Download Editorial Response: Single Daily Dosing of Aminoglycosides

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Editorial Response: Single Daily Dosing of Aminoglycosides-A Concept Whose
Time Has Not Yet Come
Joseph S. Bertino, Jr., and John C. Rotschafer
Single daily dosing (SDD) of aminoglycosides (also known
as once-daily aminoglycoside therapy) is a concept that has
been discussed in the literature for over a decade and advocated
with zeal by many proponents. While the concept seems selfdefining, various investigators have suggested dosages of gentamicin or tobramycin that range from 4 mg/kg to 7 mg/kg.
Depending on the investigator and on the patient's underlying
renal function, one dose per day may be administered, or the
dosage interval may be extended beyond 24 hours. Needless
to say, what has been collaboratively referred to as SDD varies
substantially depending on the investigator.
See articles on pages 786-815.
Over the last few years, a plethora of papers addressing the
issue of SDD have been published in an effort to answer the
questions, Is SDD at least as efficacious and no more toxic
than multiple daily dosing (MDD) of aminoglycosides? Unfortunately, no study published to date has had sufficient statistical
power to provide the answers to these questions because they
apply to patients with diverse infectious diseases and various
underlying diseases. The three meta-analyses in this issue of
Clinical Infectious Diseases (CID) attempt to examine the efficacy and toxicity of SDD vs. the efficacy and toxicity of MDD
for various patient populations.
Although meta-analysis is a useful, powerful tool, its application cannot transform poor-quality, underpowered data into
useful information [1, 2]. The studies included in the metaanalyses in this issue of CID were evaluated for heterogeneity
and homogeneity, but they were not evaluated in terms of the
scientific and clinical quality of the data obtained in the original
trials. The quality of a meta-analysis ultimately rests on the
caliber of the trials selected for inclusion [1, 2]. Without question, the currently published literature on SDD of aminoglycosides has a number of underlying weaknesses, and thus the three
meta-analyses published in this issue of CID require prudent
scrutiny. We do not take issue with the techniques used for
Received 23 December 1996; revised 24 January 1997.
Reprints or correspondence: Dr. Joseph S. Bertino, Jr., Clinical Phannacology Research Center, Bassett Healthcare, One Atwell Road, Cooperstown,
New York 13326.
Clinical Infectious Diseases 1997; 24:820-3
© 1997 by The University of Chicago. All rights reserved.
1058-4838/97/2405 -0009$02.00
From the Departments of Pharmacy Services and Medicine, Clinical
Pharmacology Research Center, Bassett Healthcare, Cooperstown,
New York; and the Department of Pharmacy, St. Paul-Ramsey Medical
Center, St. Paul, Minnesota
these meta-analyses but with the concepts of SDD as they have
been applied in various trials. We are particularly concerned
with the issues of efficacy and pharmacodynamics, nephrotoxicity, and cost and convenience.
Efficacy and Pharmacodynamic Principles
The concept of SDD is based on the principles of concentration-dependent killing, postantibiotic effect (PAE), and adaptive resistance of aminoglycosides. The PAE of aminoglycosides against gram-negative organisms has been demonstrated
in vitro and in animal models, and this effect is postulated to
occur in humans, giving support to the concept of SDD [3, 4].
However, we believe that this postulate is problematic. Given
that the PAE varies for different organisms, aminoglycosides,
and dosing intervals in the animal model, the assumption that
the PAE will persist over a 24-hour dosing period in humans
is a matter of concern [4].
Recent data from in vitro studies suggest that the PAE decreases and disappears over a prolonged dosing interval [5].
Weare concerned that since the PAE ofaminoglycosides varies
considerably based on the infecting organism and pharmacokinetics within individual patients, the use of SDD may not be
appropriate in many patient populations or for a wide range
of pathogens or infections. In an animal model, the PAE of
aminoglycosides can be lengthened by the concomitant use of
a .B-lactamantibiotic [4]; however, this finding raises questions
concerning the increased cost of antibiotic therapy and the
usefulness of administering a ,B-Iactam antibiotic alone.
