Shripada C Rao1, Ravisha Srinivasjois2, Ronald Hagan3, Mohmed Ahmed4
Background - Methods - Results - Characteristics of Included Studies - References - Data Tables and Graphs
1Centre for Neonatal Research and Education, King Edward Memorial Hospital for Women and Princess Margaret Hospital for Children, Perth Western Australia, Australia
2Neonatal Pediatrics, King Edward Memorial Hospital for Women, Subiaco, Australia
3Neonatology, Princess Margaret Hospital for Children, Perth, Australia
4Neonatology, NMC Specialty Hospital, Dubai, United Arab Emirates
Citation example: Rao SC, Srinivasjois R, Hagan R, Ahmed M. One dose per day compared to multiple doses per day of gentamicin for treatment of suspected or proven sepsis in neonates. Cochrane Database of Systematic Reviews 2011, Issue 11. Art. No.: CD005091. DOI: 10.1002/14651858.CD005091.pub3.
Centre for Neonatal Research and Education
King Edward Memorial Hospital for Women and Princess Margaret Hospital for Children
Perth Western Australia
6008
Australia
E-mail: Shripada.Rao@health.wa.gov.au
| Assessed as Up-to-date: | 29 June 2011 |
|---|---|
| Date of Search: | 10 April 2011 |
| Next Stage Expected: | 29 June 2013 |
| Protocol First Published: | Issue 1, 2005 |
| Review First Published: | Issue 1, 2006 |
| Last Citation Issue: | Issue 11, 2011 |
| Date / Event | Description |
|---|---|
| 29 June 2011 New citation: conclusions not changed |
Dr. Ravisha Srinivasjois added to the authorship of this review. |
| 29 June 2011 Updated |
This updates the review "One dose per day compared to multiple doses per day of gentamicin for treatment of suspected or proven sepsis in neonates" published in the Cochrane Database of Systematic Reviews (Rao 2006). Search updated April 2011. No new included trials. New excluded trials added. No change to conclusion of review. |
| Date / Event | Description |
|---|---|
| 07 October 2009 Updated |
Converted to new review format. |
Animal studies and trials in older children and adults suggest that a one dose per day regimen of gentamicin is superior to a multiple doses per day regimen.
To compare the efficacy and safety of one dose per day compared to multiple doses per day of gentamicin in suspected or proven sepsis in neonates.
Eligible studies were identified by searching the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library, April 2011), MEDLINE (1966 to April 2011), EMBASE 1980 to April 2011, and CINAHL (December 1982 to April 2011). Abstracts of the Society for Pediatric Research were searched from 1980 to 2010 inclusive.
All randomised or quasi randomised controlled trials comparing one dose per day ( 'once a day') compared to multiple doses per day ( 'multiple doses a day') of gentamicin to newborn infants < 28 days of life.
Data collection and analysis was performed according to the standards of the Cochrane Neonatal Review Group.
Eleven studies were included (N = 574) and nineteen excluded. All infants in both 'once a day' as well as 'multiple doses a day' regimen showed adequate clearance of sepsis [typical RD 0.00 (95% CI - 0.19 to 0.19); 3 trials; N = 36]. For the other primary outcome measures relating to gentamicin pharmacokinetics 'once a day' dosing of gentamicin was superior. 'Once a day' gentamicin regimen was associated with less failures to attain peak level of at least 5 µg/ml [typical RR 0.22 (95% CI 0.11 to 0.47); 9 trials; N = 422] and less failures to achieve trough levels of < 2 µg/ml [typical RR 0.38 (95% CI 0.27 to 0.55); 11 trials N = 503] compared to 'multiple doses a day' regimen.
Ototoxicity and nephrotoxicity were not noted with either of the treatment regimens.
There is insufficient evidence from the currently available RCTs to conclude whether 'once a day' or 'multiple doses a day' regimen of gentamicin is superior in treating proven neonatal sepsis. However, data suggests that pharmacokinetic properties of 'once a day' gentamicin regimen are superior to 'multiple doses a day' regimen in that it achieves higher peak levels while avoiding toxic trough levels. There is no change in nephrotoxicity or auditory toxicity. Based on this assessment of pharmacokinetics, 'once a day regimen' may be superior in treating neonatal sepsis in neonates greater than 32 weeks gestation.
Gentamicin is a commonly used antibiotic that is very effective in treating bacterial infections in neonates. However, gentamicin may cause adverse effects on auditory and renal functions that may be related to the dosage, interval and in turn the drug levels in plasma. Safer and potentially more effective levels of the drug were maintained using a one dose per day treatment schedule.
Gentamicin, an aminoglycoside antibiotic, is widely used in the treatment of suspected or proven bacterial sepsis in newborn infants. It is rapidly bactericidal. Combined with beta-lactam antibiotics, it provides synergistic activity against the most commonly encountered pathogens in the neonatal period (Chattopadhyay 2002). The potential ototoxicity and nephrotoxicity has been linked to the drug levels in plasma. Higher trough concentrations are associated with drug toxicity (Swan 1997) and lower peak levels are associated with lesser efficacy (Kovarik 1989; Chambers 2001). The bactericidal effect of gentamicin is concentration dependent; the higher the concentration, the greater the bactericidal effect. The generally accepted peak concentrations are 4 to 10 µg/ml. It has been suggested that even higher peak levels (e.g. 25 µg per ml) do not increase the associated toxicity (Chambers 2001). It is also suggested that the trough concentrations should be less than 1 to 2 µg/ml to minimise the potential toxic effects (Chambers 2001). Increasing the interval between doses has the potential to maintain maximal bactericidal activity, while minimizing the side effects.
Several concepts support the benefit of a treatment regime that administers one dose per day ('once a day' dose) of gentamicin (Miron 2003).
Meta analyses of studies in adults have consistently shown that once daily dosing of aminoglycoside including gentamicin is as effective as multiple daily dosing, with similar or lesser risk of nephrotoxicity and ototoxicity (Barza 1996; Munckhof 1996; Ali 1997; Bailey 1997;Hatala 1997).
