Once-daily aminoglycoside dosing: A new look at an old drug

A MINOGLYCOSIDES CONSTITUTE ONE OF TilE OLDEST AND most versatile classes of anlimJcrobJal agents m clinical use. Despite the addition of many new antimicrobials to our therapeutic armamentarium they remain a cornerstone of therapy in the treatment of serious bacterial infections (1.2). Their major use has been for the treatment of suspected or proven Gramnegative bacillary infections and as empirical therapy of the febrile neutropenic patient. Juxtaposed with the acknowledged therapeutic efficacy of aminoglycosidcs has been the concern for aminoglycoside-induced renal and ototoxicity. These !alter adverse effects have lead to dosing strategies that have sought to maintain serum aminoglycoside concentrations within a limited range of values. Over the years a great deal of investigative effort has been expended to facilitate our undei-standing of the pharmacokinetics and pharmacodynamics of aminoglycosides in order to ensure the achievement of therapeutic concentrations and to optimize their potent antibacterial activity while simultaneously lessening their toxicity (3-5). When selecting an aminoglycoside dosing regimen. attention must be paid to pharmacokinetic properties of the agent. microbiological function of the organism or likely organism(s) causing infection. site of infections, ease of administration. toxicity . clinical efficacy and cost containment. Perusal of the literature on aminoglycoside dosing regimens accumulated over the past two decades reveals that the once-daily dosing of aminoglycosides may be associated with less toxicity while maintaining excellent therapeutic efficacy (6-9). This dosing approach is neither novel nor unique. but recent advances in pharmacokinetics and microbiology coupled with recent clinical trials on this issue and the necessity for improving quality care while reducing costs has created the opportunity for a paradigm shift in the manner in which aminoglycosides are dosed. Once-daily dosing of aminoglycosides meets or exceeds all of the desirable attributes mentioned above with respect to the selection of a dosing regimen. With regard to the pharnmcokinetic aspects of aminoglycosides. a narrow therapeutic index has been accepted as a hallmark for many years . Dosing strategies have sought to maintain serum aminoglycoside concentrations wiU1in a narrowly defined range of values in an allempt to


Once-daily aminoglycoside dosing: A new look at an old drug
A MINOGLYCOSIDES CONSTITUTE ONE OF TilE OLDEST AND most versatile classes of anlimJcrobJal agents m clinical use.Despite the addition of many new antimicrobials to our therapeutic armamentarium they remain a cornerstone of therapy in the treatment of serious bacterial infections (1.2).Their major use has been for the treatment of suspected or proven Gramnegative bacillary infections and as empirical therapy of the febrile neutropenic patient.Juxtaposed with the acknowledged therapeutic efficacy of aminoglycosidcs has been the concern for aminoglycoside-induced renal and ototoxicity.These !alter adverse effects have lead to dosing strategies that have sought to maintain serum aminoglycoside concentrations within a limited range of values.Over the years a great deal of investigative effort has been expended to facilitate our undei-standing of the pharmacokinetics and pharmacodynamics of aminoglycosides in order to ensure the achievement of therapeutic concentrations and to optimize their potent antibacterial activity while simultaneously lessening their toxicity (3)(4)(5).When selecting an aminoglycoside dosing regimen.attention must be paid to pharmacokinetic properties of the agent.microbiological function of the organism or likely organism(s) causing infection.site of infections, ease of administration.toxicity.clinical efficacy and cost containment.
Perusal of the literature on aminoglycoside dosing regimens accumulated over the past two decades reveals that the once-daily dosing of aminoglycosid es may be associated with less toxicity while maintaining excellent therapeutic efficacy (6)(7)(8)(9).This dosing approach is neither novel nor unique.but recent advances in pharmacokinetics and microbiology coupled with recent clinical trials on this issue and the necessity for improving quality care while reducing costs has created the opportunity for a paradigm shift in the manner in which aminoglycosides are dosed.
Once-daily dosing of aminoglycosides meets or exceeds all of the desirable attributes mentioned above with respect to the selection of a dosing regimen.With regard to the pharnmcokinetic aspects of aminoglycosides.a narrow therapeutic index has been accepted as a hallmark for many years.Dosing strategies have sought to maintain serum aminoglycoside concentrations wiU1in a narrowly defined range of values in an allempt to optimize efficacy by exceeding the minimum inhibitory concentration (MIC) for the offending pathogen and to minimize toxicity by avoid ing excessive concentrations.Guidelines for dosing adjustments with compromised renal function and the concept of closely monitoring serum aminoglycoside concentra tions have become an accepted and routine practice in many hospital settings.The need to maintain aminoglycoside serum concentrations within such strict limits to maintain therapeutic efficacy and to reduce toxicity may be challenged on several fronts.
The aminoglycosid es demonstrate a properly known as concentration-dependent killing (10.11).Clinical studies have demonstrated that achievement of high peak serum concentrations of the aminoglycoside relative to the MIC of the microorganism being treated may be a major determinant of the clinical response lo the aminoglycosides .This optimization of the peak:MIC ratio can best be obtained by the once-daily administration of aminoglycosides that results in high peak concentrations of the drug (peak target is about 20 mg/L).In addition to concentration-dependent killing.aminoglycosides also demonstrate a property known as the poslantibiotic effect (12), which may be defined as a period of lime after complete remova l of the antibiotic during which there is no grovvth of the target organism.Although once-daily dosing of aminoglycosides may result in a period of up to 12 h during which there are no delectable serum concentrations of the drug, the postantibiotic effect of the aminoglycosides allows for oncedaily dosing wiU1oul compromising therapeutic efficacy.

