Vol. 8, No. 1 Printed in U.SA.
ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, JUIY, 1975, p. 58-62 Copyright 0 1975 American Society for Microbiology
Gentamicin Blood Levels:
a
Guide to Nephrotoxicity
JAMES G. DAHLGREN, ELIZABETH T. ANDERSON, AND WILLIAM L.
HEWITT*
University of California School of Medicine, The Center for the Health Sciences, Los Angeles, California 90024 Received for publication 6 February 1975
Gentamicin blood levels were monitored in 86 patients. Twenty-one patients had valley levels over 2 ,ig/ml and 36% of these patients developed abnormal serum creatinine or a further rise in creatinine. No patient had a rise in creatinine without a valley level over 2. The peak levels in patients with valleys over 2 were above 10 ug/ml in only one case, whereas four patients had peaks over 10 4g/ml without nephrotoxicity. The mean peak blood levels in patients with a normal creatinine were dose related. An initial dose of 2.0, 1.5, and 1.3 or less mpk (mg/kg) yielded mean peak blood levels of 5.2, 4.7, and 3.7, respectively. To assure an initial peak blood level over 4 ug/ml a loading dose of 2 mpk was required. A rise in peak and valley levels during therapy appeared dose related, being observed in all patients treated with 4.5 mpk daily but not in those receiving 3.0 mpk daily. A radioenzymatic assay was used to validate the standard agar diffusion assay method. The results from the two assays were statistically identical. Valley blood levels of gentamicin may be useful for predicting accumulation of gentamicin which in tum may be correlated with early renal impairment before potentially toxic serum levels of gentamicin develop. Patients were selected at random from among all patients receiving gentamicin at the University of California at Los Angeles during one 10-month period. No patient was excluded from the monitoring study for any reason. An attempt was made to classify the severity of illness in each patient at the time of entry into the study. On this basis 7% of the patients had mild problems of infection and a similar percentage had critical illness from which they were not expected to survive; 56% of the patients had serious infections with a good prognosis, and 29% had serious infections of uncertain outcome. Doses ranged from 0.8 to 2.0 mg/kg (mpk) at hourly dose intervals determined by multiplying the serum creatinine times eight. The interval between doses in patients with normal renal function with 8 h. In patients with elevation of MATERIALS AND METHODS the serum creatinine the interval between doses was All gentamicin serum levels were determined by determined by multiplying the serum creatinine the agar diffusion method of Winters et al. (8). The times eight, which gave the number of hours between radioenzymatic method of Smith et al. (6), utilizing doses (1). an adenylating enzyme, was used as an additional RESULTS assay on 360 specimens. The radioenzymatic assay Peak serum concentrations varied widely was modified by soaking the phosphocellulose paper (Whatman PC-81) in 20 mM adenosine (Sigma) for 12 even with identical doses. For example, even on h. This step assured a reproducible background level days 1 to 3 the peaks after the 1.5 mpk dose which was not obtained with unsoaked paper. varied from 1.1 to 6.8 ug/ml and the overall Serum samples from 86 patients were obtained at variation of peaks after this dose was 1.1 to 18.0 various intervals to determine peak and valley serum concentrations after an intramuscular or intravenous ,ug/ml (Table 1). However, the mean peak dose. Extreme care was exercised in timing blood serum blood level rose as the the dose was insamples representing peak determinations 30 to 45 creased from 0.8 to 2.0 mpk in patients with min after intramuscular injections and within 30 min normal renal function (Fig. 1). An initial dose of after completion of intravenous infusion. Valley sam- 2.0 mpk yielded serum levels over 4 ,ug/ml in ples were obtained during the hour preceding a dose. 91% of the patients. Initial doses of 0.8 to 1.2 58
Gentamicin is an aminoglycoside antimicrobial agent widely used in the treatment of serious gram-negative bacillary infections. The range between effective and toxic blood levels is narrow. Administration of a given dose of gentamicin results in widely differing blood levels. Monitoring of blood levels has been recommended to assure effective therapy and avoidance of toxicity with this drug (4). This paper reports a prospective study of gentamicin dose-blood level relationships and examines the value of blood levels as a guide to preventing nephrotoxicity.
