|Rational||The Post-Antiobiotic Effect|
|Concentraton-dependent Kill Rate||Adaptive Post-Exposure Resistance|
|Advantages of Extended-interval Dosing||Dosing and Monitoring Guidelines|
Since their introduction into clinical use 50 years ago and despite the advent of newer agents
(carbapenems, monobactams, and fluoroquinolones) , aminoglycoside antibiotics (AGAs) continue to play
an important role in the treatment of severe infections, particularly those due to aerobic,
Gram-negative bacilli (GNB). Several factors account for their durability and continued clinical usefulness:
therapeutic efficacy, synergy with the ß-lactam antibiotics, low rate of development of true resistance, and low drug cost. Their main drawback has been the occurrence of (reversible) nephrotoxicity and ototoxicity in a significant number of patients (5 - 25%).
Traditionally, aminoglycosides are administered in multiple daily doses (once every 8 or 12 hrs). However, clinicians worldwide are becoming increasingly aware that the standard "80 mg every 8 hrs" regimen is no longer an acceptable practice. Clinical experience over the past 50 years has shown the multiple daily dosing strategy to be both labor- and lab-intensive. Correct multiple daily dosing of aminoglycosides often requires pharmacokinetics expertise and close monitoring of drug serum levels and renal function. Therapeutic drug monitoring has been used extensively to guide dosage adjustments to maximize efficacy and minimize toxicity. Aminoglycoside-associated therapeutic monitoring usually accounts for most of the cost of aminoglycoside therapy. It is not unusual to see three or more sets of peak/trough levels taken during a single gentamicin therapy course lasting less than ten days. In addition, there are other important problems associated with the standard dosing of aminoglycosides - sub-therapeutic dosing (low peaks) , inconvenience for patients due to frequent administration, inaccurate timing of drug administration and blood sampling, and misinterpretation of drug levels.
The multiple daily dosing regimen is based on the assumption that therapeutic efficacy requires that the serum level of the antimicrobial agent be maintained above the minimum inhibitory concentration (MIC) for the target organism at all times during the course of therapy. The validity of this assumption for aminoglycosides has been strongly challenged during the past decade. During this period a rapid evolution in aminoglycoside dosing strategies has taken place. The primary aim of these changes is not only to minimize toxicity but also reduce treatment failure, morbidity, and mortality.
The high-peak-extended-interval dosing of aminoglycosides has also been called "once-daily" or "single-daily" and "pulse" dosing. It was first used by Labovitz (1) in 1974 and then rediscovered by several groups during the 1980s. Due to its ease and comparable safety and efficacy it quickly gained popularity worldwide. A survey conducted in 1994 by Schumock and co-workers (2) estimated that in the USA over 27% of hospitals of 400 beds or larger used the once-daily dosing routinely. Currently many centers are adopting the "once-daily aminoglycosides" (or ODA ) as their standard / preferred dosing method for aminoglycosides. By the year 2000, this figure may be as high as 80%.
As of Apr '97, over 50 human clinical trials dealing with the "once-daily dosing of aminoglycosides" have been published. Over 20 of these represent randomized studies involving collectively > 3000 patients. The vast majority of these trials failed individually to find a significant difference between the single and multiple dosing regimens largely because of the limited number of patients involved in a single trial. Therefore, to the enhance statistical power, data from individual trials were pooled for meta-analysis by at least four independent groups. In a statistical study published in 1995, Galloe and co-workers (3) analyzed the results of trials involving a total of about 1200 patients. They concluded that there is no significant difference in either efficacy or safety between the single-dose and the multiple-dose regimes. However the results of the three meta-analyses published in 1996 (4, 5, 6) which included data from a much larger pool of patients clearly favor the high-peak-extended-interval dosing strategy. Ferriols-Lisart and Alos-Alminana (4) analyzed the results of 18 randomized, clinical trials involving a total of 2317 patients. They concluded that pulse dosing is therapeutically more effective (odds ratio = 1.47) and less nephrotoxic (odds ratio = 0.60). Similarly, Barza and coworkers (5) concluded that, compared to multiple dosing, the single daily administration of aminoglycosides to patients without pre-existing renal impairment is at least as effective, has a significantly lower risk of nephrotoxicity, and no greater risk of ototoxicity. It was also observed that the efficacy of pulse dosing was superior in those clinical trials with a higher percentage of Pseudomonas isolates. Hatal and co-workers (6) evaluated 17 randomized trials comparing once-daily versus the standard dosing in 3,089 infected, immuno-competent adults. Even taking into consideration the heterogeneity of the pooled studies, the meta-analysis still indicated that the two regimens are equal in therapeutic efficacy, but that the pulse dosing was superior in terms of safety. The relative risks of nephrotoxicity and ototoxicity were found to be respectively 13% and 33% lower with pulse dosing. These conclusions are further supported by several individual clinical trials, whose results strongly suggest that the single daily dosing regimen significantly reduces the risk for nephrotoxicity (7-9) and ototoxicity (10, 11).
During the last five years, over a hundred articles have been published on the topic of aminoglycoside dosing
including reports of original clinical trials, in vitro studies, animal studies, accounts of clinical experience (16),
meta-analyses (3 - 6), book chapters (17), surveys (2), newsletters, and review articles (18 - 20).
There appears to be a general consensus that pulse dosing of aminoglycosides offers the following advantages:
The initial dosing interval is determined by the creatinine clearance (CLcr):
The main objectives of the pulse dosing strategy are to:
Some clinicians express the concern that in patients with low creatinine clearance (CLcr < 40 mL/min) the aminoglycoside level may remain significantly elevated (> 2 mg/L) for long periods of time which would further damage the kidneys. Thus, if a dosing interval longer than 48 hours would be necessary to achieve the 2nd objective (above), then an alternative antimicrobial agent should be considered. Also, in patients with high clearance (e.g., young adults, cystic fibrosis, burns, etc) dosing intervals shorter than 24 hrs may be more appropriate.