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Three Part Question

[In neonates receiving Gentamicin] is [once daily dosing vs multiple dosing] equally [safe and effective]?

Clinical Scenario

A term baby is admitted to the neonatal unit with a history of grunting 1 hour after birth. You are the SHO on call and plan to start the baby on antibiotics-Benzylpenicillin and Gentamicin for suspected sepsis. One of the Neonatal Nurses asks you about once daily dosing and multiple dosing of Gentamicin and you wonder which of these regimens would be more safe and effective?

Search Strategy

Medline 1966-Nov 2004 using the OVID interface ([gentamicin OR aminoglycosides.mp]AND[neonates OR newborn OR children.mp])
The search was limited to randomised controlled trials and meta- analysis.
This search was repeated in Cochrane Central Register of Controlled Trials.

Search Outcome

A total of 76 papers were found of which 10 papers were found to be relevant.

Relevant Paper(s)

Author, date and country	Patient group	Study type (level of evidence)	Outcomes	Key results	Study Weaknesses
Kosalaraksa et al. (2004) J Med Assoc Thai.Thailand.	N=64 between May 2000-Aug 2001. Neonates with gestational age > 34 weeks, birth weight (BW) > 2000 g, between 0-7 days old, with an APGAR score of >6 at 5 min and with suspected sepsis were considered. N=33 in the Once daily dosing (ODD) group (5 mg/kg every 24 hours) and N=31 in the Twice Daily dosing (TDD) Group (2.5 mg/kg every 12 hours).	RCT (1A)	1) Mean Gentamicin Peak concentration measured 30 min after infusion-(after the 3rd dose in ODD group and 6th dose in TDD group)(4-12 µg/ml)	ODD vs TDD:(10.1±3.0 vs 7.8±2.0; p<0.05).	Ototoxicity not assessed. Neonates with metabolic disturbances, congenital heart disease (CHD) and Gram positive bacterial infection were excluded from the study. No significant changes in the serum creatinine levels and no oliguria or polyuria during therapy.
			2) Mean Gentamicin Trough Concentration-measured immediately before the 4th dose in ODD group and 7th dose in TDD group(<2 µg/ml).	ODD vs TDD:(1.6±1.1 vs 2.6±1.2; p<0.05).
Agarwal et al. 2002 J of Perinatol.USA.	Neonates born between March 1999-Nov 1999 with Birth weight (BW) >2500 g, age <7 days, Apgar score >5 at 5 min and suspected systemic or focal bacterial infection were considered. N=20 in ODD / Study group (4 mg/kg/dose every 24 hrs). N=21 in TDD/ Control group (2.5 mg/kg/dose every 12 hours).	PRCT (1A)	1) Initial Peak Serum Gentamicin Concentration(SGC)(collected 30 min after completion of infusion)	Study vs Control :8.2±1.7 vs 6.4±1.5; p=0.001.	ODD achieved higher SGC and safer trough concentration than TDD. Neonates with History of asphyxia, shock, cardiopulmonary arrest, seizures, anomalies of kidney or ear, congenital abnormalities and presence of neuromuscular disorder were excluded from the study. No differences in urine output, serum creatinine or creatinine clearance between the two groups. All infants passed hearing test prior to discharge.
			2) 24 hour SGCs:a) Trough(measured 30 min before the next dose is due)(<2 µg/ml)	Study vs Control:0.9±0.4 vs 1.9±0.5; p=0.0001.
			b)Peak SGC	Study vs Control: 9.4±1.6 vs 7.0±1.6; p=0.0001.
			3) Toxic Trough SGCs (>2.0µg/ml): a) 24 hours	Study vs control group:0 vs 9(43%); p=0.001
			b) 48 hours	Study vs control group:0 vs 6(29%); p=0.02.
