THE JOURNAL OF INFECTIOUS DISEASES. VOL. 137, NO.5. MAY 1978 © 1978 by the University of Chicago. 0022-1899/78/3705-0033$00.75
Clinical Pharmacology of Tobramycin in Children J. L. Hoecker, L. K. Pickering, J. Swaney, W. G. Kramer, J. van Eys, S. Feldman, and S. Kohl
From the Program in Infectious Diseases and Clinical Microbiology, The University of Texas Medical School at Houston; the Department of Pediatrics, The University of Texas System Cancer Center; and the Department of Pharmaceutics, University of Houston, Houston, Texas
Tobramycin is an aminoglycoside antibiotic that is bactericidal at low concentrations against most gram-negative bacilli [1J. It is equivalent in activity to gentamicin against the majority of Enterobacteriaceae, but is more active in vitro against strains of Pseudomonas aeruginosa. Tobramycin has been shown to be ototoxic and nephrotoxic when high serum concentrations are achieved or prolonged therapy is given. Since the therapeutic index of aminoglycosides is small, underdosing may occur in an attempt to prevent side effects. Underdosing of patients with neutropenia and severe life-threatening infections may offer a partial explanation for reported failures in the 'past [2]. The recommended dose of tobramycin in children and older infants with normal renal
function who have serious infections due to susceptible organisms is 3-5 mg/kg per 24 hr administered every 8 hr [3]. The rationale for this dose in children and older infants appears to be an extrapolation of pharmacokinetic data obtained in adults since pharmacologic data concerning tobramycin in pediatric patients other than newborn infants [4, 5] are scant. This report describes a pharmacokinetic evaluation of tobramycin in children with malignancies and suggests a need to change the currently recommended dose and frequency of administration of tobramycin in children. Materials and Methods
Population of patients. Fifty patients (two to 18 years of age) admitted to the pediatric service of The University of Texas System Cancer Center-l\f.D. Anderson Hospital and Tumor Institute (Houston, Tex.) with leukemia (40) or lymphoma (10) were evaluated. Antibiotic therapy including tobramycin was initiated in these children for treatment of suspected bacterial infection. All children had normal renal function as determined by normal base-line levels of serum creatinine and blood urea nitrogen and by normal urinalysis. These determinations were repeated every
Received for publication September 7, 1977, and in revised form December 5,1977. This paper was presented at the Seventeenth Interscience Conference on Antimicrobial Agents and Chemotherapy, New York, New York, October 1977. We thank Ms. Pamela Gearhart for technical assistance, Drs. H. L. DuPont and C. D. Ericsson for suggestions, and Ms. Sandra Cobb and Ms. I. Bujnoch for help with preparation of the manuscript. Please address requests for reprints to Dr. Larry K. Pickering, The University of Texas Medical School at Houston, 6400 West Cullen Street, Houston, Texas 77030.
592
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The pharmacokinetics of tobramycin were evaluated in 50 pediatric patients (two to 18 years of age) with malignancies and normal renal function. Patients receiving either 240 or 300 mg/m 2 per 24 hr (8 or 10 mg/kg per 24 hr) divided into doses given every 4 hr had peak serum concentrations (mean::!::: standard error) of 3.10 ::!::: 0.23 fLg! ml and 4.23 ::!::: 0.25 fLg/ml, respectively, at the end of a I-hr infusion. Serum concentrations at 4 hr were 0.82 ::!::: 0.15 and 1.05 ::!::: 0.15 fLg/m1, respectively. The half-life of the drug was 96.6 min and was inversely correlated with age of the patients. The total clearance rate of tobramycin was 164 ::!::: 15 mg/min per 1.73 m 2 and was directly correlated with age. The mean volume of distribution was 0.42 ± 0.038 liter/kg and was inversely correlated with age. No accumulation of tobramycin was noted, and no side effects occurred. If therapeutic serum concentrations of tobramycin are to be achieved and maintained in children, the currently recommended dose and frequency of administration should be changed to 300 mg/m 2 per 24 hr given in divided doses every 4 hr.
Pharmacology of Tobramycin in Children
593
Table 1.
semilogari thmie plot of the concentration of tobramycin in serum vs. time showed monoexponential decay from the end of the infusion to the end of the dosage interval. Consequently, the data were analyzed according to a one-compartment open model. The tY2 of tobramycin was calculated according to the equation tY2 O.693/K, where K is the negative slope of the apparent log-linear decay portion of the tobramycin concentration in serum-vs.-time plot. All slopes were calculated by linear least-squares regression of the natural logarithm of tobramycin concentration vs. time. The rate of total body clearance (C Tm) of tobramycin was calculated using the formula C Tm = dose/AUe, where AVe is the area under the tobramycin concentration in serum-vs.-time curve. All areas were calculated by the trapezoidal method, and each clearance was normalized to 1.73 m 2 of body surface area. The volume of distribution (Vd,) of tobramycin was calculated using the formula V d = CTm/K, and all volumes were expressed as liters/kg of body weight.
