Aminoglycosides are among the most potent antibiotics available in the era of increasing prevalence of antibiotic-resistant Gram-negative bacteria. The standard daily dosing (SDD) in infants and children is twice or three times daily depending on age. Recent studies in adults have shown that once daily dosing (ODD) maximizes the bactericidal activity and might minimize the toxicity of gentamicin. 1–7 Several concepts support the benefit of ODD of gentamicin. First aminoglycosides exhibit a concentration-dependent bactericidal effect in which a linear relationship exists between higher peak-MIC ratio and improved clinical response. Second the post-antibiotic effect (PAE) is concentration-dependent. 2 Because ODD produces higher peak drug concentrations, a prolonged PAE would be expected. Finally adaptive resistance is thought to occur after continuous exposure of bacteria to antibiotic concentrations that are less than the MIC. 1, 2, 9 ODD may help to avoid the development of resistance by achieving a higher bacteria kill initially, thereby decreasing the length of time viable bacteria are in contact with the drug.
With regard to nephrotoxicity and ototoxicity, ODD may even be less toxic that SDD. This is probably best explained by the saturable uptake kinetics of aminoglycosides in the inner ear and proximal renal tubular cells. According to this mechanism the amount of drug that enters such cells is independent of the blood concentrations. The amount of drug accumulated intracellularly is similar to that of the peak value, because there is still aminoglycoside available to continue internal transport. A longer serum drug-free period in patients receiving ODD would allow most of the previously internalized drug to be transported out of the cell, potentially resulting in less toxicity. 1, 2
Pharmacokinetic, pharmacodynamic and clinical studies in animals and human adult populations have established the safety and efficacy of ODD regimen. 1–4 In infants and children the most frequently used aminoglycoside is gentamicin. It has a broad coverage against most Gram-negative pathogenic bacteria and, with ampicillin, has a synergistic effect against pathogenic bacteria such as Enterococcus sp. viridans streptococci and Listeria monocytogenes. Ampicillin and gentamicin are used for empiric antibiotic therapy of many childhood infections such as urinary tract infections, intraabdominal infections, endocarditis and nosocomial infections, as well as in neonates and young infants with suspected sepsis and meningitis. 8–11
The aim of this paper is to review the current data regarding the safety and effectiveness of ODD of gentamicin in children. To this end, a Medline search was conducted on the key words daily dosing, gentamicin, aminoglycoside, drug concentration, peak, trough, nephrotoxicity, ototoxicity, neonate and child. We included in the review only papers that had been published in the English literature. To be included the article had to be a comparison study between ODD and standard dosing of aminoglycoside and to present data of at least steady state peak and/or trough plasma concentrations.
Overall 13 studies describing ODD of gentamicin in children were found suitable for this review. 6, 8–19 Eleven were published since 1990, and we also included in this review results of two of our own studies presented in 2 international conferences, 15, 18 describing ODD of gentamicin in infants younger than 2 months and in preterm babies. In 1 study netilmicin was used, 9 in 11 studies gentamicin was used 6, 8, 10–18 and in 1 study either gentamicin or tobramycin was used. 19 In 5 studies infants and children age 1 month to 18 years were studied, 8–10, 12, 13 and in 8 studies neonates including preterm babies were reported. 6, 11, 14–19 Eleven studies were prospective, and in 1 study, 17 the prospective ODD group was compared with a retrospective control group. In all studies but 1, 13 patients were also given other antibacterial agents, mainly ampicillin. Exclusion criteria were not similar in all studies; however, patients with impaired renal function, renal malformation, shock, granulopenia and hearing deficit were excluded in most.
Steady state pharmacologic assessments were performed in one study after 24 h 10 and in 12 studies after 48 to 96 h of therapy 6, 8, 9, 11–19 (Tables 1 to 3 ). As shown in Tables 1 and 2, the aminoglycoside daily dose was 4 to 5 mg/kg in 11 studies 6, 8, 9, 11, 12, 14–19 and 7.5 mg/kg in 1. 10 In 1 study 13 the daily dose was calculated according to ages of children: 7.5 mg/kg/day in children <5 years old, 6.0 mg/kg/day in children 5 to 10 years old and 4.5 mg/kg/day in children 10 to 12 years old. Numbers of children in each group were not specified. In one study 17 a loading dose of 5 mg/kg of gentamicin was given to the ODD group at the initiation of therapy.