A systematic review of similar studies in children and infants concluded that a 'once a day' regimen is more efficacious and has no higher toxicity compared with multiple daily dosing (Miron 2001). A meta analysis (Contopoulos 2004) of extended interval aminoglycoside dosing (the dose is higher and administered less frequently than in traditional dosing regime) in children reported that an extended dose aminoglycoside regimen provided similar or potentially improved efficacy and safety, compared to multiple doses a day regimen. A total of 24 studies in paediatric populations up to 20 years of age, including six studies in neonatal populations, were included in their review. Five neonatal studies used gentamicin and one study used amikacin.
Recently published reports suggest that 'multiple doses a day' regimen resulted in sub therapeutic levels and the new practice of extended dosage schedules achieved safe and adequate levels (Bajaj 2004; Darmstadt 2008; Begg 2009; Hagen 2009). It has also been suggested that a dose interval of > 24 hours is less likely to produce toxic trough levels in preterm neonates (Langlass 1999; Thingvoll 2008; Gonzalez-Santacruz M 2008).
Despite this information, the appropriate dose and dose interval for gentamicin in neonates is still a matter of debate. Caution has been expressed against the use of 'once a day' dose of gentamicin in neonatal infections (Chambers 2001). This approach has yet to become standard practice in most paediatric hospitals (Knoderer 2003). A random survey of acute care hospitals in the USA in 1993 found that extended interval aminoglycoside dosing was not practiced in neonates, whereas, in 1998, 11.3% of the hospitals were using extended interval dosing (Chuck 2000).
In this review, we compared 'one dose per day' versus 'multiple doses per day' of gentamicin in neonates with suspected or proven sepsis.
To compare the efficacy and safety of one dose per day ('once a day') gentamicin compared to multiple doses per day ('multiple doses a day') of gentamicin in suspected or proven sepsis in neonates.
Subgroup analysis was performed according to:
Newborn infants (< 28 days after birth) with suspected or proven sepsis commenced on gentamicin. Suspected sepsis was defined as any condition in the neonate which led to the commencement of antibiotics. Proven sepsis was defined as clinical condition necessitating use of antibiotics and presence of positive blood, other body fluid or tissue cultures.
One dose per day ('once a day') compared to multiple doses per day ('multiple doses a day') of gentamicin.
Studies comparing extended dose regimens such as dosing once in 36 to 48 hours versus 'once a day' dosing were not included.
Studies comparing regimens with or without loading dosage were not included. If a trial used a loading dose of gentamicin in both groups, it was included.
Since gentamicin is almost always used along with a second antibiotic, studies which used the same second antibiotic in both groups were included.
Studies using gentamicin either intramuscularly or intravenously were included provided both study and control groups were administered gentamicin by the same route.
If a study used a different second antibiotic along with gentamicin in the study and control groups, it was excluded.
A difference of up to 25% while calculating the total daily dose was allowed between 'once a day' and 'multiple doses a day' regimens.
We used the standard search strategy of the Cochrane Neonatal Review Group was used. This included electronic searches of the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library, Issue 2, 2011), MEDLINE (1966 to April 2011), EMBASE (1980 to April 2011) and CINAHL (1982 to October 2011) and previous reviews including cross-references. Abstracts of Paediatric Academic Societies meetings (1995 to 2010) were also searched. MEDLINE and EMBASE were searched for relevant articles using the following MeSH terms or text words: (Gentamicin/OR aminoglycoside) AND (sepsis OR septicaemia OR septicemia) AND (infant, newborn/OR infant, low birth weight/OR infant, very low birth weight/OR infant, premature/OR Infant, Premature, Diseases) OR (neonate: OR prematur*: OR newborn) AND (clinical trial OR Randomised Controlled Trials). Reference lists of published narrative and systematic reviews were also reviewed. No language restrictions were applied.
We used the standard methods of the Cochrane Neonatal Review Group.
Two review authors independently assessed the eligibility of studies for inclusion.
We used a data collection form was to aid extraction of relevant information and data from each included study. Two review authors extracted the data separately, compared data, and resolved differences by consensus. Any disagreements were resolved by consultation with the third review author.
We contacted the authors of all studies to clarify reported data or provide additional data and information including details of methodology. They were sent a standardised table and asked to provide missing data not included in their article if it was available. Skopnik 1992; Krishnan 1997; Romero 1998; Thureen 1999; Chotigeat 2001; Hagan 2002; Miron 2003 and Kosalaraksa 2004 provided additional information, clarified existing data and also clarified methodology of studies. Hayani 1997; Agarwal 2002 and Solomon 1999 were contacted initially by e-mail and subsequently by post four weeks later, but did not respond.
The criteria and standard methods of the Cochrane Neonatal Review Group were used to assess the methodological quality of the included trials. Quality of the trials included was evaluated in terms of adequacy of sequence generation, allocation concealment, blinding of parents or caregivers and assessors to intervention, and completeness of follow up in all randomised individuals. This was defined as yes, no or not clear for each category. Differences in the inclusion of trials according to their quality were resolved after consultation with the third review author.
In addition, for the update in 2010, the following issues were evaluated and entered into the Risk of Bias table:
If needed, we planned to explore the impact of the level of bias through undertaking sensitivity analyses.
We used the standard methods of the Neonatal Review Group. We performed statistical analyses using Review Manager software. We analysed categorical data using relative risk (RR), risk difference (RD) and the number needed to treat (NNT). We analysed continuous data using mean difference (MD). We reported the 95% confidence interval (CI) on all estimates.
We examined heterogeneity in the results of the trials using the I2 statistic.
We used the standard methods of the Neonatal Review Group to synthesize the data. We expressed effects as relative risk (RR), risk difference (RD) and 95% confidence intervals (CI) for categorical data, and mean difference (MD) and 95% CI for continuous data. The fixed effect model was used for meta-analysis. Change scores of auditory and vestibular tests and tests for nephrotoxicity were planned to be meta-analysed separately from the final value scores. For significant differences the number needed to treat (NNT) based on 1/RD was calculated.
Twenty-nine studies were identified as potentially eligible. Eighteen were excluded and 11 studies were included for the review.
