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Extended interval aminoglycoside dosing: from concept to clinic
International Journal of Antimicrobial Agents 19 (2002) 341 /348 www.isochem.org
Extended interval aminoglycoside dosing: from concept to clinic Dana Maglio a, Charles H. Nightingale c,*, David P. Nicolau a,b a
Department of Pharmacy Research, Hartford Hospital, Hartford, CT 06102, USA b Division of Infectious Diseases, Hartford Hospital, Hartford, CT 06102, USA c Office for Research Administration, Hartford Hospital, 80 Seymour Street, Hartford, CT 06102, USA
Abstract Extended-interval aminoglycoside dosing (EIAD), while a relatively recent concept in mainstream clinical practice, actually has its roots in the mid 1970s. Early trial and error approaches of manipulating the dosage regimen to avoid toxicity and improve efficacy have helped to characterize the pharmacodynamic properties of these drugs. The increasing successful use of EIAD and improved understanding of pharmacodynamics has helped this dosing regimen gain acceptance into routine clinical practice. A 1998 United States survey demonstrated that approximately 75% of hospitals have adopted EIAD into routine patient care. However, controversy still exists regarding some aspects of infrequent aminoglycoside administration, such as length of the drug-free interval and patient exclusion criteria. After more than 50 years of experience with the aminoglycosides we continue to learn how to most appropriately use these drugs. # 2002 Elsevier Science B.V. and International Society of Chemotherapy. All rights reserved. Keywords: Extended-interval aminoglycosides dosing (EIAD); Aminoglycosides; Global acceptance
1. Introduction More than 50 years of clinical experience with aminoglycosides exists supporting conventional or traditional dosing. Conventionally, doses have been given on an every 8 or 12 h schedule with peak and trough levels drawn to assess clinical effect and monitor toxicity. However, over the years our expanding knowledge of pharmacodynamic and pharmacokinetic concepts coupled with the history of aminoglycoside use has prompted exploration of alternative dosing strategies in an effort to maximize their therapeutic potential and minimize toxicity risk (Fig. 1). The concept of once-daily aminoglycosides has existed since the early 1970s based on trial and error experience. The dynamics between the aminoglycoside, the infecting organism and the host hold several properties that have reinforced the basis for changing the dosing strategy to high-dose, infrequent administration. This strategy is commonly called oncedaily dosing or extended-interval aminoglycoside dosing (EIAD). This paper reflects on the historical perspective
* Corresponding author. Tel.: /1-860-545-2865; fax: /1-860-5455112. E-mail address: [email protected] (C.H. Nightingale).
of aminoglycoside usage leading up to the current acceptance into practice of EIAD.
2. Toxicity The potential for aminoglycosides to cause nephro and ototoxicity has been the main feature limiting their use. It has also been an important factor prompting the discovery of new dosing strategies. After glomerular filtration a portion of the administered dose is retained in the cells of the proximal tubules. Drug and phospholipids accumulate within lysosomes until the lysosomes become overloaded and rupture. Their contents of high concentrations of aminoglycoside and enzymes are released into the cytoplasm where they elicit a variety of structural and functional defects of the cell [1]. Clinically, nephrotoxicity manifests as non-oliguric renal failure. Progression to oliguric or anuric renal failure is rare and recovery occurs upon discontinuing the drug in most cases. The incidence of aminoglycosideinduced nephrotoxicity varies depending on the aminoglycoside used, duration of therapy, and presence of other risk factors for nephrotoxicity including other drugs [2].
0924-8579/02/$ - $20 # 2002 Elsevier Science B.V. and International Society of Chemotherapy. All rights reserved. PII: S 0 9 2 4 - 8 5 7 9 ( 0 2 ) 0 0 0 3 0 - 4
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Fig. 1. History of aminoglycoside use leading up to extended-interval aminoglycoside dosing.
Our knowledge of the exact origin of aminoglycoside toxicity still remains ambiguous and it has been through trial and error approaches of various dosing schemes that we have discovered factors that are associated with aggravating or mitigating toxicity. Years ago, conventional wisdom held that it was necessary to maintain serum antibiotic levels above the minimum inhibitory concentration (MIC) of the infecting organism for the entire dosing interval. This approach was favored by the observation that breakthrough positive blood cultures often occur when serum antibiotic concentrations fall
below levels inhibiting growth in vitro [3]. This perception in the mid 1970s prompted continuous infusion dosing regimens with aminoglycosides in an effort to maximize efficacy and simplify the dosing regimen. Continuous infusion was also suggested as being less toxic compared with intermittent dosing [4 /6]. However, the popularity of continuous infusion aminoglycosides decreased when in fact a high incidence of nephrotoxicity occurred [7,8]. It was actually during this same era that the concept of once-daily aminoglycosides began to evolve, mostly as single daily gentamicin
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for urinary tract infections. In 1977, one of the first studies administering once-daily gentamicin for pyelonephritis was conducted [9]. In 1978 continuous infusion and once-daily aminoglycosides were compared. The investigators found aminoglycosides administered as a continuous infusion to be more nephrotoxic than the same daily dose given once a day. Further, high aminoglycoside concentrations (peaks) did not correlate with toxicity in this investigation [10]. The mechanism of aminoglycoside toxicity mentioned earlier as a saturable process was elucidated and increased understanding of dosing related toxicity. Renal injury is proportional to the degree of drug accumulation in renal tissue. Single daily dosing of aminoglycosides has resulted in decreased renal cortical accumulation compared with multiple daily dosing. It has been shown that the uptake kinetics into the renal cortex for gentamicin, netilmicin and, to a degree, amikacin are non-linear [11]. Lower percentages of the total administered dose will accumulate in renal tissue if the drug is given in larger doses less frequently. Higher renal tissue concentrations were observed in animal studies with a three-times-a-day aminoglycoside regimen than with a once-daily regimen (total daily dose was held constant) [12,13]. This finding was duplicated in two studies involving patients scheduled for nephrectomy where single daily doses of aminoglycoside correlated with less renal cortical uptake compared with the same daily dose given as a continuous infusion [14,15]. Thus giving more drug less frequently effectively reduces the drug burden [16]. There is also evidence suggesting that aminoglycoside nephrotoxicity is temporally related to circadian rhythm and/or sleep and wake cycles. In a pyelonephritis rat infection model, single daily doses of gentamicin administered at 07:00, 13:00, 19:00 or 01:00 h produced variable degrees of toxicity. Signs of gentamicin toxicity including tubular cell necrosis were observed in rats treated at 13:00 h (rest time) but not in rats treated at 01:00 h (wake time). Additionally, creatinine clearance was significantly lower after treatment with gentamicin once daily at 13:00 h compared with the same regimen given at 07:00 or 01:00 h. Administration of gentamicin during the wake period also appeared to more efficacious based on change in log colony forming units (CFU) per gram of tissue and per cent sterile kidney tissue [17]. A prospective study in human patients also showed an increased incidence of nephrotoxicity when aminoglycosides were given during the sleeping period [18]. However, periods of rest and activity may be altered in hospitalized patients and these changes should be considered when evaluating this approach. This dosing strategy is an interesting approach to toward decreasing aminoglycoside nephrotoxicity that deserves further study.
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The correlation between ototoxicity and dosage regimen has been less well studied, partly due to the inherent difficulty in measuring ototoxicity in the clinical setting. Damage of the sensory hair cells of the organ of Corti and reduction of cochlear ganglion cells are the reported mechanisms leading to auditory dysfunction, while the hair cells of the vestibular epithelia are the targets for damage causing vestibular injury. While it is clear that accumulation of aminoglycosides in the inner ear leads to the auditory and vestibular manifestations of ototoxicity, variations in patient toxicity threshold, the impact of dose/dosing interval, and the lack of adequate baseline data contribute to the poor differentiation of this toxicity in the patient care arena. Similar to nephrotoxicity, ototoxicity results from accumulation of aminoglycoside due to slow elimination in these tissues. It may be that the processes involved in drug elimination in kidney and ear tissue are similar and may explain why nephro- and ototoxicity are both often attributable to the same drug. Although less ototoxicity data is available, the results we have seem to parallel the effects found in the kidneys. Less structural and functional evidence of cochlear injury occurred in guinea pigs that received once-daily aminoglycosides compared with the same dose of aminoglycoside given as multiple doses [19]. Similarly, other animal studies have shown less drug accumulation in the organ of Corti with discontinuous aminoglycoside administration [20,21].