The peak serum aminoglycoside values were statistically higher in the ODD than in the SDD group for all of ages. Moreover steady state peak gentamicin concentrations <5 μg/ml (considered as the lower level of efficacy 6, 7) were documented in 6 to 20% of infants and children treated with SDD as compared with fewer than 4% in infants treated with ODD. 10, 11, 15, 18 In three studies 8, 10, 13 the steady state peak concentrations were higher than 12 μg/ml. Clinical standards for the peak range of gentamicin given once daily have not yet been properly established.
Studies in animals and adults have shown a direct relationship between high gentamicin concentration and longer PAE and bactericidal effect. In vitro studies have suggested that a peak concentration 10 times the MIC is desirable for eradication of Pseudomonas.20 Other studies have demonstrated that an improved outcome in patients with Gram-negative infections was directly related to the peak value of the aminoglycoside plasma values. 1, 2, 12, 21 Although in the above studies no gentamicin toxicity was demonstrated, the safety of very high serum peak values in children is yet to be proved.
The steady state trough values were similar in the ODD and SDD groups in three studies, whereas in the others they were significantly higher in the SDD groups. Moreover steady state trough concentrations >2 μg /ml (considered toxic in some references 6, 7) were documented in 5 to 55% of patients treated with the SDD 11, 15–17, 19 as compared with 0 to 24% in the ODD groups. 13, 17–19 These studies show that from the pharmacokinetic point of view, ODD might theoretically be more efficacious and less toxic than SDD.
Data regarding volume of distribution at steady state (Vd), rate of elimination constant (Ke) and t1/2 were published in three papers (Table 3). Bass et al. 10 showed that the Vd and Ke were similar in children age 6 months to 18 years with intraabdominal infections who were given 7.5 mg/kg/day gentamicin either once or in divided doses three times daily. Potovsky et al. 12 showed that in pediatric cancer patients who were treated with 5 mg/kg/day gentamicin either once or in divided doses three times daily for febrile neutropenia, the mean t1/2 was significantly longer and the Ke significantly lower in the ODD group than in the SDD group, whereas the Vd was similar. Hayani et al. 11 studied the Vd and t1/2 in neonates age 24 h or less with gestational age of 34 weeks or greater. These babies were treated with 5 mg/kg/day gentamicin either once or in divided doses twice daily (intravenous or intramuscular. Patients with shock, impaired renal functions or known renal malformations were not included in the study. The Vd was similar in all babies regardless of mode of administration and dosing. However, the t1/2 was statistically longer in the group treated with intravenous ODD than in the group treated with twice daily dosing (8.8 h vs. 5.4 h respectively;P < 0.05). Skopnik et al. 14 showed that the area under the curve for gentamicin concentration of >4 μg/ml was significantly higher in neonates treated with 4 mg/kg once daily as compared with 2 mg/kg twice daily which was consistent with half-life data. These studies show that the mode of dosing does not affect the volume of distribution; however, the elimination rate might be longer in children treated with ODD.
Nephrotoxicity was assessed in 10 studies by several techniques in >340 patients in each of the ODD and SDD groups. In 5 studies 8–10, 12, 13 that included infants >1 month of age and children, toxicity was assessed by rising serum creatinine values. A transient rise was documented in 3% of the patients in each group of dosing in only 1 study. 9 In one study 13 that included infants and children up to 12 years old, mild creatinine increase was documented at 48 to 72 h of therapy with gentamicin in 1 of 64 and 1 of 52 of children of the ODD and SDD groups, respectively. Three studies 11, 15, 18 (Table 4) included preterm and term neonates. In these studies no differences in renal functions were documented between the 2 dosing groups at the time of steady state at 48 to 96 h. Serum creatinine values were in normal ranges in almost all neonates.
Steady state tubular cell toxicity was also assessed in five studies that included 101 and 122 patients in the ODD and SDD groups, respectively, by comparing the urinary secretion of various specific tubular proteins between the initiation and end of therapy. No differences were documented between both dosing groups in neonates at 48 to 72 h 11, 18 or in infants and older children at the completion of therapy (7 to 10 days). 11, 13, 14 The concentrations of urinary proteins were within normal limits in almost all patients.
