Journal of Antimicrobial Chemotherapy (1978) 4 (Suppl. A), 47-52
Gentamicin and tobramycin in patients with various infections—nephrotoxicity
Gunnar Kahlmeter, Torgny Hallberg and Carl Kamme
Thirty-eight consecutive patients were treated with either gentamicin (GM) or tobramycin (TM), 19 patients in each series. Renal function was monitored by serial deteiminations of serum creatinine concentrations (SCr) and by regular determinations of endogenous creatinine clearance (CCr). In the GM series a statistically significant progressive mean rise in SCr, more pronounced in elderly patients and in patients with lower CCr values, and a reciprocal mean decrease in CCr were recorded. In patients with normal renal function exhibiting a SCr increase, the mean daily increment was +1-7 (0-8 to 4-9) nmol/1. Also in the TM series a mean rise in SCr and a mean decrease in CCr were seen. They were less pronounced than in the GM series and statistically not significant. In both series, these reactions were rapidly reversible on terminating aminoglycoside therapy. Introduction
Nephrotoxic reactions, when seen during gentamicin (GM) therapy, are usually mild and transient. Although the true incidence is difficult to assess, mainly due to variations in definitions of nephrotoxicity, investigations in retrospect of extensive clinical materials have shown that 2 to 14% of patients treated with GM exhibit signs of drug-induced renal function derangement (Jackson, 1967; Falco, Smith & Arceiri, 1969; Wilfert, Burke, Bloomer & Smith, 1971; Hewitt, 1974; Bygbjerg & Mdller, 1976). Prospective studies of smaller series have reached similar frequencies (Labovitz, Levison & Kaye, 1974; Dahlgren, Anderson & Hewitt, 1975). Comparative studies in animals, as well as evaluations of clinical materials, indicate that tobramycin (TM) has a lower nephrotoxic potential than GM (Welles et al., 1973; Sack & Freiesleben, 1975; Speirs, 1976; Madsen, Kjaer & Mosegaard, 1976; Walker & Gentry, 1976). In the present paper, GM and TM therapy in patients with various infections were compared as to the occurrence and the degree of nephrotoxic reactions. In a previous paper, the GM and TM serum concentrations and the urinary recovery of the drugs in these patients were compared (Kahlmeter, Hallberg & Kamme, 1978). Materials and methods
Thirty-eight consecutive patients were treated with either GM or TM, 19 patients in each series. Data on these patients, including type of infections, aminoglycoside dose 47
Downloaded from http://jac.oxfordjournals.org/ at Simon Fraser University on June 9, 2015
Department of Medical Microbiology,.University of Lund, Lund, Sweden
48
Gentamicin and tobramydn—nephrotoxicity
+40
+ 40
+ 30
+30 T /
+20
+ 10
+ 10
0
0
-10
- 10 -20 -30 + 20
+ 20
i
i
4 J i i i i
+ 10
-20 -30 + 20 + 10
0
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- 10
-10
- -20 -20 0 3 6 9 12 15 18 0 5 10 >IO Days during therapy Days after therapy Figure 1. Changes in serum creatinine concentrations (SCr) and endogenous creatinine clearance (CCr) during and after gentamicin (circles) and tobramycin (squares) therapy. OM, SCr (umol/1); O.D, CCr (ml/min/1-73 m 1 ); Vertical bars: standard error of mean.
