AMINOGLYCOSIDES John E
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CHAPTER 8 AMINOGLYCOSIDES John E. Murphy and Kathryn R. Matthias Aminoglycoside antibiotics have been available for the treatment of infections for over 65 years. They are active against a variety of aerobic Gram-negative and some aerobic Gram-positive bacteria. Agents currently available or that have been studied include amikacin, arbekacin, dibekacin, gentamicin, isepamicin, kanamycin, neomycin, netilmicin, paromomycin, sisomicin, spectinomycin, streptomycin, tobramycin, and trospectomycin. Pharmacokinetic monitoring is generally focused on amikacin, gentamicin, and tobramycin and will be emphasized in this chapter. Use of these agents has diminished with the advent of newer antibiotics that cover similar organisms, do not require therapeutic drug monitoring, and are generally safer. However, use of aminoglycosides continues for a variety of infections and appropriate use is necessary. USUAL DOSAGE RANGE IN ABSENCE OF CLEARANCE- ALTERING FACTORS After adjustment to achieve desired concentrations, aminoglycoside dosing regimens vary widely because of interpatient (and to some extent intrapatient) variation in pharmacokinetics. Average adult gentamicin and tobramycin doses of 80 mg every 8 hr (smaller dose-short interval [SDSI] dosing) produce low peak concentrations in many patients.1-3 Dosing schedules where the entire dose is given at one time or a larger dose is given every 24 or 48 hr (or even at longer intervals) are used frequently now, but these regimens are not included in current prescribing information in package inserts. These large dose-extended interval (LDEI) dosing approaches are generally considered at least equally effective and may be less toxic when used appropriately, as compared to SDSI where smaller doses are given every 8 or 12 hr. LDEI approaches are generally the standard for most patients now, although certain patient types should still not be dosed in this manner. Continuing development of consensus on who should not be candidates for LDEI is warranted.4,5 Because the kidneys eliminate aminoglycosides, decreased renal function affects the dosage interval used, but has less effect on the size of individual doses since high peak and low trough concentrations are generally desired. However, in patients with renal dysfunction the benefit of high peak concentrations depends somewhat on infection type and organism minimum inhibitory concentration (MIC) to the aminoglycoside. The associated risk of toxicity based on individual doses and corresponding 24-hour area under the curve (AUC24) should be evaluated in this context. Both the dose and dosing interval may need to be adjusted in certain patients with renal dysfunction. Loading dose Loading doses (Table 8-1) are used in SDSI approaches for gentamicin and tobramycin. Amikacin doses are approximately 2–4 times these amounts. In neonates, a first dose of 2.5 mg/kg generally produces a peak of less than 6 mg/L.8,10 The therapeutic implications of a low first-dose peak in this population, particularly early in life for presumed infections, are not clearly established.11-14 In adults, treatment failures may occur secondary to a low first-dose peak concentration. There is minimal accumulation with traditional SDSI aminoglycoside regimens from the first dose to steady state concentration achievement due to the use of dosing intervals of three or more times 123 124 CLINICAL PHARMACOKINETICS TABLE 8-1. LOADING DOSES FOR STANDARD DOSE-STANDARD INTERVAL APPROACHES6-9 Age SDSI Loading Dose (mg/kg)a Neonates 2.5–4 Infants 2.5–3 Children 2–2.5 Adolescents, adults, geriatrics 1.5–2 SDSI = standard dose, standard interval. aSee Dosing Strategies to determine dosing weight. the half-life. Thus, the usual reason for loading doses, rapid achievement of concentrations closer to goal steady state concentrations in situations where accumulation is extensive, does not hold. Rather, some individuals have recommended loading doses to ensure achievement of a higher first-dose peak concentration. This may enhance the potential for therapeutic success due to the concentration- dependent killing of organisms by aminoglycosides, although some suggest that there is little evidence of a relationship of peak concentration to therapeutic outcome.3 Loading doses are not administered in the LDEI approach because it is generally expected that the concentration reaches zero or very near zero before the next dose is given. Little or no accumulation therefore occurs and high peak concentrations are achieved, negating the need for a loading dose with LDEI approaches. Maintenance dose LDEI and traditional SDSI maintenance doses for gentamicin and tobramycin are shown in Table 8-2. Amikacin doses are approximately 2–4 times these amounts. Arbekacin doses are similar to gentamicin and tobramycin.10 For LDEI, amikacin doses have tended to be 15 mg/kg for adults and 20 mg/kg in neonates. Uncomplicated urinary tract infections and infections with organisms with low aminoglycoside MIC may respond to lower doses in all patients. Reduced renal function necessitates increases in length of the dosing interval, in some cases beyond usual recommendations. Some clinicians may use the higher end of the dosing range for more severe infections and vice versa. However, others use target concentrations or the usual averages. The Dosing Strategies section later in the chapter provides more in-depth dosing guidelines. DOSAGE FORM AVAILABILITY9 Although these drugs are distributed as the sulfate salts, the manufacturers express the doses in terms of drug equivalence; thus, S = 1 for calculations. Pharmacokinetic monitoring of aminoglycosides is generally reserved for intramuscular (IM) and intravenous (IV) dosage forms. Irrigations or implanted bone cement with aminoglycosides have resulted in nephrotoxicity and ototoxicity; however, size of dose used, site, contact time, and degree of denuding present are all factors that affect the amount systemically absorbed. One study found very high wound concentrations (median 304 mg/L), but peak serum concentrations tended to be quite low in comparison (median 2.1 mg/L).29 Caution should be exercised when using high doses in localized sites for long periods and serum concentration measurement may be warranted. When used as an intratympanic injection in the treatment of Meniere disease, ototoxicity may occur, although serum concentrations are negligible and the incidence is similar to standard medical measures.30,31 Toxicity has been reported, but topical dosage forms (creams, ointments, and solutions) of gentamicin and tobramycin do not appear to require pharmacokinetic monitoring. Inhalation dosing of aminoglycosides, particularly tobramycin, is used in patients with cystic fibrosis. There have also been studies on inhalation dosing of tobramycin for treatment of Pseudomonas .