=
Results
Tobramycin concentrations in serum. The concentration of tobramycin in sera according to dose and duration of infusion is shown in table l. In each group the mean peak concentration of tobramycin in serum coincided with termination of the iv infusion. A significantly (P < 0.005)
Concentrations of tobramycin in sera of children by age, dose, and duration of infusion.
----------
Duration Dose of infusion (min) (mg/m 2 )
Group, age in years
Time after initiation of infusion (min) 30
60
120
240
3.68 ± 0.66 3.93 ± 0.33
3.87 ± 0.32 4.20 ± 0.93
2.85 ± 0.41 2.90 ± 0.78
1.67 ± 0.32 1.90 ± 0.38
0.90 ± 0.18 0.80 ± 0.26
4.10 ± 0.53
4.01 ±0.37
2.87 ± 0.35
1.74 ± 0.24
0.83 ± 0.14
1.47 ± 0.20 1.6M ± 0.25
2.02 ± 0.35 2.49 ± 0.39
3.08 ± 0.33 3.13 ± 0.36
2.27 ± 0.33 1.65 ± 0.24
1.07 ± 0.27 0.84 ± 0.17
1.59 ± 0.16
2.3 ± 0.27
3.10±0.23
1.91 ±0.21
0.82 ± 0.15
3.00 ± 0.50 2.71 ± 0.54
4.29 ± 0.47 3.22 ± 0.46
4.04 ± 0.15 4.44 ± 0.45
2.48 ± 0.27 2.13 ± 0.25
1.24 ± 0.26 0.86±0.13
2.85 ± 0.36
3.70 ± 0.35
4.23 ± 0.25
2.29 ±0.18
1.05±0.15
15
-----
Group 1 2-6 (n = 7) 12-18 (n = 4) Total Group 2 3-8 (n = 6) 11-18(n=9) Total Group 3 2-8 (n = 7) 11-18(n=8) Total
-----------
NOTE.
40
40
50
30
60
60
--------
Values are given in J.lg/ml and are expressed as the mean ± SE. Samples were obtained on day 2 of therapy.
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three days during and seven days after therapy. Tobramycin was diluted in 100 ml of 5% glucose in water and administered by constant infusion to patients who were divided into three tobramycin treatment groups. Patients in group 1 received 210 mg/m 2 per 24 hr (8 mg/kg per 24 hr) given -every ·1 hr iv over 30 min; group 2 received 240 mg/m 2 per 24 hr (8 mg/kg per 24 hr) given every 4 hr iv over 60 min; and group 3 received 300 mg/m 2 per 24 hr (10 mg/kg per 24 hr) given every 4 hr iv over 60 min. Informed consent was obtained after a detailed description of the purpose and potential complications of the study was given. Tobramycin assay. Peak (end of infusion) and trough (prior to infusion) concentrations of tobramycin in serum were determined on the first day and every three days thereafter for all 50 patients while receiving tobramycin. Serum samples were obtained from 41 children on the third day of therapy, prior to an infusion, and at 15, 30, 60, 120, and 240 min after initiation of the infusion. The beginning of the infusion was considered to be zero-time. Nine of the 50 patients had addi tional, timed sam ples of serum obtained on the sixth day of therapy. The dosage of tobramycin was increased for three patients. Concentrations of tobramycin in serum were determined by the radioenzymatic assay [6, 7]. All serum samples were stored at -4 C and were assayed within 48 hr. Pharmacokinetic analysis. For 41 patients, a
Hoecker et al,
594
Table 2.