3. Concentration dependent bactericidal activity While the understanding of aminoglycoside toxicodynamics was increasing, so was the understanding of aminoglycoside dynamics with respect to efficacy. It was suggested in 1974 by Noone et al. that high serum levels of aminoglycosides are required for therapeutic success [22]. It was subsequently shown after evaluating several clinical trials of Gram-negative pneumonia that patients with peaks of 7 mg/ml or greater for gentamicin and tobramycin or 28 mg/ml or greater for amikacin had a greater chance for a successful outcome than patients with peaks less than this [23]. Similarly, high peaks were associated with decreased mortality in the setting of Gram-negative bacteraemia [24]. This concept was taken a step further in another evaluation that demonstrated that high peaks in relation to a drug’s MIC for a particular organism (peak/MIC ratio) were a major determinant of response to aminoglycoside therapy [25]. This dose /response relationship exhibited by aminoglycosides has been termed concentration dependent bactericidal activity. Bactericidal activity is a function of the amount of time antimicrobial concentrations remain above a critical value, such as the MIC. When increasing drug concentrations causes the rate of killing to increase
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such that most of the organisms die within a short period of time, the contribution of time of bacterial exposure becomes minimal and bacterial eradication is only a function of drug concentration. In contrast, the bactericidal activity of beta-lactams is optimized once they remain at a certain relatively fixed concentration above the organism’s MIC [26]. This dynamic is termed time-dependent bactericidal activity where no increase in bacterial killing occurs with increasing concentrations. Time-kill curves generated from in vitro studies have been used to illustrate these effects clearly [27]. It is important to understand, however, that the definitions of ‘concentration dependence’ and ‘time dependence’ are not absolute. There is a point beyond which increasing a drug’s concentration relative to the MIC will not increase bacterial killing rate. For aminoglycosides this point appears to be at a peak/MIC ratio of 10 /12 [25,28]. While aminoglycosides are generally considered to be concentration dependent, when a peak/MIC ratio of /10 occurs, further increases in concentration probably do not influence the efficacy of the drug and the aminoglycoside under these conditions, is not concentration dependent. This information has provided a strong basis for extended-interval aminoglycoside administration where peak/MIC ratios in this range can be achieved.
4. Post antibiotic effect The concept of concentration dependent activity explains how for certain antimicrobials, drug concentrations can fall below an organism’s MIC without compromising bactericidal effect. The amount of time that bacterial growth remains inhibited in the absence of drug exposure represents the post antibiotic effect (PAE) [29 /31]. A PAE exists for almost all antibiotics but the duration depends on various factors including the antibiotic /pathogen combination [32]. Cell wall active antibiotics (beta-lactams, glycopeptides) exhibit prolonged PAEs against Gram-positive organisms, mostly staphylococci. Antibiotics that effect protein synthesis, such as aminoglycosides, exhibit prolonged PAEs against Gram-positive and Gram-negative organisms as well. A PAE of 1/3 h against Pseudomonas aeruginosa and 0.9 /2 h against Enterobacteriaceae has been demonstrated with aminoglycosides in vitro [33]. A PAE of up to 7.5 h against P. aeruginosa and Enterobacteriaceae has been observed in animal models [34,35]. In addition the PAE for aminoglycosides is longer when higher concentrations are achieved [36]. Thus, the concept of PAE supports higher, infrequent dosing of aminoglycosides, however, one must be careful that the dosing interval is not too long. While a long PAE tends to extend the dosing interval, if the dosing interval is too long, regrowth of the organism can occur.
5. Adaptive resistance Adaptive resistance refers to the decreased uptake of a drug by bacteria after initial exposure to the drug [37]. Down-regulation of enzymes responsible for the energydependent uptake of aminoglycosides into bacteria is the proposed mechanism of adaptive resistance. Adaptive resistance has been observed in in vitro and animal studies [38 /40]. It appears to be reversible after a sufficient drug-free interval [41]. Additionally, higher aminoglycoside doses may avoid selecting out more resistant mutants within a population. Thus higher aminoglycoside doses with longer drug free intervals may be an effective way to preserve their bactericidal activity. While this claim may be supported by in vitro studies, the meaning of this phenomenon in the infected patient is much less clear. Bactericidal activity may be preserved against strains that are obtainable and studied in the laboratory. However, such strains may not be representative of the population or network causing the infections. Many bacteria, including P. aeruginosa , possess the ability to exist as a network, also called biofilm. Research done on biofilms has increased awareness of how bacteria live in nature and may further understanding of antimicrobial failures [42]. A discussion on biofilms is beyond the context of this paper but it is an important concept to keep in mind when considering strategies against antimicrobial resistance.
6. Decisions for practice regarding extended-interval aminoglycoside dosing The increased understanding of the dynamics of aminoglycosides with respect to toxicity and efficacy has encouraged the implementation of EIAD in one form or another. The development of EIAD regimens has been rather empirical and variation among dosing regimens exists as a result, although they are based on the same theoretical principles. The goal of any extended-interval regimen is to use a dose high enough to optimize the concentration-dependent killing of the aminoglycosides and PAE, and to create an interval long enough to accommodate a sufficient drug-free period. Doses used are generally in the range of 4/7 mg/kg for gentamicin, tobramycin and netilmicin, and 15 mg/kg or greater for amikacin [43]. Nicolau et al. used a 7 mg/kg dose based on achieving a peak:MIC ratio of 10 with gentamicin for their institution’s most troublesome pathogen, P. aeruginosa with an MIC of 2. This dosing regimen was applied routinely as a means of standardizing practice, although the peak:MIC ratio achieved would probably exceed 10 for more susceptible pathogens [44]. In addition, identification of the infecting pathogen and its MIC are often unknown at the
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initiation of therapy and many patients would benefit from empirically covering for P. aeruginosa . The ‘Portland Method’ uses a maximum mg/kg dose of 5.1 based on multiplying the conventional dose by three (three times daily dose) [45]. The selection of a 24 h dosing interval is largely based on convenience and the optimal drug-free period remains to be determined. In the setting of renal impairment, the length of the drug-free interval becomes more variable. Some regimens require a dose reduction for renal insufficiency while others extend the interval and maintain the same dose. A prolonged drug free interval is supported by the PAE, which varies depending on a number of factors such as the infecting pathogen and presence or absence of neutrophils. This is an important consideration in neutropenic patients who may have a shortened PAE. Evaluation of neutropenic animal models has revealed decreased efficacy with once-daily regimens due to bacterial regrowth. However, studies in neutropenic cancer patients revealed equal efficacy between thrice-daily and once-daily aminoglycosides if they were administered with a cephalosporin [46 /48]. The pharmacokinetics of neonates also deserves special consideration. Aminoglycoside pharmacokinetics in neonates is associated with a larger volume of distribution and decreased clearance due to a higher percentage of total body water. To safely accommodate the prolonged dosing intervals needed in these patients, de Hoog et al. developed a specific tobramycin dosing schedule based on population pharmacokinetics over various gestational ages for 24, 36 and 48 h [49]. A similar dosing regimen for neonates based on weight has been discovered by Stickland et al. as well [50]. There are also differences in serum aminoglycoside monitoring among the various regimens. A study by Lent-Evers et al. highlights the importance of active therapeutic drug monitoring of aminoglycosides in regards to traditional dosing [54]. Patients followed by a pharmacokinetics service were compared with patients who were treated with an aminoglycoside and dosed and monitored at the discretion of the physician without a formal pharmacokinetic service. Patients in the active therapeutic monitoring group had a shorter hospital stay, shorter duration of therapy, increased antibiotic efficacy and a 13.4% lower incidence of nephrotoxicity. The importance of appropriate patient monitoring with aminoglycosides cannot be overemphasized, regardless of the clinician’s choice of monitoring techniques. However, the degree of monitoring depends on how the dose is administered. High, infrequent doses of aminoglycosides require less monitoring because the accumulation in tissues is less. In addition, the risk for aminoglycoside toxicity increases with a longer duration of therapy. When dosing aminoglycosides with an extended interval, many investigators continue to moni-
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tor peaks and an additional level, either a trough or midpoint level [51]. Another method describes using serum concentrations to calculate the AUC and modifying the dose towards a target AUC [52]. Still others advocate using pharmacokinetic computer modeling, such as Bayesian simulation, of multiple serum collections to individualize once-daily regimens [53]. Additionally nomograms have been developed such as the Hartford Nomogram to guide dose adjustments [44]. Nomograms have become increasingly popular [62], probably because of their ease of use. A disadvantage to their use, however, is that they cannot be applied across all patient populations. Extended-interval aminoglycoside dosing may still be appropriate for patients whose kinetics exclude them from established nomograms, but alternative monitoring schemes or nomograms should be applied. Currently issues regarding which method is most appropriate remain unresolved.
