Amikacin levels in bronchial secretions of 10

Amikacin levels in bronchial secretions of 10
pneumonia patients with respiratory support
treated once daily versus twice daily.
C Santré, H Georges, J M Jacquier, O Leroy, C Beuscart, D
Buguin and G Beaucaire
Antimicrob. Agents Chemother. 1995, 39(1):264. DOI:
10.1128/AAC.39.1.264.
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ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, Jan. 1995, p. 264–267
0066-4804/95/$04.0010
Copyright q 1995, American Society for Microbiology
Vol. 39, No. 1
Amikacin Levels in Bronchial Secretions of 10 Pneumonia
Patients with Respiratory Support Treated Once
Daily versus Twice Daily
´ ,1* H. GEORGES,1 J. M. JACQUIER,1 O. LEROY,1 C. BEUSCART,1
C. SANTRE
D. BUGUIN,2 AND G. BEAUCAIRE1
Intensive Care and Infectious Diseases Unit1 and Department of Microbiology,2 Centre Hospitalier
Tourcoing, Lille University Medicine School, F-59208 Tourcoing, France
Received 22 March 1994/Returned for modification 23 June 1994/Accepted 24 October 1994
lowing conventional clinical, radiological, biological, and
bacteriological diagnosis criteria were used to define bronchopneumonia: fever above 388C, a peripheral leucocyte count of
.10,000/mm3, purulent endotracheal secretions, and pulmonary infiltrates on chest radiographs that were not otherwise
explainable. Patients with previous renal insufficiency, defined
as a serum creatinine concentration greater than 180 mmol/
liter, and those with a lack of bronchial secretions were excluded from the study. No patient had previously received
amikacin or other aminoglycosides within 7 days of entry into
the study. The patients were divided into two groups by using
an open randomization schedule, and they received amikacin
either once daily (od group) or twice daily (bid group). The
patients in the once-daily treatment group received 15 mg of
amikacin per kg of body weight every 24 h, and the twice-daily
treatment group received 7.5 mg of amikacin per kg every 12 h.
Both groups were administered amikacin as an intravenous
infusion given over 30 min. The antibiotic treatment was performed in an empirical way, and amikacin was commonly administered with beta-lactams to achieve broad-spectrum coverage, including coverage for gram-negative strains, and highlevel bactericidal activity in mechanically ventilated patients
with life-threatening disease.
Bronchial secretions were collected by endotracheal suction
in the usual manner (Vygon 534.16). No nebulization or antibacterial filters were used. Blood and bronchial secretion samples were collected at 0, 1, 3, 4, 6, 9, 12, 15, 18, and 24 h after
the start of amikacin infusion on days 1 and 3. Samples were
frozen at 2208C until completion of the study. Bronchial secretions were diluted in an equivalent sterile water volume and
then centrifuged after incubation at 378C for 18 h to provide
better viscosity. Cell smears were made to exclude hemorrhagic samples. Measurements of concentrations in bronchial
secretions were performed on the supernatant. Amikacin concentrations in the serum and bronchial secretions were determined by a fluorescence polarization immunoassay (Abbott
TDX). The assay sensitivity was 0.8 mg/liter, and the intrarun
coefficient of variation was between 3 and 7% in the concen-
Aminoglycosides are widely used for the treatment of gramnegative bronchopneumonia. A critical factor in their effectiveness is their ability to achieve therapeutic concentrations at
the site of infection. Although concentrations in bronchial secretions do not necessarily reflect parenchymal or bronchial
wall concentrations, these measurements provide information
on blood-bronchioalveolar barrier. Previous studies revealed a
nonsaturable transport system for aminoglycosides which involves a passive mechanism (8). Thus, high serum antibiotic
concentrations should theoretically lead to high concentrations
in bronchial secretions. Endotracheal administration of aminoglycosides has been postulated to provide therapeutic concentrations in the treatment of gram-negative pneumonias, but
to date no study has exhibited superiority of this administration
method compared with usual regimens (1, 14). Numerous recent in vitro and clinical studies have shown that once-daily
aminoglycoside administration is as effective as and less toxic
than twice-daily administration in the case of severe gramnegative infections (12). A previous clinical study conducted
with 91 patients hospitalized in an intensive care unit demonstrated that once-daily amikacin administration was highly effective against gram-negative infections, particularly in the
case of 45 patients with bronchopneumonia (4). We proposed
that these results could be related to higher in situ amikacin
concentrations in the patients treated once daily. In this study,
we performed serial measurements of concentrations in serum
and bronchial secretions of patients treated with amikacin
twice daily and once daily.