Skopnik 1995; Davies 1998; Kaspers 1998; Lundergan 1999; Stickland 2001; Alsaedi 2003; Hansen 2003; Lanao 2004; Tantiprabha 2007; Thingvoll 2008; Gonzalez-Santacruz M 2008; Serane 2009; Hagen 2009 were excluded because they were not randomised or quasi randomised controlled trials. English 2004 was excluded because loading dose of 8 mg/kg was used in 'once a day' gentamicin regimen, whereas no loading dose was used in multiple doses a day regimen. Mercado 2004 and Rastogi 2002 were excluded because they compared 'once a day' to 'once in 48 hours' regimen of gentamicin. Isemann 1996 and Semchuk 1995 were excluded because regimen of loading dose was compared to the regimen of no loading dose of gentamicin. Tiwari 2009 was excluded because relevant data from the neonatal subgroup could not be obtained from the published article. Three attempts were made by us to contact the authors, but there was no response.
The details are listed in the table 'Characteristics of excluded studies'.
Eleven studies were included in this review. All of them were single centre studies. All of the included studies were undertaken since the early 1990s by investigators attached to perinatal centres in North America, India, Thailand, Germany, Spain and Australia. A total of 574 neonates were enrolled in the 11 included trials. Krishnan 1997; Miron 2003 and Solomon 1999 enrolled infants > 32 weeks gestation. Chotigeat 2001; Hagan 2002; Hayani 1997; Kosalaraksa 2004 and Thureen 1999 enrolled infants > 34 weeks gestation. Agarwal 2002 enrolled infants > 2500 g birth weight. All except three of the neonates enrolled were > 37 weeks gestation in their study. Skopnik 1992 enrolled only full term neonates. Romero 1998 enrolled infants > 1200 g birth weight and is the only study to enrol preterm infants less than 32 weeks gestational age.
All the studies used intravenous infusion of gentamicin except Krishnan 1997, where gentamicin was given as a bolus over one minute. Hagan 2002 and Hayani 1997 used gentamicin both intravenously and intramuscularly. Of the 574 infants enrolled in the trial, only 39 infants had proven sepsis (Hayani 1997; Romero 1998; Hagan 2002; Miron 2003; Kosalaraksa 2004). The rest were treated for suspected sepsis. All studies used gentamicin in the dose of 4 to 5 mg/kg/day either as a single dose or as multiple divided doses. The main outcomes assessed were peak and trough levels of gentamicin and renal function. Three studies assessed hearing prior to discharge (Thureen 1999; Agarwal 2002; Hagan 2002) and one study assessed hearing at one to two months of age (Miron 2003). One study assessed the cost of therapy (Thureen 1999). The details are described in the table 'Characteristics of included studies'.
We assessed the quality of the trials using the criteria of the Cochrane Neonatal Review Group. Assessment was based on allocation concealment, blinding of intervention, blinding of outcome assessment and completeness of follow up.
Adequacy of sequence generation was accomplished in Skopnik 1992; Krishnan 1997; Agarwal 2002; Hagan 2002 and Kosalaraksa 2004 and using computer generated random numbers.
Allocation concealment was accomplished in Skopnik 1992; Krishnan 1997; Romero 1998; Chotigeat 2001; Agarwal 2002; Hagan 2002 and Kosalaraksa 2004 using sealed envelopes. It was not clear if allocation was concealed in Solomon 1999 and Hayani 1997. Allocation was not concealed in Miron 2003 and Thureen 1999. Miron 2003 was a quasi random study with 'once a day' gentamicin being administered in period one (January to March 1998) and multiple doses a day gentamicin being administered in period two (April to June 1998). Thureen 1999 was also a quasi random study (assignment to a particular study group was dependent on the intensive care site, with monthly rotation of dosing regimens).
Blinding of intervention was not done in any of the studies.
Outcome assessment was blinded in Krishnan 1997; Romero 1998; Chotigeat 2001; Hagan 2002; Miron 2003; Kosalaraksa 2004. It is not clear whether outcome assessment was blinded in Hayani 1997; Solomon 1999; Agarwal 2002. It was not blinded in Skopnik 1992 and Thureen 1999.
Skopnik 1992; Krishnan 1997; Solomon 1999; Thureen 1999; Chotigeat 2001; Agarwal 2002; Miron 2003 and Kosalaraksa 2004 reported complete follow up. Follow up was incomplete in the Hayani 1997; Hagan 2002 and Romero 1998 trials, in that more than 10% of enrolled infants did not have outcomes assessed.
Details of the methodological quality of studies are included under the table 'Characteristics of Included Studies'.
Eleven studies fulfilled our selection criteria and were included in this review (Skopnik 1992; Krishnan 1997; Hayani 1997; Romero 1998; Solomon 1999; Thureen 1999; Chotigeat 2001; Agarwal 2002; Hagan 2002; Miron 2003; Kosalaraksa 2004). These studies included a total of 574 infants. There was no disagreement regarding inclusion/exclusion of studies, quality assessment or data extraction. Available data were pooled and analysed as listed below.
Hayani 1997 and Hagan 2002 used gentamicin intramuscularly in some of their study infants. Separate data for the intramuscular gentamicin was not available from Hagan 2002. Hayani 1997 reported the outcomes on four infants with 'once a day' gentamicin, but combined the data for intramuscular and intravenous gentamicin in 'multiple doses a day' regimen because there was no significant difference in the pharmacokinetic parameters between these groups. The peak gentamicin levels in 'once a day ' group were significantly higher (P < 0.05) than the 'multiple doses a day' group (11.2 ± 2.0 versus 6.6 ± 1.3 µg/ml). The trough levels were significantly lower (P < 0.05) in the 'once a day' group compared to the 'multiple doses a day' group (1.1 ± 0.3 versus 1.7 ± 0.5 µg/ml).
As previously noted, few infants had proven sepsis in any of the studies. In the Romero study (1998), 14 infants (42%) in 'once a day' group and 15 infants (47%) in 'multiple doses a day' group had bacteriological sepsis. All infants had clearance of sepsis in both groups. Only one infant had proven sepsis in the study by Hayani 1997. The outcome of this infant was not reported. Two infants had proven gram positive sepsis in the study by Kosalaraksa 2004. One in each group of 'once a day' and 'multiple doses a day' regimen; however, they were excluded from analysis. Hagan 2002 study reported that all five infants with proven bacteriological sepsis in the 'once a day' gentamicin group responded by clearance of sepsis. There were no cases of proven sepsis in 'multiple doses a day' gentamicin group. Miron 2003 had one infant in each group with proven sepsis. Both infants had clearance of sepsis after institution of antibiotic therapy. Meta-analysis of all the studies did not show significant difference between the two groups (Typical RD 0.00 (95% CI - 0.19, 0.19); 3 trials N = 36]. Other outcomes were not reported for this subgroup of infants.