and tY2' The mean tY2 value was 97 min (range, 52-137 min). In children younger than eight years of age, the tY2 value (± SE) was 120.5 ± 13.7 min, and in older children this value was 84.2 ± 5.8 min. V d of tobramycin. The V d values of tobramycin are shown in table 2. The V d was similar when patients were grouped by dose and rate of infusion of tobramycin. The V d of tobramycin was inversely correlated with age and surface area of patients. The peak concentration of tobramycin in serum was inversely correlated with the Va of tobramycin in the majority of patients evaluated. Rates of C T IW The C T m value was not significantly different when patients were grouped according to dose or to rate of tobramycin administration. C T m was directly correlated with age and surface area (table 2). The mean (± SE) C T m was 124 ± 10 ml rmin per 1.73 m 2 in children younger than eight years of age and 195 ± 16.0 mlj'min per 1.73 m 2 in older children. Discussion
Pharmacokinetic evaluation of tobramycin in newborns has been performed [4, 5], but information concerning adequate dose and frequency of administration of drug to older infants and children is scant. Little data can be found to support the recommended dose of 5 mg/kg per 24 hr given every 8 hr [8-13]. Of the children reported to have received this dosage, more than half had peak serum concentrations of < 3 p.g/ml, and all had trough concentrations near zero. In several children, doses higher than those recommended were used to achieve therapeutic concentrations in serum [11, 12]. Detailed pharmacokinetic data are not available from these studies. When a close of 300 mg/m 2 per 24 hr adminis-
Pharmacokinetic parameters of tobramycin in children according to age and surface area. -----------------
Age in years
2-8 (n = 19) 11-18 (n = 22)
Range of surface area (m 2 )
Serum tY2 (min)
0.44-1.07 0.97-1.48
NOTE. Values (except surface area) represent mean ± SE. *Given as liter/kg. tGiven as ml/min per 1.73 m 2.
120 ± 13.7 84.2 ± 5.8
Volume of distribution* 0.49 0.40
± 0.06 ± 0.04
Total body clearance T 123.5 ± 10.2 195.0 ± 16
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greater peak serum concentration (mean ± SE) occurred in group 3 (4.23 ± 0.25 p.g/ml) than in group 2 (3.10 ± 0.23 p.g/ml), as determined by Student's t-test. No significant difference in peak serum levels occurred between groups 1 and 2. Serum concentrations of tobramycin 240 min after infusion were> 0.8 ttg/ml in all groups. Although mean peak serum concentrations were lower in younger children, no significant difference in serum concentrations occurred when children were analyzed according to age, sex, underlying disease, surface area, or presence of fever. The concentration of tobramycin in serum 4 hr after the dose was inversely correlated with age in all groups (table 1). Concentrations of tobramycin in serum from 21 additional children who received the recommended dose of 150 mg/m 2 per 24 hr (5 mg/kg per 24 hr) administered every 8 hr were evaluated. Peak serum concentrations (mean ± SE) were 2.1 ± 0.8 ttg/ml (range, 0.92.8 ttg/ml), and trough levels were 0.1 ± 0.1 ttg/ ml (range, 0-0.3 ttg/ml). Two or more curves of tobramycin concentration in serum vs. time were determined for nine patients. There was no increase in serum concentration in six patients when the same dose was employed; however, a 20% increase in peak serum concentration occurred when the dose of tobramycin was increased from 240 to 300 mg/m 2 per 24 hr (40-50 mg/m 2 per dose) in three patients. Accumulation of tobramycin in serum did not occur in any of the 50 children during the six- to nine-day period of measurement. All measurements of renal function remained normal. Tobramycin tY2 values. The t02 of tobramycin in serum was not significantly different among patients who received tobramycin over a 30- or 60-min period. The t02 was inversely correlated with age and surface area (table 2). No correlation was found between sex, underlying disease,
595
Pharmacology of Tobramycin in Children
levels that approximate this value, tobramycin should be administered to children at a dose of 300 mg/m 2 per 24 hr every 4 hr. Because of interpatient variation in serum concentrations of tobramycin, optimal therapy requires monitoring of serum levels.