From November 1990 to July 1991, 13 patients admitted to
an intensive care unit for acute respiratory failure related to
bronchopneumonia were enrolled in a prospective study. The
protocol was approved by the Ethics Committee of the Lille
University Medicine School. Informed consent was not
deemed to be mandatory. All patients were mechanically ventilated through a nasotracheal tube upon admission. The fol-
* Corresponding author. Phone: (33) 20764697. Fax: (33) 20254291.
264
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In this study, concentrations of amikacin in blood and bronchial secretions of 10 patients with mechanical
ventilation for acute respiratory failure due to pneumonia were measured. One-half of the patients received
amikacin twice daily, and the others received once-daily administration. Concentrations in bronchial secretions of the patients treated twice daily ranged from 3 to 4 mg/liter, i.e., they were similar to those in previously
published reports. Peak concentrations in bronchial secretions occurred between 3 and 4 h after the onset of
infusion, and they reached 4.8 6 2.6 mg/liter on day 1 and 4.0 6 2.7 mg/liter on day 3. For the patients treated
with amikacin once daily, concentrations in bronchial secretions were more than twofold higher, above 8
mg/liter for 12 h. Peak concentrations in bronchial secretions occurred between 3 and 4 h after the onset of infusion
and reached 13.6 6 9.3 mg/liter on day 1 and 10.4 6 3.5 mg/liter on day 3. These concentrations are higher than
the MICs for less sensitive bacterial strains, such as Acinetobacter spp. and Pseudomonas aeruginosa.
VOL. 39, 1995
NOTES
265
TABLE 1. Clinical data, amikacin treatment groups, and bacteriological outcomes for patients
Group
Patient
Sexa
Age (yr)
Microorganism
Dosage
(mg)
ATB 1b
ATB 2c
od
1
2
3
4
5
M
F
F
F
M
55
76
66
82
46
S. pneumoniae
No pathogen
No pathogen
S. marcescens
No pathogen
1,000
1,000
1,000
500
600
ATM
CTX
CTX
IMP
CAZ
VAN
bid
1
2
3
4
5
M
F
M
M
M
55
44
78
41
51
H. influenzae
S. pneumoniae
S. pneumoniae
S. pneumoniae
S. pneumoniae
500
500
400
500
500
CAZ
CAZ
CAZ
CTX
CTX
a
b
M, male. F, female.
ATB 1, combined antimicrobial agent 1. ATM, aztreonam; CAZ, ceftazidime; CTX, cefotaxime; IMP, imipenem-cilastatin.
ATB 2, combined antimicrobial agent 2. VAN, vancomycin.
tration range of 0 to 30 mg/liter. Results were expressed in
milligrams per liter of serum or bronchial secretion.
Samples of blood and bronchial secretions (obtained by
bronchial aspiration or with a fiber-optic distal protected
brush) were cultured under aerobic and anaerobic conditions.
A microorganism was considered the etiologic agent of the
pneumonia only if it was isolated from the lower respiratory
secretions obtained from bronchial aspirate (105 CFU/ml)
and/or a fiber-optic distal brush with a cutoff point of 103
CFU/ml or if it was isolated from blood.
Pharmacokinetic analysis was performed with a pharmacokinetics software program (SIPHAR) to determine areas under the curve (AUCs). AUCs from time zero to the last measured concentration were computed by using a linear
trapezoidal rule. Data were expressed as means 6 standard
deviations. AUCs for each patient of the two groups were
compared by means of the Wilcoxon rank-sign test. A P value
of ,0.05 was considered statistically significant.
A total of 3 patients, 2 with hemorrhagic bronchial secretions and 1 with renal insufficiency, were excluded before day
3 of the study; 10 patients completed the trial. General clinical
data are included in Table 1. The mean patient age was 59.4 6
14.3 years (range, 41 to 82 years). Six male patients and four
female patients were enrolled. Renal function was normal at
entry and remained normal during the entire study in every
patient. Eight patients had community-acquired bronchopneumonia, and two had nosocomial infections. Seven patients had
bacteriologically proven bronchopneumonia, and the isolated
pathogens were Streptococcus pneumoniae for five patients,
Haemophilus influenzae for one patient, and Serratia marcescens for one patient. The following antimicrobial agents were
combined with amikacin: ceftazidime (six patients), cefotaxime
(three patients), imipenem (one patient), aztreonam (one patient), and vancomycin (two patients). All patients were ultimately cured according to clinical definitions.