Romero 1998 had seven infants with gestational age less than 32 weeks. All were treated for suspected sepsis. All infants in both groups achieved peak levels more than 5 microgram/ml. Three out of five infants in 'once a day' group had toxic trough levels of > 2 µg/ml. Both infants in 'multiple doses a day' regimen had toxic trough levels of > 2 µg/ml. No other study enrolled infants less than 32 weeks gestation.
None of the studies used a loading dose of gentamicin in both the study and control regimens.
The outcome of 574 neonates from 11 RCTs comparing 'once a day' versus 'multiple doses a day' gentamicin have been reported in this review. For the primary outcome of 'clearance of proven sepsis', there was no statistically significant difference between the 'once a day' and 'multiple doses a day' regimens of gentamicin. Both treatment regimes were successful at treating infants with proven sepsis. However, the numbers were too small to arrive at any definite conclusions. This is expected because only a very small percentage of neonates with suspected sepsis have a culture positive infection (Stoll 1996 A; Stoll 1996 B). For the primary outcomes of 'Failure to attain peak levels of at least 5 µg/ml', and 'Failure to achieve trough levels of < 2 µg/ml', meta-analysis showed a statistically significant difference favouring 'once a day' gentamicin group. 'Once a day' gentamicin was associated with less pharmacokinetic failure rates than 'multiple doses a day' regimen.
For the secondary outcomes of 'actual peak levels' and 'actual trough levels' attained, meta-analysis showed that 'once a day' regimen achieved higher peak levels and lower trough levels compared to 'multiple doses a day regimen'. However significant heterogeneity was noticed for these two outcomes. These results need to be interpreted with caution. Heterogeneity was explored by re-checking of data that was entered and by excluding individual studies one at a time. Individual trials were studied in detail to explore the cause of heterogeneity. Krishnan 1997; Solomon 1999 and Miron 2003 enrolled infants > 32 weeks gestation. Hayani 1997; Thureen 1999; Chotigeat 2001; Hagan 2002 and Kosalaraksa 2004 enrolled infants > 34 weeks gestation. Agarwal 2002 enrolled infants > 2500 g birth weight. Skopnik 1992 enrolled only full term neonates. Romero 1998 enrolled infants > 1200 g birth weight. These differences in gestational age and birth weight might have contributed to heterogeneity. All studies used a similar dose of gentamicin (4 to 5 mg/kg/day). Timing of collection of the blood samples for trough levels was the same in all the studies (within 30 minutes of administration of the next dose). Samples for peak levels were collected between 30 to 60 minutes after administration of the dose. The day of therapy on which samples were collected varied between day one to day five. This variation in the day and time of collection of the samples may also have led to heterogeneity. Hagan 2002 and Hayani 1997 used gentamicin both intramuscularly and intravenously. However, significant heterogeneity still remained even when these two studies were excluded from the meta-analysis. Results remained the same when data were re-analysed using a random effects model instead of a fixed effect model.
Romero 1998 reported less nephrotoxicity in 'once a day' gentamicin regimen compared to 'multiple doses a day' regimen. They measured urinary levels of N-acetyl-beta-d-glucosaminidase as marker of nephrotoxicity. All other seven studies found no difference in the risk of nephrotoxicity between 'once a day' and 'multiple doses a day' gentamicin regimens. In a prospective study, Nielsen 2009 evaluated the use of cystatin C along with serum creatinine as a marker of gentamicin clearance and concluded that neither of them were correlated with gentamicin clearance. They also concluded that serum creatinine and cystatin C were not predictive markers of renal function in their population set (Nielsen 2009). A recent study (Coscia 2008) evaluated the nephrotoxic effects of once a day netilmicin with multiple doses a day in preterm neonates (GA < 37 weeks). Once a day regimen had the same low rates of nephrotoxicity compared to multiple doses a day suggesting the possible advantages of once a day regimen. A recent RCT in adults (Olsen 2004) measured urinary alanine aminopeptidase (AAP) and N-acetyl-beta-d-glucosaminidase (NAG) as markers of nephrotoxicity and found that 'once a day' tobramycin was less nephrotoxic than 'multiple doses a day' regimen.
Only five studies assessed and four studies reported auditory toxicity. No difference was noted between the two groups. Vestibular toxicity was not assessed in any of the studies.
The findings of this review are consistent with the meta analysis in adults and older children in that 'once a day' gentamicin achieves better pharmacokinetic profile than 'multiple doses a day' gentamicin regimen with no difference in ototoxicity or nephrotoxicity.
'Once a day' gentamicin regimen requires less pharmacy preparation time and less nursing administration time. Thureen 1999 evaluated the cost-effectiveness analysis of 'once a day' gentamicin among neonates and found that 'once a day' gentamicin regimen was more cost effective than 'multiple doses a day' regimen. Individualized dosing regimens may be ideal, but are more expensive as they require more frequent measurement of gentamicin levels. Measurement of gentamicin levels is the major contributor to the expense of administering this relatively inexpensive drug (Thureen 1999; Bajaj 2004). As the great majority of infants treated with gentamicin are treated only for a short time (48 to 72 hours) until deep infection is excluded, this would increase the cost and complexity of their care with no clinical benefit.
Five out of seven infants less than 32 week gestation developed toxic trough levels of > 2 µg/ml. This occurred in both 'once a day' and 'multiple doses a day' regimen. The possible explanation is that very preterm infants have lower glomerular filtration rate and hence clear gentamicin more slowly than the more mature infants. Hence, even the 'once a day' regimen may also be toxic (Serane 2009). Begg et al published their experience of administering extended interval dosing practiced in their unit over the last few years. They found that extending the dosing interval improved the success in achieving the target peak and trough levels while revising the dosing equation did not (Begg 2009). Evidence is accumulating that an extended dosing regimen of once in 36 to 48 hours may be more suitable for very preterm infants less than 32 weeks gestation (Rastogi 2002; Hansen 2003; Mercado 2004; Thingvoll 2008). More studies would be needed to decide appropriate dosing regimen for this subset of very preterm infants.
