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Three Part Question

In [children aged 1 month to 18 years with UTI] is [OD gentamicin as compared with TD gentamicin] as effective in [resolving UTI and as safe]?

Clinical Scenario

An 8-month-old infant is admitted with fever and vomiting. Urinary tract infection (UTI) is diagnosed. You decide to commence IV treatment with gentamicin. In your paediatric ward, gentamicin is routinely administered in three times daily dose (TD) regimens but you look up gentamicin administration in the BNF for children and find that it can be given once daily (OD). This prompts debate amongst staff as to whether the same can be done on your ward. Everyone wonders whether there is any supportive evidence for efficacy and safety when OD gentamicin is used in the treatment of UTI.

Search Strategy

Medline (Ovid Medline) 1966–February 2007
"Urinary Tract Infection" and "Gentamicin or gentam$"
Limits: human, English language, all child (0 to 18 years), clinical trial

Search Outcome

32 citations (medline); three were relevant
No appropriate primary studies could be found from Cochrane Central, Cinahl or Embase.
Cochrane database, DARE, ACP Journal Club and EBM were explored. We could not find any systematic reviews explicitly answering our question.

Relevant Paper(s)

Author, date and country	Patient group	Study type (level of evidence)	Outcomes	Key results	Study Weaknesses
Chong et al, 2003,	210 children (1 month to 9 years) recruited with presumed UTI 172 were analysable (OD 84, TD 88) OD dose at 5 mg/kg/day and TD dose at 6 mg/kg/day (level 1b). Mean age 11 months	Randomised controlled trial (RCT).	Primary: Microbiological efficacy	Microbiological efficacy OD vs TD (98.7% vs 97.7%, p = 0.353) Nephrotoxicity (1.2% vs 2.3%, p = 0.627)	No mention how randomisation was done 1 week follow up for assessment of adverse effects of ototoxicity and nephrotoxicity is questionable
			Secondary: Nephrotoxicity and ototoxicity	Ototoxicity (0 vs 0, p = 0.506)
Carapetis et al, 2001,	184 children (1 month to 12 years) with UTI were recruited 179 were analysable (OD 90, TD 89) Daily doses of gentamicin in both groups were 7.5 mg/kg/day (<5 years old),6.0 mg/kg/day (5–10 years old) and 4.5 mg/kg/day (>10 years old)	RCT (level 1b).	Primary: Clinical efficacy (ie cure)	Clinical efficacy (cure): OD 96%, TD 98%. Relative risk (RR) of cure with OD gentamicin was 0.98 (95% CI, 0.93 to 1.03). Median (IQR)	Follow-up for assessment of adverse events was incomplete Author questions the sensitivity of the method used to detect nephrotoxicity
			Secondary: Bacteriological efficacy, nephrotoxicity, ototoxicity	Time to fever resolution in OD was 27 h (13.5 to 47.5), and in TD was 31.0 h (9.8 to 48) with p = 0.61.
Tapaneya-Olarn et al, 1999,	49 children (6 months to 12 years) with presumed UTI enrolled in the study. 24 were analysable (OD 13, TD 11). Gentamicin dose used was 4.5 mg/kg either OD or TD	RCT (level 2b).	Clinical and microbiological efficacy	Clinical efficacy (indicated by resolution of fever). Most patients in group afebrile by 24 h (mean 8.69 h) as compared with TD group (mean 15.31 h), p = 0.067.	Small sample size is the major weakness of this study Also ototoxicity was not accounted as an adverse event
			Nephrotoxicity	Laboratory nephrotoxicity measured by urine N-acetyl-D-glucosaminidase (NAG)/creatinine ratio, was detected in 2/13 (15%) of patients in OD group and 5/11 (45%) in TD group with p = 0.182.

Comment(s)