References 1. Bendush, C. L., Weber, R. Tobramycin sulfate: a summary of worldwide experience from clinical trials. J. Infect. Dis. 134(Suppl.):S219-S234, 1976. 2. Bodey, G. P., Middleman, E., Umsawasdi, T., Rodriguez, V. Intravenous gentamicin therapy for infections in patients with cancer. J. Infect. Dis. 124 (Suppl): SI74-S179, 1971. 3. Physicians' desk reference. 31st ed. Medical Economics Company, Oradell, N.J., 1978, p. 1033-1034. 4. Kaplan, J. M., McCracken, G. H., Jr., Thomas, M. L., Horton, L. J., Davis, N. Clinical pharmacology of tobramycin in newborns. Am. J. Dis. Child. 125:656660. 1973. 5. Karman. M. M., Dalton, H. P., Escobar, M. R. Tobramycin in the neonatal period. Virginia Medical Monthly 100: 1030-1034,1973. 6. Smith, A. L.. Smith, D. H. Gentamicin: adenine mononucleotide transferase: partial purification. characterization. and usc in the clinical quantitation of gentamicin. J. Infect. Dis. 129:391-401, 1974. 7. Broughton, A.. Strong. J. E., Pickering, L. K., Bodey, G. P. Radioimmunoassay of iodinated tobramycin. Antimicrob. Agents Chemother. 10:652-656, 1976. 8. Setia, D., Gross. P. A. Administration of tobramycin and gentamicin by the intravenous route every 6 hr in patients with normal renal function. J. Infect. Dis. 134(Suppl.):SI25-S129,1976. 9. Raine, P. A. M .. Young, D. G., McAllister, T. A., Tait, S. C. Tobramycin in pediatric use. J. Infect. Dis. 134 (Suppl.):SI65-S169,1976. 10. Cohen . .J. D .. Miale, T. D. Tobramycin and cephalothin for treatment of suspected sepsis in neutropenic children with cancer. J. Infect. Dis. 134(Suppl.): SI75-S177,1976. II. Crozier. D. N., Khan, S. R. Tobramycin in treatment of infections due to Pseudomonas aeruginosa in patients with cystic fibrosis. J. Infect. Dis. 134(Suppl.): SI87--S190, 1976. 12. McCrae, W. M., Raeburn, J. A., Hanson, E. J. Tobramycin therapy of infections due to Pseudomonas aeruginosa in patients with cystic fibrosis: effect of dosage and concentration of antibiotic in sputum. J. Infect. Dis. 134(SlIppI.):SI91-S193, 1976. 13. Parry, M. F.. Neu, H. C. Tobrarnycin and ticarcillin therapy for exacerbations of pulmonary disease in patients with cystic fibrosis. J. Infect. Dis. 13·1 (SuppI.):SI94-S197,1976. 14. Israel. K. S.. Welles, J. S., Black, H. R. Aspects of the pharmacology and toxicology of tobramycin in ani-
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tereel every 4 hr was used, therapeutic serum concentrations were achieved and maintained for a 4-hr period. Low peak serum concentrations in children may be secondary to a larger Vd than that seen in adults. In this study, the Va of tobramycin was 49% of body weight in children younger than eight years of age and 40% in children older than eight years of age. These values are higher than the 30% Va reported in adults with normal renal function [14]. The serum t~ of tobramycin in adults with normal renal function is "...120 min [14], a value which is similar to that found in this study in children younger than eight years of age. The lower tY2 and greater C T m in older children may account for the lower trough concentration of tobramycin in serum from this group than in serum from younger children. Multiple doses of tobramycin administered iv every 4 hr for up to 10 days were well tolerated without accumulation in serum. With a dosage of 240-300 mg/m 2 per 24 hr given every 4 hr, all serum analyzed for tobramycin revealed concentrations within a safe range « 10 JLgjml). Over 500 serum samples were assayed, and the highest concentration of tobramycin was found to be 7.2 JLg/ml. No patient had trough concentrations of >2 JLg/ml, a value that has been shown to correlate with nephrotoxicity [15]. In addition, all patients had serum trough concentrations of "...1 JLgjml, which is above that necessary to inhibit the growth of most Enterobacteriaceae and P. aeruginosa, the most common gram-negative organisms infecting pediatric patients with malignancy [16]. Predictable levels of an effective antimicrobial agent are of particular importance in the neutropenic patient who has inadequate host defense mechanisms to assist in the eradication of infection. The peak serum concentration of 4 /lg/ml attained in the present study is adequate if the drug is administered at a 4-hr interval. Dosage recommendations for tobramycin in children should be made after consideration of pharmacokinetic properties, renal function, and the MICs of tobramycin for the offending pathogens. The data from this study indicate the need for alteration in tobramycin dosage schedules in children to maintain adequate serum antibiotic concentrations. To achieve peak serum concentrations of tobramycin that exceed the l\UC for most gram-negative bacilli and trough serum
596
mals and humans. J. Infect. Dis. 134(Suppl.):S97SI03,1976. 15. Dahlgren, J. G., Anderson, E. T., Hewitt, W. L. Gentamicin blood levels: a guide to nephrotoxicity. Antimicrob. Agents Chemother. 8:58-62, 1975.
Hoecker et al.
16. Hoecker, J. L., Pickering, L. K., Kohl, S., Groschel, D. Septicemia in children with malignancies [abstract]. In Program of the l IOth annual session of the Texas Medical Association, May 12-15, 1977. Texas Medical Association, Houston, 1977, p. 166.
