SINGLE DAILY DOSING OF AMINOGLYCOSIDES
The aminoglycosides are a group of structurally related antibiotics that kill bacteria by inhibiting protein synthesis. They share similar pharmacokinetic profiles, and their structure does not allow easy penetration into cells. Aminoglycosides are excreted primarily by the kidney, and they are active mainly against gram-negative bacteria. These compounds have been available for approximately 50 years. During that time, they have waxed and waned in favor based on the availability of other, similar products, presumed toxicity, and questions of efficacy in some clinical instances. By the early 1990s, some clinicians questioned whether these products would survive, as numerous other agents with similar spectra of activity and enhanced safety records emerged. However, during the past several years in the United States, gentamicin, tobramycin, and amikacin have acquired renewed importance, in part because of new information about dosing that renders them safer and probably more effective than previously. Potential parenteral uses of these aminoglycosides include (a) empiric therapy of presumed gram-negative infections, (b) therapy of proven gram-negative infections caused by organisms not treatable by alternative agents, (c) therapy against selected gram-positive pathogens in combination with penicillins or vancomycin for synergy, (d) empiric therapy of the febrile granulocytopenic patient, and (e) management of selected mycobacterial infections.
Parenterally administered aminoglycosides historically have been considered difficult to use in seriously ill patients because of their narrow toxic-therapeutic ratio. This was based on the premise that toxicity was in part related to peak concentrations of the product. For gentamicin and tobramycin, toxic levels have historically been considered to be greater than 12 µg/mL (peak) or greater than 2 µg/mL (trough). Clinical variables such as weight, renal function, hemoglobin, temperature, obesity, and “metabolic state” influence aminoglycoside levels. Nomograms attempting to predict dosing generally were unsuccessful, and several studies exist that demonstrate the problem of obtaining therapeutic levels early in the course of severe illness. Lack of such levels was associated with adverse outcomes, especially in critically ill patients.
The toxic effects of aminoglycosides include ototoxicity, nephrotoxicity, and neuromuscular blockade. Classic investigations of the ototoxicity and nephrotoxicity of these products concluded that ototoxicity (either auditory or vestibular) occurs in up to 5% of patients, is difficult to monitor, and is often irreversible. The mechanism of toxicity appears to be related to uptake and accumulation by cochlear or vestibular cells. The time of contact between affected cells and antibiotic seems to be important. Nephrotoxicity (generally defined by relatively minor changes in serum creatinine values) has been seen in up to 25% of patients, appears more commonly with gentamicin than with tobramycin, and is generally minor clinically and often reversible. However, some investigations have indicated a prolonged hospitalization, and occasional patients have required dialysis. The mechanism of toxicity is related to the reabsorption of the drug in the lumen of the renal tubule. Animal data suggest that this process can become saturated and thus does not continue beyond a specific level. Neuromuscular blockade is rarely noted and is associated with rapid administration of the drug. Thus, difficulties with both therapeutic efficacy and toxicity are major reasons why aminoglycosides appear to have been used sparingly in recent years.
The rationale for once-daily dosing of aminoglycosides is based on the fact that bacterial killing with these agents is related to drug concentration; progressively increased bactericidal activity is demonstrated by concentrations up to 10 to 12 times the minimum inhibitory concentration (MIC) for an organism. Because Pseudomonas aeruginosa is the most resistant organism likely to be treated, and because the MIC of gentamicin for this organism is 2 µg/mL, peak levels of gentamicin above 20 µm/mL should be sought. Aminoglycosides also have a prolonged post-antibiotic effect, which indicates that killing continues after serum levels have fallen below the MIC for an organism. This is in contrast to what is noted with b-lactam antibiotics; with these agents, killing is time-dependent, and post-antibiotic effects are less pronounced. These aminoglycoside “virtues” make it likely that dosing regimens that produced higher peak levels more rapidly would be more clinically effective so long as toxicity was not augmented. More rapid killing could also decrease the emergence of resistance. Furthermore, single-dose aminoglycosides are less likely to result in toxicity because when they are given in a large single dose, contact with the agent is limited.
A number of studies have been conducted, primarily in immunocompetent patients, to compare the safety and efficacy of daily dosing with traditional dosing of aminoglycosides. In an investigation of approximately 2,200 patients, nephrotoxicity developed in fewer than 2% of patients, and ototoxicity was observed in about 0.1%. In two thirds of patients with vestibular dysfunction, the dysfunction resolved. Two metaanalyses have been completed. Data indicate that single daily dosing in patients with normal renal function is associated with decreased nephrotoxicity and equal ototoxicity in comparison with traditional dosing regimens. In one metaanalysis, nephrotoxicity (defined as an increase in serum creatinine of 50%) was reduced from 7.5% to 5.5% (p = .05). Another metaanalysis demonstrated no significant differences in therapeutic outcome or toxicity, but indicated that ease of administration, reductions in nursing and other professional time, and apparent equivalency of outcomes implied that single daily dosing is advantageous. No studies have concluded that once-daily dosing of aminoglycosides results in unfavorable outcomes.
Most investigations of once-daily aminoglycosides have been conducted in patients with normal renal function and illnesses that are not life-threatening. Use in febrile neutropenic patients and in those with critical illness needs to be studied further. However, it is the opinion of the author that the principles on which once-daily dosing is predicated should allow it to be used in these circumstances as well.