Concentrations of amikacin in bronchial secretions of 10
patients could be effectively measured on day 1, and those in
secretions of 8 patients could be effectively measured on day 3.
Thirty bronchial samples could not be assayed or were excluded for technical reasons, and 160 concentrations in bronchial secretions (84.2%) were actually measured. Mean values
for concentrations in serum and bronchial secretions are summarized in Table 2.
For bid group patients on day 1, the mean peak serum
amikacin concentration was 20.2 6 9.3 mg/liter (range, 10.3 to
36.4 mg/liter), and the mean peak concentration in bronchial
secretions, occurring 3 h after the onset of infusion, was 4.8 6
2.6 mg/liter (range, 1.1 to 8.3 mg/liter). On day 3, the mean
TABLE 2. Mean amikacin concentrations, AUC values, and ratios of concentrations in bronchial secretions to concentrations
in serum for the two treatment groups
Resulta
Day 1
Treatment
group
Once
daily
Twice
daily
Concn in
bronchial
secretions
(mg
liter21)
Day 3
Serum
AUC0–24
(mg z h
liter21)
Secretion
AUC0–24
(mg z h
liter21)
46.5 6 9.3 13.6 6 9.3
230 6 113d
153 6 99e
20.2 6 9.3
131 6 41
Peak concn
in serum
(mg
liter21)
4.8 6 2.6
d
60 6 38
e
Peak
concn
ratio
(%)b
Secretion
AUC0–24
(mg z h
liter21)
30.6 66 6 23 37.2 6 7.6 10.4 6 3.5
223 6 85f
151 6 85g
40.5 81 6 16
29.4 46 6 20 20.2 6 5.3
140 6 40
79 6 45
31.3 57 6 20
Except those for peak concentration ratios, data are means 6 standard deviations.
Ratio of peak concentration in bronchial secretions to peak concentration in serum.
c
Ratio of bronchial secretion AUC to serum AUC.
d
P 5 0.21.
e
P 5 0.21.
f
P 5 0.18.
g
P 5 0.13.
a
b
Concn in
bronchial
secretions
(mg
liter21)
Serum
AUC0–24
(mg z h
liter21)
AUC
ratio
(%)c
Peak concn
in serum
(mg
liter21)
4.0 6 2.7
f
g
Peak
concn
ratio
(%)b
AUC
ratio
(%)c
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c
VAN
266
NOTES
ANTIMICROB. AGENTS CHEMOTHER.
FIG. 2. Amikacin pharmacokinetics for the od treatment group. Mean concentrations in serum (`) and in bronchial secretions (1) on day 1 (plus standard
deviations) are shown.
peak concentrations were 20.2 6 5.3 mg/liter in serum and 4.0
6 2.7 mg/liter in bronchial secretions. Mean trough concentrations in serum were 0.8 6 0.7 mg/liter and 0.7 6 0.6 mg/liter
on day 1 and day 3, respectively. Figure 1 shows that the mean
concentrations in bronchial secretions remained constant (3 to
4 mg/liter) over the 24-h monitoring period and that they were
permanently below 5 mg/liter. There was no cumulative effect
between day 1 and day 3. Important individual variations in the
bronchial peak concentrations were noted (range, 1.1 to 8.3
mg/liter). As shown in Table 2, the mean ratio of peak concentrations in bronchial secretions to mean peak concentrations in serum (BC max/SC max) was 29.4% on day 1 and
31.3% on day 3 (range, 12 to 51.5%). The mean bronchial
secretion AUC from 0 to 24 h (AUC0–24) was 59.9 mg z h/liter
on day 1 and 79.4 mg z h/liter on day 3. The mean ratio of
bronchial secretion AUC0–24 to serum AUC0–24 was 46% on
day 1 and 57% on day 3 (Table 2).
For od patients on day 1, the mean peak concentration in
serum was 46.5 6 9.3 mg/liter, and the mean peak concentration in bronchial secretions, occurring 3 h after the onset of
infusion, was 13.6 6 9.3 mg/liter. On day 3, the corresponding
results were 37.2 6 7.6 mg/liter and 10.4 6 3.5 mg/liter, respectively. Despite the high peak concentrations in serum,
mean trough concentrations were low: 1.1 6 1.1 mg/liter on
day 1 and 2.1 6 1.2 mg/liter on day 3. Mean concentrations in
bronchial secretions were above 8 mg/liter for 12 and 16 h after
the onset of infusion on days 1 and 3, respectively (Fig. 2).
