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PEDIATRICS Vol. 103 No. 4 April 1999, p. e48
,,
From the * Department of Pharmacy and the College of Pharmacy
and the Department of Pediatrics and Communicable Diseases,
University of Michigan Health Systems, Ann Arbor, Michigan; and the
§ Department of Pharmacy, University of Kentucky Medical Center,
Lexington, Kentucky.
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ABSTRACT |
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Top
Abstract
Methods
Results
Discussion
Conclusion
References
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Objective. The purpose of this study was
to compare the incidence of nephrotoxicity, defined as doubling of
baseline serum creatinine concentration, in newborn infants with peak
vancomycin serum concentrations 
40 µg/mL at steady state to infants
with peak vancomycin serum concentrations >40 µg/mL. A secondary
objective was to correlate concomitant disease states and potentially
nephrotoxic drug therapy with rises in serum creatinine in vancomycin
recipients.
Methods. Newborn infants with culture-proven
Staphylococcus aureus or coagulase-negative
staphylococcal septicemia who received vancomycin therapy for >3 days
between 1985 and 1995 were identified from an existing database and a
review of medical record. All 69 patients included in the study had
serial serum creatinine determinations, including a baseline value
within 48 hours of starting treatment with vancomycin, and serum
vancomycin concentrations determined after at least three doses, with
peak and trough concentrations determined 1 hour after a 60-minute
infusion and 15 to 30 minutes before a dose, respectively. Infants with
congenital renal or cardiac anomalies were excluded. Demographic
characteristics, vancomycin dosing regimen, serum vancomycin
concentrations and sample times, concomitant drug therapy, and disease
states were recorded. Patients were divided into group A (peak
vancomycin concentration 40 µg/mL) and group B (peak vancomycin
concentration >40 µg/mL). The change in serum creatinine
concentration between the start and end of vancomycin therapy was
determined. Nephrotoxicity was identified if serum creatinine doubled
at any time from the start to the end of vancomycin therapy.
Alternative definitions of nephrotoxicity (any rise in serum creatinine
to >0.6 mg/dL or new abnormalities of urine sediment) were used in
additional analyses.
Results. A total of 69 evaluable patients (gestational age, 28.9 ± 3.0 weeks; birth weight, 1219 ± 516 g) were identified, 61 in group A and 8 in group B. Six patients in group A underwent doubling of serum creatinine concentration during vancomycin therapy, whereas none in group B did so. Serum creatinine doubled to >0.6 mg/dL in only 3 infants (all in group A). Any increase in serum creatinine to >0.6 mg/dL was seen in 10 infants, 9 of whom were in group A. No confounding variable, including previous or concomitant underlying disease states associated with renal dysfunction or treatment with other potentially nephrotoxic agents, were associated with a significant rise in serum creatinine.
Conclusion. Vancomycin-associated nephrotoxicity is rare in neonates, even with serum peak concentrations >40 µg/mL. Key words: vancomycin, nephrotoxicity, newborn infants, NICU, Staphylococci, creatinine, renal, antibiotics.
Vancomycin is a bactericidal glycopeptide antibiotic that
exerts its antimicrobial effect by inhibition of bacterial cell wall
synthesis. Early pharmaceutical preparations of vancomycin were
associated with considerable toxicity, including infusion-related phlebitis, anaphylaxis, eighth cranial nerve dysfunction, and nephrotoxicity.1,2 The introduction of the less toxic
penicillinase-resistant penicillins led to a decline in the use of this
agent. Resurgent interest in vancomycin therapy developed in the 1980s
because of an increasing number of nosocomial infections caused by
resistant strains of Staphylococcus aureus and
coagulase-negative staphylococci.3,4 Newer formulations of
vancomycin, with fewer contaminants and unwanted side effects, became
available at approximately the same time and have become widely used in
infants and children.5
Although dosage regimens and therapeutic drug ranges for vancomycin
have been established in adult patients over the last 2 decades,6-10 controversy still exists about the ideal
dosing regimen and desired serum concentration for vancomycin in
premature and full-term newborn infants and children.11-21 Recently, the effect of a commonly
accepted dosing regimen for vancomycin on renal function in very low
birth weight infants was evaluated and reported to be safe in their
population. No data on the achieved plasma vancomycin concentrations or
concomitant drug therapy were included.22 There are a few
reports of nephrotoxicity with simultaneous administration of an
aminoglycoside and vancomycin,23,24 although one study
found the combination to be safe.25 No reports have
addressed the role of other concomitant potentially nephrotoxic drugs
or underlying disease states on vancomycin nephrotoxicity in neonates.