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Clinical Pharmacology of Tobramycin in Children J. L. Hoecker, L. K. Pickering, J. Swaney, W. G. Kramer, J. van Eys, S. Feldman, and S. Kohl
From the Program in Infectious Diseases and Clinical Microbiology, The University of Texas Medical School at Houston; the Department of Pediatrics, The University of Texas System Cancer Center; and the Department of Pharmaceutics, University of Houston, Houston, Texas
Tobramycin is an aminoglycoside antibiotic that is bactericidal at low concentrations against most gram-negative bacilli [1J. It is equivalent in activity to gentamicin against the majority of Enterobacteriaceae, but is more active in vitro against strains of Pseudomonas aeruginosa. Tobramycin has been shown to be ototoxic and nephrotoxic when high serum concentrations are achieved or prolonged therapy is given. Since the therapeutic index of aminoglycosides is small, underdosing may occur in an attempt to prevent side effects. Underdosing of patients with neutropenia and severe life-threatening infections may offer a partial explanation for reported failures in the 'past [2]. The recommended dose of tobramycin in children and older infants with normal renal
function who have serious infections due to susceptible organisms is 3-5 mg/kg per 24 hr administered every 8 hr [3]. The rationale for this dose in children and older infants appears to be an extrapolation of pharmacokinetic data obtained in adults since pharmacologic data concerning tobramycin in pediatric patients other than newborn infants [4, 5] are scant. This report describes a pharmacokinetic evaluation of tobramycin in children with malignancies and suggests a need to change the currently recommended dose and frequency of administration of tobramycin in children. Materials and Methods
Population of patients. Fifty patients (two to 18 years of age) admitted to the pediatric service of The University of Texas System Cancer Center-l\f.D. Anderson Hospital and Tumor Institute (Houston, Tex.) with leukemia (40) or lymphoma (10) were evaluated. Antibiotic therapy including tobramycin was initiated in these children for treatment of suspected bacterial infection. All children had normal renal function as determined by normal base-line levels of serum creatinine and blood urea nitrogen and by normal urinalysis. These determinations were repeated every
Received for publication September 7, 1977, and in revised form December 5,1977. This paper was presented at the Seventeenth Interscience Conference on Antimicrobial Agents and Chemotherapy, New York, New York, October 1977. We thank Ms. Pamela Gearhart for technical assistance, Drs. H. L. DuPont and C. D. Ericsson for suggestions, and Ms. Sandra Cobb and Ms. I. Bujnoch for help with preparation of the manuscript. Please address requests for reprints to Dr. Larry K. Pickering, The University of Texas Medical School at Houston, 6400 West Cullen Street, Houston, Texas 77030.
592
Downloaded from http://jid.oxfordjournals.org/ at University of Arizona on July 13, 2015
The pharmacokinetics of tobramycin were evaluated in 50 pediatric patients (two to 18 years of age) with malignancies and normal renal function. Patients receiving either 240 or 300 mg/m 2 per 24 hr (8 or 10 mg/kg per 24 hr) divided into doses given every 4 hr had peak serum concentrations (mean::!::: standard error) of 3.10 ::!::: 0.23 fLg! ml and 4.23 ::!::: 0.25 fLg/ml, respectively, at the end of a I-hr infusion. Serum concentrations at 4 hr were 0.82 ::!::: 0.15 and 1.05 ::!::: 0.15 fLg/m1, respectively. The half-life of the drug was 96.6 min and was inversely correlated with age of the patients. The total clearance rate of tobramycin was 164 ::!::: 15 mg/min per 1.73 m 2 and was directly correlated with age. The mean volume of distribution was 0.42 ± 0.038 liter/kg and was inversely correlated with age. No accumulation of tobramycin was noted, and no side effects occurred. If therapeutic serum concentrations of tobramycin are to be achieved and maintained in children, the currently recommended dose and frequency of administration should be changed to 300 mg/m 2 per 24 hr given in divided doses every 4 hr.
Pharmacology of Tobramycin in Children
593
Table 1.
semilogari thmie plot of the concentration of tobramycin in serum vs. time showed monoexponential decay from the end of the infusion to the end of the dosage interval. Consequently, the data were analyzed according to a one-compartment open model. The tY2 of tobramycin was calculated according to the equation tY2 O.693/K, where K is the negative slope of the apparent log-linear decay portion of the tobramycin concentration in serum-vs.-time plot. All slopes were calculated by linear least-squares regression of the natural logarithm of tobramycin concentration vs. time. The rate of total body clearance (C Tm) of tobramycin was calculated using the formula C Tm = dose/AUe, where AVe is the area under the tobramycin concentration in serum-vs.-time curve. All areas were calculated by the trapezoidal method, and each clearance was normalized to 1.73 m 2 of body surface area. The volume of distribution (Vd,) of tobramycin was calculated using the formula V d = CTm/K, and all volumes were expressed as liters/kg of body weight.