Ototoxicity associated with aminoglycoside therapy was assessed in six studies after completion of therapy, at discharge from the hospital, or after 2 months. Brain stem evoked response audiometry or pure tone audiometry was used in infants > 1 month of age and children who were treated for 3 to 10 days. 8–10, 13 Brain stem evoked response audiometry was used in preterm and term neonates. 17, 18 Ototoxicity was documented in only 2 studies. Vigano et al. 9 detected mild increase in wave V threshold (25 dB instead of 20 dB in 2 of 40 ears of patients who had been treated by the ODD regimen (no age was specified). Elhanan et al. 8 documented abnormal audiometric results in 2 of 26 and 2 of 24 of patients in the ODD and SDD groups, respectively, 7 days after completion of therapy. These abnormalities were not detected 2 months later.
These studies suggest that ODD compared with SDD of gentamicin has no higher toxicity at 48 to 96 h in neonates and at 3 to 10 days of therapy in older infants and children.
The effectiveness of ODD of gentamicin was assessed in 7 studies. In 4 studies 10, 12, 14, 17 clinical effectiveness was reported, and it was similar in the ODD and SDD groups. Microbiologic data were provided in 3 studies. Vigano et al. 9 treated 74 and 70 infants and children who had Gram-negative pyelonephritis with netilmicin either 5 mg/kg once daily or 2 mg/kg 3 times daily. They reported cure rates of 99 and 100% at 1 week and relapse rates of 7 and 6% at 4 weeks in the ODD and 3 times daily groups, respectively. Carapetis et al. 13 showed bacteriologic cure rates at 48 h of therapy in 58 of 60 (97%) and 58 of 59 (98%) infants and children with urinary tract infection caused by Gram-negative bacilli who were given gentamicin 4.5 to 7.5 mg/kg/day either once or 3 times daily (according to age), respectively. Skopnik et al. 14 developed an in vitro model to study the effectiveness of ODD or twice daily regimens of gentamicin (4 mg/kg/day in neonates who were concomitantly treated with ampicillin. In this dynamic model both dosage schedules showed comparable bactericidal effects on pathogens inhibited by low concentrations of gentamicin such as Escherichia coli and Staphylococcus aureus. However, the ODD regimen was significantly superior in isolates with high minimal inhibitory concentrations.
Multiple daily dose aminoglycoside therapy increases the cost of therapy because of the need for additional equipment, nursing administration time, pharmacy preparation time and serum gentamicin concentration analyses. Thureen et al. 6 studied the performance and cost analysis for two gentamicin regimens in infants of ≥34 weeks gestation who were given gentamicin (and ampicillin) for 72 h pending results of blood cultures obtained for sepsis evaluation. They compared the ODD of 4 mg/kg with 2.5 mg/kg given twice daily. ODD of gentamicin was more cost effective based on: (1) improved serum gentamicin concentrations (peak and trough); (2) elimination of the need for serum gentamicin values collection and analysis in infants on short courses of therapy. They calculated a $290 antibiotic-associated hospital cost saving per patient with the ODD regimen compared with three times daily dosing and serum gentamicin concentration analysis.
These data provide sufficient information to draw several conclusions: (1) on a pharmacokinetic basis ODD of gentamicin is theoretically more efficacious and less toxic than SDD; (2) ODD of gentamicin appears to be safe in term and preterm neonates during the first 72 to 96 h and for older infants and children for 3 to 10 days of therapy; (3) significant cost saving can be associated with ODD of gentamicin; (4) although sufficient clinical and microbiologic efficacy data are limited, the existing information shows that ODD is at least is efficacious as SDD. The total number of patients included in the above studies is not large. Additional, preferably multicenter, controlled prospective studies are required in larger numbers of infants and children to determine the safety and efficacy of the ODD regimen in these patients before ODD of gentamicin or other aminoglycosides can be recommended for routine use.
We thank Professor Ron Dagan for his extensive assistance in preparing the manuscript.
1. Lacy MK, Nicolau DP, Nightingale CH, Quintnlliani R. The pharmacodynamics of aminoglycosides. Clin Infect Dis 1998; 27: 23–7.