There is insufficient evidence from the currently available RCTs to conclude whether 'once a day' or 'multiple doses a day' regimen of gentamicin is superior in treating bacteriologically confirmed neonatal sepsis. However, the pharmacokinetic properties of 'once a day' gentamicin regimen are superior to 'multiple doses a day' gentamicin in that it achieves higher peak levels while avoiding toxic trough levels. There is no change in nephrotoxicity or auditory toxicity. Hence 'once a day' regimen may be superior in treating neonatal sepsis in neonates more than 32 weeks gestation.
Studies comparing the 'multiple doses per day' and 'one dose per day' regimens for microbiologically confirmed sepsis requiring prolonged antibiotic therapy need to be done to confirm if the pharmacokinetic benefits translate into clinical efficacy and safety. It is also important to follow such neonates long term to find out the effects on hearing and speech.
We are thankful to Krishnan 1997; Romero 1998; Thureen 1999Chotigeat 2001; Hagan 2002; Miron 2003; Kosalaraksa 2004 and Skopnik 1992 for responding to our queries. We are thankful to Gonzalez-Santacruz M 2008 for providing the translated version of their Spanish article. We are also very thankful to Kathleen Martin, reference librarian at The Canberra Hospital library, Australia for her help in performing the literature search. We are very much thankful to Jane Bell, Research Officer, Australasian Coordinating Network for the Cochrane Neonatal Review Group for her valuable help in the literature search and suggestions in editing the protocol.
The Cochrane Neonatal Review Group has been funded in part with Federal funds from the Eunice Kennedy Shriver National Institute of Child Health and Human Development National Institutes of Health, Department of Health and Human Services, USA, under Contract No. HHSN267200603418C.
Shripada Rao (SR) framed the questions for the protocol, wrote the protocol, performed the literature search, selected relevant studies, assessed the methodological quality of studies, checked the data entered into RevMan by Mohamed Ahmed (for the original review), corresponded with authors of the studies to get additional information, wrote the review and compiled other references. SR was also responsible for all the above activities for the updated review.
Mohamed Ahmed (MA) was involved in data entry and analysis for the original version of the Cochrane review.
Ravisha Srinivasjois (RS) performed the literature search and assessed the eligibility of the studies for inclusion/exclusion, and added additional references for the updated review.
Ronald Hagan (RH) revised and edited the drafts of the protocol, provided guidance in selecting outcomes of interest and edited the manuscript of the original version of the review. He was also the referee author for the original version of the review.
One of the review authors (RH) is also the author of one of the included studies (Hagan 2002).
| Methods | Randomised controlled trial; single centre; USA |
|---|---|
| Participants | N = 44. Infants with BW >= 2500 g, age <= 7 days, Apgar scores of >= 5 at 5 minutes, suspected systemic or focal bacterial infection. Exclusion criteria were history of perinatal asphyxia, shock or cardiorespiratory arrest, seizures, anomalies of the kidney or major congenital anomalies incompatible with life and evidence of neuromuscular disorder. 'Once a day' gentamicin: N = 20. |
| Interventions | 'Once a day' gentamicin group were given gentamicin at 4 mg/kg/dose once every 24 h. 'Multiple doses a day' gentamicin group were given gentamicin at 2.5 mg/kg/dose every 12 h. |
| Outcomes | Blood for peak serum gentamicin was drawn 30 minutes after completion of the gentamicin infusion and for trough concentration, 30 minutes prior to the start of gentamicin infusion. Trough and peak SGCs drawn with the dose at 48 h were considered to reflect steady state. Other outcomes that were measured were urine output, serum creatinine, creatinine clearance and hearing screen test prior to discharge. |
| Notes |
| Bias | Authors' judgement | Support for judgement |
|---|---|---|
| Random sequence generation (selection bias) | Low risk | Computer generated numbers. |
| Allocation concealment (selection bias) | Low risk | Using sealed envelopes |
| Blinding (performance bias and detection bias) | Unclear risk | |
| Incomplete outcome data (attrition bias) | Low risk | Only three infants were excluded after enrolment. |
| Selective reporting (reporting bias) | Low risk | |
| Other bias | Low risk |
| Methods | Randomised Controlled Trial; single centre; Thailand |
|---|---|
| Participants | N = 54. Infants with BW >= 2000 g age < 7 days, gestational age>= 34 weeks, Apgar scores of more than or equal to 4 at 1 minute and 6 at 5 minutes, suspected or proven bacterial infection. Exclusion criteria were allergy to aminoglycoside, congenital anomalies, renal failure and neuromuscular disorder. 'Once a day' gentamicin: N = 27. |
| Interventions | 'Once a day' gentamicin group were given gentamicin at 4-5 mg/kg/dose once every 24 h. 'Multiple doses a day' gentamicin group were given gentamicin at 2-2.5 mg/kg/dose every 12 h. |
| Outcomes | In 'once a day' gentamicin group blood was drawn for peak serum concentration within in 30 minutes after completion of 3rd dose and the trough blood sample was drawn within 30 minutes prior to the 3rd dose. In 'multiple doses a day' gentamicin group blood was drawn for peak serum concentration within 30 minutes after completion of 5th dose and the trough level blood sample was drawn within 30 minutes prior to the 5th dose. Other outcomes that were measured were serum creatinine level on day 1,day 3, and on the day when gentamicin was discontinued. |
| Notes | Additional information and methodology were clarified by the authors. |
| Bias | Authors' judgement | Support for judgement |
|---|---|---|
| Random sequence generation (selection bias) | Unclear risk | |
| Allocation concealment (selection bias) | Low risk | Using sealed envelopes. |
| Blinding (performance bias and detection bias) | Low risk | Outcome assessors were blinded to the intervention |
| Incomplete outcome data (attrition bias) | Low risk | |
| Selective reporting (reporting bias) | Low risk | |
| Other bias | Low risk |
| Methods | Randomised Controlled Trial; single centre; Australia |
