing regimens of gentamicin , which reliably produce favourable pharmacokinetics , are already available , and further testing was , thus , not warranted . pharmacokinetics of gentamicin by neonatal weight category sd = standard deviation the dose was pushed intravenously over a 30-second period , followed by a flush with 0.5 ml of normal saline . for monitoring trough concentrations of gentamicin , blood was obtained 30 minutes prior to the administration of the third dose , and the peak level was monitored in serum separated from blood collected one hour after the administration of the third dose . since renal excretion of gentamicin is slower in low - birthweight ( lbw ) babies , the safety of administration in patients with very lbw , weighing < 2,000 g was further ensured by giving the doses only at 48-hour intervals . the monitoring strategy for these babies was modified so that the serum level of drug was available as early as possible . thus , serum levels were obtained 2 and 24 hours after the first dose of gentamicin rather than the trough and peak levels around the third dose as for patients weighing > 2,000 g. serum levels of gentamicin were measured by chemiluminescent assay with immulite 2000 ( diagnostic products corporation , los angeles , ca ) . pharmacokinetic indices , including peak and trough levels of genatmicin , were determined as described previously ( 13 ) . for infants weighing > 2,000 g , whenever abnormal gentamicin trough levels were detected , i.e. > 2 g / ml if the peak concentration was > 12 g / ml , the dose was decreased by 1015% , and if the peak was < 4 g / ml , the dose was increased by 1015% . blood samples were collected from 23 , 12 , and 24 patients in the three weight categories : < 2,000 g , 2,0002,249 g , and 2,5003,000 g respectively . haemoglobin concentration , serum electrolytes , plasma creatinine , and urine output were monitored during the study period . all the enrolled patients were followed up once for hearing assessment between 6 and 12 weeks of age . of the 59 patients , 30 ( 51% ) were preterm ( < 37 completed weeks of gestation ) , 46 ( 78% ) were male , and 29 ( 49% ) were aged one day . the isolated organisms were escherichia coli ( n=2 ) , klebsiella pneumoniae ( n=1 ) , staphylococcus aureus ( n=1 ) , salmonella spp . total doses of gentamicin given to patients across the three weight categories ranged from 1 to 10 , and the duration of treatment was 210 days ( table ) . initial peak concentrations of gentamicin were > 12 g / ml and < 4 g / ml in 28.8% and 1.7% of the patients respectively ( table ) . nineteen ( 32.2% ) neonates required adjustment of gentamicin dose ; nine were in the category of < 2,000 g and five each were in the categories of 2,0002,249 g and 2,5003,000 g. nine patients each weighing < 2,000 g had a high peak level ; none had a high trough level . in the category of 2,0002,249 g , adjustment of dose was needed for three patients for high peak , one for high trough , and one for low peak . five ( 24.0% ) patients in the group of 2,5003,000 g needed correction ; two for both high peak and trough serum concentrations , and three for high peak concentration only . on enrollment , mol / l ) in 91.4% ( 53/58 ) of the patients . at the time of discharge , all the patients , except one ( serum creatinine level 169 mol / l ) , including the cases with elevated serum gentamicin peak and/or trough levels , had normal plasma creatinine levels . the frequency of urine output was also normal in 98.3% ( 57/58 ) of the cases . causes of death included prematurity with septicaemia ( n=2 ) , birth asphyxia with septicaemia ( n=2 ) , and birth asphyxia ( n=3 ) . three patients left against medical advice , and two of them had an abnormal level of gentamicin . two patients ( 5% ; 2/40 ) were labelled as impaired for hearing on assessment at 612 weeks of age . however , gentamicin levels of all these cases were normal ( peak 8.9 g / ml to 9.7 g / ml , trough 0.1 g / ml to 2.0 g / ml ) . this study evaluated the dosing of gentamicin at an interval of 2448 hours in different weight groups , considering pharmacokinetics and safety . studies have shown that pharmacokinetics of gentamicin are essentially equivalent following intravenous and intramuscular injections ( 15 ) . the results of this study , which involved intravenous administration , can be extrapolated to intramuscular injections , the suitable mode to use in the community , including peripheral health facilities , where intravenous access is not available . pharmacokinetic data of gentamicin indicate that half - lives are longer in neonates compared to older children ( 1618 ) . these data lend support to the recommendation to increase the dosing - interval from 12 to 18 hours up to 24 hours or more . there has been recent interest in extended ( e.g. daily or less frequent ) dosing of aminoglycosides because higher doses given at longer intervals are likely to improve efficacy and reduce the toxic effects ( 9,12,14 ) . in a developing country like bangladesh , once - daily dosing of gentamicin can be used as an important treatment option in neonatal sepsis whereas more frequent dosing is not feasible for use in the community and peripheral health - facili - ty settings ( 14,19 ) . in our study , the mean peak concentrations around the third dose in patients weighing 2,0002,249 g and 2,5002,999 g were consistent with other studies of once - daily dosing of gentamicin ( 9,11,12,2022 ) . skopnik compared two groups of neonates