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820 Editorial Response: Single Daily Dosing of Aminoglycosides-A Concept Whose Time Has Not Yet Come Joseph S. Bertino, Jr., and John C. Rotschafer Single daily dosing (SDD) of aminoglycosides (also known as once-daily aminoglycoside therapy) is a concept that has been discussed in the literature for over a decade and advocated with zeal by many proponents. While the concept seems selfdefining, various investigators have suggested dosages of gentamicin or tobramycin that range from 4 mg/kg to 7 mg/kg. Depending on the investigator and on the patient's underlying renal function, one dose per day may be administered, or the dosage interval may be extended beyond 24 hours. Needless to say, what has been collaboratively referred to as SDD varies substantially depending on the investigator. See articles on pages 786-815. Over the last few years, a plethora of papers addressing the issue of SDD have been published in an effort to answer the questions, Is SDD at least as efficacious and no more toxic than multiple daily dosing (MDD) of aminoglycosides? Unfortunately, no study published to date has had sufficient statistical power to provide the answers to these questions because they apply to patients with diverse infectious diseases and various underlying diseases. The three meta-analyses in this issue of Clinical Infectious Diseases (CID) attempt to examine the efficacy and toxicity of SDD vs. the efficacy and toxicity of MDD for various patient populations. Although meta-analysis is a useful, powerful tool, its application cannot transform poor-quality, underpowered data into useful information [1, 2]. The studies included in the metaanalyses in this issue of CID were evaluated for heterogeneity and homogeneity, but they were not evaluated in terms of the scientific and clinical quality of the data obtained in the original trials. The quality of a meta-analysis ultimately rests on the caliber of the trials selected for inclusion [1, 2]. Without question, the currently published literature on SDD of aminoglycosides has a number of underlying weaknesses, and thus the three meta-analyses published in this issue of CID require prudent scrutiny. We do not take issue with the techniques used for Received 23 December 1996; revised 24 January 1997. Reprints or correspondence: Dr. Joseph S. Bertino, Jr., Clinical Phannacology Research Center, Bassett Healthcare, One Atwell Road, Cooperstown, New York 13326. Clinical Infectious Diseases 1997; 24:820-3 © 1997 by The University of Chicago. All rights reserved. 1058-4838/97/2405 -0009$02.00 From the Departments of Pharmacy Services and Medicine, Clinical Pharmacology Research Center, Bassett Healthcare, Cooperstown, New York; and the Department of Pharmacy, St. Paul-Ramsey Medical Center, St. Paul, Minnesota these meta-analyses but with the concepts of SDD as they have been applied in various trials. We are particularly concerned with the issues of efficacy and pharmacodynamics, nephrotoxicity, and cost and convenience. Efficacy and Pharmacodynamic Principles The concept of SDD is based on the principles of concentration-dependent killing, postantibiotic effect (PAE), and adaptive resistance of aminoglycosides. The PAE of aminoglycosides against gram-negative organisms has been demonstrated in vitro and in animal models, and this effect is postulated to occur in humans, giving support to the concept of SDD [3, 4]. However, we believe that this postulate is problematic. Given that the PAE varies for different organisms, aminoglycosides, and dosing intervals in the animal model, the assumption that the PAE will persist over a 24-hour dosing period in humans is a matter of concern [4]. Recent data from in vitro studies suggest that the PAE decreases and disappears over a prolonged dosing interval [5]. Weare concerned that since the PAE ofaminoglycosides varies considerably based on the infecting organism and pharmacokinetics within individual patients, the use of SDD may not be appropriate in many patient populations or for a wide range of pathogens or infections. In an animal model, the PAE of aminoglycosides can be lengthened by the concomitant use of a .B-lactamantibiotic [4]; however, this finding raises questions concerning the increased cost of antibiotic therapy and the usefulness of administering a ,B-Iactam antibiotic alone. Concentration-dependent killing of gram-negative bacteria is another important concept that supports SDD therapy. The