7. Global acceptance The various methods of EIAD have been compared against conventional dosing in numerous clinical studies and meta-analyses [55 /59]. The efficacy and incidence of toxicity with EIAD has been shown to be similar. In some studies a trend toward increased efficacy or decreased toxicity has been associated with EIAD compared with conventional dosing. The observed trends favoring EIAD in meta-analyses have been validated in a prospective, randomized, double-blind study by Ryback et al. This study evaluated the toxicity of single daily aminoglycoside administration versus twice daily administration. The investigators found a 15.4% incidence of nephrotoxicity in the twice-daily group. In comparison, zero patients in the once-daily group had evidence of nephrotoxicity. One patient developed ototoxicity measured by audiometric evaluations in the twice-daily group, compared with zero patients in the once-daily group [60]. In spite of these findings, some critics have questioned the principles upon which EIAD is based, such as the reliability of the PAE and methods used to assess toxicity risk, and have expressed concern over lack of statistical power supporting it in the clinical trials [43]. These considerations, while valid, are theoretical as well and are less of a concern as more clinicians successfully use EIAD without an increase in toxicity. The use of EIAD has been surveyed by many investigators to gauge its acceptance into practice. Schumock et al. reported the practice of using EIAD in 500 acute care hospitals in the United States in 1993/ 1994 [61]. At that time only 19% of hospitals surveyed were using EIAD. A higher proportion of positive responses occurred in areas where the leaders of this practice are located, the New England and Pacific
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regions. Use of EIAD in this study also was associated with pharmacist participation and a higher incidence of use occurred in hospitals affiliated with a pharmacy practice residency programme. The extent to which EIAD was employed in those hospitals using it was not ascertained. As of 1998 /1999, the routine use of EIAD had increased 4-fold according to a second survey [62]. In addition, the contraindications to using EIAD had decreased from 1993 to 1998, according to these surveys. Although more practitioners appeared to have adopted EIAD regimens into practice, variability in dosing was prevalent. Doses /5 mg/kg for gentamicin and tobramycin, as recommended by the Hartford method, were increasingly used. However, slightly more than half of the respondents use 3 /5 mg/kg doses for gentamicin and tobramycin. The method used to monitor serum aminoglycoside concentrations also varied, however, more than half of the respondents have moved toward a single level drawn at 6 /18 h. Recently opinion leaders in the field of Infectious Diseases outside the United States were polled to gauge the acceptance of EIAD in their regions. Results from seven hospitals in five regions (UK, The Netherlands, China, Australia, Canada) were obtained. The number of hospitals responding to this informal poll are too few to make any firm conclusions regarding EIAD in each region, however, the results seem to support its use. EIAD was reported to be used for more than 80% of the time in three hospitals, two in the Netherlands and one in Australia. The two hospitals in the UK estimated EIAD use at 40/60% in one hospital and 60 /80% in another. The hospitals in China and Canada reported less than 20% usage of EIAD. Half of the respondents reported using doses of 3/5 mg/kg and half reported using /5 mg/kg doses for gentamicin, tobramycin or netilmicin. In general doses were doubled for amikacin. In one hospital using 3/5 mg/kg dosing, higher doses are considered when P. aeruginosa is the suspected pathogen. There was variability among institutions regarding exclusion criteria, however, enterococcal endocarditis was the most common patient group considered to be ineligible for EIAD, followed by patients with altered pharmacokinetics such as burns and renal failure. The methods of therapeutic drug monitoring also varied. These surveys and others, can be a useful way to characterize, but not define, the standard of practice in a certain area. In many instances practice standards may change rapidly with advances in technology and drug development. With respect to aminoglycoside dosing, it appears that the majority of clinicians have adopted EIAD into their practice within a relatively short time period since their introduction into mainstream practice. These surveys also highlight the fact that responsible application of EIAD requires further study in certain areas of practice. Certain patient groups continue to be
re-evaluated for their eligibility to receive EIAD, such as endocarditis patients [63]. It is important to note that while the best monitoring technique has not been agreed upon, the need for appropriate monitoring is required with any aminoglycoside dosing regimen. Extendedinterval dosing regimens can reduce toxicity risk but do not eliminate it completely, especially with a prolonged duration of therapy.
References [1] Mingeot-Leclerq M, Tulkens PM. Aminoglycosides: nephrotoxicity. Antimicrob Agents Chemother 1999;43:1003 /12. [2] Begg EJ, Barclay ML. Aminoglycosides: 50 years on. Br J Clin Pharmacol 1995;39:597 /603. [3] Anderson ET, Young LS, Hewitt WL. Simultaneous antibiotic levels in ‘breakthrough’ gram-negative rod bacteremia. Am J Med 1976;61:493 /7. [4] Bodey GP, Chang HY, Rodriguez V, Stewart D. Feasibility of administering aminoglycoside antibiotics by continuous intravenous infusion. Antimicrob Agents Chemother 1975;8:328 /33. [5] Valdivieso M, Feld R, Rodrigues V, Bodey GP. Amikacin therapy of infections in neutropenic patients. Am J Med Sci 1975;270:453 /63. [6] DeRosa F, Buoncristiani U, Capitanucci P, Frongillo RF. Tobramycin: toxicological and pharmacological studies in animals and pharmacokinetic research in patients with varying degrees of renal impairment. J Int Med Res 1974;2:100 /14. [7] Feld R, Valdivieso M, Bodey GP, Rodriguez V. A comparative trial of sisomicin therapy by intermittent versus continuous infusion. Am J Med Sci 1977;274:178 /88. [8] Feld R, Rachlis A, Tuffnell PG, et al. Empiric therapy for infections in patients with granulocytopenia. Continuous versus interrupted infusion of tobramycin plus cefamandole. Arch Int Med 1984;144:1005 /10. [9] Hatala M, Moravek J, Prat V, Schuch O, Liska M, Spousta J. Daily single-dose gentamicin therapy in experimental pyelonephritis. Infection 1977;4:232 /5. [10] Reiner NE, Bloxham DD, Thompson WL. Nephrotoxicity of gentamicin and tobramycin given once daily or continuously in dogs. J Antimicrob Chemother 1978;4(Suppl A):85 /101. [11] Giuliano RA, Verpooten GA, Verbist L, Wedeen R, De Broe ME. In vivo uptake kinetics of aminoglycosides in the kidney cortex of rats. J Pharmacol Exp Ther 1986;236:470 /5. [12] Frame PT, Phair JP, Watanakunaorn C, Bannister TWP. Pharmacologic factors associated with gentamicin nephrotoxicity in rabbits. J Infect Dis 1977;135:952 /6. [13] Bennett WM, Plamp CE, Gilbert DN, Parker RA, Porter GA. The influence of dosage regimen on experimental gentamicin nephrotoxicity: dissociation of peak serum levels from renal failure. J Infect Dis 1979;140:576 /80. [14] Verpooten GA, Giuliano RA, Verbist L, Eestermans G, De Broe ME. Once-daily dosing decreases renal accumulation of gentamicin and netilmicin. Clin Pharmacol Ther 1989;45:22 /7. [15] De Broe ME, Verbist L, Verpooten GA. Influence of dosage schedule on renal cortical accumulation of amikacin and tobramycin in man. J Antimicrob Chemother 1991;27(Suppl C):41 /7. [16] Gilbert DN. Once-daily aminoglycoside therapy. Antimicrob Agents Chemother 1991;35:399 /405. [17] LeBrun M, Grenier L, Gourde P, et al. Effectiveness and toxicity of gentamicin in an experimental model of pyelonephritis: effect of the time of administration. Antimicrob Agents Chemother 1999;43:1020 /6.
