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The nephrotoxicity and ototoxicity associated with once-daily versus twice-daily administration of aminoglycosides was assessed in patients with suspected or proven gram-negative bacterial infections in a randomized, double-blind clinical trial. Patients who received therapy for >72 h were evaluated for toxicity. Patients
also received concomitant antibiotics as deemed necessary for treatment of their infection. Plasma aminoglycoside concentrations, prospective aminoglycoside dosage adjustment, and serial audiologic and renal status
evaluations were performed. The probability of occurrence of a nephrotoxic event and its relationship to doses
and daily aminoglycoside exposure served as the main outcome measurement. One hundred twenty-three
patients were enrolled in the study, with 83 patients receiving therapy for at least 72 h. For 74 patients plasma
aminoglycoside concentrations were available for analysis, and the patients formed the group evaluable for
toxicity. The primary infectious diagnosis for the patients who were enrolled in the study were bacteremia or
sepsis, respiratory infections, skin and soft tissue infections, or urosepsis or pyelonephritis. Of the 74 patients
evaluable for toxicity, 39 received doses twice daily and 35 received doses once daily and a placebo 12 h later.
Nephrotoxicity occurred in 6 of 39 (15.4%) patients who received aminoglycosides twice daily and 0 of 35
patients who received aminoglycosides once daily. The schedule of aminoglycoside administration, concomitant
use of vancomycin, and daily area under the plasma concentration-time curve (AUC) for the aminoglycosides
were found to be significant predictors of nephrotoxicity by multivariate logistic regression analysis (P <
0.001). The time to a nephrotoxic event was significantly influenced by vancomycin use and the schedule of
administration, as assessed by Cox proportional hazards modeling (P < 0.002). The results of the multivariate
logistic regression analysis and the Cox proportional hazards modeling demonstrate that both the probability
of occurrence and the time to occurrence of aminoglycoside nephrotoxicity are influenced by the schedule on
which the aminoglycoside is administered as well as by the concomitant use of vancomycin. Furthermore, this
risk of occurrence is modulated by the daily AUC for aminoglycoside exposure. These data suggest that
once-daily administration of aminoglycosides has a predictably lower probability of causing nephrotoxicity
than twice-daily administration.
phospholipases A1 and A2 by aminoglycosides results in the
formation of lamellar bodies which are postulated to cause
cellular toxicity (37). The method of uptake into PRTE cells is
closely linked to the rationale underlying the use of once-daily
dosing to delay the onset of nephrotoxicity. The uptake of
aminoglycosides is limited to the luminal border of the PRTE
cell. It is likely that they bind to the cell surface and are taken
up by pinocytosis, which is inherently limited to a maximal rate.
Consequently, no matter how much aminoglycoside is present
in the tubular lumen, only a maximal amount can be taken up
per unit of time. The administration of larger doses less frequently allows high concentrations of drug to be present in the
tubular lumen early in the dosing interval. Consequently, with
high concentrations of aminoglycosides in the tubular lumen,
when uptake is saturated, the rate of uptake is maximal and
thus is not increased with higher concentrations. Therefore,
much of the aminoglycoside bypasses the PRTE cell and is
excreted. Smaller amounts of the drug are present for longer
periods of time. The total amount of drug taken up by the cells
per 24 h is smaller, as seen from the data of Verpooten et al.
(39).
Traditionally, aminoglycosides have been administered in
two to three divided doses per day by intermittent infusion.
Numerous studies conducted with animals and humans have
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RYBAK ET AL.
demonstrated equal efficacy (5, 11, 12, 1416, 18, 2022, 2631,
34, 35, 38, 41) and nephrotoxicity (11, 12, 1416, 2022, 26, 27,
29, 31, 3335, 38, 39, 41) with once-daily dosing of aminoglycosides compared with those with conventional dosing. All
clinical studies to date have been unblinded. Moreover, many
patients have received therapy for short periods of time. Such
limited therapy may minimize toxicity and may thus obscure
any difference between the effects of different dosing schedules. Recently, five different investigations by meta-analysis
examined the data from the majority of published studies of
once- versus multiple-daily dosing of aminoglycosides (1, 3, 4,
25, 36). The results of those studies indicated that the rates of
toxicity with once-daily dosing were less than or equal to those
with multiple-daily dosing. Furthermore, one of the analyses
indicated a more favorable clinical outcome with once-daily
dosing with dosed aminoglycosides compared with that from
multiple-daily dosing (25). Meta-analysis may point the way to
a correct hypothesis, but the ultimate proof of that hypothesis
is still in the realm of the prospective randomized trial. We
designed and carried out a prospective, randomized, doubleblind study of once-daily aminoglycoside therapy compared
to twice-daily therapy to examine toxicity in patients being
treated for at least 72 h for suspected gram-negative bacterial
infections.
