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Gentamicin nephrotoxic effects in the neonate
Volume 113 Number 3
Editorial correspondence
Reply To the Editor: Dr. Greene offers a useful clarification of our statements concerning the genetics of Dubin-Johnson syndrome. The intent of our comments about the family history in familial disorders of conjugated hyperbilirubinemia was to indicate that these disorders are characterized by the autosomal recessive mode of inheritance, as opposed to an autosomal dominant mode, in which one would be much more likely to encounter a positive family history. Dr. Rosenthal adds an interesting comment about the role of serum bilirubin fractional analysis in the diagnosis of DubinJohnson syndrome. However, in Dr. Rosenthal's publication on bilirubin conjugates (reference 1 in his letter), there were no normative data in the newborn period, and there was only one analysis of a single child with Dubin-Johnson syndrome. Until more data are available, this type of analysis should probably supplement, but not take the place of, more standard methods of establishing the diagnosis of Dubin-Johnson syndrome in young infants.
Kathleen B. Schwarz, MD Assistant Professor Pediatric and Gastroenterology Nutrition Department of Pediatrics The Johns Hopkins University School of Medicine The Johns Hopkins Hospital Baltimore, MD 21205
Gentarnicin nephrotoxic effects in the neonate To the Editor: The recent article by Adelman et al. (J PEDIATR 1987;111:88893) reports a smaller postnatal fall in mean serum creatinine concentration and a corresponding diminished postnatal rise in mean creatinine clearance in neonates receiving gentamicin and ampicillin, in comparison with those receiving mezlocillin alone. The authors conclude that gentamicin is nephrotoxic in the neonate. Although aminoglycosides have been associated with nephrotoxic effects in older patients and have the potential for this effect in neonates, the significance of the reported data is limited by several factors: (1) the sensitivity of the serum creatinine assay, (2) the accuracy of short-term urinary creatinine collections for measured creatinine clearance, (3) the gentamicin dosing regimen used, and (4) the lack of evaluation of long-term effects. Clinical laboratory methods for serum creatinine determinations are not accurate to two significant figures? In evaluating the data, the authors have taken the mean value to more significant figures than the actual measured values. The comparison should be between the final serum creatinine value of 0.8 mg/dl in the mezlocillin-treated group and 0.9 mg/dl in the gentamicin- and ampicillin-treated group. Statistical significance may be reached, but clinical significance is doubtful. Measured creatinine clearance values were based on 3- to 4-hour urine collections. Short urine collections (<8 hours) have a high degree of variability (20%) in estimating creatinine clear-
619
ance. 2 Even with 12- to 24-hour collection periods, its use appears to have significant limitations in estimating glomerular filtration rate in the neonate. 1 The initial creatinine clearance was higher in the gentamicin-treated group than in the mezlocillin-treated group. Final mean creatinine clearance for each group of patients appeared to be similar. Thus the gentamicin-treated group had a smaller percent change between final and initial creatinine clearance, but overall final creatinine clearance was similar to that in the mezlocillin treatment group. A further complicating factor is that the patients received doses that have been shown to result in significant drug accumulation, resulting in higher-than-desired trough serum gentamicin concentrations in low birth weight infants. 3,4 Trough concentrations >2 /zg/ml may have led to an increased, although still clinically insignificant, effect of gentamicin on renal function. Finally, and perhaps most important, long-term effects on serum creatinine and creatinine clearance were not evaluated. Do the serum creatinine and the creatinine clearance differ between these groups at 1 week, 2 weeks, or 1 month later? Until the clinical significance of the effect of gentamicin and other aminoglycosides on the renal function of neonates can be more fully determined, we caution the application of this study's conclusion to charge the choice of antibiotics used in the neonate.
Mariane H. Gabriel, PharmD Carl IV. Kildoo, PharmD Arthur B. Strauss, MD Departments of Pharmacy and Neonatology Miller Children's Hospital Memorial Medical Center Long Beach, CA 90801-1428 REFERENCES
1. 2.
3.
4.
Arant BS. Estimating glomerular filtration rate in infants. J PEDIATR 1984;104:890. Baumann T J, Staddon JE, Horst HM, Bivins BA. Minimum urine collection periods for accurate determination of creatinine clearance in critically ill patients. Clin Pharm 1987; 6:393. Kildoo CW, Modanlou HD, Komatsu G, Harralson AF, Hodding JH. Developmental pattern of gentamicin kinetics in very low birth weight sick infants. Dev Pharmacol Ther 1984;7:345. Szefler S J, Wynn R J, Clarke DF. Relationship of gentamicin serum concentrations to gestational age in preterm and term neonates, J PEDIATR 1980;97:312.