D. Maglio et al. / International Journal of Antimicrobial Agents 19 (2002) 341 /348 [18] Prins JM, Weverling GJ, van Ketel RJ, et al. Circadian variations in serum levels and the renal toxicity of aminoglycosides in patients, Clin Pharmacol Ther 1997;62:106 /11. [19] Brummett RE. Ototoxicity of aminoglycoside antibiotics in animal models. INSERM 1982;102:359 /76. [20] Tran Ba Huy P, Bernards P, Schacht J. Kinetics of gentamicin uptake and release in the rat. J Clin Invest 1986;77:1492 /500. [21] Tran Ba Huy P, Deffrennes D. Aminoglycoside ototoxicity: influence of dosage regimen on drug uptake and correlation between membrane binding and some clinical features. Acta Otolaryngol 1988;105:511 /5. [22] Noone P, Pattison JR. The effective use of gentamicin in lifethreatening sepsis. Postgraduate Med 1974;50(Suppl 4):9 /16. [23] Moore RD, Smith CR, Lietman PS. Association of aminoglycoside plasma levels with therapeutic outcome in gram-negative pneumonia. Am J Med 1984;77:657 /62. [24] Moore RD, Smith CR, Lietman PS. The association of aminoglycoside plasma levels with mortality in patients with gramnegative bacteremia. J Infect Dis 1984;149:443 /8. [25] Moore RD, Lietman PS, Smith CR. Clinical response to aminoglycoside therapy: importance of the ratio of peak concentration to minimal inhibitory concentration. J Infect Dis 1987;155:93 /9. [26] Lacy MK, Nicolau DP, Nightingale CH, Quintiliani R. The pharmacodynamics of aminoglycosides. Clin Infect Dis 1998;27:23 /7. [27] Craig WA, Leggett J, Totsuka K, Vogelman B. Key pharmacokinetic parameters of antibiotic efficacy in experimental animal infections. J Drug Dev 1988;1(Suppl 3):7 /15. [28] Ebert SC, Craig WA. Pharmacodynamic properties of antibiotics: application to drug monitoring and dosage regimen design. Infect Control Hosp Epidemiol 1990;11:319 /26. [29] Bundtzen RW, Gerber AU, Cohn DL, Craig WA. Postantibiotic suppression of bacterial growth. Rev Infect Dis 1981;3:28 /37. [30] Vogelman B, Craig WA. Kinetics of antimicrobial activity. J Pediatr 1986;108:835 /40. [31] Zhanel GG, Hoban DJ, Harding GKM. The postantibiotic effect: a review of in vitro and in vivo data. Ann Pharmacother 1991;25:153 /63. [32] Craig WA, Vogelman B. The postantibiotic effect. Ann Intern Med 1987;106:900 /2. [33] Fantin B, Ebert S, Leggett J. Factors affecting duration of in-vivo postantibiotic effect for aminoglycosides against gram-negative bacilli. J Antimicrob Chemother 1991;27:829 /36. [34] Begg EJ, Peddie BA, Chambers ST, Boswell DR. Comparison of gentamicin dosing regimens using an in vitro model. J Antimicrob Chemother 1992;29:427 /33. [35] Vogelman B, Gdmundsson S, Turnidge J, Leggett J, Craig WA. In vivo postantibiotic effect in a thigh infection in neutropenic mice. J Infect Dis 1988;157:287 /98. [36] Barclay ML, Begg EJ, Hickling KG. What is the evidence for once-daily aminoglycoside therapy. Clin Pharmacokinet 1994;27:32 /48. [37] Preston SL, Briceland LL. Single daily dosing of aminoglycosides. Pharmacotherapy 1995;15:297 /316. [38] Daikos GL, Jackson GG, Lolans VT, Livermore DM. Adaptive resistance to aminoglycoside antibiotics from first-exposure down-regulation. J Infect Dis 1990;162:414 /20. [39] Daikos GL, Lolans VT, Jackson GG. First-exposure adaptive resistance to aminoglycoside antibiotics in vivo wit meaning for optimal clinical use. Antimicrob Agents Chemother 1991;35:117 / 23. [40] Gerber AU, Vastola AP, Brandel J, Craig WA. Selection of aminoglycoside-resistant variants of Pseudomonas aeruginosa in an in vivo model. J Infect Dis 1982;146:691 /7. [41] McGrath BJ, Lamp KC, Rybak MJ. Pharmacodynamic effects of extended dosing intervals o imipenem alone and in combination
[42] [43]
[44]
[45]
[46]
[47]
[48]
[49]
[50]
[51]
[52]
[53]
[54]
[55]
[56]
[57]
[58]
[59]
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with amikacin against Pseudomonas aeruginosa in an in vitro model. Antimicrob Agents Chemother 1993;37:1931 /7. Costerton JW, Stewart PS. Battling biofilms. Scientific American; July 2001:75 /81. Bertino JS, Rotschafer JC. Editorial response: single daily dosing of aminoglycosides-a concept whose time has not yet come. Clin Infect Dis 1997;24:820 /3. Nicolau DP, Freeman CD, Belliveau PP, Nightingale CH, Ross JW, Quintiliani R. Experience with a once-daily aminoglycoside program administered to 2184 adult patients. Antimicrob Agents Chemother 1995;39:650 /5. Gilbert DN, Lee BL, Dworkin RJ, et al. A randomized comparison of the safety and efficacy of once-daily gentamicin or thrice-daily gentamicin in combination with ticarcillin-clavulanate. Am J Med 1998;105:182 /91. Rozdzinski E, Kern WV, Reichle A, et al. Once-daily versus thrice-daily dosing of netilmicin in combination with beta-lactam antibiotics as empirical therapy for febrile neutropenic patients. J Antimicrob Chemother 1993;31:585 /98. International Antimicrobial Therapy Co-operative Group of the European Organization for Research and Treatment of Cancer. Efficacy and toxicity of single daily doses of amikacin and ceftriaxone versus multiple daily doses of amikacin and ceftazidime for infection in patients with cancer and granulocytopenia. Ann Intern Med 1993;119:584 /93. MacGowan AP, Bedford KA, Blundell E, et al. The pharmacokinetics of once-daily gentamicin in neutropenic adults with haematologic malignancy. J Antimicrob Chemother 1994;34:809 /12. De Hoog M, Schoemaker RC, Mouton JW, van den Anker JN. Tobramycin population pharmacokinetics in neonates. Clin Pharmacol Therap 1997;62:392 /9. Stickland MD, Kirkpatrick CM, Begg EJ, Duffull SB, Oddie SJ, Darlow BA. An extended interval dosing method for gentamicin in neonates. J Antimicrob Chemother 2001;48:887 /93. Prins JM, Koopmans RP, Buller HR, Kuijper EJ, Speelman P. Easier monitoring of aminoglycoside therapy with oncedaily dosing schedules. Eur J Clin Microbiol Infect Dis 1995;14:531 /5. Begg EJ, Barclay ML, Duffull S. A suggested approach to once-daily aminoglycoside dosing. Br J Clin Pharmacol 1995;39:605 /9. Garrelts JC. Exploration of once-daily dosing of aminoglycosides through bayesian simulation. Pharmacotherapy 1996;16:286 /94. Van Lent-Evers NAEM, Mathor RAA, Geus WP, et al. Impact of a goal-oriented and model based clinical pharmacokinetic dosing of aminoglycosides on clinical outcome: a cost-effectiveness analysis. Therap Drug Monit 1999;21:63 /73. Galloe AM, Graudal N, Christensen HR, Kampmann JP. Aminoglycosides: single or multiple daily dosing? A metaanalysis on efficacy and safety. Eur J Clin Pharmacol 1995;48:39 /43. Ferriols-Lisart R, Alos-alminana M. Effectiveness and safety of once-daily aminoglycosides: a meta-analysis. Am J Health-Syst Pharm 1996;53:1141 /50. Munckhof WJ, Grayson ML, Turnidge JD. A meta-analysis of studies on the safety and efficacy of aminoglycosides given either once daily or as divided doses, J Antimicrob Chemother 1996;37:645 /63. Barza M, Ioannidis JP, Cappelleri JC, Lau J. Single or multiple daily doses of aminoglycosides: a meta-analysis. Br Med J 1996;312:338 /45. Bailey TC, Little JR, Littenberg B, Reichley RM, Dunagan WC. A meta-analysis of extended-interval dosing versus multiple daily dosing of aminoglycosides. Clin Infect Dis 1997;24:786 /95.
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[60] Rybak MJ, Abate BJ, Kang SL, et al. Prospective evaluation of the effect of an aminoglycoside dosing regimen on rates of observed nephrotoxicity and ototoxicity. Antimicrob Agents Chemother 1999;43:1549 /55. [61] Schumock GT, Raber SR, Crawford S, Naderer OJ, Rodvold KA. National survey of once-daily aminoglycoside antibiotics. Pharmacotherapy 1995;15:201 /9.
[62] Chuck SK, Raber SR, Rodvold KA, Areff D. National survey of extended-interval aminoglycoside dosing. Clin Infect Dis 2000;30:433 /9. [63] Tam VH, McKinnon PS, Levine DP, Brandel SM, Rybak MJ. Once-daily aminoglycoside in the treatment of Enterococcus feacalis endocarditis: case report and review. Pharmacotherapy 2000;20:1116 /9.