Concentration-dependent killing of gram-negative bacteria
is another important concept that supports SDD therapy. The
results of clinical trials for a variety of infections suggest that
an optimal postdistributional (i.e., serum concentrations obtained in the beta phase) maximum concentration (Cmax)/MIC
ratio is an important factor in attaining cure and in favorably
altering the surrogate markers of infection, fever and WBC
count [6, 7]. Unfortunately, to our knowledge there have not
been any clinical trials on SDD of aminoglycosides that have
examined optimization of the Cmax/MIC ratio and the effect of
this optimization on clinical outcome.
The findings of Moore et al. [6] suggest that a postdistributional Cmax/MIC ratio of > lOis necessary to maximize clinical
outcome. These investigators dosed aminoglycosides three
times a day to optimize peak concentrations, irrespective of
renal function. Data from a study by Kashuba et al. [7] on
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1997; 24 (May)
Editorial Response
nosocomial gram-negative pneumonia also showed that the
postdistributional Cmax/MIC ratio is important in shortening the
time required for resolution of the surrogate markers of infection. These investigators dosed aminoglycosides with use of
individualized pharmacokinetic monitoring on an 8-hour, 12hour, or 24-hour schedule, depending on renal function, to
optimize the postdistributional Cmax/MIC ratio and limit renal
accumulation of the drug in an attempt to reduce the risk of
nephrotoxicity. It is questionable whether these data [6, 7] can
be extrapolated to a dosing regimen with which optimal Cmaxl
MIC ratios are attained only once daily, with potentially prolonged drug-free periods in patients with normal renal function.
The argument that the use of SnD more consistently results
in a "therapeutic" Cmax (and thus an optimal Cmax/MIC ratio)
may be erroneous. In the majority of studies on SDD of aminoglycosides, larger doses of the drugs have been administered,
either as 30-minute or 60-minute infusions; peak concentrations
were obtained 30 minutes after a 30-minute infusion or at the
end of the 60-minute infusion [8-10]. The latter sampling
scheme has been used to devise a nomogram for directing SDD
therapy [8]. Unfortunately, the Cmax concentrations were likely
obtained during the distribution (alpha) phase for many of these
trials and thus actually reflected transiently elevated postinfusion concentrations. If these data were to be extrapolated graphically or mathematically to determine the actual "peak" concentration, erroneous values for the Cmax would be obtained,
and therefore, the value for the Cmax/MIC ratio would also be
erroneous.
Data on gentamicin [11] and isepamicin [12] show that the
distribution time is longer with larger doses of these aminoglycosides. Thus, the majority of SDD studies have reported values
for postinfusion concentrations that were actually obtained during the distribution phase. When these trials are examined, it
appears that the reported Cmax/MIC ratios are optimal. However, as illustrated by the data of Demczar et al. [11], the
gentamicin Cmax/MIC ratio was reduced by 75% (mean, 5.5 if
the MIC was 2 ug/mL for the infecting organisms) when an
appropriate, postdistributional serum Cmax was used in the calculation instead of a "peak" concentration obtained during
the distribution phase (immediately at the end of a 60-minute
infusion of 7 mg/kg of gentamicin). The lower CmaxiMIC ratios
obtained when appropriate beta-phase sampling of the Cmax is
performed during snD therapy would be expected to result in
a reduced clinical response.
An additional difficulty in establishing a difference between
the efficacy ofMDD and SDD is the lack of a critical evaluation
of the actual aminoglycoside Cmax/MIC ratios obtained in these
various trials. In general, these data are not available to the
reader, either because appropriate serum sampling was not done
or because patients without culture-documented infection were
included, or both. SDD undoubtedly produces higher peak concentrations of aminoglycosides than does MDD. However, with
highly susceptible gram-negative bacteria (MICs of gentamicin
or tobramycin, ::s0.5 mg/L), it is quite possible that serum
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aminoglycoside CmaxiMIC ratios of ~ 10 were achieved, even
in patients who received MDD, despite substantially lower peak
aminoglycoside concentrations. Thus, for infections that are
due to extremely susceptible bacteria or that are located at
sites where aminoglycosides are known to concentrate (i.e., the
urinary tract), or both, a comparison between SDD and MDD
may be meaningless. In these instances, the use of SDD therapy
may unnecessarily expose a patient to excessive doses of
aminoglycosides.