Chotigeat et al. 2001 J Med Assoc Thailand.Thailand.	Infants admitted to the neonatal unit between 1st August-31st Dec, 1999 with BW>2000g, gestational age >34 weeks, age <7 days, Apgar score >4 and 6 at 1 and 5 min respectively were included in the study. N=27 in the Once daily dosing regimen (ODD) (4-5 mg/kg dose every 24 hours) and N=27 in the Twice daily dosing regimen (TDD) (2-2.5 mg/kg dose every 12 hours).	PRCT	1) Peak Serum Gentamicin Concentration(SGC)(µg/ml)(4-12 µg/ml)(in ODD-measured 30min after completion of infusion of the 3rd dose and in TDD measured 30min after completion of infusion of the 5th dose).	ODD vs TDD:(8.92±1.59 vs 5.94±1.57; p<0.001).	ODD achieved significantly higher peak SGL and safer troughs than TDD assuring its safety and efficacy. Neonates with congenital abnormalities, history of renal failure and neuromuscular disorder were not included. Ototoxicity was not assessed. It is not clear if ODD improves the outcome in cases of proved septicaemia. No significant difference in creatinine clearance was found between the two groups.
			2) Trough SGC (µg/ml)(<2 µg/ml)(in ODD- measured 30min prior to the 3rd dose and in TDD measured 30min prior to the 5th dose).	ODD vs TDD:(0.90±0.35 vs 1.44±0.49; p<0.001).
Thureen et al. 1999 Paediatrics.USA	N=55 with N=27 in Once daily Dosing regimen (ODD) (4 mg/kg/dose every 24 hours) and N=28 in Twice daily Dosing regimen (TDD)(2.5 mg/kg/dose every 12 hours). Neonates >34 weeks, age <7 days, Apgar scores >4 and >6 at 1 and 5 min respectively were included in the study.	Cohort study	1) Peak SGC(5-10 µg/ml)( in ODD-measured 30min after completion of infusion of the 3rd dose and in TDD measured 30min after completion of infusion of the 5th dose).	ODD vs TDD:(7.9±1.6 vs 6.7±1.1; p<0.05).	ODD of gentamicin is the preferable treatment strategy based on: 1) significantly improved SGC performance compared with TDD; 2) elimination of the need for routine SGC collection in infants on short courses of therapy; and 3) Significant antibiotic-associated hospital cost savings when compared with conventional therapy of TDD and SGC analysis. Ototoxicity and nephrotoxocity were not assessed.
			2) Range of Peak SGC: a) Number of SGC <5 µg/ml (%). b) Number of SGC >10 µg/ml (%).	ODD vs TDD:(4.9-10.9 vs 3.5-9.2). (a) 1(3.7) vs 2(7.4). (b) 1(3.7) vs 0(0).
			3) Trough SGC (<2 µg/ml)( in ODD- measured 30min prior to the 3rd dose and in TDD measured 30min prior to the 5th dose).	ODD vs TDD- (1.0±0.5 vs 2.0±1.1; p<0.05).
			4) Range of Trough SGC (a) Number of Trough SGC >2µg/ml (%).	ODD vs TDD:(<0.5-1.8- vs <0.5-3.7). (a)0(0) vs 14(50)].
			5) Cost effectiveness findings: (a) Acquisition drug cost	ODD vs TDD: (a)0.99±0.48 vs 1.98±0.96
			b) Materials and equipment cost	ODD vs TDD: 21.60±11.10 vs 26.58±13.20
			c) Labor cost	ODD vs TDD: 7.23±0.75 vs 14.46±1.5
			d) SGC analysis cost	ODD vs TDD: 132.16±74.62 vs 132.16±74.62
Solomon et al. 1999 Indian Pediatrics. India	Neonates born between Nov 1996-Oct 1997 with gestational age >32 weeks and with suspected sepsis were included in the study. N=73 with N=25 in the preterm group (Gestational age between 32-36 weeks)(N=13 in ODD group and N=12 in TDD group). N=48 in the term group (Gestational age > 37 weeks)(N=24 in ODD group and N=24 in TDD group). ODD group received 4 mg/kg every 24 hrs of Gentamicin and TDD group received 2.5 mg/kg/dose every 12 hrs.	RCT	1) Preterm Group:(a) Mean trough level (SD)(<2 µg/ml)(measured 30 min before administration of next dose)	ODD vs TDD:(a)1.85(0.86) vs 1.98(1.09).	Peak SGC were obtained in both term and preterm babies with both regimens. Also there was no significant difference in ODD/TDD regimens in terms of safer trough levels. Both regimens attained safer trough levels in preterm and term babies. ODD might be advantageous taking into consideration its prolonged post antibiotic effect and development of resistance. Ototoxicity and nephrotoxicity were not assessed.
			b) No. Of patients (pts) with trough level >2 µg/ml	(b)4(30.8) vs 7(58.3); CI (-11.0)-(66.0); p=0.06
			c) Mean peak level (SD)(4-10 µg/ml)(measured 1 hr after administration of 2nd dose)	(c)7.38(2.29) vs 6.69(2.42).
			d) No. of pts with peak level >10 µg/ml(%)	1(7.6) vs 1(8.3); CI (-19.7)-(21.0); p=0.30.