The primary purpose of this study was to determine and compare the
incidence of nephrotoxicity, defined as a doubling of serum creatinine
from a baseline value obtained within 48 hours of starting vancomycin
therapy in newborn infants with peak serum vancomycin concentrations
<40 µg/mL to that in a group with a peak This study was conducted as a retrospective chart review. All
newborn infants in the neonatal intensive care unit at our institution who were treated with vancomycin for culture-proven sepsis caused by
resistant staphylococci for a 10-year period beginning January 1985 were identified using a computerized database. Infants were included in
the present study if they had received vancomycin for at least 3 days,
had appropriate serum vancomycin concentrations (peak serum
concentrations 1 hour after a 1-hour infusion and trough concentrations
just before a dose) determined after at least three doses, and had
serum creatinine measured within 48 hours of starting vancomycin
treatment and longitudinally thereafter. Infants who had serum
vancomycin concentrations obtained >5 minutes from the indicated times
for peak and trough determinations were excluded. Infants with
congenital renal or cardiovascular anomalies were excluded.
Data collection included patient demographics and identification of
additional preexisting or concurrent diseases (patent ductus
arteriosus, respiratory distress syndrome, or urine output <0.5 mL/kg
per hour) that may influence renal function. Serum chemistries;
microscopic and dipstick urinalyses; and concomitant potentially
nephrotoxic drug therapy (loop or thiazide diuretics, aminoglycosides,
or indomethacin) were recorded from 1 week before the start of
vancomycin therapy until 2 weeks after the conclusion of treatment.
Data collected relating to vancomycin therapy included the dose and
frequency of administration, the time and length of dose infusion, time
and values for peak and trough plasma concentrations, and duration of
therapy. The appropriateness of the dosing regimen was assessed
according to guidelines contained in the manual for neonatal intensive
care issued to all our house officers at the time. From 1985 to 1991, the recommended doses were 10 mg/kg every 8 hours for infants Nephrotoxicity was evaluated based on changes in serum creatinine
concentration from a baseline value obtained within 48 hours of
starting vancomycin treatment. The principal definition was a doubling
of serum creatinine from the start any time through the end of
vancomycin therapy. Alternative definitions that were analyzed included
doubling of serum creatinine to >0.6 mg/dL (previously published
population mean value26); any rise in serum creatinine to
>0.6 mg/dL; and the new onset of hematuria, glycosuria, or
proteinuria.
Discrete variables were analyzed by Of 174 patients with blood cultures positive for S
aureus or coagulase-negative staphylococci who were identified in
the database, 69 met inclusion criteria. Among the 105 who were
excluded, 39 had organisms with susceptibility patterns that did not
require vancomycin therapy and 66 lacked requisite data (14 with
inappropriately timed or absent vancomycin serum concentrations, 10 without the necessary longitudinal serum creatinine determinations, and
42 with deficiencies in both categories). Of the 69 infants who met inclusion criteria, peak serum vancomycin concentration was TABLE 1
40 µg/mL at steady
state. A secondary objective was to correlate concomitant disease
states and potentially nephrotoxic drug therapy with rises in serum
creatinine.