In their meta-analysis, Ali and Goetz noted that the average
age of patients receiving SDD therapy was 33 years. This
finding does not allow a judgment as to whether SDD can be
applied safely to older patients who may have more underlying
conditions and reduced renal function. A recently published
study found a trend towards increased nephrotoxicity in elderly
patients receiving aminoglycosides via SDD vs. MDD [13].
Finally, the fact that patients at low risk for serious infection
or patients who could have been treated effectively with (3lactam antibiotics alone (rather than combination therapy) were
included in these trials makes a comparison between SDD and
MDD meaningless.
Another concern with the literature on SDD is that few of
the patients included in these trials actually had documented
gram-negative infections. According to the U.S. Food and Drug
Administration document on the evaluation of anti-infective
products [14], a documented gram-negative infection and bacterial susceptibility data are a priori requirements for establishing antibiotic efficacy for many types of infections. Patients in
the SDD trials often received other antibiotics effective against
gram-negative bacteria, and they also underwent appropriate
surgical intervention when needed. In the limited situations
where a gram-negative bacterium was actually recovered, the
attribution of efficacy to the method by which the patient received the aminoglycoside is at the least troublesome.
Nephrotoxicity
SDD is advocated as a way of potentially reducing the nephrotoxicity associated with MDD. The work of Verpooten and
co-workers [15] is often cited in support of SDD as a means
of reducing renal accumulation of aminoglycosides. While the
work of these investigators was scientifically sound, they compared the efficacy of a single dose of aminoglycoside, given
in a short infusion with that ofthe same dose given in a 24-hour
infusion. This comparison in no way represents a comparison of
SDD with MDD (with either method, the drug is given via
intermittent infusion); therefore, it is erroneous to draw the
conclusion that there is less renal accumulation of aminoglycosides when patients receive SDD vs. MDD.
To our knowledge, there are no data on renal accumulation
of aminoglycosides when SDD is compared to MDD in humans; thus, one cannot draw the conclusion that SDD results
in less renal accumulation ofaminoglycosides than does MDD.
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Bertino and Rotschafer
An important issue in the use of meta-analysis to examine the
nephrotoxic potential associated with SDD vs. that associated
with MDD is the large variability in definitions of nephrotoxicity.
At least 10 definitions of nephrotoxicity were used in the studies
cited in the three meta-analyses in this issue of CID. In some of
the studies, "soft" definitions of nephrotoxicity (i.e., a 25%
increase in the serum creatinine level or a total rise of 0.3
mg/dl., which is of questionable clinical significance) were used,
or patients were not observed long enough after completion of
therapy to determine actual rates of nephrotoxicity.
The largest published studies on nephrotoxicity have defined
nephrotoxicity as an increase in the serum creatinine level of 0.5
mg/dl, if the baseline level was <3 mg/dl. or as an increase of
1 mg/dl. if the baseline creatinine level was ~3 mg/dL [16-18].
Unfortunately, many of the studies cited in the meta-analyses did
not include nephrotoxicity rates; therefore, the findings cannot
be used in pooled data to evaluate these rates. This absence of
important toxicity data may introduce significant bias.
The greatest problem in evaluating the nephrotoxic potential
of SDD vs. that of MDD is that many investigators examined
SDD vs. MDD as the sole risk factor for nephrotoxicity. A
number of studies have shown that risk factors for aminoglycoside nephrotoxicity are multifactorial [16-18]. The findings of
a study conducted in the early 1980s, in which univariate analysis was performed, suggested that gentamicin is more nephrotoxic than tobramycin [19]. When these data were reanalyzed
by means of multiple logistic regression analysis, other risk
factors for aminoglycoside nephrotoxicity were identified, and
the type of aminoglycoside used was no longer a predictive
factor [16]. Thus, examining SDD vs. MDD alone as the only
risk factor for aminoglycoside nephrotoxicity without statistically analyzing the additional known risk factors may lead to
incorrect conclusions.
Prins and co-workers [20] recently used multiple logistic
regression analysis to examine the incidence of nephrotoxicity
among patients receiving aminoglycosides via SDD or MDD.