=
Results
Tobramycin concentrations in serum. The concentration of tobramycin in sera according to dose and duration of infusion is shown in table l. In each group the mean peak concentration of tobramycin in serum coincided with termination of the iv infusion. A significantly (P < 0.005)
Concentrations of tobramycin in sera of children by age, dose, and duration of infusion.
----------
Duration Dose of infusion (min) (mg/m 2 )
Group, age in years
Time after initiation of infusion (min) 30
60
120
240
3.68 ± 0.66 3.93 ± 0.33
3.87 ± 0.32 4.20 ± 0.93
2.85 ± 0.41 2.90 ± 0.78
1.67 ± 0.32 1.90 ± 0.38
0.90 ± 0.18 0.80 ± 0.26
4.10 ± 0.53
4.01 ±0.37
2.87 ± 0.35
1.74 ± 0.24
0.83 ± 0.14
1.47 ± 0.20 1.6M ± 0.25
2.02 ± 0.35 2.49 ± 0.39
3.08 ± 0.33 3.13 ± 0.36
2.27 ± 0.33 1.65 ± 0.24
1.07 ± 0.27 0.84 ± 0.17
1.59 ± 0.16
2.3 ± 0.27
3.10±0.23
1.91 ±0.21
0.82 ± 0.15
3.00 ± 0.50 2.71 ± 0.54
4.29 ± 0.47 3.22 ± 0.46
4.04 ± 0.15 4.44 ± 0.45
2.48 ± 0.27 2.13 ± 0.25
1.24 ± 0.26 0.86±0.13
2.85 ± 0.36
3.70 ± 0.35
4.23 ± 0.25
2.29 ±0.18
1.05±0.15
15
-----
Group 1 2-6 (n = 7) 12-18 (n = 4) Total Group 2 3-8 (n = 6) 11-18(n=9) Total Group 3 2-8 (n = 7) 11-18(n=8) Total
-----------
NOTE.
40
40
50
30
60
60
--------
Values are given in J.lg/ml and are expressed as the mean ± SE. Samples were obtained on day 2 of therapy.
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three days during and seven days after therapy. Tobramycin was diluted in 100 ml of 5% glucose in water and administered by constant infusion to patients who were divided into three tobramycin treatment groups. Patients in group 1 received 210 mg/m 2 per 24 hr (8 mg/kg per 24 hr) given -every ·1 hr iv over 30 min; group 2 received 240 mg/m 2 per 24 hr (8 mg/kg per 24 hr) given every 4 hr iv over 60 min; and group 3 received 300 mg/m 2 per 24 hr (10 mg/kg per 24 hr) given every 4 hr iv over 60 min. Informed consent was obtained after a detailed description of the purpose and potential complications of the study was given. Tobramycin assay. Peak (end of infusion) and trough (prior to infusion) concentrations of tobramycin in serum were determined on the first day and every three days thereafter for all 50 patients while receiving tobramycin. Serum samples were obtained from 41 children on the third day of therapy, prior to an infusion, and at 15, 30, 60, 120, and 240 min after initiation of the infusion. The beginning of the infusion was considered to be zero-time. Nine of the 50 patients had addi tional, timed sam ples of serum obtained on the sixth day of therapy. The dosage of tobramycin was increased for three patients. Concentrations of tobramycin in serum were determined by the radioenzymatic assay [6, 7]. All serum samples were stored at -4 C and were assayed within 48 hr. Pharmacokinetic analysis. For 41 patients, a
Hoecker et al,
594
Table 2.