Results Changes in mean serum creatinine levels (SCr) and endogenous creatinine clearance (CCr) during and after gentamicin and tobramycin therapy are shown in Figure 1. The mean SCr changes at end of therapy with the initial dose schedules were related to the parameters shown in Figure 3. Gentamicin series The mean (SE) SCr increments at end of therapy with the initial dose schedule and at end of the total course of therapy in 18 evaluated patients were +20-6 (3-6) umol/1 and +32-4 (7-2) umol/1 (both increments P < 0001). SCr increments of 5s 10 umol/1
Downloaded from http://jac.oxfordjournals.org/ at Simon Fraser University on June 9, 2015
schedules, initial renal function, methods for determining aminoglycoside and creatinine concentrations and for statistical analysis have been presented in a previous paper (Kahlmeter et al., 1978). Serum creatinine concentrations (SCr) were determined daily and endogenous 24 h creatinine clearance (CCr) weekly. At onset of therapy, 2 patients in the GM series and 6 patients in the TM series had clinical and laboratory findings indicating a decreased renal function. The mean (S.D.) SCr values in these patients were 130 (29) and 157-5 (83) umol/1, respectively, and the mean (S.D.) CCr values 42-5 (10-6) and 33-5 (18-5) ml/ min/l-73m 2 , respectively. In patients with normal renal function the corresponding mean values were 73-4 (15) and 78-5 (17-8) umol/1, respectively, and mean CCr values 88-9 (24-5) and 92-3 (36-9) ml/min, respectively.
G. Kahlmeter, T. Hallberg and C. Kamme
49
Table I. Changes in serum creatinine concentrations ((imol/l) during gentamicin (GM) and tobramycin (TM) therapy GM (18 pat)
TM (19 pat)
4 4 10* 0
6 5
No change « ± 10 umol/1) Increase of 10-30 umol/1 Increase of >30 umol/1 Decrease of >10 umol/1
3' 5t
• 2 patients in each series had impaired renal function at onset of therapy.
were recorded in 14 patients (Table I). In 12 of these, all with normal renal function at onset of therapy, the SCr rise was progressive with a mean daily increment of +1-7 (0-8 to 4-9) umol/1 (exemplified in Figure 2). In some patients the rise was temporarily arrested by the lowering of a dose or by an increase of the interval between injections. However, within a few days the rise continued and at the earlier rate. In 2 patients abrupt SCr rises were recorded. Both had impaired renal function at onset of therapy. Of 16 patients with initial SCr values below 110 umol/1, 6 reached values above 110 umol/1. The SCr increase was most pronounced in elderly patients and in patients with lower CCr values at onset of therapy (P > 005) (Figure 3). In 8 patients, SCr was monitored for more than 10 days after end of GM therapy. In these the SCr returned to pretreatment values, usually within 2 to 3 weeks (Figure 1). -I 8-0
^
--x».
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I
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40 :«=
5 §40 |
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:
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,
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/x-x-x
80
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60
40
X..
7O 60 (rng/kg/doy) (mg/kg) (day») (ml/min/l-73mz) (yean) Figure 3. Changes in serum creatinine concentrations (SCr; umol/l) at end of gentamicin (black bars) and tobramycin (open bars) therapy with the initial dose schedule (mean duration 9 and 10-5 days and mean total dose 29 and 28 mg'kg, resp.), related to daily and total aminoglycoside dose and duration of therapy with initial dose schedule, initial creatinine clearance and to the age of the patients. Figures at top of staples denote numbeT of patients.
In 3 patients SCr rose progressively all through the course, the final increments being >30 umol/l (Table I). Two of these had impaired renal function at onset of therapy. Of 14 patients with initial SCr values below 110 umol/l, one patient reached a SCr of >110 umol/l. In the TM series the rise in SCr appeared unrelated to either of the 5 investigated parameters (Figure 3). Only in 4 patients was SCr monitored for more than 10 days after end of therapy. A decrement of —45 umol/l in one patient brought the mean of the final observations to — ]6-3 umol/l (Figure 1). The mean (SE) of the lowest relative CCr values recorded during TM therapy in 16 evaluated patients was —4-6 (50) ml/min/1-73 mi (P> 005). Four patients exhibited a CCr decrement and 4 patients a CCr increment of more than 15 ml/min, while CCr was stable in the remaining 8 patients.
Downloaded from http://jac.oxfordjournals.org/ at Simon Fraser University on June 9, 2015
Tobramycin series The mean (SE) SCr increments at end of therapy with the initial dose schedule and at end of the total course of therapy in the 19 patients were +5-3 (71) umol/l and + 5 0 (6-3) umol/l, respectively (both increments P > 005). In 8 patients SCr increments and in 5 SCr decrements of ^10 umol/l were recorded (Table I). In 5 patients, all with normal renal function, the SCr rise occurred early in therapy and did not progress during the course, as exemplified in Figure 2. This patient had 6 weeks earlier received GM in a dose of 1 mg/kg/8 h. During this course a SCr increment of +30 umol/l and a CCr decrement of —35 ml/min were recorded.