2. Dew RB III, Susla GM. Once-daily aminoglycoside treatment. Infect Dis Clin Pract 1996; 5: 12–24.
3. Ali MZ, Goetz MB. A meta-analysis of the relative efficacy and toxicity of single daily dosing vs.
multiple daily dosing
of aminoglycosides. Clin Infect Dis 1997; 24: 796–809.
4. Bailey TC, Little JR, Littenberg B, Reichley RM, Dunagan WC. A meta-analysis of extended-interval dosing vs.
multiple daily dosing
of aminoglycosides. Clin Infect Dis 1997:786–95.
5. Fattinger K, Voseh S, Olafsson A, Viceck J, Wenk M, Follath F. Netlmicin in the neonate: population pharmacokinetic analysis and dosing
recommendations. Clin Pharmacol Ther 1991; 50: 55–65.
6. Thureen PJ, Reiter PD, Gresors A, et al. Once-vs.
twice daily gentamicin dosing
≥ 34 weeks’ gestation: cost-effectiveness analysis. Pediatrics 1999; 103: 594–8.
7. Zaske DE. Aminoglycosides. In: Evans WE, Scentag J, Jusko W, eds. Applied pharmacokinetics, principles of therapeutic drug monitoring. Vancouver, Canada: Applied Therapeutic, 1992: 14–30.
8. Elhanan K, Siplovich L, Raz R. Gentamicin
thrice daily in children. J Antimicrob Chemother 1995; 35: 327–32.
9. Vigano A, Principi N, Brivio L, Tommasi P, Stasi P, Villa AD. Comparison of 5 milligrams of netilmicin per kilogram body weight once daily vs.
2 milligrams per kilogram thrice daily for treatment of Gram-negative pyelonephritis in children. Antimicrob Agents Chemother 1993:1499–503.
10. Bass KD, Larkin SE, Paap C, Haase GM. Pharmacokinetics of once-daily gentamicin dosing
in pediatric patients. J Pediatr Surg 1998; 33: 1104–7.
11. Hayani KC, Hatzopoulos FK, Fank AL, et al. Pharmacokinetics of once-daily dosing
. J Pediatr 1997; 131: 76–80.
12. Postovsky S, Ben Arush MW, Kassis E, Elhasid R, Krivoy N. Pharmacokinetic analysis of gentamicin
thrice and single daily dosage in pediatric cancer patients. Pediatr Hematol Oncol 1997; 14: 547–54.
13. Carapetis JR, Jaquiery AI, Buttery JP, et al. Randomized, controlled trial comparing once daily
and three times daily gentamicin
in children with urinary tract infections. Pediatr Infect Dis J 2001; 20: 240–6.
14. Skopnik H, Walraf R, Nies B, Troster K, Heiman G. Pharmacokinetics and antibacterial activity of daily gentamicin
. Arch Dis Child
1992; 67: 57–61.
15. Miron D, Sacran W, Steinfeld M, Horowitz J. No Nephrotoxic effect of short course of once daily gentamicin
in young infants. Presented at the European Society for Paediatric Infectious Diseases Meeting, May, 1998, Bled, Slovenia.
16. Romero C de A, Castillo EG, Secades CM, Lopez JR, Lopez LA, Valiente PS. Once daily gentamicin dosing
. Pediatr Infect Dis J 1998; 17: 1169–70.
17. Lundergan FS, Glassock GF, Kim EH, Cohen RS. Once-daily gentamicin dosing
in newborn infants. Pediatrics 1999; 103: 1228–34.
18. Miron D, Steinfels M, Reich D. Safey of short course of once-daily-dosing
(ODD) of gentamicin
infants [Abstract 016]. Presented at the 9th European Congress of Clinical Microbiology and Infectious Diseases, Berlin, Germany, March, 1999.
19. Skopnik H, Heiman G. Once daily
aminoglycoside in full term neonetes. Pediatr Infect Dis J 1995; 14: 71–2.
20. Shanker SM, Jew R, Bell LM, Lange BJ. Pharmacokinetics of single daily dose of gentamicin
in children with cancer [Abstract 611]. J Pediatr Hematol Oncol 1996; 18: 437.
21. Moore RD, Smith CR, Lietman PS. Association of aminoglycoside plasma levels with therapeutic outcome in Gram-negative pneumonia. Am J Med 1986; 80 (Suppl 5C): 2–12.