Extended interval aminoglycoside dosing: from concept to clinic Dana Maglio a, Charles H. Nightingale c,*, David P. Nicolau a,b a
Department of Pharmacy Research, Hartford Hospital, Hartford, CT 06102, USA b Division of Infectious Diseases, Hartford Hospital, Hartford, CT 06102, USA c Office for Research Administration, Hartford Hospital, 80 Seymour Street, Hartford, CT 06102, USA
Abstract Extended-interval aminoglycoside dosing (EIAD), while a relatively recent concept in mainstream clinical practice, actually has its roots in the mid 1970s. Early trial and error approaches of manipulating the dosage regimen to avoid toxicity and improve efficacy have helped to characterize the pharmacodynamic properties of these drugs. The increasing successful use of EIAD and improved understanding of pharmacodynamics has helped this dosing regimen gain acceptance into routine clinical practice. A 1998 United States survey demonstrated that approximately 75% of hospitals have adopted EIAD into routine patient care. However, controversy still exists regarding some aspects of infrequent aminoglycoside administration, such as length of the drug-free interval and patient exclusion criteria. After more than 50 years of experience with the aminoglycosides we continue to learn how to most appropriately use these drugs. # 2002 Elsevier Science B.V. and International Society of Chemotherapy. All rights reserved. Keywords: Extended-interval aminoglycosides dosing (EIAD); Aminoglycosides; Global acceptance
1. Introduction More than 50 years of clinical experience with aminoglycosides exists supporting conventional or traditional dosing. Conventionally, doses have been given on an every 8 or 12 h schedule with peak and trough levels drawn to assess clinical effect and monitor toxicity. However, over the years our expanding knowledge of pharmacodynamic and pharmacokinetic concepts coupled with the history of aminoglycoside use has prompted exploration of alternative dosing strategies in an effort to maximize their therapeutic potential and minimize toxicity risk (Fig. 1). The concept of once-daily aminoglycosides has existed since the early 1970s based on trial and error experience. The dynamics between the aminoglycoside, the infecting organism and the host hold several properties that have reinforced the basis for changing the dosing strategy to high-dose, infrequent administration. This strategy is commonly called oncedaily dosing or extended-interval aminoglycoside dosing (EIAD). This paper reflects on the historical perspective
* Corresponding author. Tel.: /1-860-545-2865; fax: /1-860-5455112. E-mail address: [email protected] (C.H. Nightingale).
of aminoglycoside usage leading up to the current acceptance into practice of EIAD.
2. Toxicity The potential for aminoglycosides to cause nephro and ototoxicity has been the main feature limiting their use. It has also been an important factor prompting the discovery of new dosing strategies. After glomerular filtration a portion of the administered dose is retained in the cells of the proximal tubules. Drug and phospholipids accumulate within lysosomes until the lysosomes become overloaded and rupture. Their contents of high concentrations of aminoglycoside and enzymes are released into the cytoplasm where they elicit a variety of structural and functional defects of the cell [1]. Clinically, nephrotoxicity manifests as non-oliguric renal failure. Progression to oliguric or anuric renal failure is rare and recovery occurs upon discontinuing the drug in most cases. The incidence of aminoglycosideinduced nephrotoxicity varies depending on the aminoglycoside used, duration of therapy, and presence of other risk factors for nephrotoxicity including other drugs [2].
0924-8579/02/$ - $20 # 2002 Elsevier Science B.V. and International Society of Chemotherapy. All rights reserved. PII: S 0 9 2 4 - 8 5 7 9 ( 0 2 ) 0 0 0 3 0 - 4
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Fig. 1. History of aminoglycoside use leading up to extended-interval aminoglycoside dosing.
Our knowledge of the exact origin of aminoglycoside toxicity still remains ambiguous and it has been through trial and error approaches of various dosing schemes that we have discovered factors that are associated with aggravating or mitigating toxicity. Years ago, conventional wisdom held that it was necessary to maintain serum antibiotic levels above the minimum inhibitory concentration (MIC) of the infecting organism for the entire dosing interval. This approach was favored by the observation that breakthrough positive blood cultures often occur when serum antibiotic concentrations fall
below levels inhibiting growth in vitro [3]. This perception in the mid 1970s prompted continuous infusion dosing regimens with aminoglycosides in an effort to maximize efficacy and simplify the dosing regimen. Continuous infusion was also suggested as being less toxic compared with intermittent dosing [4 /6]. However, the popularity of continuous infusion aminoglycosides decreased when in fact a high incidence of nephrotoxicity occurred [7,8]. It was actually during this same era that the concept of once-daily aminoglycosides began to evolve, mostly as single daily gentamicin
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for urinary tract infections. In 1977, one of the first studies administering once-daily gentamicin for pyelonephritis was conducted [9]. In 1978 continuous infusion and once-daily aminoglycosides were compared. The investigators found aminoglycosides administered as a continuous infusion to be more nephrotoxic than the same daily dose given once a day. Further, high aminoglycoside concentrations (peaks) did not correlate with toxicity in this investigation [10]. The mechanism of aminoglycoside toxicity mentioned earlier as a saturable process was elucidated and increased understanding of dosing related toxicity. Renal injury is proportional to the degree of drug accumulation in renal tissue. Single daily dosing of aminoglycosides has resulted in decreased renal cortical accumulation compared with multiple daily dosing. It has been shown that the uptake kinetics into the renal cortex for gentamicin, netilmicin and, to a degree, amikacin are non-linear [11]. Lower percentages of the total administered dose will accumulate in renal tissue if the drug is given in larger doses less frequently. Higher renal tissue concentrations were observed in animal studies with a three-times-a-day aminoglycoside regimen than with a once-daily regimen (total daily dose was held constant) [12,13]. This finding was duplicated in two studies involving patients scheduled for nephrectomy where single daily doses of aminoglycoside correlated with less renal cortical uptake compared with the same daily dose given as a continuous infusion [14,15]. Thus giving more drug less frequently effectively reduces the drug burden [16]. There is also evidence suggesting that aminoglycoside nephrotoxicity is temporally related to circadian rhythm and/or sleep and wake cycles. In a pyelonephritis rat infection model, single daily doses of gentamicin administered at 07:00, 13:00, 19:00 or 01:00 h produced variable degrees of toxicity. Signs of gentamicin toxicity including tubular cell necrosis were observed in rats treated at 13:00 h (rest time) but not in rats treated at 01:00 h (wake time). Additionally, creatinine clearance was significantly lower after treatment with gentamicin once daily at 13:00 h compared with the same regimen given at 07:00 or 01:00 h. Administration of gentamicin during the wake period also appeared to more efficacious based on change in log colony forming units (CFU) per gram of tissue and per cent sterile kidney tissue [17]. A prospective study in human patients also showed an increased incidence of nephrotoxicity when aminoglycosides were given during the sleeping period [18]. However, periods of rest and activity may be altered in hospitalized patients and these changes should be considered when evaluating this approach. This dosing strategy is an interesting approach to toward decreasing aminoglycoside nephrotoxicity that deserves further study.
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The correlation between ototoxicity and dosage regimen has been less well studied, partly due to the inherent difficulty in measuring ototoxicity in the clinical setting. Damage of the sensory hair cells of the organ of Corti and reduction of cochlear ganglion cells are the reported mechanisms leading to auditory dysfunction, while the hair cells of the vestibular epithelia are the targets for damage causing vestibular injury. While it is clear that accumulation of aminoglycosides in the inner ear leads to the auditory and vestibular manifestations of ototoxicity, variations in patient toxicity threshold, the impact of dose/dosing interval, and the lack of adequate baseline data contribute to the poor differentiation of this toxicity in the patient care arena. Similar to nephrotoxicity, ototoxicity results from accumulation of aminoglycoside due to slow elimination in these tissues. It may be that the processes involved in drug elimination in kidney and ear tissue are similar and may explain why nephro- and ototoxicity are both often attributable to the same drug. Although less ototoxicity data is available, the results we have seem to parallel the effects found in the kidneys. Less structural and functional evidence of cochlear injury occurred in guinea pigs that received once-daily aminoglycosides compared with the same dose of aminoglycoside given as multiple doses [19]. Similarly, other animal studies have shown less drug accumulation in the organ of Corti with discontinuous aminoglycoside administration [20,21].