G. Kahlmeter, T. Hallberg and C. Kamme
51
Discussion
Downloaded from http://jac.oxfordjournals.org/ at Simon Fraser University on June 9, 2015
By monitoring serum creatinine concentrations (SCr) and endogenous creatinine clearance (CCr), a reversible renal function derangement was noted in 14 of 18 evaluated patients treated with gentamicin (GM) and in 8 of 19 patients treated with tobramycin (TM). In the GM series a statistically significant mean SCr increase of +32-4 umol/1 and a CCr decrease of —32-7 ml/min were recorded. Corresponding values in the TM series were +5-0 umol/1 and —4-6 ml/min. In the GM series the SCr increase was more pronounced in elderly patients and in patients with lower initial CCr values, but in neither series was there a statistically significant correlation between the changes in SCr and any of the 5 investigated parameters. The relationship between SCr and CCr is not linear (Enger & Blegen, 1964). A given CCr decrement in the lower CCr range causes a greater SCr increase than does the same CCr decrement at a higher basic level. This is most pronounced on a CCr level below 40 to 50 ml/min. In the GM series only one patient had an initial CCr below 50 ml/min. Most GM patients exhibited a progressive SCr increase all through therapy, while patients treated with TM usually exhibited less pronounced SCr increments, occurring early in the course. The signs of renal function derangement were more pronounced in patients receiving low daily and total doses of GM than in patients treated with high doses of TM. Our findings indicate that GM has a greater nephrotoxic potential than TM. Toxicology studies with GM and TM in animals have demonstrated histological abnormalities in renal parenchyma, from cloudy swelling of proximal tubules to frank cortical necrosis, and that these changes are more pronounced with GM than with TM (Flandre & Damon, 1967; Welles et al., 1973; Patel et al, 1975; Sack & Freiesleben, 1975). Two prospective comparative studies of GM and TM in the treatment of urinary tract infections, both found TM less nephrotoxic than GM (Walker & Gentry, 1976; Madsen et al., 1976). SCr and BUN rises were more pronounced in patients with underlying renal disease and in elderly patients (Walker & Gentry, 1976). Dahlgren et al. (1975), investigating patients treated with GM, recorded a SCr rise in patients receiving daily GM doses of 4-5 mg/kg or more and in patients with trough levels above 2-0 ug/ml. They did not report on the age or initial renal function of the patients. Labovitz et al. (1974) noted a SCr rise in patients treated with 160 mg GM once daily, but not in patients receiving 60 to 80 mg GM 3 times daily for 10 days. Seventy-five per cent of the patients older than 50 years were in the former group, and it may be that this accounts for the discrepancy. In the first part of this investigation, we reported on the aminoglycoside concentrations in serum and urine attained in these patients (Kahlmeter et al., 1978). Due to the frequent determinations of GM and TM serum concentrations, trough levels only rarely exceeded 2 0 ug/ml. In patients with normal renal function, we recorded a progressive rise in GM but not in TM serum concentrations. The correlation coefficients between the SCr rise and the rise in GM trough and 1-h concentrations were 0-83 and 0-58, respectively. In our opinion, the progressive rise in SCr and GM serum concentrations and the decrease in CCr were signs of a drug induced renal function derangement, most probably caused by an accumulation of the drug in renal parenchyma, discussed in the previous paper (Kahlmeter et al., 1978). Its major clinical significance seems to be that it causes accumulation of the drug in serum and thus increases the risk of ototoxic reactions (Banck et al., 1973; Mawer et al., 1974). Although TM in the present study appeared