Vol. 8, 1975
59
GENTAMICIN BLOOD LEVELS TABLE 1. Dose blood level relationshipsa 1h
1 Dose creatinine patients creatinine paNtoienf
Mean S.D.
Normal
Abnormal
a
1.5 h
2.5 h
Valley
Mean S.D.
Range
Mean S.D.
Range
4.2 + 1.2 4.2 ± 2.2 2.8 i 1.3 2.7 i 0.7 2.9 i 1.3 2.7 i 0.5 3.9 i 2.0 3.0 ± 1.3
3.0- 7.0 1.1-17.5 0.8- 4.9 2.1- 3.7 0.8- 4.2 1.6- 3.6 2.2- 6.1 1.0- 4.9
3.5 + 1.4 3.6 ± 2.2 2.2 ± 0.8 2.4 ± 0.6 2.3 ± 1.3 2.5 i 0.8 3.3 i 1.7 2.4 ± 1.1
2.0- 5.4 0.6-11.2 1.7- 3.5 1.7- 3.4 0.8- 4.2 1.8- 4.2 2.0- 5.2 1.6- 3.8
Range
Mean S.D.
Range
1.5 i 1.4 0.9 i 0.5 1.1 i 0.4 1.2 i 0.6 1.1 ± 0.7 1.0 i 0.5 1.1 ± 0.6
0.1-5.2 0.2-1.5 0.2-1.6 0.2-1.9 0.3-2.5 0.6-1.6 0.6-2.9
2.0 1.5 1.3 1.2 1.1 1.0 0.9 0.8
21 84
5 10 13 3 3
5.2 + 1.5 3.2-10.0 5.2 ± 2.4 1.1-18.0 4.4 ± 2.4 1.6- 9.6 3.7 ± 0.7 2.7- 4.4 3.6 ± 1.3 1.6- 5.2 3.5 ± 1.6 0.6- 5.6 5.2 ± 0.8 4.5- 6.1 3.3 i 1.2 2.1- 4.6
1.5 1.2-1.3 0.8-1.1
17 5 6
5.8 i 2.0 3.0- 9.4 5.6 i 1.8 2.7- 8.0 4.6 ± 1.8 1.4- 7.3 1.4 ± 1.2 0.3-4.8 5.3 ± 2.5 3.4- 9.6 3.7 i 1.0 3.0- 4.9 2.9 i 1.1 2.7- 3.0 1.0 i 0.4 0.8-1.5 6.1 i 1.6 3.9- 7.5 5.4 i 2.3 1.6- 8.2 4.9 ± 2.0 1.6- 7.0 2.6 ± 2.3 0.5-7.0
1l
S.D., Standard deviation. -PEAK BLOOD LEVEL RELATIONSHIPS DAY 1-3 ( In parenthesis is percentoge over 4og/ml)
Dose mpk
FIG. 1. Mean peak levels and dose level. The val ues in parenthesis indicate the percentages over 4
ug/ml.