These investigators did not find a difference in the incidence
of nephrotoxicity with dosages of <4 mg/(kg· d) vs. dosages
of 4 mg/(kg· d) (a relatively low dose for SDD therapy). Unfortunately, Prins et al. did not examine total dose, which, rather
than daily dose, has been reported to be an important risk factor
for aminoglycoside nephrotoxicity [18].
Therefore, it remains unclear whether SDD of aminoglycosides is associated with a greater, lesser, or similar risk of
nephrotoxicity than is MDD. Previous data have shown that
even when nephrotoxicity occurs, it is mild, reversible, and
rarely requires intervention with dialysis [21, 22]; this finding
suggests that the rate and significance of aminoglycoside nephrotoxicity may be overstated. It is/clear that when individualized pharmacokinetic monitoring is applied, the rates of aminoglycoside-related nephrotoxicity' are low. In our own
experience with nearly 1,500 patients treated with use of individualized pharmacokinetic monitoring, we observed a nephrotoxicity rate of 1% with 6 days of therapy.
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1997;24 (May)
Cost and Convenience
An additional argument raised by proponents of SDD is that
SDD costs less than MDD because less frequent dosing is
required, and the need for serum concentration monitoring is
reduced. It should be noted that the cost of obtaining and
assaying (labor and reagents) a serum aminoglycoside concentration at Bassett Healthcare (Cooperstown, NY) decreased
from $10 during the period 1990-1993 to $6 in 1996. This
cost reduction is due to the increased use of automated systems
for therapeutic drug monitoring. The cost of obtaining a serum
drug concentration is minuscule compared with the cost of
the numerous other interventions (including concurrent therapy
with expensive ,B-Iactam antibiotics) that are used to treat patients with infections.
There are no definitive data suggesting what therapeutic drug
monitoring goals are needed for patients who receive aminoglycosides via SDD. Some investigators (including Bailey et al.)
have advocated obtaining a single serum drug concentration at
least 6 hours after the initial dose of an aminoglycoside is
given. Others have published a nomogram using a single serum
drug concentration obtained at least 6 hours after a dose is
given to ensure that adequate peak concentrations are obtained
[8]. As noted above, the pharmacokinetic principles used to
develop such a nomogram have been questioned [11].
Relying on a single serum aminoglycoside concentration is
problematic in that if the concentration appears elevated or
reduced, the clinician is uncertain as to whether the result
represents alterations in the drug's pharmacokinetics within an
individual patient, a laboratory error, or an alteration in the
administration schedule by the nursing staff. Dosing aminoglycosides with use of individualized pharmacokinetic monitoring,
which can be performed with two postinfusion serum concentrations, is still a bargain in today's health care arena; this
process can optimize therapeutic goals while limiting exposure
to the drugs in an effort to reduce the risk of toxicity.
The published studies on SDD vs. MDD of aminoglycosides,
including the three meta-analyses in this issue of CID, do not
answer the question of whether SDD is equivalent, inferior, or
superior (in terms of efficacy, nephrotoxicity, or cost) to MDD.
The majority of the published trials are flawed for the reasons
already cited. Unfortunately, this leads to flaws in meta-analysis
of these trials. It is clear that the pharmacodynamics of aminoglycosides in humans are related to optimization of the postdistributional Cmax/MIC ratio. Individualized pharmacokinetic
monitoring has been used for over two decades to dose aminoglycosides and is a highly proven method in terms of both
achieving pharmacokinetic goals and optimizing clinical response [6, 7].
To date, few of the 40 SDD trials have reported differences
in efficacy or toxicity between SDD and MDD. However, substantial problems exist with the methods used in these trials,
which leads us to believe that the question of whether SDD is
equivalent or superior to MDD is still unanswered. We will
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1997;24 (May)
Editorial Response
not get answers to the questions about SDD therapy if we
accept the findings in the current literature. For reasons already
stated, the technique of meta-analysis as applied to these data
is unlikely to resolve the clinical questions surrounding the use
of SDD vs. MDD.
We believe that the real data supporting the adoption of SDD
of aminoglycosides are lacking, and because aminoglycosides
are generic drugs, suitable funding to answer these questions
may not be forthcoming.
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