52
Geotamidn and tobramycin—nephrotoxlcfry
less nephrotoxic than GM, the occasional individual may well exhibit gradually rising SCr and TM serum concentrations necessitating dose reduction to prevent accumulation of the drug in serum. Thus GM as well as TM therapy should be monitored with repeated determinations of drug serum concentrations as well as with frequent determinations of SCr and/or CCr. References
Downloaded from http://jac.oxfordjournals.org/ at Simon Fraser University on June 9, 2015
Banck, G., Belfrage, S., Juhlin, I., Nordstrom, L., Tjernstrom, O. & Toremalm, N. G. Retrospective study of the ototoxicity of gentamicin. Ada Pathologica el Microbiologica Scandinavica, Section B. 81 (Suppl. 241): 54-7 (1973). Bygbjerg, I. C. & Moller, R. Gentamicin-induced nephropathy. Scandinavian Journal ofInfectious Diseases 8: 203-8 (1976). Dahlgren, J. G., Anderson, E. T. & Hewitt, W. L. Gentamicin blood levels: a guide to nephrotoxicity. Antimicrobial Agents and Chemotherapy 8: 58-62 (1975). Enger, E. &. Blegen, E. M. The relationship between endogenous creatinine clearance and serum creatinine in renal failure. Scandinavian Journal of Clinical and Laboratory Investigation 16: 273-80 (1964). Falco, F. G., Smith, H. M. & Arcieri, G. M. Nephrotoxicity of aminoglycosides and gentamicin. Journal of Infectious Diseases 119: 406-9 (1969). Flandre, O. & Damon, M. Experimental study of the nephrotoxicity of gentamicin in rats. In Gentamicin, First International Symposium. Schwabe and Co. Basel (1967), pp. 47-61. Hewitt, W. L. Gentamicin: toxicity in perspective. Postgraduate Medical Journal 50 (Suppl. 7): 55-9 (1974). Jackson, G. G. Gentamicin. Current Therapeutics. Practitioner 198: 855-66 (1967). Kahlmeter, G., Hallberg, T. & Kamme, C. Gentamicin and tobramycin in patients with variou infections—concentrations in serum and urinary recovery. Journal of Antimicrobial Chemotherapy 4 (Suppl. A): 37-15 (1978). Labovitz, E., Levison, M. E. & Kaye, D. Single-dose daily gentamicin therapy in urinary tract infection. Antimicrobial Agents and Chemotherapy 6: 465-70 (1974). Madsen, P. O., Kjaer, T. B. & Mosegaard, A. Comparison of tobramycin and gentamicin in the treatment of complicated urinary tract infections. Journal of Infectious Diseases 134 (Suppl.): 150-2 (1976). Mawer, G. E., Ahmad, R., Dobbs, S. M., McGough, J. G., Lucas, S. B. & Tooth, J. A. Prescribing aids for gentamicin. British Journal of Clinical Pharmacology 1: 45-50 (1974). Patel, V., Luft, F. C , Yum, M. N., Patel, B., Zeman, W. & Kleit, S. A. Enzymuria in gentamicin-induced kidney damage. Antimicrobial Agents and Chemotherapy 7: 364-9 (1975). Sack, K. & Freiesleben, H. Experimental studies on the potential nephrotoxicity of tobramycin, gentamicin and sisomicin. Infection 3 (Suppl. 1): 40-9 (1975). Speirs, C. G. Tobramycin side effects—international results. Scottish Medical Journal 21: 78 (1976). Walker, B. D. & Gentry, L. O. A randomized, comparative study of tobramycin and gentamicin in treatment of acute urinary tract infections. Journal of Infectious Diseases 134 (Suppl.): 146-9(1976). Welles, J. S., Emmerson, J. L., Gibson, W. R., Nickander, R., Owen, N. V. & Anderson, R. C. Preclinical toxicology studies with tobramycin. Toxicology and Applied Pharmacology 25: 398-409 (1973). Wilfert, J'. N., Burke, J. P., Bloomer, H. A. & Smith, C. B. Renal insufficiency associated with gentamicin therapy. Journal of Infectious Diseases VIA (Suppl.): 148-53 (1971).