			e) No. of pts with peak level <4 µg/ml(%)	1(7.6) vs 2(16.6); CI (-15.8)-(33.7); p=0.14.
			2) Term group:(a) Mean trough level (SD)(<2 µg/ml)	ODD vs TDD: (a)1.33(1.0) vs 1.55(1.0)].
			b) No. of patients (pts) with trough level >2 µg/ml(%)	2(8.3) vs 3(12.5); CI (-12.8)-(21.2); p=0.10.
			c) Mean peak level (SD)(4-10 µg/ml).	7.1 (2.64) vs 6.96(2.83).
			d) No. of pts with peak level >10 µg/ml(%)	3(12.5) vs 2(8.3); CI (-21.2)-(12.8); p=0.50
			e) No. of pts with peak level <4 µg/ml(%)	3(12.5) vs 4(16.6); CI (-15.6)-(23.9); p=0.16.
Romero et al. 1998 Pediatr Infect Dis J. USA	Study was conducted from April-July 1994 and from April-June 1995. Neonates with Birth weight (BW) >1200 g and with suspected sepsis were included in the study. N= 80 but 65 completed the study. N=33 in Once daily dosing regimen (ODD)(Study group)(5 mg/kg 24hrly) of which neonates with gestational age <37 weeks (Preterm)=20 and gestational age >37 weeks (Term)=13. N=32 in Twice daily dosing regimen (TDD)(Control group)(5 mg/kg in 2 divided doses) of which neonates with gestational age <37 weeks (Preterm)=17 and gestational age >37 weeks (Term)=15.	PRCT	1) Peak SGC (2 hrs after administration of dose)(6-12 µg/ml).	ODD vs TDD: (9.5±1.7 vs 6.4±1.6; p<0.001). Range of Peak SGC ODD vs TDD : (5.1-12.1 vs 4.0-11.3).	ODD resulted in better therapeutic SGC than TDD with minimal side effects both in preterm and term neonates. Study conducted in two different time periods. Ototoxicity was not assessed.
			2) Full term babies Peak SGC	ODD vs TDD: (9.2±1.5 vs 5.7±1.3; p<0.001). Range of Peak SGC ODD vs TDD (6.9-11.9 vs 4.0-8.4).
			3) Preterm babies Peak SGC	ODD vs TDD: (9.7±1.8 vs 7.1±1.7; p<0.001). Range of Peak SGC ODD vs TDD (5.1-12.1 vs 4.0-11.3).
			4) Trough SGC (Measured before administration of next dose)(<2µg/ml)	ODD vs TDD- (1.4±0.7 vs 2.2±1; p=0.002).Range of Peak SGC ODD vs TDD (0.4-3 vs 0.4-4.8).
			5) Term babies Trough SGC	ODD vs TDD:(1.1±0.4 vs 1.5±0.6; p=0.001). Range of Peak SGC ODD vs TDD (0.6-1.9 vs 0.4-2.1).
			6) Preterm babies Trough SGC	ODD vs TDD:(1.6±0.8 vs 2.7±0.9; p=0.001). Range of Peak SGC ODD vs TDD (0.4-3 vs 1-4.8).
			7) N-Acetyl-beta-D-glucosaminidase (indicator of nephrotoxicity)(Units/g) : (a) 1st day of treatment	ODD vs TDD: 45±38 vs 64±65.
			(b) 7th day of treatment	ODD vs TDD: 68±32 vs 103±150
Krishnan et al. 1997 Indian Pediatrics. India	Neonates admitted between Jan-May 1994 with gestational age between 32-36 weeks, age <4 days, Serum Creatinine <1 mg/dl before therapy and those who had not received Gentamicin previously and their mothers had also not received Gentamicin before delivery were included in the study. N=18 with N=9 in ODD group (4 mg/kg every 24 hrs). N=9 in TDD group (2.5 mg/kg every 12 hrs).	Prospective Randomized Double Blind Study	1) Peak 1 SGC (Obtained 1 hr after first dose).	ODD vs TDD- (5.88±1.10 vs 3.88±0.76; p=0.000).	Small sample size. Ototoxicity was not assessed. There was no evidence of nephrotoxicity as assessed by Serum Creatinine levels.
			2) Trough SGC (Obtained prior to the dose due at 48 hrs)(<2 µg/ml)	ODD vs TDD- (1.96±0.60 vs 2.76±0.7; p=0.019).
			3) Peak 2 SGC (Obtained 1 hr after the 48 hr dose)	ODD vs TDD- (6.56±1.66 vs 5.45±1.67; p=0.177).
Hayani et al. 1997 J Pediatr.USA	Study was conducted between June 1993-Aug 1994. Infants with suspected sepsis, age <24 hrs, gestational age >34 weeks, BW >2000 g and Apgar score >7 at 5 min were included in the study. 31 patients were enrolled in the study but 26 completed the study. N=26 with N=11 in ODD group (5 mg/kg every 24 hrs) and N=15 in TDD group (2.5 mg/kg every 12 hrs). Infants were assigned to receive Gentamicin either by intravenous route (IV) or intramuscular route (IM).	PRCT	1) Trough SGC (Obtained 30 min before the next dose).	ODD-IV vs ODD-IM vs TDD-IV/IM: 1.7±0.4 vs 1.1±0.3 vs 1.7±0.5; p<0.05.	ODD achieved higher peaks and lower troughs which are important to achieve maximum bactericidal action and fewer side effects. Ototoxicity was not assessed. There were no significant differences in the change in serum Creatinine concentrations and GFR between the two groups.