who received once- and twice - daily doses of gentamicin and found that the once - daily group did better regarding efficacy and toxicity ( 21 ) . high peak concentration of aminoglycoside is the major determinant of bacterial killing rather than the minimum inhibitory concentration of the antibiotic ( 23,24 ) . the target peak concentration of gentamicin is 412 g / ml ( 25 ) but 29% ( 17/59 ) of the cases in this study had higher peak values ( range 12.120.6 g / ml ) . nonetheless , all the cases had normal renal function as measured by plasma creatinine level . further , hearing assessment of 12 of the cases at 612 weeks of age did not reveal any sign of ototoxicity attributable to antibiotic exposure . this is in accordance with previous findings about the safety of higher peak levels of gentamicin ( 25 ) . pharmacokinetic data of gentamicin administration in neonates with very low birthweight indicate that the elimination half - life is longer in preterm compared to full - term neonates ( 26 ) . thus , we fixed the initial dose for preterm babies with very low birthweight as 10 mg given every 48 hours . in this weight category , we found a high peak concentration ( > 12 g / ml ) in more than one - third ( 39.1% ) of the babies , although their trough concentrations were uniformly normal . evidence would suggest that the dose used in this weight category will be efficacious ( 14 ) , and since trough levels were normal , this dose is acceptable . a low trough concentration of < 2 g / ml is a desirable goal because aminoglycosides exhibit a marked post - antibiotic effect ( persistent suppression of microbial growth after antmicrobial drug exposure ceases ) , and longer duration of low levels helps prevent the rapid development of microbial resistance ( adaptive resistance ) and minimizes nephrotoxicity and ototoxicity ( 27 ) . in the present study , the distributions of trough levels were the same as reported in previous studies where gentamicin was given once or twice daily at doses of 45 mg / kg of body - weight per day ( 912,14,21 ) . . who showed that trough concentration is not increased if a larger dose is given at a prolonged interval ( 9 ) . clinical studies have shown that renal toxicity is less frequent in newborns ( 28,29 ) ; this is due , in part , to the lower rate of renal accumulation of gentamicin in neonates ( 28 ) . in the present study , we had only one neonate with raised plasma creatinine ; however , the infant had normal peak ( 11.2 g / ml ) and trough ( 0.1 g / ml ) levels of gentamicin . mulhall et al . showed that the incidence of nephrotoxicity is reduced when the dosing interval is > 18 hours in neonates ( 25 ) . however , this did not appear to be attributable to gentamicin therapy as none of the cases had any abnormality in peak and trough levels of gentamicin . in conclusion , this study of extended - interval dosing of gentamicin , stratified for different weight categories of neonates , indicates that this dosing scheme is simple , adequate , safe , and feasible for the treatment of neonatal sepsis in communities and peripheral health facilities . such dosages are now being manufactured in pre - filled uniject ( becton dickinson ) devices and used for the evaluation of safety and acceptability for the treatment of neonatal sepsis at the community level . this study was supported by save the children  usa through a grant from the bill & melinda gates foundation and by path . path 's contribution to this study was made possible through support provided by the  office of health , united states agency for international development ( usaid ) under the healthtech cooperative agreement no . the opinions expressed herein are those of the authors and do not necessarily reflect the views of usaid . the authors thank additional professor vinod paul of all - india institute of medical sciences , delhi , for serving on the data and safety monitoring board .
extended - interval dosing of gentamicin has several advantages over conventional multiple - daily dosing for the treatment of sepsis . 
 the study was conducted to evaluate the pharmacokinetics of gentamicin for the treatment of neonatal sepsis in predetermined doses at 24- or 48-hour intervals , according to weight category , and to develop a simplified protocol for use in peripheral healthcare settings in developing countries . 
 this prospective observational study was conducted among 59 neonates admitted to the special care nursery at dhaka shishu hospital , bangladesh , with suspected sepsis and treated with antibiotics , including gentamicin . 
 intravenous dosing of gentamicin according to weight category was : 10 mg every 48 hours if the infant weighed < 2,000 g ( n=23 ) , 10 mg every 24 hours if the infant weighed 2,0002,249 g ( n=12 ) , or 13.5 mg every 24 hours if the infant weighed 2,5003,000 g ( n=24 ) . 
 peak and trough concentrations of gentamicin and the presence of signs of nephrotoxicity and ototoxicity were determined . 
 the meanstandard deviation peak concentration of gentamicin was 12.33.7 g / ml in infants weighing < 2,000 g , 9.63.1 g / ml in infants 2,0002,249 g , and 10.03.4 g / ml in infants 2,5003,000 g. initial peak concentration of gentamicin was > 12 g / ml in 28.8% and initial trough concentration was > 2 g / ml in 6.8% of the subjects . 
 no signs of nephrotoxicity or ototoxicity were detected . 
 favourable pharmacokinetic parameters found with the simplified dosing regimen suggest that it is safe for the treatment of neonatal sepsis .