results of clinical trials for a variety of infections suggest that an optimal postdistributional (i.e., serum concentrations obtained in the beta phase) maximum concentration (Cmax)/MIC ratio is an important factor in attaining cure and in favorably altering the surrogate markers of infection, fever and WBC count [6, 7]. Unfortunately, to our knowledge there have not been any clinical trials on SDD of aminoglycosides that have examined optimization of the Cmax/MIC ratio and the effect of this optimization on clinical outcome. The findings of Moore et al. [6] suggest that a postdistributional Cmax/MIC ratio of > lOis necessary to maximize clinical outcome. These investigators dosed aminoglycosides three times a day to optimize peak concentrations, irrespective of renal function. Data from a study by Kashuba et al. [7] on em 1997; 24 (May) Editorial Response nosocomial gram-negative pneumonia also showed that the postdistributional Cmax/MIC ratio is important in shortening the time required for resolution of the surrogate markers of infection. These investigators dosed aminoglycosides with use of individualized pharmacokinetic monitoring on an 8-hour, 12hour, or 24-hour schedule, depending on renal function, to optimize the postdistributional Cmax/MIC ratio and limit renal accumulation of the drug in an attempt to reduce the risk of nephrotoxicity. It is questionable whether these data [6, 7] can be extrapolated to a dosing regimen with which optimal Cmaxl MIC ratios are attained only once daily, with potentially prolonged drug-free periods in patients with normal renal function. The argument that the use of SnD more consistently results in a "therapeutic" Cmax (and thus an optimal Cmax/MIC ratio) may be erroneous. In the majority of studies on SDD of aminoglycosides, larger doses of the drugs have been administered, either as 30-minute or 60-minute infusions; peak concentrations were obtained 30 minutes after a 30-minute infusion or at the end of the 60-minute infusion [8-10]. The latter sampling scheme has been used to devise a nomogram for directing SDD therapy [8]. Unfortunately, the Cmax concentrations were likely obtained during the distribution (alpha) phase for many of these trials and thus actually reflected transiently elevated postinfusion concentrations. If these data were to be extrapolated graphically or mathematically to determine the actual "peak" concentration, erroneous values for the Cmax would be obtained, and therefore, the value for the Cmax/MIC ratio would also be erroneous. Data on gentamicin [11] and isepamicin [12] show that the distribution time is longer with larger doses of these aminoglycosides. Thus, the majority of SDD studies have reported values for postinfusion concentrations that were actually obtained during the distribution phase. When these trials are examined, it appears that the reported Cmax/MIC ratios are optimal. However, as illustrated by the data of Demczar et al. [11], the gentamicin Cmax/MIC ratio was reduced by 75% (mean, 5.5 if the MIC was 2 ug/mL for the infecting organisms) when an appropriate, postdistributional serum Cmax was used in the calculation instead of a "peak" concentration obtained during the distribution phase (immediately at the end of a 60-minute infusion of 7 mg/kg of gentamicin). The lower CmaxiMIC ratios obtained when appropriate beta-phase sampling of the Cmax is performed during snD therapy would be expected to result in a reduced clinical response. An additional difficulty in establishing a difference between the efficacy ofMDD and SDD is the lack of a critical evaluation of the actual aminoglycoside Cmax/MIC ratios obtained in these various trials. In general, these data are not available to the reader, either because appropriate serum sampling was not done or because patients without culture-documented infection were included, or both. SDD undoubtedly produces higher peak concentrations of aminoglycosides than does MDD. However, with highly susceptible gram-negative bacteria (MICs of gentamicin or tobramycin, ::s0.5 mg/L), it is quite possible that serum 821 aminoglycoside CmaxiMIC ratios of ~ 10 were achieved, even in patients who received MDD, despite substantially lower peak aminoglycoside concentrations. Thus, for infections that are due to extremely susceptible bacteria or that are located at sites where aminoglycosides are known to concentrate (i.e., the urinary tract), or both, a comparison between SDD and MDD may be meaningless. In these instances, the use of