Reply To the Editor." We take exception to the suggestion that our data do not support the nephrotoxic effects of gentamicin in the neonate. The infants receiving gentamicin and ampicillin had a significantly smaller postnatal fall in mean sertma creatinine concentration in comparisonwith neonates receiving mezlocillin alone, even when individual creatinine values were ,rounded to a single significant figure before statistical analysis. Several investigators t,2,3 have confirmed the validity of accu-
Editorial correspondence
Reply To the Editor: Dr. Greene offers a useful clarification of our statements concerning the genetics of Dubin-Johnson syndrome. The intent of our comments about the family history in familial disorders of conjugated hyperbilirubinemia was to indicate that these disorders are characterized by the autosomal recessive mode of inheritance, as opposed to an autosomal dominant mode, in which one would be much more likely to encounter a positive family history. Dr. Rosenthal adds an interesting comment about the role of serum bilirubin fractional analysis in the diagnosis of DubinJohnson syndrome. However, in Dr. Rosenthal's publication on bilirubin conjugates (reference 1 in his letter), there were no normative data in the newborn period, and there was only one analysis of a single child with Dubin-Johnson syndrome. Until more data are available, this type of analysis should probably supplement, but not take the place of, more standard methods of establishing the diagnosis of Dubin-Johnson syndrome in young infants.
Kathleen B. Schwarz, MD Assistant Professor Pediatric and Gastroenterology Nutrition Department of Pediatrics The Johns Hopkins University School of Medicine The Johns Hopkins Hospital Baltimore, MD 21205
Gentarnicin nephrotoxic effects in the neonate To the Editor: The recent article by Adelman et al. (J PEDIATR 1987;111:88893) reports a smaller postnatal fall in mean serum creatinine concentration and a corresponding diminished postnatal rise in mean creatinine clearance in neonates receiving gentamicin and ampicillin, in comparison with those receiving mezlocillin alone. The authors conclude that gentamicin is nephrotoxic in the neonate. Although aminoglycosides have been associated with nephrotoxic effects in older patients and have the potential for this effect in neonates, the significance of the reported data is limited by several factors: (1) the sensitivity of the serum creatinine assay, (2) the accuracy of short-term urinary creatinine collections for measured creatinine clearance, (3) the gentamicin dosing regimen used, and (4) the lack of evaluation of long-term effects. Clinical laboratory methods for serum creatinine determinations are not accurate to two significant figures? In evaluating the data, the authors have taken the mean value to more significant figures than the actual measured values. The comparison should be between the final serum creatinine value of 0.8 mg/dl in the mezlocillin-treated group and 0.9 mg/dl in the gentamicin- and ampicillin-treated group. Statistical significance may be reached, but clinical significance is doubtful. Measured creatinine clearance values were based on 3- to 4-hour urine collections. Short urine collections (<8 hours) have a high degree of variability (20%) in estimating creatinine clear-
619
ance. 2 Even with 12- to 24-hour collection periods, its use appears to have significant limitations in estimating glomerular filtration rate in the neonate. 1 The initial creatinine clearance was higher in the gentamicin-treated group than in the mezlocillin-treated group. Final mean creatinine clearance for each group of patients appeared to be similar. Thus the gentamicin-treated group had a smaller percent change between final and initial creatinine clearance, but overall final creatinine clearance was similar to that in the mezlocillin treatment group. A further complicating factor is that the patients received doses that have been shown to result in significant drug accumulation, resulting in higher-than-desired trough serum gentamicin concentrations in low birth weight infants. 3,4 Trough concentrations >2 /zg/ml may have led to an increased, although still clinically insignificant, effect of gentamicin on renal function. Finally, and perhaps most important, long-term effects on serum creatinine and creatinine clearance were not evaluated. Do the serum creatinine and the creatinine clearance differ between these groups at 1 week, 2 weeks, or 1 month later? Until the clinical significance of the effect of gentamicin and other aminoglycosides on the renal function of neonates can be more fully determined, we caution the application of this study's conclusion to charge the choice of antibiotics used in the neonate.
Mariane H. Gabriel, PharmD Carl IV. Kildoo, PharmD Arthur B. Strauss, MD Departments of Pharmacy and Neonatology Miller Children's Hospital Memorial Medical Center Long Beach, CA 90801-1428 REFERENCES
1. 2.
3.
4.
Arant BS. Estimating glomerular filtration rate in infants. J PEDIATR 1984;104:890. Baumann T J, Staddon JE, Horst HM, Bivins BA. Minimum urine collection periods for accurate determination of creatinine clearance in critically ill patients. Clin Pharm 1987; 6:393. Kildoo CW, Modanlou HD, Komatsu G, Harralson AF, Hodding JH. Developmental pattern of gentamicin kinetics in very low birth weight sick infants. Dev Pharmacol Ther 1984;7:345. Szefler S J, Wynn R J, Clarke DF. Relationship of gentamicin serum concentrations to gestational age in preterm and term neonates, J PEDIATR 1980;97:312.
Reply To the Editor." We take exception to the suggestion that our data do not support the nephrotoxic effects of gentamicin in the neonate. The infants receiving gentamicin and ampicillin had a significantly smaller postnatal fall in mean sertma creatinine concentration in comparisonwith neonates receiving mezlocillin alone, even when individual creatinine values were ,rounded to a single significant figure before statistical analysis. Several investigators t,2,3 have confirmed the validity of accu-