METHODS
Top
Abstract
Methods
Results
Discussion
Conclusion
References
40
weeks' and every 6 hours for infants >40 weeks' postconceptional
age. From 1992 through the end of the study period and to the present,
dosing guidelines include 15 mg/kg at intervals of 36, 24, 18, and 12 hours for infants whose postconceptional ages were <27, 27 to 30, 31 to 34, and >34 weeks, respectively.
2 or Fisher's exact
test, depending on cell size. Continuous data were compared using the
Student's t test if normally distributed and the Wilcoxon rank-sum test if not normally distributed. The effects of concomitant drug therapy and disease states were to be evaluated using simple and
multiple regression analysis.
RESULTS
Top
Abstract
Methods
Results
Discussion
Conclusion
References
40 µg/mL in 61 infants (88%, group A) and >40 µg/mL in 8 (12%,
group B). No significant differences were found between the two groups for birth weight, gestational age, postconceptional age, or postnatal age at treatment (Table 1).
Demographic Features of Patients*
All 8 infants in group B had serum creatinine >0.6 mg/dL at the start of treatment (mean, 1.3; range, 0.8 to 2.2). None underwent doubling of serum creatinine during therapy (Table 2). Only 1 patient had any increase in serum creatinine (from 1.2 to 1.3 mg/dL), whereas 6 decreased and 1 remained unchanged. Six of the infants had abnormal urinalyses (hematuria, proteinuria, or glycosuria) at the start of treatment; 3 of these had normal findings by the end of therapy. One infant developed a new abnormal urinalysis during treatment, but had a concurrent fall in serum creatinine. Although appropriate for then-existent dosing guidelines, dosing intervals were inappropriately short for 5 infants based on current postconceptional age guidelines. Two of these 5 also received individual doses >15 mg/kg. Three infants had appropriate doses and intervals. All 8 infants had a trough serum vancomycin concentration >10 µg/mL.
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In group A, 6 (10%) of 61 patients underwent doubling of baseline
serum creatinine during vancomycin therapy (Table
3). The serum creatinine values in 3 of
these, however, still were 0.6 mg/dL. Serum creatinine >0.6 mg/mL at
the start of treatment was noted in 17 infants (27.9%). Nine of the 61 infants had an increase in serum creatinine to >0.6 mg/dL. Four
infants developed newly abnormal urinary sediment during treatment, but
all 4 had concomitant declines in serum creatinine. Sixteen of those in group A (26.2%) received starting doses of vancomycin >15 mg/kg/dose or had inappropriate dosing intervals based on current post
conceptional age guidelines; 8 of these 16 had serum creatinine >0.6
mg/dL at the start of treatment.
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Of the 61 infants in group A, 21 (34.4%) had vancomycin trough plasma concentrations >10 µg/mL. Thirteen of these 21 had serum creatinine >0.6 mg/dL at the start of treatment; 2 of these 13 also underwent doubling of serum creatinine. Three of the 21 had inappropriately short dosing intervals per current guidelines. For the remaining 5 children, no reason could be found for the elevated serum trough concentrations.
In the combined study population of 69 infants, the mean serum creatinine fell significantly from the beginning to the end of vancomycin therapy (Table 4). Although serum creatinine was not significantly different between the two study groups at the start or the end of therapy, infants in group B had a significantly greater drop in serum creatinine at the end of treatment than those in group A.
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The effects of potential confounding variables (preexisting diseases or
concurrent drug therapy with such nephrotoxic agents as
aminoglycosides, indomethacin, and loop or thiazide diuretics) on
changes in serum creatinine during vancomycin therapy were assessed
using univariate analysis. No disease or drug was statistically associated with a rise in serum creatinine. Multiple regression analysis therefore was unwarranted. Concurrent gentamicin was received
during all or part of vancomycin therapy by 49 infants, 38 of whom
received such treatment for >3 days and also had serum gentamicin
concentrations assessed. Eight of these 38 (21.0%) had a trough serum
gentamicin concentration >2 µg/mL; 3 of these 8 also had an elevated
trough vancomycin concentration. All 8 had serum creatinine 0.6 mg/dL
at the start of treatment. No infant had a peak serum gentamicin
concentration 9 µg/mL.