MATERIALS AND METHODS
One hundred twenty-three patients admitted to the Detroit Receiving Hospital and University Health Center for bacteremia or sepsis, respiratory infections,
skin and soft tissue infections, or urosepsis or pyelonephritis that were suspected
to be due to gram-negative pathogens and for whom aminoglycoside therapy was
required were enrolled in the study. Patients were identified for screening by
physician order for an aminoglycoside. Of these patients, 123 were enrolled in
the study on the basis of the following criteria; patients enrolled were greater
than 18 years of age, had suspected infection for which an aminoglycoside was
prescribed, had received no more than two aminoglycoside doses for the current
infection, and were expected to receive therapy for at least 3 days. Patients were
excluded if they had a serum creatinine concentration of 2.4 mg/dl, weighed
30% above their ideal body weight, had a history of hypersensitivity to any
aminoglycoside, had tinnitus, deafness, or vestibular disturbances, or were pregnant, neutropenic (neutrophil count, 1,000/mm3), suspected of having meningitis, or in shock.
The protocol was approved by the Human Investigation Committee of Wayne
State University, and informed consent was obtained from each patient or guardian. Patients were stratified by disease state (bacteremia or sepsis, respiratory
infection, skin and soft tissue infection, or urosepsis or pyelonephritis) and were
then randomly assigned by use of a random-numbers table to either dosing every
12 h as described below or dosing by once-daily administration of the entire daily
dose of aminoglycoside, followed 12 h later by 100 ml of 5% dextrose in water as
a placebo. Aminoglycoside doses were diluted in 100 ml of 5% dextrose in water.
Drug and placebo doses were administered over 1 h. Both the patients and the
physicians remained blinded to the treatment. Patients were also treated with
beta-lactam or other antimicrobial agents as deemed necessary by their physicians.
Aminoglycoside dosing was individualized for both groups and was guided by
targeted peak and trough concentrations in serum on the basis of the patients
individual pharmacokinetic parameters and standard equations (40). For the
twice-daily dosing group, target peak concentrations in serum were 8 to 10
mg/liter for those with respiratory infections and 5 to 6 mg/liter for those with all
other indications for gentamicin and tobramycin treatment, with trough concentrations of 2.0 mg/liter. For patients who received amikacin, peak concentrations in serum were 30 to 40 mg/liter for those with respiratory infections and 20
to 30 mg/liter for all other patients. Desired trough amikacin concentrations were
10.0 mg/liter. Target peak concentrations of gentamicin or tobramycin in serum concentrations for the once-daily dosing group were 16 to 20 mg/liter for
those with respiratory infections and 10 to 12 mg/liter for patients with other
infections. The desired peak serum amikacin concentrations were 60 to 80
mg/liter for patients with respiratory infections and 40 to 60 mg/liter for all
others. The desired trough concentrations for once-daily dosing were targeted to
be below 1.0 mg/liter. These target concentrations were based on doubling of the
conventional target ranges for the Detroit Receiving Hospital and University
Health Center (24). Initial dosing was based on population parameters in conjunction with the patients calculated creatinine clearance and estimated ideal
body weight. After serum aminoglycoside levels were obtained, dosing regimens
were adjusted to maintain peak and trough concentrations in the targeted ranges.
All patients were monitored daily by the unblinded pharmacokinetic consultation
Once-daily
dosing group
39
35
24/15
20/15
Age (yr)
Mean SD
Range
44.7 13.0
2383
47.3 15.8
2281
Wt (kg)
Mean SD
Range
72.2 17.0
46124
70.5 12.7
50108
5.7 5.1
019
5.6 4.7
021
3
19
7
10
4
11
9
11
0.9 0.3
0.41.5
1.0 0.3
0.51.9
Parameter
APACHE II score
Mean SD
Range
Primary site of infection or infection
Bacteremia or sepsis
Skin and soft tissue
Respiratory
Urosepsis or pyelonephritis
Baseline serum creatinine concn (mg/dl)
Mean SD
Range
a
No statistically significant differences were present between the two treatment groups.