mpk achieved this peak level only 20% of thE time. Survival could not be meaningfully cor related with dosage or serum levels because of sce few critically ill patients. The disappearance curve for gentamicin dupli cated that in previous reports (Fig. 2) (2). This7 is consistent with a two-compartment mode with a rapid early phase, probably reflecting,I tissue distribution, and a slower phase relatec to the rate of renal excretion. Removing thE patient group with valley levels over 2 Ag/m t made no difference in the shape of the curve. d Eight of 21 patients with valley gentamicir serum levels of 2 ,ug/ml or over developed a rise in serum creatinine (Table 2). This did noi occur in any of the patients with valley levels below 2 jig/ml but was observed in two of si)
patients with valley levels between 3 and 4
,ug/ml and in all of five patients with levels over 4 ,gg/ml. All of the patients whose serum creati-
nine rose to abnormal levels had received a loading dose of 2 mpk and a maintenance dose of 1.5 mpk; no other cause of renal dysfunction was apparent. There was no increased use of cephalosporins or diuretics in the nephrotoxic group. Serum creatinine returned to the normal range within a short period in all patients after gentamicin was discontinued. The patients with normal serum creatinine who received gentamicin at a dosage of 1.5 mpk every 8 h, with or without a loading dose of 2.0 mpk, had a progressive rise in both peak and valley serum levels (Fig. 3). The mean peak level increased at a rate of 0.040 ,Ag/ml per day. This rise in blood levels occurred in all patients receiving 1.5 mpk. These rises were not apparent in patients receiving doses of 0.8 to 1.2 mpk every 8 h or in azotemic patients for whom dosage was individualized based upon serum TYPICAL DISAPPEARANCE CURVE 54-
abnormal creatinine
3-
2L
norl creotinine 1.5 mpk
2
3
4 5 6 Hours Following Dose
7
8
FIG. 2. Gentamicin disappearance curve in patients with normal and abnormal renal function.
60
ANTIMICROB. AGENTS CHEMOTHER.
DAHLGREN, ANDERSON, AND HEWITT
TABLE 2. Relation of selected therapeutic features to renal function during treatment with gentamicin Serum creatinine
Determinants
Creatinine rise
No creatine rise
Pt. No.
Dose
Loading
Day of Rx,
Yes Yes
2 3 42
3 4
1.5 1.5 1.5 1.5
Yes Yes
5 5 6 7 8
1.5 1.5 1.5 1.5 0.8
Yes Yes Yes Yes No
6 2 6 2 4 3 6 2
9
1.5
Yes
10
1.5
Yes
11
1.5
Yes
12 13 14 15 16 17 18 19 20 21 22
1.5 1.5 0.8 0.8 0.8 1.5 1.5 1.0 1.5 1.5 1.5
No No No No No No No No Yes Yes No
1 2
5
5 2 3 4 2 3 3 20 6 7 5 3 5 8 5 7 8 4 3
Elevated valley
day of eleBefore On
R.
4.5 5.0 3.5 3.0 4.8 4.8
0.9 0.
5.2 8.5 4.3 2.0 5.1 2.9 2.9 2.1 2.1 2.7
vated
valley
After
R.
Cephalosporin
1.0 1.6 2.7
1.0 1. 1.5
Yes 3.9 3.Ye 1.6 No
2.0 6.6
2.5 4.0
1.1 11
1.1 11
No 3.1 31N
0.9 0.7 1.2
1.1 1.1 -
1.8 1.6 1.1
No No Yes
-
1.0
1.3
No
0.8
-
0.9
No
-
1.0
1.2
Yes
-
1.0 2.9 1.6 2.5
0.9 2.7 died 1.9 1.1 1.0 1.5 Died 1.3 0.8
No No No
No No
3.3 2.5 2.5 2.6 3.0 3.1 3.5 7.0 2.9 2.3 2.9 4.4 3.7 2.6 5.8
2.9 2.1 1.5 1.2 0.8 1.3 1.6 1.3 1.1
-
1.0 1.4 -
1.3 0.7
Yes Yes
No No No No
a Normal creatinine equals 0.7 to 1.3 mg%. Loading indicates that the patient received an initial dose of 2 mpk and was then maintained on the dose indicated. The after Rx, creatinine is a determination 2 to 5 days after gentamicin was stopped. Cephalosporin refers to concurrent therapy from the time of initiation of gentamicin.
creatinine concentration or gentamicin serum levels. The agar diffusion and radioenzymatic assay for serum gentamicin concentrations gave statistically similar results (360 serum samples were analyzed by both methods) (matched P = 0.18, t = 1.35 on 360 degrees of freedom). The high degree of statistical correlation between the methods is shown by a correlation coefficient of 0.82, P value
ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, JUIY, 1975, p. 58-62 Copyright 0 1975 American Society for Microbiology
Gentamicin Blood Levels:
a
Guide to Nephrotoxicity
JAMES G. DAHLGREN, ELIZABETH T. ANDERSON, AND WILLIAM L.