SDD therapy may unnecessarily expose a patient to excessive doses of aminoglycosides. In their meta-analysis, Ali and Goetz noted that the average age of patients receiving SDD therapy was 33 years. This finding does not allow a judgment as to whether SDD can be applied safely to older patients who may have more underlying conditions and reduced renal function. A recently published study found a trend towards increased nephrotoxicity in elderly patients receiving aminoglycosides via SDD vs. MDD [13]. Finally, the fact that patients at low risk for serious infection or patients who could have been treated effectively with (3lactam antibiotics alone (rather than combination therapy) were included in these trials makes a comparison between SDD and MDD meaningless. Another concern with the literature on SDD is that few of the patients included in these trials actually had documented gram-negative infections. According to the U.S. Food and Drug Administration document on the evaluation of anti-infective products [14], a documented gram-negative infection and bacterial susceptibility data are a priori requirements for establishing antibiotic efficacy for many types of infections. Patients in the SDD trials often received other antibiotics effective against gram-negative bacteria, and they also underwent appropriate surgical intervention when needed. In the limited situations where a gram-negative bacterium was actually recovered, the attribution of efficacy to the method by which the patient received the aminoglycoside is at the least troublesome. Nephrotoxicity SDD is advocated as a way of potentially reducing the nephrotoxicity associated with MDD. The work of Verpooten and co-workers [15] is often cited in support of SDD as a means of reducing renal accumulation of aminoglycosides. While the work of these investigators was scientifically sound, they compared the efficacy of a single dose of aminoglycoside, given in a short infusion with that ofthe same dose given in a 24-hour infusion. This comparison in no way represents a comparison of SDD with MDD (with either method, the drug is given via intermittent infusion); therefore, it is erroneous to draw the conclusion that there is less renal accumulation of aminoglycosides when patients receive SDD vs. MDD. To our knowledge, there are no data on renal accumulation of aminoglycosides when SDD is compared to MDD in humans; thus, one cannot draw the conclusion that SDD results in less renal accumulation ofaminoglycosides than does MDD. 822 Bertino and Rotschafer An important issue in the use of meta-analysis to examine the nephrotoxic potential associated with SDD vs. that associated with MDD is the large variability in definitions of nephrotoxicity. At least 10 definitions of nephrotoxicity were used in the studies cited in the three meta-analyses in this issue of CID. In some of the studies, "soft" definitions of nephrotoxicity (i.e., a 25% increase in the serum creatinine level or a total rise of 0.3 mg/dl., which is of questionable clinical significance) were used, or patients were not observed long enough after completion of therapy to determine actual rates of nephrotoxicity. The largest published studies on nephrotoxicity have defined nephrotoxicity as an increase in the serum creatinine level of 0.5 mg/dl, if the baseline level was <3 mg/dl. or as an increase of 1 mg/dl. if the baseline creatinine level was ~3 mg/dL [16-18]. Unfortunately, many of the studies cited in the meta-analyses did not include nephrotoxicity rates; therefore, the findings cannot be used in pooled data to evaluate these rates. This absence of important toxicity data may introduce significant bias. The greatest problem in evaluating the nephrotoxic potential of SDD vs. that of MDD is that many investigators examined SDD vs. MDD as the sole risk factor for nephrotoxicity. A number of studies have shown that risk factors for aminoglycoside nephrotoxicity are multifactorial [16-18]. The findings of a study conducted in the early 1980s, in which univariate analysis was performed, suggested that gentamicin is more nephrotoxic than tobramycin [19]. When these data were reanalyzed by means of multiple logistic regression analysis, other risk factors for aminoglycoside nephrotoxicity were identified, and the type of aminoglycoside used was no longer a predictive factor [16]. Thus, examining SDD vs. MDD alone as the only risk factor for aminoglycoside nephrotoxicity without statistically analyzing the additional known