			2) Peak SGC (Obtained 30 min after IV dose or 60 min after IM dose).	ODD-IV vs ODD-IM vs TDD-IV/IM: 10.7±2.1 vs 11.2±2.0 vs 6.6±1.3; p<0.05.
			3) 6 hr post dose SGC	ODD-IV vs ODD-IM vs TDD-IV/IM: 4.7±1.1 vs 4.9±1.5 vs 2.8±0.6; p<0.05).
Mercado et al. 2004 Am J of Perinatol. USA	N=40 May 1999 to Jan 2001. Infants with gestational age 25-33 weeks and birth weight (BW) 750-2000 g were considered. Group 1-BW 750-1500 g. N=20. 10 infants were in Conventional Interval Dosing (CID) (2.5 mg/kg/dose iv every 24 hrs) and 10 in Extended Interval Dosing (EID) (5 mg/kg/dose iv every 48 hrs). Group 2- BW 1501-2000 g. N=20. 11 infants were in CID (2.5 mg/kg/dose iv every 18 hrs) and 9 in EID (4.5 mg/kg/dose iv every 48 hrs).	RCT (1A)	1) Gentamicin peak levels(5-12 µg/ml) 30 mts after completion of the 30 mt dose infusion.	CID Vs EID: Group1 (9.0±4.8 vs 12.0±5.6). Group2 (6.6±2.4 vs 12.4±6.2). Mean peak levels were higher with EID compared to CID irrespective of BW (p<0.001).	Small sample size. Infants with conditions affecting renal function and infants whose mothers received drugs affecting renal function were excluded from the study. No significant difference detected in both groups in urine output-recorded daily during the 12-day study period. No significant difference in Volume of distribution (Vd) between CID and EID in both groups. Infants randomized to CID had higher clearance compared to EID for both groups. All infants had normal serum creatinine levels (<1 mg/dL)
			2) Gentamicin trough levels- (<2 µg/ml) 30 mts prior to the scheduled dose.[Levels were drawn at the 2nd dose for EID and 3rd dose for CID].	CID Vs EID: Group1 (2.1±0.9 vs 1.5±0.5). Group2 (1.4±0.3 vs 1.0±0.4). Mean trough levels were lower with EID compared to CID irrespective of BW. (p<0.001)
			3) Hearing screens prior to discharge.	3 infants failed the hearing screen.2 in CID group.
Rastogi et al. 2002 Pediatr Infect Dis J. USA	Study was done between March 1999-Nov 1999. Neonates with Birth weight (BW) between 600-1500 g, age<7 days, Apgar score >5 at 5 min and suspected systemic or focal bacterial infection were considered. N=58. Group I-BW 600-1000 g received 5-mg/kg/dose 48 hourly (q48h) and 2.5 mg/kg/dose 24 hourly (q24h). Group II-BW 1001-1500 g received 4.5 mg/kg/dose 48 hourly and 3 mg/kg/dose 24 hourly. N=30 in the 48 hour group and N=28 in the 24 hour group.	PRCT	1) Initial peak Serum Gentamicin Concentration(SGC)(µg/ml)(measured 30 min after completion of first dose)	q48h vs q24h:(8.19¡±.3 vs 6.04±2.2, p=0.00001).	The 48 hrly dosing regimen achieved therapeutic SGL very quickly but 13% of infants on this regimen had trough levels <1 µg/ml for >24 hrs before the next dose. It was not possible to obtain a relationship between therapeutic outcome and early attainment of therapeutic peak SGC since none of the infants had Gram negative septicaemia. No significant difference was found in Gentamicin half life, elimination constant, volume of distribution, urine output, serum creatinine and glomerular filtration rate between both the groups. All infants passed hearing screen prior to discharge.
			2) 24 hour SGC: (a) Trough (<2 µg/ml) (measured 30 min before the next dose)	q48h vs q24h: 1.72¡±0.6 vs 1.25±0.4, p=0.0013.
			(b) Peak (5-12 µg/ml)	q48h vs q24h: Not obtained vs 6.42±1.8.
			3) 48 hour SGC: (a) Trough (<2 µg/ml)	q48h vs q24h: 0.70±0.3 vs 1.32±0.4, p=0.00001.
			(b) Peak (5-12 µg/ml)	q48h vs q24h: 8.52±2.1 vs 6.51±1.71, p=0.0003.