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DISCUSSION |
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Top
Abstract
Methods
Results
Discussion
Conclusion
References
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Our findings do not support the hypothesis that peak serum
vancomycin concentration >40 µg/mL is associated with
nephrotoxicity, defined as doubling of baseline serum creatinine.
Plausible explanations include that contemporary formulations of
vancomycin are not truly nephrotoxic at this peak value, that the
definition of nephrotoxicity used was too restrictive, that vancomycin
is only toxic at higher concentrations, or combinations of the above.
Because alternative definitions of nephrotoxicity explored in this
report also resulted in more frequent abnormalities among infants with
peak vancomycin concentration 40 µg/mL, the first explanation seems
most plausible. Despite dosing regimens in several infants that are
considered inappropriate according to current guidelines, peak serum
vancomycin concentrations >40 µg/mL were seen only in infants with
baseline serum creatinine >0.6 mg/dL. These data suggest that although peak serum vancomycin concentration >40 µg/mL may not predict renal
dysfunction, the converse may be true.
Several studies have evaluated the safety of vancomycin used
concurrently with gentamicin.23-25 To the best of our
knowledge, however, this report is the first to evaluate the effect of
multiple potentially nephrotoxic drugs and underlying disease states
that may contribute to renal dysfunction. Linder and
associates25 reported an 8.6% incidence of nephrotoxicity
(defined as an increase in serum creatinine of 0.5 mg/dL from
baseline) in a study of 35 patients with peak vancomycin concentration
>30 µg/mL. We did not detect clinically important nephrotoxicity
when gentamicin was administered with vancomycin. Similar observations
were made when more than one potentially nephrotoxic agent was used
concurrently with vancomycin.
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CONCLUSION |
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Top
Abstract
Methods
Results
Discussion
Conclusion
References
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Vancomycin-associated nephrotoxicity is rare in neonates requiring
intensive care, even in the presence of other potentially nephrotoxic
drugs and disease states associated with renal dysfunction. Although
peak serum vancomycin concentration >40 µg/mL was not associated
with nephrotoxicity, monitoring serum concentration still seems
appropriate in this critically ill group of patients because the safety
of higher concentrations (eg, >60 µg/mL) is unknown and to ensure
that an effective antimicrobial concentration has been attained.
Although the current dosing regimen makes plasma concentrations >60
µg/mL highly unlikely, vigilance appears warranted when serum
creatinine is 0.6 mg/dL at the start of treatment.
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FOOTNOTES |
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Received for publication Jul 27, 1998; accepted Nov 10, 1998.
Reprint requests to (V.B.-M.) F5790 Mott/0254, University of Michigan Medical Center, 200 E Hospital Dr, Ann Arbor, MI 48109-0254.
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REFERENCES |
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Abstract
Methods
Results
Discussion
Conclusion
References
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This article has been cited by other articles:
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  L Cataldi, R Leone, U Moretti, B De Mitri, V Fanos, L Ruggeri, G Sabatino, F Torcasio, V Zanardo, G Attardo, et al. Potential risk factors for the development of acute renal failure in preterm newborn infants: a case-control study Arch. Dis. Child. Fetal Neonatal Ed., November 1, 2005; 90(6): F514 - F519. [Abstract] [Full Text] [PDF]
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W-H Tan, N Brown, A W Kelsall, and R J McClure Dose regimen for vancomycin not needing serum peak levels? Arch. Dis. Child. Fetal Neonatal Ed., November 1, 2002; 87(3): F214 - 216. [Abstract] [Full Text] [PDF]
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A Narendra, M P White, H A Rolton, Z I Alloub, G Wilkinson, J H McColl, and J Beattie Nephrocalcinosis in preterm babies Arch. Dis. Child. Fetal Neonatal Ed., November 1, 2001; 85(3): F207 - 213. [Abstract] [Full Text] [PDF]
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