RESULTS
Of a total of 123 patients enrolled in the study, 83 patients
received therapy for at least 72 h; for 74 patients plasma aminoglycoside concentrations were available for analysis, and
these patients formed the group evaluable for toxicity; 39 received doses twice daily and 35 received doses once daily. No
patient discontinued therapy due to side effects attributed to
an aminoglycoside. Of the patients not evaluable for toxicity,
the majority were changed to some other antibiotic therapy
before completing the minimum 72 h of aminoglycoside therapy: 14 of 23 (61%) were in the twice-daily dosing group and
17 of 26 (65%) were in the once-daily dosing group. Two patients in each group died before 72 h of treatment. One patient
in the twice-daily dosing group was withdrawn because of an
1551
TABLE 2. Pharmacokinetic parameters for evaluable patients receiving gentamicin, tobramycin, or Amikacin
Gentamicin or tobramycin
Infection or site
of infection
Peak
concn
(mg/liter)
Trough
concn
(mg/liter)
Peak
concn
(mg/liter)
Trough
concn
(mg/liter)a
No. of
patients
7.7 1.3
6.5 1.9
5.7 1.7
6.2 1.9
0.6 0.6
0.1 0.0
0.1 0.2
0.2 0.2
0
0
2
1
No. of
patients
Respiratory tract
7 (3, 4)b
Bacteremia or sepsis 3 (3)c
Skin or soft tissue
17 (13, 4)b
Urosepsis or pyelo9 (6, 3)b
nephritis
a
b
c
Amikacin
No. of
patients
Peak
concn
(mg/liter)
Trough
concn
(mg/liter)
1
0
1
0
Peak
concn
(mg/liter)
Trough
concn
(mg/liter)a
85.7
12.4
32.1
0.04
1552
RYBAK ET AL.
Dosing
group
Once daily
Twice daily
a
b
c
Change in
serum creatinine
concn (mg/dl)b
Cumulative dose
Duration of
therapy (days)
Amikacinc
Mean SD
Range
Mean SD
Range
No. of
patients
Mean SD
dose (mg)
Dose range
(mg)
No. of
patients
Mean SD
dose (mg)
Dose range
(mg)
0.2 0.4
0.1 0.2
02.1
00.5
8.2 6.2
10.6 9.7
339
352
36
33
2,133 2,233
3,110 2,619
72013,600
80013,400
3
2
11,250 3,470
16,500 10,750
7,00015,500
5,75027,250
No statistically significant differences were present between the two treatment groups.
Change in serum creatinine (peak serum creatinine concentration) (baseline creatinine concentration).
Data were not available for one patient who received amikacin.
tional antibiotic during the study period. Most patients received a beta-lactam as concomitant therapy. The type of
beta-lactam therapy was similar between the two groups and
consisted of the following for the twice- and once-daily dosing
groups: ampicillin, 10 and 11 patients, respectively; ampicillinsulbactam, 1 and 2 patients, respectively; cefazolin, 7 and 5
patients, respectively; imipenem, 2 and 2 patients, respectively; nafcillin, 0 and 1 patients, respectively; piperacillin, 11
and 8 patients, respectively; and ticarcillin-clavulante, 1 and 2
patients, respectively. Eleven patients received concomitant
vancomycin therapy (seven and four patients in the twice-daily
and once-daily aminoglycopeptide dosing groups, respectively). One patient in each group received amphotericin B. No
statistically significant differences were noted for the groups
with respect to baseline APACHE II score, change in serum
creatinine concentration, duration of therapy, cumulative dose,
or mean total daily dose (Tables 1 and 3). Overall, the majority
of evaluable patients defervesced during the study and were
discharged to home or rehabilitation with oral antimicrobial
therapy. One patient in the twice-daily dosing group died during the study period (post-72 h). Soon after enrollment in the
study, this patient developed multi-organ system failure. Efficacy was not evaluated in this comparative study.
According to our definition, 6 of 39 patients (15.4%) in the
twice-daily dosing group and 0 of 35 patients in the once-daily
dosing group developed nephrotoxicity. This difference was
significant when tested by the Fisher exact test (P 0.026).
Toxicity was observed to begin 8.8 3.4 days after the start of
treatment in the twice-daily dosing group.
The results of logistic regression analyses performed univariately are summarized in Table 4. Only the schedule of
administration, vancomycin use, and daily AUC of aminoglycoside were significant in affecting the probability of nephrotoxicity. All were significant in the model-building process,
as assessed by likelihood ratios. The final parameter values are
displayed in Table 5.
The probability of nephrotoxicity as a function of AUC is
displayed in Fig. 1A and B for once-daily and twice-daily administration, respectively, with and without vancomycin use.
A Kaplan-Meier analysis demonstrated that schedule of administration (primary hypothesis) significantly influenced time
to nephrotoxicity (Log-rank test/mantel variant, P 0.006; logrank test/Breslow-Gehan variant, P 0.026). Because schedule of administration influenced time to nephrotoxicity, this
was retained as a stratification variable in all subsequent Cox
proportional hazards modeling studies.
The parameters from the univariate Cox proportional hazards models (with stratification for schedule) are displayed in
Table 6. Because the final model contained only vancomycin
use with schedule of administration as a stratification variable,
the final parameter value for vancomycin coadministration is
presented in Table 6.