risk factors may lead to incorrect conclusions. Prins and co-workers [20] recently used multiple logistic regression analysis to examine the incidence of nephrotoxicity among patients receiving aminoglycosides via SDD or MDD. These investigators did not find a difference in the incidence of nephrotoxicity with dosages of <4 mg/(kg· d) vs. dosages of 4 mg/(kg· d) (a relatively low dose for SDD therapy). Unfortunately, Prins et al. did not examine total dose, which, rather than daily dose, has been reported to be an important risk factor for aminoglycoside nephrotoxicity [18]. Therefore, it remains unclear whether SDD of aminoglycosides is associated with a greater, lesser, or similar risk of nephrotoxicity than is MDD. Previous data have shown that even when nephrotoxicity occurs, it is mild, reversible, and rarely requires intervention with dialysis [21, 22]; this finding suggests that the rate and significance of aminoglycoside nephrotoxicity may be overstated. It is/clear that when individualized pharmacokinetic monitoring is applied, the rates of aminoglycoside-related nephrotoxicity' are low. In our own experience with nearly 1,500 patients treated with use of individualized pharmacokinetic monitoring, we observed a nephrotoxicity rate of 1% with 6 days of therapy. em 1997;24 (May) Cost and Convenience An additional argument raised by proponents of SDD is that SDD costs less than MDD because less frequent dosing is required, and the need for serum concentration monitoring is reduced. It should be noted that the cost of obtaining and assaying (labor and reagents) a serum aminoglycoside concentration at Bassett Healthcare (Cooperstown, NY) decreased from $10 during the period 1990-1993 to $6 in 1996. This cost reduction is due to the increased use of automated systems for therapeutic drug monitoring. The cost of obtaining a serum drug concentration is minuscule compared with the cost of the numerous other interventions (including concurrent therapy with expensive ,B-Iactam antibiotics) that are used to treat patients with infections. There are no definitive data suggesting what therapeutic drug monitoring goals are needed for patients who receive aminoglycosides via SDD. Some investigators (including Bailey et al.) have advocated obtaining a single serum drug concentration at least 6 hours after the initial dose of an aminoglycoside is given. Others have published a nomogram using a single serum drug concentration obtained at least 6 hours after a dose is given to ensure that adequate peak concentrations are obtained [8]. As noted above, the pharmacokinetic principles used to develop such a nomogram have been questioned [11]. Relying on a single serum aminoglycoside concentration is problematic in that if the concentration appears elevated or reduced, the clinician is uncertain as to whether the result represents alterations in the drug's pharmacokinetics within an individual patient, a laboratory error, or an alteration in the administration schedule by the nursing staff. Dosing aminoglycosides with use of individualized pharmacokinetic monitoring, which can be performed with two postinfusion serum concentrations, is still a bargain in today's health care arena; this process can optimize therapeutic goals while limiting exposure to the drugs in an effort to reduce the risk of toxicity. The published studies on SDD vs. MDD of aminoglycosides, including the three meta-analyses in this issue of CID, do not answer the question of whether SDD is equivalent, inferior, or superior (in terms of efficacy, nephrotoxicity, or cost) to MDD. The majority of the published trials are flawed for the reasons already cited. Unfortunately, this leads to flaws in meta-analysis of these trials. It is clear that the pharmacodynamics of aminoglycosides in humans are related to optimization of the postdistributional Cmax/MIC ratio. Individualized pharmacokinetic monitoring has been used for over two decades to dose aminoglycosides and is a highly proven method in terms of both achieving pharmacokinetic goals and optimizing clinical response [6, 7]. To date, few of the 40 SDD trials have reported differences in efficacy or toxicity between SDD and MDD. However, substantial problems exist with the methods used in these trials, which leads us to believe that the question of whether SDD is equivalent or superior to MDD is still unanswered. We will em 1997;24 (May) Editorial Response not get answers to the questions about SDD therapy if we accept the findings in the current literature. For reasons already stated, the technique of meta-analysis as applied to these data is unlikely to resolve the clinical questions surrounding the use of SDD vs. MDD. We believe that the real data supporting the adoption of SDD of aminoglycosides are lacking, and because aminoglycosides are generic drugs, suitable funding to answer these questions may not be forthcoming. References 1. Shapiro S. Meta-analysis/shmeta-analysis. Am J Epidemiol 1994; 140: 771-8. 