Letters to the Editor
Gentamicin Nephrotoxicity
Dear Sirs, In a recent article in this journal, Churchill and Seely [1] reported nephrotoxicity in 4 patients receiv ing combined gentamicin and amphotericin B therapy. The authors concluded that amphotericin B and gentamicin act synergistically to cause deterioration in kidney function. Although the combined use of these anti-infective agents may lead to renal damage, we disagree with the view that the gentamicin dosage resulting in levels of 5 ¡ag/ml 1 h prior to the next dose (trough levels) is ‘...appropriate and that nephrotoxi city should not have occurred in these cases’ [1]. Nephrotoxicity due to gentamicin has been reported in patients with trough levels of 2 or 4 frg/ml [2,3]. Dahlgren et at. [2] failed to note any decrease in renal function in those patients with trough gentamicin levels below 2 ¡xg/ml [2], The manufacturer also re commends that ‘...trough levels above 2 ug/ml should be avoided’ [4] and states that prolonged therapy and high dosages increase the risk of gentamicin-induced nephrotoxicity. In view of the above data, we feel that nephrotoxi city from gentamicin alone in the 2 patients [1] with high trough levels cannot be ruled out. In general, we suggest that the optimum gentamicin dosage regimen
be designed to achieve the appropriate peak levels and trough levels of less than 2 ¡¿g/ml. Samuel James Matthews and Moses Chow, Hartford Hospital, Hartford, CT 06115 (USA), and University of Connecticut School of Pharmacy, Storrs, Conn. (USA)
References
1 Churchill, D.N. and Seely, J.: Nephrotoxicity associated with combined gentamicin-amphotericin B therapy. Nephron 19: 176-181 (1977). 2 Dahlgren, J.G .; Anderson, F..T., and Hewitt, W. H.: Gentamicin blood levels: a guide to neph rotoxicity, Antimicrob. Agents Chemother. 8: 5862(1975). 3 Goodman, E.L.; Van Gelder, J.; Holmes, R.; Hull, A.R., and Sanford, J.P.: Prospective com parative study of variable dosage and variable frequency regimens for administration of genta micin. Antimicrob. Agents Chemother. 8: 434-438 (1975). 4 Baker, C.E.: Physicians’ desk reference (Medical Economics, Oradell 1977).
597
Letters to the Editor
Reply to Letter by Matthews and Chow
Dear Sirs, Nephrotoxicity has been reported in patients with trough serum gentamicin values greater than 2 [xg/rnl [1], Matthews and Chow feel that nephrotoxicity from gentamicin alone cannot be excluded in 2 of 4 patients reported by us [2] as the trough serum gentamicin value in each was 5 ¡¿g/ml. We have studied 16 patients treated with gentamicin on 22 occasions [3] with dosages determined by creatinine clearance values and administered on an 8 hourly schedule [4]. The mean peak and trough serum gentamicin values were 6.4 and 3.6 ¡¿g/ml. For 17 courses of treatment, the creati nine clearance value was between 15 and 65 ml/min. Despite mean trough serum gentamicin values of greater than 2 [¿g/ml for 12 of 17 courses, there was a decrease in renal function in only 1 patient and this was clearly related to a hypotensive episode. The trough value was greater than 4 ug/ml during 6 courses of treatment and yet no patient suffered a deteriora tion in renal function. Dahlgren et al. [1] reported that renal function deteriorated in all 5 patients with a trough serum gentamicin value greater than 4 ¡¿g/ml. We cannot explain the discrepancy between our results and those of Dahlgren. We agree that one cannot exclude a possible nephrotic effect of gentamicin alone but feel that the rapid development of renal insufficiency following addition of small doses of amphotericin B to 4 con secutive patients receiving gentamicin provides strong circumstantial evidence for synergistic action. Although peak serum gentamicin values of 4-5 [j.g/ml are generally considered adequate for treatment of serious gram-negative sepsis, R iff [5] has suggested that patients with poor host defense mechanisms should
have a sustained therapeutic serum gentamicin con centration, as long periods of sub-inhibitory levels are undesirable. Although there is no proven added effec tiveness from sustained high serum gentamicin levels and there is a possibly increased toxicity, the relation ship between therapeutic effect and toxicity deserves further prospective study. David N. Churchill The General Hospital and Memorial University of Newfoundland, St. John’s, Newfoundland (Canada) John Seely Division of Nephrology, Royal Victoria Hospital, McGill University, Montreal, P.Q. (Canada)
References
1 Dahlgren, J.G .; Anderson, E.T., and Hewitt, W. H .: Gentamicin blood levels: a guide to nephro toxicity. Antimicrob. Agents Chemother. 8: 58-62 (1975). 2 Churchill, D .N . and Seely, J.: Nephrotoxicity as sociated with combined gentamicin-amphotericin B therapy. Nephron 19: 176-181 (1977). 3 Churchill, D .N .; McNamara, A.; Bowner, I.; Ahmed, M., and Gault, M .H.: Predictability of scrum gentamicin concentrations in renal failure. Cardiovasc. Med. (in press). 4 Chan, R.A .; Benner, E.J., and Hoeprich, P.D .: Gentamicin therapy in renal failure. A nomogram for dosage. Ann. intern. Med. 76: 773-778 (1972). 5 Riff, L.J.: Pseudomonas bacteremia. Evaluation of factors influencing response to therapy. Acta path, microbiol. scand., suppl. 241, pp. 79-88 ( 1973).