and tY2' The mean tY2 value was 97 min (range, 52-137 min). In children younger than eight years of age, the tY2 value (± SE) was 120.5 ± 13.7 min, and in older children this value was 84.2 ± 5.8 min. V d of tobramycin. The V d values of tobramycin are shown in table 2. The V d was similar when patients were grouped by dose and rate of infusion of tobramycin. The V d of tobramycin was inversely correlated with age and surface area of patients. The peak concentration of tobramycin in serum was inversely correlated with the Va of tobramycin in the majority of patients evaluated. Rates of C T IW The C T m value was not significantly different when patients were grouped according to dose or to rate of tobramycin administration. C T m was directly correlated with age and surface area (table 2). The mean (± SE) C T m was 124 ± 10 ml rmin per 1.73 m 2 in children younger than eight years of age and 195 ± 16.0 mlj'min per 1.73 m 2 in older children. Discussion
Pharmacokinetic evaluation of tobramycin in newborns has been performed [4, 5], but information concerning adequate dose and frequency of administration of drug to older infants and children is scant. Little data can be found to support the recommended dose of 5 mg/kg per 24 hr given every 8 hr [8-13]. Of the children reported to have received this dosage, more than half had peak serum concentrations of < 3 p.g/ml, and all had trough concentrations near zero. In several children, doses higher than those recommended were used to achieve therapeutic concentrations in serum [11, 12]. Detailed pharmacokinetic data are not available from these studies. When a close of 300 mg/m 2 per 24 hr adminis-
Pharmacokinetic parameters of tobramycin in children according to age and surface area. -----------------
Age in years
2-8 (n = 19) 11-18 (n = 22)
Range of surface area (m 2 )
Serum tY2 (min)
0.44-1.07 0.97-1.48
NOTE. Values (except surface area) represent mean ± SE. *Given as liter/kg. tGiven as ml/min per 1.73 m 2.
120 ± 13.7 84.2 ± 5.8
Volume of distribution* 0.49 0.40
± 0.06 ± 0.04
Total body clearance T 123.5 ± 10.2 195.0 ± 16
Downloaded from http://jid.oxfordjournals.org/ at University of Arizona on July 13, 2015
greater peak serum concentration (mean ± SE) occurred in group 3 (4.23 ± 0.25 p.g/ml) than in group 2 (3.10 ± 0.23 p.g/ml), as determined by Student's t-test. No significant difference in peak serum levels occurred between groups 1 and 2. Serum concentrations of tobramycin 240 min after infusion were> 0.8 ttg/ml in all groups. Although mean peak serum concentrations were lower in younger children, no significant difference in serum concentrations occurred when children were analyzed according to age, sex, underlying disease, surface area, or presence of fever. The concentration of tobramycin in serum 4 hr after the dose was inversely correlated with age in all groups (table 1). Concentrations of tobramycin in serum from 21 additional children who received the recommended dose of 150 mg/m 2 per 24 hr (5 mg/kg per 24 hr) administered every 8 hr were evaluated. Peak serum concentrations (mean ± SE) were 2.1 ± 0.8 ttg/ml (range, 0.92.8 ttg/ml), and trough levels were 0.1 ± 0.1 ttg/ ml (range, 0-0.3 ttg/ml). Two or more curves of tobramycin concentration in serum vs. time were determined for nine patients. There was no increase in serum concentration in six patients when the same dose was employed; however, a 20% increase in peak serum concentration occurred when the dose of tobramycin was increased from 240 to 300 mg/m 2 per 24 hr (40-50 mg/m 2 per dose) in three patients. Accumulation of tobramycin in serum did not occur in any of the 50 children during the six- to nine-day period of measurement. All measurements of renal function remained normal. Tobramycin tY2 values. The t02 of tobramycin in serum was not significantly different among patients who received tobramycin over a 30- or 60-min period. The t02 was inversely correlated with age and surface area (table 2). No correlation was found between sex, underlying disease,
595
Pharmacology of Tobramycin in Children
levels that approximate this value, tobramycin should be administered to children at a dose of 300 mg/m 2 per 24 hr every 4 hr. Because of interpatient variation in serum concentrations of tobramycin, optimal therapy requires monitoring of serum levels.