Comment(s)

Gentamicin dosing is monitored using Serum Peak and Trough concentrations. The bactericidal action of Gentamicin is dependant on its higher peak levels (defined as the highest concentration measured 15-30 minutes after intravenous administration). The trough level (defined as the concentration measured just before the next dose is due) reflects the prolonged post antibiotic effect and may influence the incidence of side effects. All of the studies show that extending the dose interval of Gentamicin administration results in higher peak and lower trough levels when compared with more frequent dosing regimens. Certain studies compare multiple daily dosing with once daily dosing as per the standard 24 hrly and 12 hrly regimen1,2,3,4,5,6,7,9 while there are 2 studies which compare once daily dosing with a more extended regimen and are included in the study as well8,10. Some studies include preterm1,2,3,4,5,6,7,10 and low birth weight infants1,2,4,7,8,10. The study by Mercado et al looked at pre-term infants (25-33 weeks) and suggests the safety and efficacy of Gentamicin used as a once daily dose.10 Similarly the study by Rastogi et al supports the use of once daily dosing in very low birth weight infants (BW between 600-1500 g).8 Side effects associated with Gentamicin use were considered. There were no differences noted in the incidence of ototoxicity (as determined by the results of hearing screening)8,9,10 or nephrotoxicity (as measured by creatinine clearance and urine output)1,2,4,7,8,9,10 between the different dosing regimens. None of the studies quote the percentage of neonates who were septic during the study period and some papers specifically exclude babies who are unwell. It may be that the pharmacokinetic profile of Gentamicin is different in some patient groups e.g. extremely sick, septic infants, infants with history of birth asphyxia and renal compromise and neonates with metabolic disturbances, congenital heart disease (CHD), seizures. For these groups close monitoring of Serum Gentamicin Concentration (SGC) would be advisable with appropriate individualised dose adjustments. The studies by Mercado et al 10 and Rastogi et al 8 compare 24 hourly with 48 hourly dosing. These studies show that extending the dose interval further than 24 hours does give higher peak and lower trough levels than more frequent dosing. The paper by Rastogi, however, highlights a number of babies with very low trough levels for > 24 hours before the next dose. This suggests that there is a limit to how far you can extend the dose interval without compromising antibiotic effect. Thureen et al in their study additionally comment on the cost effectiveness associated with single dosing regimen. Their study states that single daily dosing of Gentamicin is more cost effective than multiple dosing and eliminates the need for routine SGC sample collection in infants on short courses of therapy.6 A survey of the antibiotic policies of the use of Gentamicin in UK within a deanery [West Midlands] in the Neonatal Unit has shown that about one in ten hospitals[10%] still use the multiple dosing regimen of Gentamicin. In summary the evidence suggests the safety, efficacy and also cost effectiveness of a Once daily dosing regimen in all neonates irrespective of their gestational age and birth weight. However careful monitoring is suggested in compromised neonates.