HEWITT*
University of California School of Medicine, The Center for the Health Sciences, Los Angeles, California 90024 Received for publication 6 February 1975
Gentamicin blood levels were monitored in 86 patients. Twenty-one patients had valley levels over 2 ,ig/ml and 36% of these patients developed abnormal serum creatinine or a further rise in creatinine. No patient had a rise in creatinine without a valley level over 2. The peak levels in patients with valleys over 2 were above 10 ug/ml in only one case, whereas four patients had peaks over 10 4g/ml without nephrotoxicity. The mean peak blood levels in patients with a normal creatinine were dose related. An initial dose of 2.0, 1.5, and 1.3 or less mpk (mg/kg) yielded mean peak blood levels of 5.2, 4.7, and 3.7, respectively. To assure an initial peak blood level over 4 ug/ml a loading dose of 2 mpk was required. A rise in peak and valley levels during therapy appeared dose related, being observed in all patients treated with 4.5 mpk daily but not in those receiving 3.0 mpk daily. A radioenzymatic assay was used to validate the standard agar diffusion assay method. The results from the two assays were statistically identical. Valley blood levels of gentamicin may be useful for predicting accumulation of gentamicin which in tum may be correlated with early renal impairment before potentially toxic serum levels of gentamicin develop. Patients were selected at random from among all patients receiving gentamicin at the University of California at Los Angeles during one 10-month period. No patient was excluded from the monitoring study for any reason. An attempt was made to classify the severity of illness in each patient at the time of entry into the study. On this basis 7% of the patients had mild problems of infection and a similar percentage had critical illness from which they were not expected to survive; 56% of the patients had serious infections with a good prognosis, and 29% had serious infections of uncertain outcome. Doses ranged from 0.8 to 2.0 mg/kg (mpk) at hourly dose intervals determined by multiplying the serum creatinine times eight. The interval between doses in patients with normal renal function with 8 h. In patients with elevation of MATERIALS AND METHODS the serum creatinine the interval between doses was All gentamicin serum levels were determined by determined by multiplying the serum creatinine the agar diffusion method of Winters et al. (8). The times eight, which gave the number of hours between radioenzymatic method of Smith et al. (6), utilizing doses (1). an adenylating enzyme, was used as an additional RESULTS assay on 360 specimens. The radioenzymatic assay Peak serum concentrations varied widely was modified by soaking the phosphocellulose paper (Whatman PC-81) in 20 mM adenosine (Sigma) for 12 even with identical doses. For example, even on h. This step assured a reproducible background level days 1 to 3 the peaks after the 1.5 mpk dose which was not obtained with unsoaked paper. varied from 1.1 to 6.8 ug/ml and the overall Serum samples from 86 patients were obtained at variation of peaks after this dose was 1.1 to 18.0 various intervals to determine peak and valley serum concentrations after an intramuscular or intravenous ,ug/ml (Table 1). However, the mean peak dose. Extreme care was exercised in timing blood serum blood level rose as the the dose was insamples representing peak determinations 30 to 45 creased from 0.8 to 2.0 mpk in patients with min after intramuscular injections and within 30 min normal renal function (Fig. 1). An initial dose of after completion of intravenous infusion. Valley sam- 2.0 mpk yielded serum levels over 4 ,ug/ml in ples were obtained during the hour preceding a dose. 91% of the patients. Initial doses of 0.8 to 1.2 58
Gentamicin is an aminoglycoside antimicrobial agent widely used in the treatment of serious gram-negative bacillary infections. The range between effective and toxic blood levels is narrow. Administration of a given dose of gentamicin results in widely differing blood levels. Monitoring of blood levels has been recommended to assure effective therapy and avoidance of toxicity with this drug (4). This paper reports a prospective study of gentamicin dose-blood level relationships and examines the value of blood levels as a guide to preventing nephrotoxicity.
