Download Meta-Analyses Are No Longer Required for Determining the Efficacy

816
Editorial Response: Meta-Analyses Are No Longer Required for Determining the
Efficacy of Single Daily Dosing of Aminoglycosides
David N. Gilbert
Investigators conducting clinical trials may have trouble replicating in ill patients results obtained in tightly controlled
models of efficacy and toxicity that use healthy animals [1].
Trials of single daily dosing (SDD) of aminoglycosides (also
known as once-daily aminoglycoside therapy) vs. multiple
daily dosing (MDD) are a good example. The rationale for
SDD therapy is clear [1]: SDD of aminoglycosides results in
high peak serum concentrations that enhance the concentrationdependent bactericidal activity of these drugs against susceptible aerobic gram-negative bacilli. Aminoglycosides have a
postantibiotic effect (PAE) that is longer when the peak drug
level is higher. SDD results in the absence of detectable drug
in serum for several hours at the end of a dosage interval,
whereas the drug remains detectable with MDD. Because of
the PAE, this drug-free period does not appear to compromise
antibacterial efficacy (although it may be compromised in cases
of infective endocarditis).
The clearance of aminoglycosides from serum has two advantages, including a lower risk of nephrotoxicity and ototoxicity and a reduced likelihood that "adaptive resistance" to the
drug might occur [2-5]. Hence, the clinical assessment ofSDD
vs. MDD of aminoglycosides requires documentation that the
patients randomized to SDD have high peak levels and low
(< 1 j.lg/mL) or undectable drug levels for several hours at the
end of the 24-hour dosage interval.
See articles on pages 786-815.
Ideally, clinical trials designed to compare the safety and
efficacy of SDD vs. MDD of aminoglycosides would include
only otherwise healthy patients with normal renal, vestibular,
and cochlear function. The same aminoglycoside would be
used in all trials, as there is potential variability in antibacterial
efficacy and toxicity among the drugs in this group [6]. The
patients would receive either no companion antibacterial or the
same companion antibacterial, as concomitant administration
of .B-lactams and vancomycin can influence both antibacterial
Received 2 January 1997; revised 28 January 1997.
Reprints or correspondence: Dr. David Gilbert, Director of Medical Education, Providence Portland Medical Center, 5050 NE Hoyt, Suite 540, Portland,
Oregon 97213.
Clinical Infectious Diseases 1997;24:816-9
© 1997 by The University of Chicago. All rights reserved.
1058-4838/97/2405 -0008$02.00
From the Earle A. Chiles Research Institute, Providence Portland
Medical Center, Portland, Oregon
efficacy and the risk of toxicity [6]. One method of overcoming
these and other variables is meta-analysis. Meta-analysis combines quantitative information from individual sources to yield
a summary statistic that is more powerful than the statistics
generated by smaller, individual trials.
The ultimate value ofa meta-analysis depends on the validity
of the data in the individual clinical trials and the methods
used to perform the meta-analysis.
Three meta-analyses of clinical trials that compared MDD
with SDD of aminoglycosides appear in this issue of Clinical
Infectious Diseases (CID). Another five meta-analyses have
been published [7 -11]. The number of clinical trials accepted as valid for the individual meta-analysis ranged from
four to 26 [12 -41]. The published meta-analyses are consistent in that they included only those clinical trials that enrolled patients who received the same dosage (rng/Ikg- d])
of an aminoglycoside, given either in MDDs or SDDs, for
the treatment of an active infection. The individual clinical
trials and, hence, the meta-analyses have lacked uniformity
in terms of the enrolled patient populations, the specific
aminoglycoside used, the comparison antibacterials administered, and the use of other potentially nephrotoxic or ototoxic
drugs.
The investigators conducting the clinical trials have allowed great variability in baseline renal function, which is
of particular relevance to the theoretical advantage of SDD
of aminoglycosides. As summarized in table 3 of the metaanalysis of Ali and Goetz in this issue of CID, some trials
excluded patients with baseline serum concentrations of
> 1.0 mg/dL, while others allowed baseline values of ~4.0
mg/dL. Hence, with the exception of children, it is fair to
say that a substantial percentage of patients enrolled in these
trials had baseline reductions in renal function sufficient to
prolong the serum half-life (t l 12) of the administered aminoglycoside.
How were the issues of adjustment of dosage and documentation of low trough serum levels in patients with predictable
prolongation of the t1/2 of the aminoglycoside handled in the
26 trials [22-41]? A variety of approaches were used. In at
least four of the studies, patients were excluded if the baseline
serum creatinine concentration exceeded 1.4- 1.8 mg/dL or the
estimated creatinine clearance was <60 mL/min [13, 22, 34,
39]. Either low trough serum levels « I j.lg/mL) were documented [34, 39], the single daily dose was reduced [13], or
high trough serum levels were documented [25]. In four other
studies, the baseline dosage of the amino glycoside was adjusted
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1997;24 (May)
Editorial Response
on the basis of estimated creatinine clearance values [21, 27,
28, 32]. In most cases the 24-hr mglkg dose was reduced, and
the dosing interval was not extended. The majority of the studies did not address the issue.