3. Concentration dependent bactericidal activity While the understanding of aminoglycoside toxicodynamics was increasing, so was the understanding of aminoglycoside dynamics with respect to efficacy. It was suggested in 1974 by Noone et al. that high serum levels of aminoglycosides are required for therapeutic success [22]. It was subsequently shown after evaluating several clinical trials of Gram-negative pneumonia that patients with peaks of 7 mg/ml or greater for gentamicin and tobramycin or 28 mg/ml or greater for amikacin had a greater chance for a successful outcome than patients with peaks less than this [23]. Similarly, high peaks were associated with decreased mortality in the setting of Gram-negative bacteraemia [24]. This concept was taken a step further in another evaluation that demonstrated that high peaks in relation to a drug’s MIC for a particular organism (peak/MIC ratio) were a major determinant of response to aminoglycoside therapy [25]. This dose /response relationship exhibited by aminoglycosides has been termed concentration dependent bactericidal activity. Bactericidal activity is a function of the amount of time antimicrobial concentrations remain above a critical value, such as the MIC. When increasing drug concentrations causes the rate of killing to increase
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such that most of the organisms die within a short period of time, the contribution of time of bacterial exposure becomes minimal and bacterial eradication is only a function of drug concentration. In contrast, the bactericidal activity of beta-lactams is optimized once they remain at a certain relatively fixed concentration above the organism’s MIC [26]. This dynamic is termed time-dependent bactericidal activity where no increase in bacterial killing occurs with increasing concentrations. Time-kill curves generated from in vitro studies have been used to illustrate these effects clearly [27]. It is important to understand, however, that the definitions of ‘concentration dependence’ and ‘time dependence’ are not absolute. There is a point beyond which increasing a drug’s concentration relative to the MIC will not increase bacterial killing rate. For aminoglycosides this point appears to be at a peak/MIC ratio of 10 /12 [25,28]. While aminoglycosides are generally considered to be concentration dependent, when a peak/MIC ratio of /10 occurs, further increases in concentration probably do not influence the efficacy of the drug and the aminoglycoside under these conditions, is not concentration dependent. This information has provided a strong basis for extended-interval aminoglycoside administration where peak/MIC ratios in this range can be achieved.
4. Post antibiotic effect The concept of concentration dependent activity explains how for certain antimicrobials, drug concentrations can fall below an organism’s MIC without compromising bactericidal effect. The amount of time that bacterial growth remains inhibited in the absence of drug exposure represents the post antibiotic effect (PAE) [29 /31]. A PAE exists for almost all antibiotics but the duration depends on various factors including the antibiotic /pathogen combination [32]. Cell wall active antibiotics (beta-lactams, glycopeptides) exhibit prolonged PAEs against Gram-positive organisms, mostly staphylococci. Antibiotics that effect protein synthesis, such as aminoglycosides, exhibit prolonged PAEs against Gram-positive and Gram-negative organisms as well. A PAE of 1/3 h against Pseudomonas aeruginosa and 0.9 /2 h against Enterobacteriaceae has been demonstrated with aminoglycosides in vitro [33]. A PAE of up to 7.5 h against P. aeruginosa and Enterobacteriaceae has been observed in animal models [34,35]. In addition the PAE for aminoglycosides is longer when higher concentrations are achieved [36]. Thus, the concept of PAE supports higher, infrequent dosing of aminoglycosides, however, one must be careful that the dosing interval is not too long. While a long PAE tends to extend the dosing interval, if the dosing interval is too long, regrowth of the organism can occur.
5. Adaptive resistance Adaptive resistance refers to the decreased uptake of a drug by bacteria after initial exposure to the drug [37]. Down-regulation of enzymes responsible for the energydependent uptake of aminoglycosides into bacteria is the proposed mechanism of adaptive resistance. Adaptive resistance has been observed in in vitro and animal studies [38 /40]. It appears to be reversible after a sufficient drug-free interval [41]. Additionally, higher aminoglycoside doses may avoid selecting out more resistant mutants within a population. Thus higher aminoglycoside doses with longer drug free intervals may be an effective way to preserve their bactericidal activity. While this claim may be supported by in vitro studies, the meaning of this phenomenon in the infected patient is much less clear. Bactericidal activity may be preserved against strains that are obtainable and studied in the laboratory. However, such strains may not be representative of the population or network causing the infections. Many bacteria, including P. aeruginosa , possess the ability to exist as a network, also called biofilm. Research done on biofilms has increased awareness of how bacteria live in nature and may further understanding of antimicrobial failures [42]. A discussion on biofilms is beyond the context of this paper but it is an important concept to keep in mind when considering strategies against antimicrobial resistance.
6. Decisions for practice regarding extended-interval aminoglycoside dosing The increased understanding of the dynamics of aminoglycosides with respect to toxicity and efficacy has encouraged the implementation of EIAD in one form or another. The development of EIAD regimens has been rather empirical and variation among dosing regimens exists as a result, although they are based on the same theoretical principles. The goal of any extended-interval regimen is to use a dose high enough to optimize the concentration-dependent killing of the aminoglycosides and PAE, and to create an interval long enough to accommodate a sufficient drug-free period. Doses used are generally in the range of 4/7 mg/kg for gentamicin, tobramycin and netilmicin, and 15 mg/kg or greater for amikacin [43]. Nicolau et al. used a 7 mg/kg dose based on achieving a peak:MIC ratio of 10 with gentamicin for their institution’s most troublesome pathogen, P. aeruginosa with an MIC of 2. This dosing regimen was applied routinely as a means of standardizing practice, although the peak:MIC ratio achieved would probably exceed 10 for more susceptible pathogens [44]. In addition, identification of the infecting pathogen and its MIC are often unknown at the
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initiation of therapy and many patients would benefit from empirically covering for P. aeruginosa . The ‘Portland Method’ uses a maximum mg/kg dose of 5.1 based on multiplying the conventional dose by three (three times daily dose) [45]. The selection of a 24 h dosing interval is largely based on convenience and the optimal drug-free period remains to be determined. In the setting of renal impairment, the length of the drug-free interval becomes more variable. Some regimens require a dose reduction for renal insufficiency while others extend the interval and maintain the same dose. A prolonged drug free interval is supported by the PAE, which varies depending on a number of factors such as the infecting pathogen and presence or absence of neutrophils. This is an important consideration in neutropenic patients who may have a shortened PAE. Evaluation of neutropenic animal models has revealed decreased efficacy with once-daily regimens due to bacterial regrowth. However, studies in neutropenic cancer patients revealed equal efficacy between thrice-daily and once-daily aminoglycosides if they were administered with a cephalosporin [46 /48]. The pharmacokinetics of neonates also deserves special consideration. Aminoglycoside pharmacokinetics in neonates is associated with a larger volume of distribution and decreased clearance due to a higher percentage of total body water. To safely accommodate the prolonged dosing intervals needed in these patients, de Hoog et al. developed a specific tobramycin dosing schedule based on population pharmacokinetics over various gestational ages for 24, 36 and 48 h [49]. A similar dosing regimen for neonates based on weight has been discovered by Stickland et al. as well [50]. There are also differences in serum aminoglycoside monitoring among the various regimens. A study by Lent-Evers et al. highlights the importance of active therapeutic drug monitoring of aminoglycosides in regards to traditional dosing [54]. Patients followed by a pharmacokinetics service were compared with patients who were treated with an aminoglycoside and dosed and monitored at the discretion of the physician without a formal pharmacokinetic service. Patients in the active therapeutic monitoring group had a shorter hospital stay, shorter duration of therapy, increased antibiotic efficacy and a 13.4% lower incidence of nephrotoxicity. The importance of appropriate patient monitoring with aminoglycosides cannot be overemphasized, regardless of the clinician’s choice of monitoring techniques. However, the degree of monitoring depends on how the dose is administered. High, infrequent doses of aminoglycosides require less monitoring because the accumulation in tissues is less. In addition, the risk for aminoglycoside toxicity increases with a longer duration of therapy. When dosing aminoglycosides with an extended interval, many investigators continue to moni-
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tor peaks and an additional level, either a trough or midpoint level [51]. Another method describes using serum concentrations to calculate the AUC and modifying the dose towards a target AUC [52]. Still others advocate using pharmacokinetic computer modeling, such as Bayesian simulation, of multiple serum collections to individualize once-daily regimens [53]. Additionally nomograms have been developed such as the Hartford Nomogram to guide dose adjustments [44]. Nomograms have become increasingly popular [62], probably because of their ease of use. A disadvantage to their use, however, is that they cannot be applied across all patient populations. Extended-interval aminoglycoside dosing may still be appropriate for patients whose kinetics exclude them from established nomograms, but alternative monitoring schemes or nomograms should be applied. Currently issues regarding which method is most appropriate remain unresolved.