2. Greenland S. Can meta-analysis be salvaged? Am J Epidemio11994; 140: 783-7. 3. Preston SL, Briceland LL. Single daily dosing of aminoglycosides. Pharmacotherapy 1995; 15:297-316. 4. Craig WA, Gudmundsson S. Postantibiotic effect. In: Lorian V, ed. Antibiotics in laboratory medicine. 4th ed. Baltimore: Williams and Wilkins, 1996:296-329. 5. den Hollander JG, Mouton JW, van Goor MP, Vleggaar FP, Verbrugh HA. Alteration of postantibiotic effect during one dosing interval of tobramycin, simulated in an in vitro pharmacokinetic model. Antimicrob Agents Chemother 1996;40:784-6. 6. Moore RD, Lietman PS, Smith CR. Clinical response to aminoglycoside therapy: importance of the ratio of peak concentrations to minimal inhibitory concentration. J Infect Dis 1987; 155:93-9. 7. Kashuba ADM, Nafziger AN, Drusano GL, Bertino JS Jr. Early optimization of aminoglycoside pharmacokinetic goals reduces time to therapeutic response in gram-negative pneumonia [abstract A100]. In: Program and abstracts of the 36th Interscience Conference on Antimicrobial Agents and Chemotherapy (New Orleans). Washington, DC: American Society for Microbiology, 1996. 8. Nico1au DP, Freeman CD, Belliveau P, et al. Experience with a oncedaily aminog1ycoside program administered to 2184 adult patients. Antimicrob Agents Chemother 1995; 39:650-5. 9. Blaser J, Konig C, Simmen HP, Thurnheer U. Monitoring serum concentrations for once-daily netilmicin dosing regimens. J Antimicrob Chemother 1994;33:341-8. 823 10. Prins JM, Buller HR, Kuijper EJ, et al. Once versus thrice daily gentamicin in patients with serious infections. Lancet 1993;341:335-9. 11. Demczar DD, Nafziger AN, Bertino JS Jr. The effect of distribution on appropriate once daily aminoglycoside dosing using the Hartford nomogram [abstract A 103]. In: Program and abstracts of the 36th Interscience Conference on Antimicrobial Agents and Chemotherapy (New Orleans). Washington, DC: American Society for Microbiology, 1996. 12. Lin C, Korduba C, Affrime M, et al. Pharmacokinetics and metabolism of l 4C-isepamicin in humans following intravenous administration. Antimicrob Agents Chemother 1995;39:2201-3. 13. Koo J, Tight R, Rajkumar V, Hawa Z. Comparison of once-daily versus pharmacokinetic dosing of aminog1ycosides in elderly patients. Am J Med 1996; 101:177-83. 14. Beam TR Jr, Gilbert DN, Kunin CM. General guidelines for the clinical evaluation of anti-infective drug products. Clin Infect Dis 1992; 15(suppl 1):S5-32. 15. Verpooten GA, Giuliano RA, Verbist L, Eestermaus G, De Broe ME. Once-daily dosing decreases renal accumulation of gentamicin and netilmicin. C1in Pharmacol Ther 1989;45:22-7. 16. Moore RD, Smith CR, Lipsky JJ, Mellits ED, Lietman PS. Risk factors for nephrotoxicity in patients treated with aminoglycosides. Ann Intern Med 1984; 100:352- 7. 17. Sawyers CL, Moore RD, Lerner SA, Smith CR. A model for predicting nephrotoxicity in patients treated with aminoglycosides. J Infect Dis 1986; 153:1062-8. 18. Bertino JS Jr, Booker LA, Franck PA, Jenkins PL, Franck KR, Nafziger AN. Incidence of and significant risk factors for aminoglycoside-associated nephrotoxicity in patients dosed by using individualized pharmacokinetic monitoring. J Infect Dis 1993; 167: 173-9. 19. Smith CR, Lipsky JJ, Laskin OL, et al. Double-blind comparison of the nephrotoxicity and auditory toxicity of gentamicin and tobramycin. N Eng1 J Med 1980;302:1106-9. 20. Prins JM, Weverling GJ, deBlok K, et al. Validation and nephrotoxicity of a simplified once-daily aminog1ycoside dosing schedule and guidelines for monitoring therapy. Antimicrob Agents Chemother 1996;40: 2494-9. 21. Holloway JJ, Smith CR, Moore RD, et al. Comparative cost effectiveness of gentamicin and tobramycin. Ann Intern Med 1984; 101:764~9. 22. Bertino JS Jr, Timm EG, Nafziger AN. Individualized pharmacokinetic dosing of aminoglycosides: impact ofmonitoring by a clinical pharmacy service on the incidence of aminoglycoside nephrotoxicity and its associated costs [abstract]. Clin Pharmacol Ther 1991;49:150.