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).
The rational for the pulse dosing of aminoglycosides is rooted in the following observations:
- Aminoglycosides exhibit a significant post-antibiotic effect
(PAE) against aerobic GNB both in vitro and in vivo (12) The PAE
refers to the continued suppression of bacterial growth despite
the decline of the antimicrobial concentration to zero. The duration
of this effect (2 - 8 hrs) depends on several factors, chief among
them is the height of the preceding aminoglycoside peak. The PAE
phenomenon suggests that the aminoglycoside serum level may be
allowed to fall below the MIC of the pathogen without comprising
antimicrobial efficacy. The PAE lasts longer in vivo than in vitro,
and its duration in vivo may be dependent on host factors. Animal
studies suggest that the PAE duration may be shortened by neutropenia.
In addition, in vitro studies suggest that the aminoglycoside
PAE is extended by the addition of a ß-lactam antibiotic.
- The bactericidal action of aminoglycosides is concentration
dependent, i.e., the higher the peak/MIC ratio the higher
the kill rate (13). The multiple daily dosing regimen usually results in relatively low
peak/MIC ratios (<5 ), but when the same total daily dose is
given as a single bolus (infused over 30-60 minutes), much higher
ratios are obtained (>10). Adult and pediatric patients receiving
single-daily doses of amikacin showed significantly higher cure
rates than those receiving multiple daily doses (14).
- Aminoglycoside uptake into renal tubule cells and the inner
ear appears to be saturated at relatively low serum levels,
suggesting that higher peaks do not necessarily result in a greater
risk of toxicity. Also, serum troughs that are at or near zero
may promote tissue drug disposition, shorten tissue exposure,
and promote recovery. In addition to the well known risk factors
(age, volume depletion, liver disease, co-administration of certain
drugs, etc.), duration of exposure to the aminoglycoside appears
to be a more important determinant of toxicity than the serum
aminoglycoside level. Although definitive evidence is still lacking,
animal and human studies strongly suggest that pulse dosing is
less nephrotoxic. Further, when the data of 17 clinical studies
are considered together, the conclusion that the pulse dosing
of aminoglycosides is safer is inevitable (6).
- In vitro studies indicate that more frequent dosing of aminoglycosides
tends to reduce their uptake into the bacterial cell of aerobic
GNB. This phenomenon ("adaptive post-exposure resistance")
is observed as an apparent increase in the MIC90 (i.e.,
reduced efficacy). Longer dosing intervals appear to shorten the
time required for the MIC to revert to its original value (15).
These observations may have significant clinical implications
- persistent low level exposure of the target organism as occurs
with multiple daily dosing may markedly reduce the antimiccrobial
activity of aminoglycosides
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:
- Relatively easy, straightforward initial dosing.
- Enhanced efficacy due to higher peak levels (stamps subtherapeutic dosing).
- Enhanced safety due to shorter effective exposure time.
- Convenience for both patients and nurses.
- Likely on-time administration.
- A much reduced need for serum aminoglycoside levels (reduced cost).
- Facilitation of drug administration through home care services (reduce cost).
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