|---|---|
| Participants | N = 100. Infants of gestational age more than 33 weeks, age < 7 days and presumed sepsis. Exclusion criteria were BW < 2000 g, history of significant asphyxia, congenital malformation and antenatal diagnosis of renal tract abnormalities. 'Once a day' gentamicin: N = 46. |
| Interventions | 'Once a day' gentamicin group were given gentamicin at 5 mg/kg/dose once every 24 h. 'Multiple doses a day' gentamicin group were given gentamicin at 2.5 mg/kg/dose every 18 h. Gentamicin was given either intravenously or intramuscularly. |
| Outcomes | In 'once a day' gentamicin group blood was drawn for peak serum concentration within 30 minutes after completion of 3rd dose and the trough blood sample was drawn within 30 minutes prior to the 3rd dose. In 'multiple doses a day' gentamicin group blood was drawn for peak serum concentration within 30 minutes after completion of 3rd dose and the trough level blood sample was drawn within 30 minutes prior to the 3rd dose. Other outcomes that were measured were daily serum creatinine estimation and otoacoustic emission tests 12 h before the first dose and after the third dose of gentamicin. |
| Notes | Additional information and methodology were clarified by the authors. |
| Bias | Authors' judgement | Support for judgement |
|---|---|---|
| Random sequence generation (selection bias) | Low risk | Computer generated numbers |
| Allocation concealment (selection bias) | Low risk | Using sealed envelopes. |
| Blinding (performance bias and detection bias) | Low risk | Lab personnel and the people performing hearing tests were blinded to the allocations. |
| Incomplete outcome data (attrition bias) | High risk | Gentamicin levels were done in only 65 out of 100 infants. Otoacoustic emission test was done in only 59 infants. Serum creatinine levels were measured in 93 infants. Four infants were excluded because of withdrawal of parental consent. |
| Selective reporting (reporting bias) | Low risk | |
| Other bias | Low risk |
| Methods | Randomised Controlled Trial; single centre, USA |
|---|---|
| Participants | N = 31. Infants of gestational age more than or equal to 34 weeks, age <= 24 h with suspected sepsis or focal bacterial infection, BW >=2000 g and Apgar score of 7 or more at 5 minutes. Exclusion criteria were history of cardiopulmonary arrest, shock, seizures, congenital malformation incompatible with life anomalies of kidney or ear, or presence of neuromuscular disorder. 'Once a day' gentamicin: N = 11. |
| Interventions | 'Once a day' gentamicin group were given gentamicin at 5 mg/kg/dose once every 24 h. 'Multiple doses a day' gentamicin group were given gentamicin at 2.5 mg/kg/dose every 12 h . Gentamicin was given either intravenously or intramuscularly. |
| Outcomes | Serum gentamicin levels were measured on day 3 of life. Peak serum gentamicin levels were obtained 30 minutes after the end of intravenous dose or 60 minutes after an intramuscular dose .Trough levels were obtained 30 minutes before the dose. Other outcomes that were urine output, serum creatinine, serum electrolytes, blood urea nitrogen, urine sodium, urine creatinine, urine Beta 2 microglobulin levels and glomerular filtration rate. |
| Notes |
| Bias | Authors' judgement | Support for judgement |
|---|---|---|
| Random sequence generation (selection bias) | Unclear risk | |
| Allocation concealment (selection bias) | Unclear risk | |
| Blinding (performance bias and detection bias) | Unclear risk | |
| Incomplete outcome data (attrition bias) | High risk | 5 patients treated intravenously didn't complete study. 4 infants were discharged home before gentamicin concentration was due for measurement. One infant developed hypotension and shock and was excluded. |
| Selective reporting (reporting bias) | Low risk | |
| Other bias | Low risk |
| Methods | Randomised Controlled Trial; Single centre; Thailand. |
|---|---|
| Participants | N = 64. Inclusion criteria were BW >= 2000 g, age <= 7 days Apgar score of > 6 at 5 minutes and suspected sepsis. Exclusion criteria were history of perinatal asphyxia, shock, cardiopulmonary arrest, seizure, neuromuscular disorder or anomalies of kidney or ear. 'Once a day' gentamicin: N = 33. |
| Interventions | 'Once a day' gentamicin group were given gentamicin at 5 mg/kg/dose once every 24 h. 'Multiple doses a day' gentamicin group were given gentamicin at 2.5 mg/kg/dose every 12 h. Gentamicin was given as intravenous infusion over 60 minutes. |
| Outcomes | The peak serum gentamicin level was measured 30 minutes after infusion (after the 3rd dose in 'once a day' group and the 6th dose in the multiple doses group. Trough levels were measured immediately before the 4th dose in 'once a day' group and the 7th dose in the 'multiple doses a day' group. Other outcomes that were measured were urine output, serum creatinine on day 0,3 and 7 or on the discontinuation day. |
| Notes | Additional information and methodology were clarified by the authors. |
| Bias | Authors' judgement | Support for judgement |
|---|---|---|
| Random sequence generation (selection bias) | Low risk | Computer generated random numbers. |
| Allocation concealment (selection bias) | Low risk | Sealed envelopes. |
| Blinding (performance bias and detection bias) | Low risk | Outcome assessors were blinded. |
| Incomplete outcome data (attrition bias) | Low risk | Only three out of the 64 study infants did not have blood levels of gentamicin measured. |
| Selective reporting (reporting bias) | Low risk | |
| Other bias | Low risk |
| Methods | Randomised Controlled Trial; single centre; India |
|---|---|
| Participants | N = 18. Inclusion criteria were neonates requiring gentamicin therapy as per unit protocol, 32 -36 weeks gestation, < 96 h of age and serum creatinine < 1 mg/dl. 'Once a day' gentamicin: N = 9. |
| Interventions | 'Once a day' gentamicin group were given gentamicin at 4 mg/kg/dose once every 24 h. 'Multiple doses a day' gentamicin group were given gentamicin at 2.5 mg/kg/dose every 12 h. Gentamicin was given as one minutes bolus intravenously followed by normal saline flush of 0.5 ml. |
| Outcomes | Peak levels were collected one hour after the first dose and the dose given at 48 h. Trough levels were collected just prior to the dose of gentamicin due at 48 h after the start of the therapy. Other outcomes measured were serum creatinine. |