UTIs are the second most common infection in children, after those of the ear and throat (Bonadio). If intravenous antibiotics are required, aminoglycosides or third generation cephalosporins are usually used. Escherichia coli is a causative organism in 80–90% of cases (Poole) of UTI in children, making it a suitable clinical setting for aminoglycoside use in children. When compared to cephalosporins, aminoglycosides are favoured because of their efficacy, low rate of resistance (Lortholary) widespread availability and low cost. Gentamicin is frequently used to treat UTI in children because of experience with its use and its relatively low cost (Hardman). In addition, because other aminoglycosides, such as tobramycin, may be more useful in other clinical settings, gentamicin is used in UTI to minimise use of such drugs and, the development of drug resistance. Many clinical trials in adults and neonates (Bates, Barza, Gilbert, Ali, Nestaas) have proven that OD gentamicin can be used with equal or better efficacy and similar or decreased ototoxicity and nephrotoxicity as compared with conventional TD dosing. A meta-analysis recently assessed the safety and efficacy of OD dosing of aminoglycosides as compared with multiple dosing in children (Contopoulos-Ioannidis ). This meta-analysis included 24 studies where different aminoglycosides were used in different clinical settings. The authors concluded that although single trials have been small, the available randomised evidence supports the general adoption of OD dosing of aminoglycosides in paediatric clinical practice. Specifically, the use of OD versus TD dosing of gentamicin in children with UTI is addressed by the three studies (Chong, Carapetis, Tapaneya-Olarn) selected, The evidence extracted from these studies supports the use of OD gentamicin in the treatment of UTI in children, but certain gaps have been identified. These include the variation in gentamicin dose (OD varied from 4.5 to 7.5 mg/kg/day) and the estimation of ototoxicity and nephrotoxicity. Since it is thought that the prevalence of ototoxicity due to aminoglycoside is low in paediatric patients, large patient samples are needed with near complete follow-up of participants. These aspects were weak in these three studies. In the study conducted by Carapetis et al, base-line and follow-up audiology examinations were obtained in 28 (31%) and 39 (43%) patients in the OD group and 16 (18%) and 33 (37%) in the TD group. Tapaneya-Olarn et al did not measure ototoxicity in their outcome. As regards nephrotoxicity, there is lack of consensus regarding the best way to assess renal damage Carapetis et al referred to a method of assessing renal damage through the presence of tubular enzymes in urine but did not use this method in their study.

Clinical Bottom Line

Available evidence supports the efficacy of OD gentamicin in children with UTI. (Grade A) There is limited evidence regarding the safety of OD gentamicin. (Grade B) Issues of nephrotoxicity and ototoxicity require further clarification by well-structured RCTs with larger samples and complete follow-up of participants

References

1. Bonadio W. Evaluation and management of serious bacterial infections in the febrile young infant. Paediatr Infect Dis J 1990; 12: 905–12.
2. Poole C. Diagnosis and management of urinary tract infection in children. Nurs Stand 2002; 16 (38): 47–55.
3. Lortholary O, Tod M, Cohen Y, et al. Aminoglycosides. Med Clin North Am 1995; 79: 761–87.
4. Hardman JG, Limbird LE, eds. Goodman and Gilman's the pharmacological basis of therapeutics. 10th ed. New York: McGraw-Hill, 2001: 1231.
5. Bates RD, Nahata MC. Once daily administration of aminoglycosides. Ann Pharmacother 1994; 28: 757–65.
6. Barza M, Ioannidis JPA, Cappelleri JC, et al. Single or multiple doses of aminoglycosides: a meta analysis. BMJ 1996; 312: 338–45.
7. Gilbert DN. Editorial response: meta-analyses are no longer required for determining the efficacy of single daily dosing of aminoglycosides. Clin Infect Dis 1997; 24: 816–19.
8. Ali MZ, Goetz MB. A meta-analysis on the relative efficacy and toxicity of single daily dosing versus multiple daily dosing of aminoglycosides. Clin Infect Dis 1997; 24: 796–809.
9. Nestaas E, Bangstad HJ, Sandvik L, et al. Aminoglycosides extended interval dosing in neonates is safe and effective: a meta-analysis. Arch Dis Child Fetal Neonatal Ed 2005; 90: F294–300.
10. Contopoulos-Ioannidis DG, Giotis ND, Baliasta DV, et al. Extended-interval aminoglycoside administration for children: a meta-analysis. Pediatrics 2004; 114: 111–18.
11. Chong C-Y, Tan AS-L, Ng W, et al. Treatment of urinary tract infection with gentamicin once or three times daily. Acta Paediatr 2003; 92: 291–6.
12. Carapetis JR, Jacquiery AL, Buttery JP, et al. Randomised controlled trial comparing once daily and three times daily gentamicin in children with urinary tract infections. Paediatr Infect Dis J 2001; 20: 240–6.
13. Tapaneya-Olarn C, Tapaneya-Olarn W, et al. Single daily dose of gentamicin in the treatment of pediatric urinary tract infection. J Med Assoc Thailand 1999; 82 (1): 93–7.