Gentamicin and tobramycin in patients with various infections—nephrotoxicity
Gunnar Kahlmeter, Torgny Hallberg and Carl Kamme
Thirty-eight consecutive patients were treated with either gentamicin (GM) or tobramycin (TM), 19 patients in each series. Renal function was monitored by serial deteiminations of serum creatinine concentrations (SCr) and by regular determinations of endogenous creatinine clearance (CCr). In the GM series a statistically significant progressive mean rise in SCr, more pronounced in elderly patients and in patients with lower CCr values, and a reciprocal mean decrease in CCr were recorded. In patients with normal renal function exhibiting a SCr increase, the mean daily increment was +1-7 (0-8 to 4-9) nmol/1. Also in the TM series a mean rise in SCr and a mean decrease in CCr were seen. They were less pronounced than in the GM series and statistically not significant. In both series, these reactions were rapidly reversible on terminating aminoglycoside therapy. Introduction
Nephrotoxic reactions, when seen during gentamicin (GM) therapy, are usually mild and transient. Although the true incidence is difficult to assess, mainly due to variations in definitions of nephrotoxicity, investigations in retrospect of extensive clinical materials have shown that 2 to 14% of patients treated with GM exhibit signs of drug-induced renal function derangement (Jackson, 1967; Falco, Smith & Arceiri, 1969; Wilfert, Burke, Bloomer & Smith, 1971; Hewitt, 1974; Bygbjerg & Mdller, 1976). Prospective studies of smaller series have reached similar frequencies (Labovitz, Levison & Kaye, 1974; Dahlgren, Anderson & Hewitt, 1975). Comparative studies in animals, as well as evaluations of clinical materials, indicate that tobramycin (TM) has a lower nephrotoxic potential than GM (Welles et al., 1973; Sack & Freiesleben, 1975; Speirs, 1976; Madsen, Kjaer & Mosegaard, 1976; Walker & Gentry, 1976). In the present paper, GM and TM therapy in patients with various infections were compared as to the occurrence and the degree of nephrotoxic reactions. In a previous paper, the GM and TM serum concentrations and the urinary recovery of the drugs in these patients were compared (Kahlmeter, Hallberg & Kamme, 1978). Materials and methods
Thirty-eight consecutive patients were treated with either GM or TM, 19 patients in each series. Data on these patients, including type of infections, aminoglycoside dose 47
Downloaded from http://jac.oxfordjournals.org/ at Simon Fraser University on June 9, 2015
Department of Medical Microbiology,.University of Lund, Lund, Sweden
48
Gentamicin and tobramydn—nephrotoxicity
+40
+ 40
+ 30
+30 T /
+20
+ 10
+ 10
0
0
-10
- 10 -20 -30 + 20
+ 20
i
i
4 J i i i i
+ 10
-20 -30 + 20 + 10
0
0
- 10
-10
- -20 -20 0 3 6 9 12 15 18 0 5 10 >IO Days during therapy Days after therapy Figure 1. Changes in serum creatinine concentrations (SCr) and endogenous creatinine clearance (CCr) during and after gentamicin (circles) and tobramycin (squares) therapy. OM, SCr (umol/1); O.D, CCr (ml/min/1-73 m 1 ); Vertical bars: standard error of mean.
Results Changes in mean serum creatinine levels (SCr) and endogenous creatinine clearance (CCr) during and after gentamicin and tobramycin therapy are shown in Figure 1. The mean SCr changes at end of therapy with the initial dose schedules were related to the parameters shown in Figure 3. Gentamicin series The mean (SE) SCr increments at end of therapy with the initial dose schedule and at end of the total course of therapy in 18 evaluated patients were +20-6 (3-6) umol/1 and +32-4 (7-2) umol/1 (both increments P < 0001). SCr increments of 5s 10 umol/1
Downloaded from http://jac.oxfordjournals.org/ at Simon Fraser University on June 9, 2015
schedules, initial renal function, methods for determining aminoglycoside and creatinine concentrations and for statistical analysis have been presented in a previous paper (Kahlmeter et al., 1978). Serum creatinine concentrations (SCr) were determined daily and endogenous 24 h creatinine clearance (CCr) weekly. At onset of therapy, 2 patients in the GM series and 6 patients in the TM series had clinical and laboratory findings indicating a decreased renal function. The mean (S.D.) SCr values in these patients were 130 (29) and 157-5 (83) umol/1, respectively, and the mean (S.D.) CCr values 42-5 (10-6) and 33-5 (18-5) ml/ min/l-73m 2 , respectively. In patients with normal renal function the corresponding mean values were 73-4 (15) and 78-5 (17-8) umol/1, respectively, and mean CCr values 88-9 (24-5) and 92-3 (36-9) ml/min, respectively.