Gentamicin Nephrotoxicity
Dear Sirs, In a recent article in this journal, Churchill and Seely [1] reported nephrotoxicity in 4 patients receiv ing combined gentamicin and amphotericin B therapy. The authors concluded that amphotericin B and gentamicin act synergistically to cause deterioration in kidney function. Although the combined use of these anti-infective agents may lead to renal damage, we disagree with the view that the gentamicin dosage resulting in levels of 5 ¡ag/ml 1 h prior to the next dose (trough levels) is ‘...appropriate and that nephrotoxi city should not have occurred in these cases’ [1]. Nephrotoxicity due to gentamicin has been reported in patients with trough levels of 2 or 4 frg/ml [2,3]. Dahlgren et at. [2] failed to note any decrease in renal function in those patients with trough gentamicin levels below 2 ¡xg/ml [2], The manufacturer also re commends that ‘...trough levels above 2 ug/ml should be avoided’ [4] and states that prolonged therapy and high dosages increase the risk of gentamicin-induced nephrotoxicity. In view of the above data, we feel that nephrotoxi city from gentamicin alone in the 2 patients [1] with high trough levels cannot be ruled out. In general, we suggest that the optimum gentamicin dosage regimen
be designed to achieve the appropriate peak levels and trough levels of less than 2 ¡¿g/ml. Samuel James Matthews and Moses Chow, Hartford Hospital, Hartford, CT 06115 (USA), and University of Connecticut School of Pharmacy, Storrs, Conn. (USA)
References
1 Churchill, D.N. and Seely, J.: Nephrotoxicity associated with combined gentamicin-amphotericin B therapy. Nephron 19: 176-181 (1977). 2 Dahlgren, J.G .; Anderson, F..T., and Hewitt, W. H.: Gentamicin blood levels: a guide to neph rotoxicity, Antimicrob. Agents Chemother. 8: 5862(1975). 3 Goodman, E.L.; Van Gelder, J.; Holmes, R.; Hull, A.R., and Sanford, J.P.: Prospective com parative study of variable dosage and variable frequency regimens for administration of genta micin. Antimicrob. Agents Chemother. 8: 434-438 (1975). 4 Baker, C.E.: Physicians’ desk reference (Medical Economics, Oradell 1977).
597
Letters to the Editor
Reply to Letter by Matthews and Chow
Dear Sirs, Nephrotoxicity has been reported in patients with trough serum gentamicin values greater than 2 [xg/rnl [1], Matthews and Chow feel that nephrotoxicity from gentamicin alone cannot be excluded in 2 of 4 patients reported by us [2] as the trough serum gentamicin value in each was 5 ¡¿g/ml. We have studied 16 patients treated with gentamicin on 22 occasions [3] with dosages determined by creatinine clearance values and administered on an 8 hourly schedule [4]. The mean peak and trough serum gentamicin values were 6.4 and 3.6 ¡¿g/ml. For 17 courses of treatment, the creati nine clearance value was between 15 and 65 ml/min. Despite mean trough serum gentamicin values of greater than 2 [¿g/ml for 12 of 17 courses, there was a decrease in renal function in only 1 patient and this was clearly related to a hypotensive episode. The trough value was greater than 4 ug/ml during 6 courses of treatment and yet no patient suffered a deteriora tion in renal function. Dahlgren et al. [1] reported that renal function deteriorated in all 5 patients with a trough serum gentamicin value greater than 4 ¡¿g/ml. We cannot explain the discrepancy between our results and those of Dahlgren. We agree that one cannot exclude a possible nephrotic effect of gentamicin alone but feel that the rapid development of renal insufficiency following addition of small doses of amphotericin B to 4 con secutive patients receiving gentamicin provides strong circumstantial evidence for synergistic action. Although peak serum gentamicin values of 4-5 [j.g/ml are generally considered adequate for treatment of serious gram-negative sepsis, R iff [5] has suggested that patients with poor host defense mechanisms should
have a sustained therapeutic serum gentamicin con centration, as long periods of sub-inhibitory levels are undesirable. Although there is no proven added effec tiveness from sustained high serum gentamicin levels and there is a possibly increased toxicity, the relation ship between therapeutic effect and toxicity deserves further prospective study. David N. Churchill The General Hospital and Memorial University of Newfoundland, St. John’s, Newfoundland (Canada) John Seely Division of Nephrology, Royal Victoria Hospital, McGill University, Montreal, P.Q. (Canada)
References
1 Dahlgren, J.G .; Anderson, E.T., and Hewitt, W. H .: Gentamicin blood levels: a guide to nephro toxicity. Antimicrob. Agents Chemother. 8: 58-62 (1975). 2 Churchill, D .N . and Seely, J.: Nephrotoxicity as sociated with combined gentamicin-amphotericin B therapy. Nephron 19: 176-181 (1977). 3 Churchill, D .N .; McNamara, A.; Bowner, I.; Ahmed, M., and Gault, M .H.: Predictability of scrum gentamicin concentrations in renal failure. Cardiovasc. Med. (in press). 4 Chan, R.A .; Benner, E.J., and Hoeprich, P.D .: Gentamicin therapy in renal failure. A nomogram for dosage. Ann. intern. Med. 76: 773-778 (1972). 5 Riff, L.J.: Pseudomonas bacteremia. Evaluation of factors influencing response to therapy. Acta path, microbiol. scand., suppl. 241, pp. 79-88 ( 1973).