A few of the published trials do document the desired low
or undetectable levels of aminoglycosides at the end of the
dosage interval in patients randomized to the SDD regimen
[13, 32, 34, 39]. In one trial, the aminoglycoside dosage was
reduced on the basis of baseline renal function estimates [32],
and in another, the baseline renal function of the enrolled patients was predictably good because they were young [23]. It
is of interest that the first trial [32] showed a significant reduction in nephrotoxicity in the patients receiving the SDD regimen (P = .016) and that the second trial showed higher clinical
and bacteriologic cure rates for the patients receiving the SDD
regimen (P ~ .005), while the incidence of nephrotoxicity was
low for patients receiving either regimen [23].
Aside from the issue of end-of-dosage-interval clearance of
aminoglycosides with SDD, what do the eight meta-analyses
tell us? In six of these meta-analyses, a decreased risk of clinicalor microbiological failure and a relative decrease in the
risk of mortality were observed for the SDD group [7,9, 11].
A decrease in the relative risk of nephrotoxicity [7, 9, 11] was
observed in three of the eight analyses, and in one, a 33%
decrease in the risk of ototoxicity was observed [9].
The difficulty in accruing ototoxicity data is reflected by low
numbers of evaluable patients in the published clinical trials.
For example, it is not possible to obtain valid bedside audiograms for critically ill patients with metabolic encephalopathy.
Furthermore, the earliest evidence of aminoglycoside-induced
cochlear injury is high-frequency hearing loss. In addition, ageinduced decrements in high-frequency hearing loss are common and thus result in the exclusion of many patients from
evaluation.
There are no comparative data on the vestibular toxicity of
aminoglycosides. Anecdotal reports indicate that this toxicity
occurs with SDD; however, to date there are no data indicating
either an increased or reduced incidence of vestibular injury
[42].
There are additional relevant data from nonrandomized trials
that were not included in the published meta-analyses. For
example, Nicolau et al. [42] reported their experience with
2,184 patients who received aminoglycosides in single daily
doses. These results were compared with those obtained with
MDD regimens for which careful monitoring of peak and
trough serum levels was performed.
Two points are of interest: (l) The single daily dose of
gentamicin or tobramycin used by Nicolau et al. was larger
than that used in most studies. Most investigators have
multiplied the standard multiple-dose regimen by two or three
to establish the single daily dose (e.g., for gentamicin, 1.7
mglkg X 3 = 5.1 mg/[kg· dJ). However, on the basis of
preliminary drug kinetic studies, Nicolau et al. selected a
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dose of 7 mg/kg. (2) The single daily dose was adjusted for
decrements in estimated renal function by extending the dosage interval to 36 or 48 hours. Nicolau et al. did not report
any evidence of microbiologic failures. It is of interest that
the incidence of nephrotoxicity fell from a historical rate of
3-5% to 1.2%.
The safety and efficacy of isepamicin are also relevant. Isepamicin is an amino glycoside that has been licensed recently in
Europe, but it has not been marketed in the United States. The
clinical trials with isepamicin evaluated only single daily doses
of either 8 mglkg or 15 mg/(kg· d), depending on the severity
of the infection. Amikacin, the comparator drug, was dosed at
7.5 mg/kg b.i.d. Overall, rates of clinical cure or improvement
were comparable [43]. Increases in serum creatinine levels
occurred in 4.6% of patients receiving isepamicin and 5.1 of
patients receiving amikacin. The incidence of ototoxicity was
low, with no difference between the two drugs [44].
Thus, if the current evidence indicates that SDD of aminoglycosides is at least as safe and effective as MDD, do we
need another meta-analysis? I do not believe so. Could we use
additional prospective randomized trials? Of course, such trials
would be instructive, but the same multiple obstacles in design
and implementation would be present. Additional trials of SDD
in children, pregnant women, and patients with endocarditis
would be of particular interest. In animal models of endocarditis, the results appear dependent on the etiologic bacteria. The
best results for experimental enterococcal endocarditis required
MDD of an aminoglycoside in combination with a ,B-lactam
[45], while the best results for an infection due to a viridans
group streptococcus was achieved with a single daily dose of
an amino glycoside [46].
How high should single daily doses of aminoglycosides be?
For patients with normal renal function (e.g., estimated creatinine clearance, ;::80 mL/min) at baseline, the choice is between
the U.S. Food and Drug Administration-approved maximum
daily dose (e.g., 5.1 mg/[kg· d] for gentamicin) or the somewhat higher dose (7 mg/[kg· dJ) reported by Nicolau et al. [42].
For patients with a baseline estimated creatinine clearance of
<80 mL/min, should the daily dose be lower, with a constant
24-hour dosage interval, as Bennett and I have proposed [6,
47], or should the dose remain constant and the dosage interval
be extended to 36 or 48 hours, as outlined by Nicolau et al.
[42]? Space constraints preclude a discussion of the pros and
cons of each approach. There are no clinical data that address
this issue, and there is no animal model of stable, chronic
impaired renal function that could be used to compare the two
methods.
In summary, SDD of aminoglycosides has been studied in
enough adult nonpregnant patients without endocarditis. SDD
appears to be a safe and efficacious approach that does not
prevent drug toxicity but may reduce the risk. SDD of aminoglycosides is simpler, less time-consuming, and intuitively
more cost-effective than traditional MDD regimens [48].
818
Gilbert
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