| Notes | Additional information and methodology were clarified by the authors. |
| Bias | Authors' judgement | Support for judgement |
|---|---|---|
| Random sequence generation (selection bias) | Low risk | Computer generated random numbers |
| Allocation concealment (selection bias) | Low risk | Sealed envelopes |
| Blinding (performance bias and detection bias) | Low risk | Outcome assessors were blinded. |
| Incomplete outcome data (attrition bias) | Low risk | |
| Selective reporting (reporting bias) | Low risk | |
| Other bias | Low risk |
| Methods | Quasi Randomised Controlled Trial; single centre, Israel. Allocation based on the month of the year: single dose a day in January to March 1998; multiple doses a day in April/May1998. |
|---|---|
| Participants | N = 35. Inclusion criteria were BW >= 1500 g, age </= 24 h, gestational age 32-37 weeks and suspected sepsis. Exclusion criteria were shock, impaired renal function and known kidney, ear or heart malformations and metabolic disease. 'Once a day' gentamicin: N = 17. |
| Interventions | 'Once a day' gentamicin group were given gentamicin at 5 mg/kg/dose once every 24 h. 'Multiple doses a day' gentamicin group were given gentamicin at 2.5 mg/kg/dose every 12 h. |
| Outcomes | The serum gentamicin levels were measured at 72 to 96 h of therapy. The peak serum gentamicin level was measured 30 minutes after infusion. Trough levels were measured 30 minutes before the next dose. Other outcomes that were measured were serum and urine creatinine and sodium concentrations, urinary lysozyme excretion, glomerular filtration rate and fractional excretion of sodium at 72 to 96 h of therapy. Pure tone audiometric evaluation was performed at one to two months of age. Brainstem evoked response audiometry was performed if there was suspicion on pure tone audiometry. |
| Notes | Additional information and methodology were clarified by the authors. |
| Bias | Authors' judgement | Support for judgement |
|---|---|---|
| Random sequence generation (selection bias) | High risk | |
| Allocation concealment (selection bias) | High risk | |
| Blinding (performance bias and detection bias) | Low risk | Lab personnel and statisticians were blinded to the intervention. |
| Incomplete outcome data (attrition bias) | Low risk | |
| Selective reporting (reporting bias) | Low risk | |
| Other bias | Unclear risk |
| Methods | Randomised Controlled Trial; single centre; Spain |
|---|---|
| Participants | N = 80. Inclusion criteria were BW >= 1200 g, with suspected sepsis. Exclusion criteria were known renal impairment (serum creatinine > 1.2 mg/dl), severe neonatal asphyxia and unavailability of blood samples. 'Once a day' gentamicin: N = 33. |
| Interventions | 'Once a day' gentamicin group were given gentamicin at 5 mg/kg/dose once every 24 h. 'Multiple doses a day' gentamicin group were given gentamicin at 2.5 mg/kg/dose every 12 h. Gentamicin was given as intravenous infusion over 60 minutes. All patients received ampicillin concomitantly. |
| Outcomes | The peak serum gentamicin level was measured 60 minutes after completion of the infusion on the 4th day of treatment. Trough levels were measured immediately before the administration of the dose on 4th day of treatment. Other outcomes that were measured were urinary N acetyl-D glucose-aminidase:creatinine ratio within the first 2 days and on the 7th day of treatment, serum creatinine on the 4th day of treatment. |
| Notes | Additional information and methodology were clarified by the authors. |
| Bias | Authors' judgement | Support for judgement |
|---|---|---|
| Random sequence generation (selection bias) | Unclear risk | |
| Allocation concealment (selection bias) | Low risk | Using sealed envelopes. |
| Blinding (performance bias and detection bias) | Low risk | Outcome assessors were blinded to the intervention. |
| Incomplete outcome data (attrition bias) | High risk | Only 65 out of the 80 completed the study. |
| Selective reporting (reporting bias) | Low risk | |
| Other bias | Low risk |
| Methods | Randomised Controlled Trial; single centre; Germany |
|---|---|
| Participants | N=20. Inclusion criteria were neonates with pneumonia, meconium aspiration, suspected bacterial sepsis, and premature rupture of membranes > 36 h before delivery. Exclusion criteria were gestational age < 37 weeks, BW < 2500 g, Apgar score of </= 4 at one minute and <=6 at 5 minutes, serum creatinine > 85 micromol/l and those requiring diuretics during the course of treatment and those who were exposed to aminoglycoside prenatally. 'Once a day' gentamicin: N = 10. |
| Interventions | 'Once a day' gentamicin group were given gentamicin at 4 mg/kg/dose once every 24 h. 'Multiple doses a day' gentamicin group were given gentamicin at 2 mg/kg/dose every 12 h. Gentamicin was given as intravenous infusion over 30 minutes. All patients were treated with ampicillin concomitantly. |
| Outcomes | The pharmacokinetic profile of gentamicin was determined on the fourth day of treatment. Peak levels, trough levels and area under the concentration time curves, urinary excretion of alanine aminopeptidase as a marker of nephrotoxicity. |
| Notes | Additional information and methodology were clarified by the authors. |
| Bias | Authors' judgement | Support for judgement |
|---|---|---|
| Random sequence generation (selection bias) | Low risk | Computer generated random numbers. |
| Allocation concealment (selection bias) | Unclear risk | |
| Blinding (performance bias and detection bias) | High risk | |
| Incomplete outcome data (attrition bias) | Low risk | |
| Selective reporting (reporting bias) | Low risk | |
| Other bias | Low risk |
| Methods | Randomised Controlled Trial; single centre; India |
|---|---|
| Participants | N = 73. Inclusion criteria were gestational age >= 32 weeks, with suspected or confirmed sepsis. 48 term and 25 preterm infants were included. 'Once a day' gentamicin: N = 37. |
| Interventions | 'Once a day' gentamicin group were given gentamicin at 4 mg/kg/dose once every 24 h. 'Multiple doses a day' gentamicin group were given gentamicin at 2.5 mg/kg/dose every 12 h. Gentamicin was given as intravenous infusion over 30 minutes followed by normal saline flush. |