G. Kahlmeter, T. Hallberg and C. Kamme
49
Table I. Changes in serum creatinine concentrations ((imol/l) during gentamicin (GM) and tobramycin (TM) therapy GM (18 pat)
TM (19 pat)
4 4 10* 0
6 5
No change « ± 10 umol/1) Increase of 10-30 umol/1 Increase of >30 umol/1 Decrease of >10 umol/1
3' 5t
• 2 patients in each series had impaired renal function at onset of therapy.
were recorded in 14 patients (Table I). In 12 of these, all with normal renal function at onset of therapy, the SCr rise was progressive with a mean daily increment of +1-7 (0-8 to 4-9) umol/1 (exemplified in Figure 2). In some patients the rise was temporarily arrested by the lowering of a dose or by an increase of the interval between injections. However, within a few days the rise continued and at the earlier rate. In 2 patients abrupt SCr rises were recorded. Both had impaired renal function at onset of therapy. Of 16 patients with initial SCr values below 110 umol/1, 6 reached values above 110 umol/1. The SCr increase was most pronounced in elderly patients and in patients with lower CCr values at onset of therapy (P > 005) (Figure 3). In 8 patients, SCr was monitored for more than 10 days after end of GM therapy. In these the SCr returned to pretreatment values, usually within 2 to 3 weeks (Figure 1). -I 8-0
^
--x».
6-O
I
X
I6O
x^*
80
x—"
40 .
40 :«=
5 §40 |
E
T
60 X
I
80 \
2 0
60
^'°
>
i
I
• 100
:
1
1
i
,
i
I
I
I
,
°
/x-x-x
80
Tt
60
40
X..
7O 60 (rng/kg/doy) (mg/kg) (day») (ml/min/l-73mz) (yean) Figure 3. Changes in serum creatinine concentrations (SCr; umol/l) at end of gentamicin (black bars) and tobramycin (open bars) therapy with the initial dose schedule (mean duration 9 and 10-5 days and mean total dose 29 and 28 mg'kg, resp.), related to daily and total aminoglycoside dose and duration of therapy with initial dose schedule, initial creatinine clearance and to the age of the patients. Figures at top of staples denote numbeT of patients.
In 3 patients SCr rose progressively all through the course, the final increments being >30 umol/l (Table I). Two of these had impaired renal function at onset of therapy. Of 14 patients with initial SCr values below 110 umol/l, one patient reached a SCr of >110 umol/l. In the TM series the rise in SCr appeared unrelated to either of the 5 investigated parameters (Figure 3). Only in 4 patients was SCr monitored for more than 10 days after end of therapy. A decrement of —45 umol/l in one patient brought the mean of the final observations to — ]6-3 umol/l (Figure 1). The mean (SE) of the lowest relative CCr values recorded during TM therapy in 16 evaluated patients was —4-6 (50) ml/min/1-73 mi (P> 005). Four patients exhibited a CCr decrement and 4 patients a CCr increment of more than 15 ml/min, while CCr was stable in the remaining 8 patients.
Downloaded from http://jac.oxfordjournals.org/ at Simon Fraser University on June 9, 2015
Tobramycin series The mean (SE) SCr increments at end of therapy with the initial dose schedule and at end of the total course of therapy in the 19 patients were +5-3 (71) umol/l and + 5 0 (6-3) umol/l, respectively (both increments P > 005). In 8 patients SCr increments and in 5 SCr decrements of ^10 umol/l were recorded (Table I). In 5 patients, all with normal renal function, the SCr rise occurred early in therapy and did not progress during the course, as exemplified in Figure 2. This patient had 6 weeks earlier received GM in a dose of 1 mg/kg/8 h. During this course a SCr increment of +30 umol/l and a CCr decrement of —35 ml/min were recorded.