7. Global acceptance The various methods of EIAD have been compared against conventional dosing in numerous clinical studies and meta-analyses [55 /59]. The efficacy and incidence of toxicity with EIAD has been shown to be similar. In some studies a trend toward increased efficacy or decreased toxicity has been associated with EIAD compared with conventional dosing. The observed trends favoring EIAD in meta-analyses have been validated in a prospective, randomized, double-blind study by Ryback et al. This study evaluated the toxicity of single daily aminoglycoside administration versus twice daily administration. The investigators found a 15.4% incidence of nephrotoxicity in the twice-daily group. In comparison, zero patients in the once-daily group had evidence of nephrotoxicity. One patient developed ototoxicity measured by audiometric evaluations in the twice-daily group, compared with zero patients in the once-daily group [60]. In spite of these findings, some critics have questioned the principles upon which EIAD is based, such as the reliability of the PAE and methods used to assess toxicity risk, and have expressed concern over lack of statistical power supporting it in the clinical trials [43]. These considerations, while valid, are theoretical as well and are less of a concern as more clinicians successfully use EIAD without an increase in toxicity. The use of EIAD has been surveyed by many investigators to gauge its acceptance into practice. Schumock et al. reported the practice of using EIAD in 500 acute care hospitals in the United States in 1993/ 1994 [61]. At that time only 19% of hospitals surveyed were using EIAD. A higher proportion of positive responses occurred in areas where the leaders of this practice are located, the New England and Pacific
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regions. Use of EIAD in this study also was associated with pharmacist participation and a higher incidence of use occurred in hospitals affiliated with a pharmacy practice residency programme. The extent to which EIAD was employed in those hospitals using it was not ascertained. As of 1998 /1999, the routine use of EIAD had increased 4-fold according to a second survey [62]. In addition, the contraindications to using EIAD had decreased from 1993 to 1998, according to these surveys. Although more practitioners appeared to have adopted EIAD regimens into practice, variability in dosing was prevalent. Doses /5 mg/kg for gentamicin and tobramycin, as recommended by the Hartford method, were increasingly used. However, slightly more than half of the respondents use 3 /5 mg/kg doses for gentamicin and tobramycin. The method used to monitor serum aminoglycoside concentrations also varied, however, more than half of the respondents have moved toward a single level drawn at 6 /18 h. Recently opinion leaders in the field of Infectious Diseases outside the United States were polled to gauge the acceptance of EIAD in their regions. Results from seven hospitals in five regions (UK, The Netherlands, China, Australia, Canada) were obtained. The number of hospitals responding to this informal poll are too few to make any firm conclusions regarding EIAD in each region, however, the results seem to support its use. EIAD was reported to be used for more than 80% of the time in three hospitals, two in the Netherlands and one in Australia. The two hospitals in the UK estimated EIAD use at 40/60% in one hospital and 60 /80% in another. The hospitals in China and Canada reported less than 20% usage of EIAD. Half of the respondents reported using doses of 3/5 mg/kg and half reported using /5 mg/kg doses for gentamicin, tobramycin or netilmicin. In general doses were doubled for amikacin. In one hospital using 3/5 mg/kg dosing, higher doses are considered when P. aeruginosa is the suspected pathogen. There was variability among institutions regarding exclusion criteria, however, enterococcal endocarditis was the most common patient group considered to be ineligible for EIAD, followed by patients with altered pharmacokinetics such as burns and renal failure. The methods of therapeutic drug monitoring also varied. These surveys and others, can be a useful way to characterize, but not define, the standard of practice in a certain area. In many instances practice standards may change rapidly with advances in technology and drug development. With respect to aminoglycoside dosing, it appears that the majority of clinicians have adopted EIAD into their practice within a relatively short time period since their introduction into mainstream practice. These surveys also highlight the fact that responsible application of EIAD requires further study in certain areas of practice. Certain patient groups continue to be
re-evaluated for their eligibility to receive EIAD, such as endocarditis patients [63]. It is important to note that while the best monitoring technique has not been agreed upon, the need for appropriate monitoring is required with any aminoglycoside dosing regimen. Extendedinterval dosing regimens can reduce toxicity risk but do not eliminate it completely, especially with a prolonged duration of therapy.
References [1] Mingeot-Leclerq M, Tulkens PM. Aminoglycosides: nephrotoxicity. Antimicrob Agents Chemother 1999;43:1003 /12. [2] Begg EJ, Barclay ML. Aminoglycosides: 50 years on. Br J Clin Pharmacol 1995;39:597 /603. [3] Anderson ET, Young LS, Hewitt WL. Simultaneous antibiotic levels in ‘breakthrough’ gram-negative rod bacteremia. Am J Med 1976;61:493 /7. [4] Bodey GP, Chang HY, Rodriguez V, Stewart D. Feasibility of administering aminoglycoside antibiotics by continuous intravenous infusion. Antimicrob Agents Chemother 1975;8:328 /33. [5] Valdivieso M, Feld R, Rodrigues V, Bodey GP. Amikacin therapy of infections in neutropenic patients. Am J Med Sci 1975;270:453 /63. [6] DeRosa F, Buoncristiani U, Capitanucci P, Frongillo RF. Tobramycin: toxicological and pharmacological studies in animals and pharmacokinetic research in patients with varying degrees of renal impairment. J Int Med Res 1974;2:100 /14. [7] Feld R, Valdivieso M, Bodey GP, Rodriguez V. A comparative trial of sisomicin therapy by intermittent versus continuous infusion. Am J Med Sci 1977;274:178 /88. [8] Feld R, Rachlis A, Tuffnell PG, et al. Empiric therapy for infections in patients with granulocytopenia. Continuous versus interrupted infusion of tobramycin plus cefamandole. Arch Int Med 1984;144:1005 /10. [9] Hatala M, Moravek J, Prat V, Schuch O, Liska M, Spousta J. Daily single-dose gentamicin therapy in experimental pyelonephritis. Infection 1977;4:232 /5. [10] Reiner NE, Bloxham DD, Thompson WL. Nephrotoxicity of gentamicin and tobramycin given once daily or continuously in dogs. J Antimicrob Chemother 1978;4(Suppl A):85 /101. [11] Giuliano RA, Verpooten GA, Verbist L, Wedeen R, De Broe ME. In vivo uptake kinetics of aminoglycosides in the kidney cortex of rats. J Pharmacol Exp Ther 1986;236:470 /5. [12] Frame PT, Phair JP, Watanakunaorn C, Bannister TWP. Pharmacologic factors associated with gentamicin nephrotoxicity in rabbits. J Infect Dis 1977;135:952 /6. [13] Bennett WM, Plamp CE, Gilbert DN, Parker RA, Porter GA. The influence of dosage regimen on experimental gentamicin nephrotoxicity: dissociation of peak serum levels from renal failure. J Infect Dis 1979;140:576 /80. [14] Verpooten GA, Giuliano RA, Verbist L, Eestermans G, De Broe ME. Once-daily dosing decreases renal accumulation of gentamicin and netilmicin. Clin Pharmacol Ther 1989;45:22 /7. [15] De Broe ME, Verbist L, Verpooten GA. Influence of dosage schedule on renal cortical accumulation of amikacin and tobramycin in man. J Antimicrob Chemother 1991;27(Suppl C):41 /7. [16] Gilbert DN. Once-daily aminoglycoside therapy. Antimicrob Agents Chemother 1991;35:399 /405. [17] LeBrun M, Grenier L, Gourde P, et al. Effectiveness and toxicity of gentamicin in an experimental model of pyelonephritis: effect of the time of administration. Antimicrob Agents Chemother 1999;43:1020 /6.