Covariate
Constant
Estimate
Site
Skin or soft tissue
Respiratory tract
Urosepsis or pyelonephritis
Bacteremia or sepsis
2.639
0.732
0.0
0.069
0.357
1.723
1.266
1.259
1.112
AUC
4.751
1.309
0.031
0.015
DOT
2.614
0.017
0.595
0.035
Sched
QD
Q12h
30.202
CumAUC
2.911
Vanco
Use
Use
3.418
AmphoB
Use
Use
2.595
0.0
1.822
0.001
0.719
0.0
2.858
0.464
0.0
2.595
P value
0.1
0.444
0.04
0.1
0.004
28.497
0.597
0.0004
0.1
0.002
0.954
0.1
1.488
1553
Constant
Vanco
Use
Use
37.239
Sched
QD
Q12h
AUC
a
Estimate
Standard error
2.482
0.0
3.531
1.411
0.0
30.757
0.001
0.049
0.026
P value
0.000065
toxicity as a function of once-daily dosing, and most importantly, all were unblinded. However, a meta-analysis investigation by Barza et al. (4) has demonstrated that examination of
data from multiple studies demonstrates a difference in the
rate of aminoglycoside nephrotoxicity in favor of the oncedaily dosing group. Munckhof et al. (25), using a similar metaanalysis approach to data from published once-daily versus
multiple-daily aminoglycoside dosing studies (2,881 patients),
found equal rates of nephrotoxicity between the two regimens
but demonstrated a more favorable clinical outcome (P
0.027) with once-daily administration of these drugs. More
recently, three additional meta-analyses have evaluated oncedaily versus multiple-daily dosing of aminoglycosides. None of
those studies found differences in efficacy, and all studies reported similar rates of toxicity between once-daily and multiple-daily aminoglycoside dosing (1, 3, 36).
Our study represents the first prospective, double-blind evaluation of this question. We found that once-daily dosing did,
indeed, alter the risk of aminoglycoside nephrotoxicity. The
factors identified in the logistic regression analysis as altering
the probability of occurrence of nephrotoxicity and the factors
that affect the time to nephrotoxicity, as identified in the Cox
proportional hazards model, are concordant with each other
and with the findings with animal models.
Examination of the data of terBraak et al. (35) demonstrates
that once-daily dose administration and multiple-daily dose
administration each will ultimately produce toxicity. What one
purportedly gains from single-daily-dose administration is a
lower daily intracellular accumulation rate, consistent with the
clinical findings of Verpooten et al. (39) and the animal model
data of Wood et al. (41). Therefore, the once-daily dosing
schedule should provide a longer time of administration until
the threshold for toxicity is met. This is precisely what is seen
in our data, in which the AUC primarily drives the probability
of nephrotoxicity but is modulated by the schedule of administration and the concurrent use of vancomycin. More explicitly, the time to nephrotoxicity was affected by both the schedule of administration and vancomycin use in the Cox model.
The concurrent use of vancomycin plus an aminoglycoside
and the effect on the development of nephrotoxicity have been
areas surrounded by controversy (7, 32). The use of vancomycin in this study was not controlled, and the effect of its concurrent use on nephrotoxicity was not the primary hypothesis
being tested. As such, conclusions drawn from these data need
to be viewed with caution. Nevertheless, both multivariate
analyses indicated that concurrent vancomycin use significantly
affects the patients probability of developing nephrotoxicity
and shortening the time to its occurrence. While this finding
needs to be validated prospectively, clinicians would be prudent to monitor intensively the renal functions of patients who
are receiving both agents.
FIG. 1. (A) Curve of probability of development of aminoglycoside nephrotoxicity for patients receiving the drug on a twice-daily basis as estimated by
multivariate logistic regression analysis. The probability rises as a function of
increasing daily exposure to aminoglycoside, as indexed to the AUC. Concurrent
vancomycin use provides a marked increase in the probability of nephrotoxicity
for equivalent exposure to aminoglycosides, as indexed to the daily AUC. (B)
Once-daily administration shifts the curves of probability of nephrotoxicity as
influenced by daily aminoglycoside AUC to the right.
Estimate
Standard
deviation
2 log likelihood
difference
P value
Site of infection
AUC
DOT
CumAUC
Vanco
AmphoB
1.102
0.024
0.041
0.0005
2.980
0.574
0.477
0.014
0.071
0.00079
1.122
1.191
6.076
2.766
0.418
0.471
9.508
0.210
0.014
0.096
0.1
0.1
0.002
0.1
a
Schedule of administration was used as a stratification variable for all analyses. See footnote a of Table 4 for definitions of covariates.
1554
RYBAK ET AL.
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