Aminoglycosides are also employed for their synergistic activity in selected streptococcal infections. Once-daily regimens are adequate for the management of viridans streptococcal endocarditis, but they should not be used for enterococcal endocarditis. Other clinical situations in which once-daily dosing is currently not indicated include severe burns, pregnancy, and dialysis. Table 75-1 summarizes the clinical conditions in which once-daily dosing is not appropriate.
Table 75-1. Situations in which once-daily aminoglycosides are not indicated
When once-daily aminoglycoside dosing is utilized, the initial dose should be at least the total daily dose. Data generated at Hartford Hospital suggest that a 7-mg dose of gentamicin or tobramycin per kilogram be employed. The initial dose of amikacin would be 15 mg/kg. These doses provide optimal peak levels against P. aeruginosa, the target organism in most cases. Dose adjustments might be necessary depending on the MIC90 values for target organisms at other institutions. Such dosing routinely results in peak antibiotic concentrations above 20 µg/mL (gentamicin and tobramycin), which is approximately 10 times the MIC. The need for aminoglycoside monitoring is controversial. No antibiotic levels have to be obtained initially if patients are less than 60 years of age, have normal values of serum creatinine, are neither quadriplegics nor amputees, and are not receiving other potential nephrotoxic agents. Repeated doses are then administered at 24-hour intervals. However, all patients should have serum creatinine values regularly monitored, and patients who receive aminoglycosides for longer than 5 days require determination of a trough aminoglycoside level; this should be done thereafter at weekly intervals. This result should be below 2 µg/mL. For patients at higher risk, trough levels are monitored after the third dose. Once-daily aminoglycoside dosing is also appropriate for patients with renal dysfunction. The dosing interval is based on creatinine clearance (Cockcroft-Gault equation). The dosing interval is 24 hours (creatinine clearance >60 mL/min), 36 hours (clearance 40 to 60 mL/min), or 48 hours (clearance 20 to 40 mL/min).
Economic data demonstrate that once-daily aminoglycoside dosing can conserve hospital resources and save money. One study showed a net saving of $128,000 based on decreased nephrotoxicity and lower administration and preparation costs. (R.B.B.)
Ambrose PG, Owens RC Jr, Quintiliani R. The aminoglycosides: rationale and guidelines for once-daily dosing. Contemp Intern Med 1997;9:9–13.
This article provides an excellent overview of the principles and practices of once-daily aminoglycoside dosing. It stresses the need to individualize dosing by hospital, based on likely target organisms, and provides data for dose modification in patients with renal dysfunction.
Barza M, et al. Single or multiple daily doses of aminoglycosides: a metaanalysis. BMJ 1996;312:338–345.
A second metaanalysis performed by different investigators demonstrates a tendency toward enhanced clinical outcomes with once-daily aminoglycoside dosing, and a clear advantage in regard to prevention of nephrotoxicity.
Edson RS, Terrell CL. The aminoglycosides. Mayo Clin Proc 1991;66:1158–1164.
Excellent and succinct overview of the structure, mode of action, mechanisms of resistance, in vitro activity, and clinical uses of the aminoglycosides.
Hatala R, Dinh T, Cook DJ. Once-daily aminoglycoside dosing in immunocompetent adults: a metaanalysis. Ann Intern Med 1996;124:717–725.
In a metaanalysis of 13 investigations of aminoglycoside dosing that met the criteria of the authors, no differences could be detected in bacteriologic cure as an outcome variable. Once-daily dosing trended toward decreased mortality and lessened toxicity.
Lietman PS, Smith CR. Aminoglycoside nephrotoxicity in humans. Rev Infect Dis 1983;5 (Suppl 2):S284–S293.
Reviews the pathophysiology, incidence, and risk factors of aminoglycoside-induced nephrotoxicity in humans. Studies employed multiple doses daily. Investigators describe comparative differences among the aminoglycosides, based on their previous investigations, and point out that serious nephrotoxicity is uncommon. Issues related to toxicity include dosage, agent, concomitant agents, and personal factors.
McCormack JP, Jewesson PJ. A critical reevaluation of the “therapeutic range” of aminoglycosides. Clin Infect Dis 1992;14:320–329.
A thorough review of the aminoglycoside literature that assesses several issues: (a) relationship between peak serum levels and outcome, (b) relationship between minimum serum level and outcome, (c) whether monitoring of levels improves treatment outcome, (d) relationship between serum levels and toxicity, and (e) relationship between monitoring of serum levels and decreased toxicity. The critical literature review fails to answer most of these questions, but suggestions for aminoglycoside use and monitoring are provided.
Prins JM, et al. Once versus thrice daily gentamicin in patients with serious infections. Lancet 1993;341:335–339.
The authors conducted a randomized trial of once-daily (4 mg/kg per day) versus thrice-daily (1.3 mg/kg every 8 hours) dosing in patients hospitalized with a variety of serious infections. Patients with neutropenia or severe renal dysfunction were excluded. Efficacy was equivalent in the two groups, whereas nephrotoxicity was 5% (once-daily dosing) versus 24% (thrice-daily dosing). No differences were noted in ototoxicity. The authors concluded that once-daily dosing for this population was as effective and less nephrotoxic than the standard treatment regimen.