Clinical Bottom Line

Once daily dosing of Gentamicin is safe and effective as compared with multiple dosing regimen irrespective of gestational age and birthweight.

References

1. Kosalaraksa P., Janthep P., Jirapradittha J.,Taksaphan S. Once versus twice daily dose of gentamicin therapy in Thai neonates. Journal of the Medical Association of Thailand. 87(4):372-6, 2004
2. Agarwal G, Rastogi A, Pyati S, Wilks A, Pildes RS. Comparison of once-daily versus twice-daily gentamicin dosing regimens in infants > or = 2500 g. J Perinatol. 2002; 22: 268-C274
3. Chotigeat U, Narongsanti A, Ayudhya DP. Gentamicin in neonatal infection: once versus twice daily dosage. J Med Assoc Thai. 2001; 84: 1109-1115.
4. Thureen PJ, Reiter PD, Gresores A, Stolpman NM, Kawato K, Hall DM. Once- versus twice-daily gentamicin dosing in neonates 34 weeks' gestation: cost-effectiveness analyses. Pediatrics. 1999; 103: 5
5. Solomon R. Kuruvilla KA. Job V. Selvakumar R. Jeyaseelan L. Kanagasabapathy AS. Jana AK. Randomized controlled trial of once vs. twice daily gentamicin therapy in newborn. Indian Pediatrics. 36(2): 133-7, 1999 Feb.
6. de Alba Romero, Concepción M.D., Ph.D.; Castillo, Elvira Gómez M.D.; Secades, Cecilia Manzanares Pharm.D.; López, Jesús Rodriguez M.D.; López, Luisa Arreaza Pharm.D.; Valiente, Pilar Saenz Pha. Once daily Gentamicin Dosing in neonates. Pediatr Infect Dis J. Dec 1998; 17(12): 1169-1171
7. Krishnan L. George SA. Gentamicin therapy in preterms: a comparison of two dosage regimens. Indian Pediatrics. 34(12):1075-80, 1997 Dec.
8. Hayani KC, Hatzopoulos FK, Frank AL, et al. Pharmacokinetics of once-daily dosing of gentamicin in neonates. J Pediatr. 1997; 131: 76-80
9. Mercado MC, Brodsky NL, McGuire MK, Hurt H. Extended interval dosing of gentamicin in preterm infants. Am J Perinatol. 2004 Feb; 21(2): 73-7.
10. Rastogi, Alok MD, Agarwal, Ghanshyam MD; PyatiI, Suma MD; Pildes, Rosita S. MD. Comparison of two gentamicin dosing schedules in very low birth weight infants. Pediatr Infect Dis J. March 2002; 21(3): 234-240.