Vol. 8, 1975
59
GENTAMICIN BLOOD LEVELS TABLE 1. Dose blood level relationshipsa 1h
1 Dose creatinine patients creatinine paNtoienf
Mean S.D.
Normal
Abnormal
a
1.5 h
2.5 h
Valley
Mean S.D.
Range
Mean S.D.
Range
4.2 + 1.2 4.2 ± 2.2 2.8 i 1.3 2.7 i 0.7 2.9 i 1.3 2.7 i 0.5 3.9 i 2.0 3.0 ± 1.3
3.0- 7.0 1.1-17.5 0.8- 4.9 2.1- 3.7 0.8- 4.2 1.6- 3.6 2.2- 6.1 1.0- 4.9
3.5 + 1.4 3.6 ± 2.2 2.2 ± 0.8 2.4 ± 0.6 2.3 ± 1.3 2.5 i 0.8 3.3 i 1.7 2.4 ± 1.1
2.0- 5.4 0.6-11.2 1.7- 3.5 1.7- 3.4 0.8- 4.2 1.8- 4.2 2.0- 5.2 1.6- 3.8
Range
Mean S.D.
Range
1.5 i 1.4 0.9 i 0.5 1.1 i 0.4 1.2 i 0.6 1.1 ± 0.7 1.0 i 0.5 1.1 ± 0.6
0.1-5.2 0.2-1.5 0.2-1.6 0.2-1.9 0.3-2.5 0.6-1.6 0.6-2.9
2.0 1.5 1.3 1.2 1.1 1.0 0.9 0.8
21 84
5 10 13 3 3
5.2 + 1.5 3.2-10.0 5.2 ± 2.4 1.1-18.0 4.4 ± 2.4 1.6- 9.6 3.7 ± 0.7 2.7- 4.4 3.6 ± 1.3 1.6- 5.2 3.5 ± 1.6 0.6- 5.6 5.2 ± 0.8 4.5- 6.1 3.3 i 1.2 2.1- 4.6
1.5 1.2-1.3 0.8-1.1
17 5 6
5.8 i 2.0 3.0- 9.4 5.6 i 1.8 2.7- 8.0 4.6 ± 1.8 1.4- 7.3 1.4 ± 1.2 0.3-4.8 5.3 ± 2.5 3.4- 9.6 3.7 i 1.0 3.0- 4.9 2.9 i 1.1 2.7- 3.0 1.0 i 0.4 0.8-1.5 6.1 i 1.6 3.9- 7.5 5.4 i 2.3 1.6- 8.2 4.9 ± 2.0 1.6- 7.0 2.6 ± 2.3 0.5-7.0
1l
S.D., Standard deviation. -PEAK BLOOD LEVEL RELATIONSHIPS DAY 1-3 ( In parenthesis is percentoge over 4og/ml)
Dose mpk
FIG. 1. Mean peak levels and dose level. The val ues in parenthesis indicate the percentages over 4
ug/ml.