D. Maglio et al. / International Journal of Antimicrobial Agents 19 (2002) 341 /348 [18] Prins JM, Weverling GJ, van Ketel RJ, et al. Circadian variations in serum levels and the renal toxicity of aminoglycosides in patients, Clin Pharmacol Ther 1997;62:106 /11. [19] Brummett RE. Ototoxicity of aminoglycoside antibiotics in animal models. INSERM 1982;102:359 /76. [20] Tran Ba Huy P, Bernards P, Schacht J. Kinetics of gentamicin uptake and release in the rat. J Clin Invest 1986;77:1492 /500. [21] Tran Ba Huy P, Deffrennes D. Aminoglycoside ototoxicity: influence of dosage regimen on drug uptake and correlation between membrane binding and some clinical features. Acta Otolaryngol 1988;105:511 /5. [22] Noone P, Pattison JR. The effective use of gentamicin in lifethreatening sepsis. Postgraduate Med 1974;50(Suppl 4):9 /16. [23] Moore RD, Smith CR, Lietman PS. Association of aminoglycoside plasma levels with therapeutic outcome in gram-negative pneumonia. Am J Med 1984;77:657 /62. [24] Moore RD, Smith CR, Lietman PS. The association of aminoglycoside plasma levels with mortality in patients with gramnegative bacteremia. J Infect Dis 1984;149:443 /8. [25] Moore RD, Lietman PS, Smith CR. Clinical response to aminoglycoside therapy: importance of the ratio of peak concentration to minimal inhibitory concentration. J Infect Dis 1987;155:93 /9. [26] Lacy MK, Nicolau DP, Nightingale CH, Quintiliani R. The pharmacodynamics of aminoglycosides. Clin Infect Dis 1998;27:23 /7. [27] Craig WA, Leggett J, Totsuka K, Vogelman B. Key pharmacokinetic parameters of antibiotic efficacy in experimental animal infections. J Drug Dev 1988;1(Suppl 3):7 /15. [28] Ebert SC, Craig WA. Pharmacodynamic properties of antibiotics: application to drug monitoring and dosage regimen design. Infect Control Hosp Epidemiol 1990;11:319 /26. [29] Bundtzen RW, Gerber AU, Cohn DL, Craig WA. Postantibiotic suppression of bacterial growth. Rev Infect Dis 1981;3:28 /37. [30] Vogelman B, Craig WA. Kinetics of antimicrobial activity. J Pediatr 1986;108:835 /40. [31] Zhanel GG, Hoban DJ, Harding GKM. The postantibiotic effect: a review of in vitro and in vivo data. Ann Pharmacother 1991;25:153 /63. [32] Craig WA, Vogelman B. The postantibiotic effect. Ann Intern Med 1987;106:900 /2. [33] Fantin B, Ebert S, Leggett J. Factors affecting duration of in-vivo postantibiotic effect for aminoglycosides against gram-negative bacilli. J Antimicrob Chemother 1991;27:829 /36. [34] Begg EJ, Peddie BA, Chambers ST, Boswell DR. Comparison of gentamicin dosing regimens using an in vitro model. J Antimicrob Chemother 1992;29:427 /33. [35] Vogelman B, Gdmundsson S, Turnidge J, Leggett J, Craig WA. In vivo postantibiotic effect in a thigh infection in neutropenic mice. J Infect Dis 1988;157:287 /98. [36] Barclay ML, Begg EJ, Hickling KG. What is the evidence for once-daily aminoglycoside therapy. Clin Pharmacokinet 1994;27:32 /48. [37] Preston SL, Briceland LL. Single daily dosing of aminoglycosides. Pharmacotherapy 1995;15:297 /316. [38] Daikos GL, Jackson GG, Lolans VT, Livermore DM. Adaptive resistance to aminoglycoside antibiotics from first-exposure down-regulation. J Infect Dis 1990;162:414 /20. [39] Daikos GL, Lolans VT, Jackson GG. First-exposure adaptive resistance to aminoglycoside antibiotics in vivo wit meaning for optimal clinical use. Antimicrob Agents Chemother 1991;35:117 / 23. [40] Gerber AU, Vastola AP, Brandel J, Craig WA. Selection of aminoglycoside-resistant variants of Pseudomonas aeruginosa in an in vivo model. J Infect Dis 1982;146:691 /7. [41] McGrath BJ, Lamp KC, Rybak MJ. Pharmacodynamic effects of extended dosing intervals o imipenem alone and in combination
[42] [43]
[44]
[45]
[46]
[47]
[48]
[49]
[50]
[51]
[52]
[53]
[54]
[55]
[56]
[57]
[58]
[59]
347
with amikacin against Pseudomonas aeruginosa in an in vitro model. Antimicrob Agents Chemother 1993;37:1931 /7. Costerton JW, Stewart PS. Battling biofilms. Scientific American; July 2001:75 /81. Bertino JS, Rotschafer JC. Editorial response: single daily dosing of aminoglycosides-a concept whose time has not yet come. Clin Infect Dis 1997;24:820 /3. Nicolau DP, Freeman CD, Belliveau PP, Nightingale CH, Ross JW, Quintiliani R. Experience with a once-daily aminoglycoside program administered to 2184 adult patients. Antimicrob Agents Chemother 1995;39:650 /5. Gilbert DN, Lee BL, Dworkin RJ, et al. A randomized comparison of the safety and efficacy of once-daily gentamicin or thrice-daily gentamicin in combination with ticarcillin-clavulanate. Am J Med 1998;105:182 /91. Rozdzinski E, Kern WV, Reichle A, et al. Once-daily versus thrice-daily dosing of netilmicin in combination with beta-lactam antibiotics as empirical therapy for febrile neutropenic patients. J Antimicrob Chemother 1993;31:585 /98. International Antimicrobial Therapy Co-operative Group of the European Organization for Research and Treatment of Cancer. Efficacy and toxicity of single daily doses of amikacin and ceftriaxone versus multiple daily doses of amikacin and ceftazidime for infection in patients with cancer and granulocytopenia. Ann Intern Med 1993;119:584 /93. MacGowan AP, Bedford KA, Blundell E, et al. The pharmacokinetics of once-daily gentamicin in neutropenic adults with haematologic malignancy. J Antimicrob Chemother 1994;34:809 /12. De Hoog M, Schoemaker RC, Mouton JW, van den Anker JN. Tobramycin population pharmacokinetics in neonates. Clin Pharmacol Therap 1997;62:392 /9. Stickland MD, Kirkpatrick CM, Begg EJ, Duffull SB, Oddie SJ, Darlow BA. An extended interval dosing method for gentamicin in neonates. J Antimicrob Chemother 2001;48:887 /93. Prins JM, Koopmans RP, Buller HR, Kuijper EJ, Speelman P. Easier monitoring of aminoglycoside therapy with oncedaily dosing schedules. Eur J Clin Microbiol Infect Dis 1995;14:531 /5. Begg EJ, Barclay ML, Duffull S. A suggested approach to once-daily aminoglycoside dosing. Br J Clin Pharmacol 1995;39:605 /9. Garrelts JC. Exploration of once-daily dosing of aminoglycosides through bayesian simulation. Pharmacotherapy 1996;16:286 /94. Van Lent-Evers NAEM, Mathor RAA, Geus WP, et al. Impact of a goal-oriented and model based clinical pharmacokinetic dosing of aminoglycosides on clinical outcome: a cost-effectiveness analysis. Therap Drug Monit 1999;21:63 /73. Galloe AM, Graudal N, Christensen HR, Kampmann JP. Aminoglycosides: single or multiple daily dosing? A metaanalysis on efficacy and safety. Eur J Clin Pharmacol 1995;48:39 /43. Ferriols-Lisart R, Alos-alminana M. Effectiveness and safety of once-daily aminoglycosides: a meta-analysis. Am J Health-Syst Pharm 1996;53:1141 /50. Munckhof WJ, Grayson ML, Turnidge JD. A meta-analysis of studies on the safety and efficacy of aminoglycosides given either once daily or as divided doses, J Antimicrob Chemother 1996;37:645 /63. Barza M, Ioannidis JP, Cappelleri JC, Lau J. Single or multiple daily doses of aminoglycosides: a meta-analysis. Br Med J 1996;312:338 /45. Bailey TC, Little JR, Littenberg B, Reichley RM, Dunagan WC. A meta-analysis of extended-interval dosing versus multiple daily dosing of aminoglycosides. Clin Infect Dis 1997;24:786 /95.
348
D. Maglio et al. / International Journal of Antimicrobial Agents 19 (2002) 341 /348
[60] Rybak MJ, Abate BJ, Kang SL, et al. Prospective evaluation of the effect of an aminoglycoside dosing regimen on rates of observed nephrotoxicity and ototoxicity. Antimicrob Agents Chemother 1999;43:1549 /55. [61] Schumock GT, Raber SR, Crawford S, Naderer OJ, Rodvold KA. National survey of once-daily aminoglycoside antibiotics. Pharmacotherapy 1995;15:201 /9.
[62] Chuck SK, Raber SR, Rodvold KA, Areff D. National survey of extended-interval aminoglycoside dosing. Clin Infect Dis 2000;30:433 /9. [63] Tam VH, McKinnon PS, Levine DP, Brandel SM, Rybak MJ. Once-daily aminoglycoside in the treatment of Enterococcus feacalis endocarditis: case report and review. Pharmacotherapy 2000;20:1116 /9.