References 1. Bendush, C. L., Weber, R. Tobramycin sulfate: a summary of worldwide experience from clinical trials. J. Infect. Dis. 134(Suppl.):S219-S234, 1976. 2. Bodey, G. P., Middleman, E., Umsawasdi, T., Rodriguez, V. Intravenous gentamicin therapy for infections in patients with cancer. J. Infect. Dis. 124 (Suppl): SI74-S179, 1971. 3. Physicians' desk reference. 31st ed. Medical Economics Company, Oradell, N.J., 1978, p. 1033-1034. 4. Kaplan, J. M., McCracken, G. H., Jr., Thomas, M. L., Horton, L. J., Davis, N. Clinical pharmacology of tobramycin in newborns. Am. J. Dis. Child. 125:656660. 1973. 5. Karman. M. M., Dalton, H. P., Escobar, M. R. Tobramycin in the neonatal period. Virginia Medical Monthly 100: 1030-1034,1973. 6. Smith, A. L.. Smith, D. H. Gentamicin: adenine mononucleotide transferase: partial purification. characterization. and usc in the clinical quantitation of gentamicin. J. Infect. Dis. 129:391-401, 1974. 7. Broughton, A.. Strong. J. E., Pickering, L. K., Bodey, G. P. Radioimmunoassay of iodinated tobramycin. Antimicrob. Agents Chemother. 10:652-656, 1976. 8. Setia, D., Gross. P. A. Administration of tobramycin and gentamicin by the intravenous route every 6 hr in patients with normal renal function. J. Infect. Dis. 134(Suppl.):SI25-S129,1976. 9. Raine, P. A. M .. Young, D. G., McAllister, T. A., Tait, S. C. Tobramycin in pediatric use. J. Infect. Dis. 134 (Suppl.):SI65-S169,1976. 10. Cohen . .J. D .. Miale, T. D. Tobramycin and cephalothin for treatment of suspected sepsis in neutropenic children with cancer. J. Infect. Dis. 134(Suppl.): SI75-S177,1976. II. Crozier. D. N., Khan, S. R. Tobramycin in treatment of infections due to Pseudomonas aeruginosa in patients with cystic fibrosis. J. Infect. Dis. 134(Suppl.): SI87--S190, 1976. 12. McCrae, W. M., Raeburn, J. A., Hanson, E. J. Tobramycin therapy of infections due to Pseudomonas aeruginosa in patients with cystic fibrosis: effect of dosage and concentration of antibiotic in sputum. J. Infect. Dis. 134(SlIppI.):SI91-S193, 1976. 13. Parry, M. F.. Neu, H. C. Tobrarnycin and ticarcillin therapy for exacerbations of pulmonary disease in patients with cystic fibrosis. J. Infect. Dis. 13·1 (SuppI.):SI94-S197,1976. 14. Israel. K. S.. Welles, J. S., Black, H. R. Aspects of the pharmacology and toxicology of tobramycin in ani-
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tereel every 4 hr was used, therapeutic serum concentrations were achieved and maintained for a 4-hr period. Low peak serum concentrations in children may be secondary to a larger Vd than that seen in adults. In this study, the Va of tobramycin was 49% of body weight in children younger than eight years of age and 40% in children older than eight years of age. These values are higher than the 30% Va reported in adults with normal renal function [14]. The serum t~ of tobramycin in adults with normal renal function is "...120 min [14], a value which is similar to that found in this study in children younger than eight years of age. The lower tY2 and greater C T m in older children may account for the lower trough concentration of tobramycin in serum from this group than in serum from younger children. Multiple doses of tobramycin administered iv every 4 hr for up to 10 days were well tolerated without accumulation in serum. With a dosage of 240-300 mg/m 2 per 24 hr given every 4 hr, all serum analyzed for tobramycin revealed concentrations within a safe range « 10 JLgjml). Over 500 serum samples were assayed, and the highest concentration of tobramycin was found to be 7.2 JLg/ml. No patient had trough concentrations of >2 JLg/ml, a value that has been shown to correlate with nephrotoxicity [15]. In addition, all patients had serum trough concentrations of "...1 JLgjml, which is above that necessary to inhibit the growth of most Enterobacteriaceae and P. aeruginosa, the most common gram-negative organisms infecting pediatric patients with malignancy [16]. Predictable levels of an effective antimicrobial agent are of particular importance in the neutropenic patient who has inadequate host defense mechanisms to assist in the eradication of infection. The peak serum concentration of 4 /lg/ml attained in the present study is adequate if the drug is administered at a 4-hr interval. Dosage recommendations for tobramycin in children should be made after consideration of pharmacokinetic properties, renal function, and the MICs of tobramycin for the offending pathogens. The data from this study indicate the need for alteration in tobramycin dosage schedules in children to maintain adequate serum antibiotic concentrations. To achieve peak serum concentrations of tobramycin that exceed the l\UC for most gram-negative bacilli and trough serum
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mals and humans. J. Infect. Dis. 134(Suppl.):S97SI03,1976. 15. Dahlgren, J. G., Anderson, E. T., Hewitt, W. L. Gentamicin blood levels: a guide to nephrotoxicity. Antimicrob. Agents Chemother. 8:58-62, 1975.
Hoecker et al.
16. Hoecker, J. L., Pickering, L. K., Kohl, S., Groschel, D. Septicemia in children with malignancies [abstract]. In Program of the l IOth annual session of the Texas Medical Association, May 12-15, 1977. Texas Medical Association, Houston, 1977, p. 166.
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