mpk achieved this peak level only 20% of thE time. Survival could not be meaningfully cor related with dosage or serum levels because of sce few critically ill patients. The disappearance curve for gentamicin dupli cated that in previous reports (Fig. 2) (2). This7 is consistent with a two-compartment mode with a rapid early phase, probably reflecting,I tissue distribution, and a slower phase relatec to the rate of renal excretion. Removing thE patient group with valley levels over 2 Ag/m t made no difference in the shape of the curve. d Eight of 21 patients with valley gentamicir serum levels of 2 ,ug/ml or over developed a rise in serum creatinine (Table 2). This did noi occur in any of the patients with valley levels below 2 jig/ml but was observed in two of si)
patients with valley levels between 3 and 4
,ug/ml and in all of five patients with levels over 4 ,gg/ml. All of the patients whose serum creati-
nine rose to abnormal levels had received a loading dose of 2 mpk and a maintenance dose of 1.5 mpk; no other cause of renal dysfunction was apparent. There was no increased use of cephalosporins or diuretics in the nephrotoxic group. Serum creatinine returned to the normal range within a short period in all patients after gentamicin was discontinued. The patients with normal serum creatinine who received gentamicin at a dosage of 1.5 mpk every 8 h, with or without a loading dose of 2.0 mpk, had a progressive rise in both peak and valley serum levels (Fig. 3). The mean peak level increased at a rate of 0.040 ,Ag/ml per day. This rise in blood levels occurred in all patients receiving 1.5 mpk. These rises were not apparent in patients receiving doses of 0.8 to 1.2 mpk every 8 h or in azotemic patients for whom dosage was individualized based upon serum TYPICAL DISAPPEARANCE CURVE 54-
abnormal creatinine
3-
2L
norl creotinine 1.5 mpk
2
3
4 5 6 Hours Following Dose
7
8
FIG. 2. Gentamicin disappearance curve in patients with normal and abnormal renal function.
60
ANTIMICROB. AGENTS CHEMOTHER.
DAHLGREN, ANDERSON, AND HEWITT
TABLE 2. Relation of selected therapeutic features to renal function during treatment with gentamicin Serum creatinine
Determinants
Creatinine rise
No creatine rise
Pt. No.
Dose
Loading
Day of Rx,
Yes Yes
2 3 42
3 4
1.5 1.5 1.5 1.5
Yes Yes
5 5 6 7 8
1.5 1.5 1.5 1.5 0.8
Yes Yes Yes Yes No
6 2 6 2 4 3 6 2
9
1.5
Yes
10
1.5
Yes
11
1.5
Yes
12 13 14 15 16 17 18 19 20 21 22
1.5 1.5 0.8 0.8 0.8 1.5 1.5 1.0 1.5 1.5 1.5
No No No No No No No No Yes Yes No
1 2
5
5 2 3 4 2 3 3 20 6 7 5 3 5 8 5 7 8 4 3
Elevated valley
day of eleBefore On
R.
4.5 5.0 3.5 3.0 4.8 4.8
0.9 0.
5.2 8.5 4.3 2.0 5.1 2.9 2.9 2.1 2.1 2.7
vated
valley
After
R.
Cephalosporin
1.0 1.6 2.7
1.0 1. 1.5
Yes 3.9 3.Ye 1.6 No
2.0 6.6
2.5 4.0
1.1 11
1.1 11
No 3.1 31N
0.9 0.7 1.2
1.1 1.1 -
1.8 1.6 1.1
No No Yes
-
1.0
1.3
No
0.8
-
0.9
No
-
1.0
1.2
Yes
-
1.0 2.9 1.6 2.5
0.9 2.7 died 1.9 1.1 1.0 1.5 Died 1.3 0.8
No No No
No No
3.3 2.5 2.5 2.6 3.0 3.1 3.5 7.0 2.9 2.3 2.9 4.4 3.7 2.6 5.8
2.9 2.1 1.5 1.2 0.8 1.3 1.6 1.3 1.1
-
1.0 1.4 -
1.3 0.7
Yes Yes
No No No No
a Normal creatinine equals 0.7 to 1.3 mg%. Loading indicates that the patient received an initial dose of 2 mpk and was then maintained on the dose indicated. The after Rx, creatinine is a determination 2 to 5 days after gentamicin was stopped. Cephalosporin refers to concurrent therapy from the time of initiation of gentamicin.
creatinine concentration or gentamicin serum levels. The agar diffusion and radioenzymatic assay for serum gentamicin concentrations gave statistically similar results (360 serum samples were analyzed by both methods) (matched P = 0.18, t = 1.35 on 360 degrees of freedom). The high degree of statistical correlation between the methods is shown by a correlation coefficient of 0.82, P value