G. Kahlmeter, T. Hallberg and C. Kamme
51
Discussion
Downloaded from http://jac.oxfordjournals.org/ at Simon Fraser University on June 9, 2015
By monitoring serum creatinine concentrations (SCr) and endogenous creatinine clearance (CCr), a reversible renal function derangement was noted in 14 of 18 evaluated patients treated with gentamicin (GM) and in 8 of 19 patients treated with tobramycin (TM). In the GM series a statistically significant mean SCr increase of +32-4 umol/1 and a CCr decrease of —32-7 ml/min were recorded. Corresponding values in the TM series were +5-0 umol/1 and —4-6 ml/min. In the GM series the SCr increase was more pronounced in elderly patients and in patients with lower initial CCr values, but in neither series was there a statistically significant correlation between the changes in SCr and any of the 5 investigated parameters. The relationship between SCr and CCr is not linear (Enger & Blegen, 1964). A given CCr decrement in the lower CCr range causes a greater SCr increase than does the same CCr decrement at a higher basic level. This is most pronounced on a CCr level below 40 to 50 ml/min. In the GM series only one patient had an initial CCr below 50 ml/min. Most GM patients exhibited a progressive SCr increase all through therapy, while patients treated with TM usually exhibited less pronounced SCr increments, occurring early in the course. The signs of renal function derangement were more pronounced in patients receiving low daily and total doses of GM than in patients treated with high doses of TM. Our findings indicate that GM has a greater nephrotoxic potential than TM. Toxicology studies with GM and TM in animals have demonstrated histological abnormalities in renal parenchyma, from cloudy swelling of proximal tubules to frank cortical necrosis, and that these changes are more pronounced with GM than with TM (Flandre & Damon, 1967; Welles et al., 1973; Patel et al, 1975; Sack & Freiesleben, 1975). Two prospective comparative studies of GM and TM in the treatment of urinary tract infections, both found TM less nephrotoxic than GM (Walker & Gentry, 1976; Madsen et al., 1976). SCr and BUN rises were more pronounced in patients with underlying renal disease and in elderly patients (Walker & Gentry, 1976). Dahlgren et al. (1975), investigating patients treated with GM, recorded a SCr rise in patients receiving daily GM doses of 4-5 mg/kg or more and in patients with trough levels above 2-0 ug/ml. They did not report on the age or initial renal function of the patients. Labovitz et al. (1974) noted a SCr rise in patients treated with 160 mg GM once daily, but not in patients receiving 60 to 80 mg GM 3 times daily for 10 days. Seventy-five per cent of the patients older than 50 years were in the former group, and it may be that this accounts for the discrepancy. In the first part of this investigation, we reported on the aminoglycoside concentrations in serum and urine attained in these patients (Kahlmeter et al., 1978). Due to the frequent determinations of GM and TM serum concentrations, trough levels only rarely exceeded 2 0 ug/ml. In patients with normal renal function, we recorded a progressive rise in GM but not in TM serum concentrations. The correlation coefficients between the SCr rise and the rise in GM trough and 1-h concentrations were 0-83 and 0-58, respectively. In our opinion, the progressive rise in SCr and GM serum concentrations and the decrease in CCr were signs of a drug induced renal function derangement, most probably caused by an accumulation of the drug in renal parenchyma, discussed in the previous paper (Kahlmeter et al., 1978). Its major clinical significance seems to be that it causes accumulation of the drug in serum and thus increases the risk of ototoxic reactions (Banck et al., 1973; Mawer et al., 1974). Although TM in the present study appeared
52
Geotamidn and tobramycin—nephrotoxlcfry
less nephrotoxic than GM, the occasional individual may well exhibit gradually rising SCr and TM serum concentrations necessitating dose reduction to prevent accumulation of the drug in serum. Thus GM as well as TM therapy should be monitored with repeated determinations of drug serum concentrations as well as with frequent determinations of SCr and/or CCr. References
Downloaded from http://jac.oxfordjournals.org/ at Simon Fraser University on June 9, 2015
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