demonstrate netilmicin nephrotoxicity as similar to that of gentamicin (10, 12, 20, 21) in humans, although in rats, netilmicin is consistently less nephrotoxic (1, 9 ...
ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, May 1982, p. 721-726
Vol. 21, No. 5
00664804/82/050721-06$02.00/0
Clinical and Pharmacokinetic Characteristics of Aminoglycoside Nephrotoxicity in 201 Critically Ill Patients JEROME J. SCHENTAG,l* FRANK B. CERRA,3 AND MARTIN E. PLAUT2 Departments of Pharmaceutics,1 Medicine,2 and Surgery,3 Schools of Pharmacy1 and Medicine,2'3 State University of New York at Buffalo; The Buffalo General Hospital;2'3 and The Clinical Pharmacokinetics Laboratory, Millard Fillmore Hospital,' Buffalo, New York 14209
Received 23 November 1981/Accepted 18 February 1982
We studied 201 critically ill patients during 267 courses of gentamicin (139 courses) or tobramycin (128 courses) therapy. Clinical and pharmacokinetic data were obtained on 240 of 267 courses (120 courses each of gentamicin and tobramycin). Two judgments of nephrotoxicity and its cause were made independently in this study, using a clinical and a pharmacokinetic definition of nephrotoxicity. The two sets of criteria were generally in good agreement, as all but 10 of 41 patients who were judged nephrotoxic by pharmacokinetic criteria were independently judged nephrotoxic by the clinical definition. Groups of patients judged nontoxic did not differ from groups judged nephrotoxic in age, sex, weight, initial creatinine clearance, total dose given, duration of treatment, initial aminoglycoside trough serum levels, number of dosage adjustments, concurrent use of furosemide, or concurrent cephalosporins. Prior aminoglycosides (usually gentamicin) had been used more frequently in the nontoxic group (P < 0.05). Two major conclusions of this study are at variance with those of previous investigators: (i) we found no clinical parameters of value in predicting nephrotoxicity in critically ill patients; and (ii) aminoglycoside serum concentrations, once in the therapeutic range, were of limited value in prevention of aminoglycoside nephrotoxicity in our patients. We and others have previously shown that the various aminoglycosides differ in their intrinsic nephrotoxic potential in animals (1, 9, 11, 13) and humans (10, 17, 18, 19). In such studies, both nontoxic and nephrotoxic patients must have precise control of the serum concentrations before the population can be analyzed for the factors predisposing to nephrotoxicity. We have treated 201 critically ill patients with suspected or proven infections, with aminoglycosides administered in regimens that were closely monitored by measured blood levels (17). Dosing adjustments were made as required to maintain the recommended concentration range. The judgment of nephrotoxicity was made independently by both clinical and pharmacokinetic criteria. Gentamicin was more frequently (24%) nephrotoxic than was tobramycin (12%). In this analysis, we compared all nontoxic patients with all nephrotoxic patients so as to use our large groups of nephrotoxic patients to define the characteristics of those who experienced renal damage when appropriately dosed with aminoglycosides. METHODS
Patients. We gave 201 acutely ill patients 267 courses of aminoglycoside therapy. Pharmacokinetic
and clinical data were available on 240 courses, which were used for analysis. The patients were older adults in critical care units, with serious infections complicating either major medical or surgical disorders. Most infections were intra-abdominal or pneumonic. Patients were entered into this study at the time of request for dosing and pharmacokinetic monitoring. Dosing and sample collection. Aminoglycosides were administered by intravenous infusion over 30 to 60 min. Dosing rates were determined initially by nomograms and then adjusted to the desired range based on measured peak and trough serum concentrations. Peak and trough serum concentrations were obtained every 2 to 3 days throughout treatment, and blood level monitoring was continued for 10 to 20 days after stopping treatment. The peak serum concentrations (measured at 1 h after the start of infusion) were adjusted to a range of 4.0 to 10.0 Fg/ml, and trough serum concentrations were adjusted to 0.5 to 2.0 ,ug/ ml. When a urinary catheter was in place, daily 24-h urines were collected to verify tissue accumulation and to measure indices of renal damage. Assays. Serum, urine, and postmortem tissue concentrations of aminoglycoside were measured by radioimmunoassay as previously described (15). Serum creatinine and 24-h creatinine clearance values were determined by autoanalyzer methods. We determined 24-h urinary excretion of 032-microglobulin by radioimmunoassay; values in excess of 50 mg per 24 h were defined as nephrotoxic damage (16). Quantitative cast counts were performed daily on random urines collect721