| Outcomes | The peak serum gentamicin level was measured 60 minutes after completion of the infusion of the 2nd dose of gentamicin. Trough levels were measured 30 minutes before the administration of the 2nd dose of gentamicin. |
| Notes |
| Bias | Authors' judgement | Support for judgement |
|---|---|---|
| Random sequence generation (selection bias) | Unclear risk | |
| Allocation concealment (selection bias) | Unclear risk | |
| Blinding (performance bias and detection bias) | Unclear risk | |
| Incomplete outcome data (attrition bias) | Low risk | |
| Selective reporting (reporting bias) | Low risk | |
| Other bias | Unclear risk |
| Methods | Quasi Randomised controlled trial; single centre; USA. Dose schedules were rotated on a monthly basis. |
|---|---|
| Participants | N = 55. Inclusion criteria were gestational age >= 34 weeks, postnatal age < 7 days, Apgar scores of > 4 at 1 minute and > 6 at 5 minutes respectively, urine output > 0.5 ml/kg/hour in the first 24 h of life or > 1 ml/kg/h in the second 24 h of life and absence of inotropic support. 'Once a day' gentamicin: N = 27. |
| Interventions | 'Once a day' gentamicin group were given gentamicin at 4 mg/kg/dose once every 24 h. 'Multiple doses a day' gentamicin group were given gentamicin at 2.5 mg/kg/dose every 12 h . Gentamicin was given as intravenous infusion over 30 minutes. All patients received ampicillin concomitantly. |
| Outcomes | The peak serum gentamicin level was measured 30 minutes after completion of the infusion on day three of therapy (fifth dose of 'multiple doses a day' and third dose of 'once a day' gentamicin group).Trough levels were measured immediately before the administration of the dose on day three of therapy (fifth dose of 'multiple doses a day' and third dose of 'once a day' gentamicin group). Other outcomes that were measured were cost of therapy. |
| Notes | Additional information and methodology were clarified by the authors. |
| Bias | Authors' judgement | Support for judgement |
|---|---|---|
| Random sequence generation (selection bias) | High risk | Quasi randomised trial; dose schedules were rotated on a monthly basis. |
| Allocation concealment (selection bias) | High risk | |
| Blinding (performance bias and detection bias) | High risk | |
| Incomplete outcome data (attrition bias) | Low risk | |
| Selective reporting (reporting bias) | Low risk | |
| Other bias | Unclear risk |
vs = versus
| Reason for exclusion | Not an RCT. The controls were historical. Multiple doses a day regimen was practiced between November 1999 to October 2000 and once a day gentamicin regimen was used between November 2000 to October 2002. Information from the first period was gathered from retrospective chart reviews. |
|---|
| Reason for exclusion | Not an RCT. It was a retrospective study of neonates born in the last half of 1995 who received gentamicin. |
|---|
| Reason for exclusion | RCT. Loading dose of 8 mg/kg was used in once a day gentamicin regimen whereas no loading dose was used in multiple doses a day regimen. |
|---|
| Reason for exclusion | Not an RCT. This was a retrospective study comparing the outcomes prior to and after implementation of the change in protocol to once a day regimen. |
|---|
| Reason for exclusion | Not an RCT. This was a retrospective comparative study of two periods involving change in regimen. |
|---|
| Reason for exclusion | Not an RCT. It was an audit of use of once -daily gentamicin for preterm and term infants for the period 31/3/1999 and 31/12/2000 |
|---|
| Reason for exclusion | RCT. Compared the peak and trough concentrations of gentamicin in neonates after a standard dose or a loading dose on the first day of life. |
|---|
| Reason for exclusion | Not RCT. It was a retrospective and subsequently prospective descriptive study. Newborn infants were administered gentamicin twice a day in the year 1995 and their results were analysed retrospectively. Infants were administered gentamicin once a day in the year 1996. |
|---|
| Reason for exclusion | Not an RCT. Retrospective study |
|---|
| Reason for exclusion | Not an RCT. Information from controls were derived from retrospective chart review. |
|---|
| Reason for exclusion | RCT. Compared 'once a day' to ' extended interval dosing of once in 48 hours' regimen of gentamicin. |
|---|
| Reason for exclusion | RCT. Once a day gentamicin regimen was compared to once in 48 hours regimen of gentamicin. |
|---|
| Reason for exclusion | RCT. Use of loading dose was compared to the regimen of no loading dose of gentamicin. |
|---|
| Reason for exclusion | Not an RCT. Only patients who received once a day dosage were studied. There was no comparison group. |
|---|
| Reason for exclusion | Not an RCT. It was an audit. |
|---|
| Reason for exclusion | Not an RCT. It was an audit of the use of extended interval dosing method for gentamicin in neonates. |
|---|
| Reason for exclusion | Not an RCT. Only patients who received once a day dosage were studied. |
|---|
| Reason for exclusion | Not an RCT. This was an observational study. Participants were less than 28 weeks of gestation. |
|---|
| Reason for exclusion | Data from 0-12 year age group were published. Relevant data from neonatal population could not be derived from the published article. Three attempts were made by us to obtain relevant data from the authors, but authors did not respond. |
|---|
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For graphical representations of the data/results in this table, please use link under "Outcome or Subgroup".
| Outcome or Subgroup | Studies | Participants | Statistical Method | Effect Estimate |
|---|---|---|---|---|
| 1.1 Clearance of proven sepsis | 3 | 37 | Risk Ratio (M-H, Fixed, 95% CI) | 1.00 [0.84, 1.19] |
| 1.2 Failure to achieve peak levels of at least 5 microgram/ml | 9 | 422 | Risk Ratio (M-H, Fixed, 95% CI) | 0.22 [0.11, 0.47] |
| 1.3 Failure to achieve trough levels of <= 2 microgram/ml | 11 | 503 | Risk Ratio (M-H, Fixed, 95% CI) | 0.38 [0.27, 0.55] |
| 1.4 Ototoxicity | 5 | 214 | Risk Ratio (M-H, Fixed, 95% CI) | 1.69 [0.18, 16.25] |
| 1.5 Nephrotoxicity | 8 | 348 | Risk Ratio (M-H, Fixed, 95% CI) | Not estimable |
| 1.6 Treatment failure | 3 | 37 | Risk Ratio (M-H, Fixed, 95% CI) | Not estimable |
| 1.7 Actual peak levels (µg/ml) | 10 | 440 | Mean Difference (IV, Fixed, 95% CI) | 2.58 [2.26, 2.89] |
| 1.8 Actual trough levels (µg/ml). | 10 | 440 | Mean Difference (IV, Fixed, 95% CI) | -0.57 [-0.69, -0.44] |