DRUG TOXICITY
The major determinant of aminoglycoside-induced renal and ototoxicity is the accumulation of these agents within the renal cortex and the perilymph of the inner ear, respectively (3,13).Uptake and accumu lation of aminoglycosides into renal cortical tissue demonstrate saturable kinetics.The saturable feature of these kinetics make p eak aminoglycoside concentrations irrelevant when considering tissue accumulation of the drug.Less frequent dosing of aminoglycosides allows for serum concentrations of the drug to fall well below the threshold for binding to tissue receptors, also allowing for the back-diffusion of the aminoglycos id es from the renal cortex and inner ear, which may theore tically limit drug toxicity.In animal models, rats receiving a single daily dose of aminoglycoside have demonstrated less nephrotoxicity and less renal accumu la tion of the drug than rats receiving the same total daily dose by a multiple daily dosing schedule (3).

COST CONTAINMENT
The once-daily dosing of aminoglycosicles would h ave a direct and immediate impact on both the cost of therape utic drug monitoring and on the nursing and pharmacy time r equired for drug a dminis tration and prepara tion.Once-daily administration of a minoglycos ides would eliminate the n ecessity for routine therapeutic drug monitoring of a minoglycoside levels .

CLINICAL EFFICACY
Twelve published studies h ave compared the oncedaily dosing of aminoglycosides with more conventional multipl e-daily dosing regimens.Included in these studies is the recent publication of a r a ndomized multicentre trial involving 677 patie nts r eceiving aminoglycosides for th e treatment of febril e n e utropeni a (1 4 ) .In all of these studies , once-daily dosing of a minoglycosides was as effective as and no more toxic than multiple-daily dosing of the drug.
A recent survey (15) at The Toronto Hospital indicated th at of 71 serum a minoglycoside pairs only 18 (25.4%)were a ppropriately p erformed with respect to collection time and its documentation.This observation underscores the n eed to scrutinize car efully th e n eed for serum aminoglycoside levels.Taking into consideration conservative figures for the costs of s erum aminoglycoside concentration determinations (personal communication).the numbers of levels done per year, a nd the costs of once-daily admini stration of gentamicin and tobramycin versus the actual costs of conventional (every 6, 8 or 12 h) dosing for one month a nd extr apolating these figures for one year.assuming no changes in risks or benefits .th e cost savings for The Toronto Hospital are just over $100,000.If the cost savings a r e expressed as a ratio a nd a pplied to six m ajor Toronto teaching hospitals, the savings exceed $0 .5 million per annum.
Given the weight of the evidence available, should once-daily a minoglycoside ther apy b e a dopted as a standard of practice?The answer to this question is.unequivocally, yes! Th e simplicity of dosing, m a intenance (and possibly improvement) of clinica l efficacy and potentially r educed toxicity, combined with minima l needs for serum a minoglycoside monitoring and th e reduced costs associated with this prac tice, presents a powerful argument for its adoption into routine m edical care.The Anti-lnfectives Drug Products Advisory Committee of the Food and Drug Administration in the United States has recently conclud ed tha t ther e is sufficient information availa ble to justifY once-a-day dosing of am inoglycosides, and the agency is willing to consider ch a nges in package inserts to refl ect th is .From our perspective we are presented with an opportunity for change with regard to a minoglycosid e closing.and it is a change t11at encompasses a territory well b eyond the confines of the infectious d iseases specia list.However, the implementation of fuis change in m edical practice in Canada r equires a committed leadersh ip effort by the members of the infectious d iseases community a nd others who are familiar with the concepts of aminoglycoside dosing.Lei us s eize the op portun ity and move forward with this quality improvement e ffort.