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ed in the morning. Values exceeding 500 casts per ml for 3 days were defined as nephrotoxic damage (14). Pharmacokinetics. In all patients, aminoglycoside tissue accumulation was calculated from aminoglycoside serum concentrations, using a two-compartment pharmacokinetic model (15). Values were verified by urine collection or, in some cases, by analyses on tissues obtained at autopsy. Nephrotoxicity. Nephrotoxicity was determined for each course of aminoglycoside therapy, using two sets of criteria: the clinical assessment of nephrotoxicity was performed in blinded fashion independently of the pharmacokinetic assessment. The clinical criterion for nephrotoxicity was an increase in serum creatinine of 0.5 mg/dl or more during therapy or within 7 days of the last dose. Unless another cause of the creatinine rise, such as septic shock, was clearly apparent, the change was always attributed to the aminoglycoside in the clinical analysis. From the pharmacokinetic perspective, the primary criterion used to ascribe nephrotoxic damage was excessive accumulation of the aminoglycoside in tissue, defined as an amount greater than two standard deviations above the mean value in an earlier series of patients who did not demonstrate a rise in serum creatinine. These abnormal values were 200 mg or more for gentamicin and 175 mg or more for tobramycin (18). The second pharmacokinetic criterion was a sequential elevation in urine 32-microglobulin (50 mg/ 24 h) and casts (>500 per ml) occurring before a rise in serum creatinine in a specific pattern previously described (18). When an elevation occurred in serum creatinine that was not preceded by indices of renal tubular damage or abnormal tissue accumulation, the nephrotoxicity was ascribed to other causes. From the pharmacokinetic perspective, a rise in serum creatinine, even if clinically significant, was not attributed to the aminoglycoside unless excessive tissue accumulation or signs of specific tubular damage, or both, also preceded the elevation. Analysis. This analysis compared all nephrotoxic courses with all nontoxic courses by both clinical and pharmacokinetic criteria. Each course of aminoglycoside therapy was examined separately, even if given to a patient previously treated, since the clinical state and risk factors could change from course to course. About 25% of the patients were studied during two or more courses of therapy. A separate analysis was also done to determine the influence of prior aminoglycoside therapy in our patients. Differences between groups were analyzed by the Student t test, the chi-square test with Yates corrections, and linear regression analysis. Differences were considered statistically significant at P < 0.05.
RESULTS
Nephrotoxicity incidence and clinical risk factors. Defined by a rise in serum creatinine, 69 nephrotoxic reactions complicated 240 courses of aminoglycoside therapy (29%). As defined by abnormal tissue accumulation and renal tubular damage, there were 41 nephrotoxic reactions (17%). The overall agreement between the two criteria was 76%, since 31 of the 41 patients
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judged nephrotoxic by pharmacokinetic criteria were also clinically nephrotoxic. The demographic data for nontoxic versus nephrotoxic courses revealed no significant differences in age, sex, weight, base-line creatinine clearance, incidence of bacteremia, satisfactory
response to treatment, mortality, or exposure to concurrent cephalosporins (78% cephalothin and 14% cefazolin) in either the clinical or pharmacokinetic analysis. Concurrent diuretic therapy (96% furosemide) was more frequent in nephrotoxic courses as judged by clinical criteria (P < 0.05), whereas prior aminoglycoside exposure was less frequent in those patients judged nephrotoxic by pharmacokinetic criteria (P < 0.05). In all cases in which the patient survived the renal insufficiency and its complications, renal function returned to base-line values. However, as long as 60 to 90 days were occasionally required. Eleven patients (4.6%) died with aminoglycoside-associated renal failure as a major contribution to their demise. Dose and duration. Duration of treatment did not differ in the nontoxic and nephrotoxic groups, regardless of toxicity criteria. No differences were observed in the number of dosing adjustments made during treatment, although the nephrotoxic courses tended to require more frequent dosing adjustments than did the nontoxic courses. Total dosage did not differ in the clinically nephrotoxic courses, but a higher total dose was given to those patients nephrotoxic by pharmacokinetic criteria. Duration of treatment was important, as short courses (