There was no cumulative effect, as was previously observed
with the bid treatment group. Peak concentrations in serum
ranged from 26.2 to 59.0 mg/liter, and peak concentrations in
bronchial secretions ranged from 9.1 to 26.1 mg/liter. The BC
max/SC max mean ratio was 30.6% on day 1 and 40.5% on day
3 (range, 13.3 to 46.6%). The mean bronchial secretion
AUC0–24 was 153 mg z h/liter on day 1 and 181.1 mg z h/liter on
day 3. The mean ratio of bronchial secretion AUC to serum
AUC was 66% on day 1 and 81% on day 3.
The serum amikacin concentrations noted for the patients in
this study were similar to those reported by other investigators.
Since most gram-negative bacteria are inhibited by amikacin
concentrations of 1 to 4 mg/liter, all the patients, particularly
those in the od treatment group, exhibited a high serum amikacin concentration-to-MIC ratio. For the od treatment group,
mean peak concentrations in bronchial secretions were more
than twice those observed for the bid treatment group. These
peak concentrations were obtained between 3 and 4 h after the
start of infusion, and thus they occurred later than the peak
concentrations in serum.
For the conventional twice-daily administration group, mean
concentrations in bronchial secretions approached 3 to 4 mg/
liter, and they were continuously below 5 mg/liter. These results for the bid treatment group are consistent with previous
observations with amikacin (6, 8). The reported MICs of amikacin for Acinetobacter spp. and Pseudomonas aeruginosa are
usually greater than 6 mg/liter. Thus, these low amikacin levels
could be inadequate to cure some gram-negative bronchopneumonias. As previously reported in the literature (7), there
was no cumulative effect between day 1 and day 3. In the case
of one patient administered amikacin twice daily, concentrations in bronchial secretions obtained on day 6 confirmed these
results.
For the group administered amikacin once daily, mean concentrations in bronchial secretions were greater than 10 mg/
liter at 12 h after the last dose of amikacin, and they remained
above 5 mg/liter for 16 h after the last dose. These concentrations would be expected to inhibit in situ most gram-negative
organisms, including Acinetobacter spp. and P. aeruginosa.
Garraffo et al. demonstrated, in a study involving six healthy
volunteers, that the concentration-dependent bactericidal activity of amikacin may be improved by increasing in vivo concentrations (10). For the od treatment group, concentrations in
bronchial secretions were about three- or fourfold higher than
the MICs for most gram-negative strains. Regarding P. aeruginosa and Enterobacter cloacae, Garraffo et al. demonstrated
that the length of time for which amikacin levels were main-
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FIG. 1. Amikacin pharmacokinetics for the bid treatment group. Mean concentrations in serum (`) and in bronchial secretions (1) on day 1 (plus standard
deviations) are shown.
VOL. 39, 1995
267
daily administration regimens. These results should provide a
good rationale for once-daily administration of aminoglycosides in the treatment of severe gram-negative bronchopneumonia. Further clinical trials are needed to confirm this hypothesis.
This study was supported in part by a grant from Bristol-Myers
Squibb Company.
We are indebted to Paul Santella for his helpful assistance.
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tained above the MICs was an important parameter for bactericidal activity. In bronchial secretions from patients administered amikacin once daily, amikacin levels were above 8 mg/
liter for more than 12 h. Several clinical studies, some
including critically ill patients, have shown that once-daily amikacin treatment can be as effective as the usual regimen (3, 11,
16). In a population of 45 patients with gram-negative bronchopneumonias, once-daily amikacin treatment could achieve
a high clinical success rate, above 70%; moreover, Acinetobacter spp. and P. aeruginosa behaved in the same way as did
other gram-negative strains (4). These high success rates with
gram-negative bronchopneumonias, even when Acinetobacter
spp. and P. aeruginosa were involved, could be related to the
high concentrations in bronchial secretions of the patients
treated once daily with amikacin.
The ratio of concentrations in serum to concentrations in
bronchial secretions (BC max/SC max) remained relatively
constant at about 30%, and it involved a nonsaturable transport system that was a purely passive mechanism. These results
are consistent with previous results obtained with twice-daily
regimens (6, 8). In another study conducted with 12 tracheostomized patients, Even et al. noted bronchial secretion-toserum ratios between 15 and 30%, which also occurred in the
case of patients with impaired renal function (9).
Few investigators have used AUCs to evaluate blood-bronchioalveolar aminoglycoside transport in clinical situations.
Klastersky studied the penetration of netilmicin into bronchial
secretions after intermittent or continuous infusion in tracheostomized patients. There was no difference between the two
regimens, and the AUC ratio was approximately 20% (15). As
indicated in Table 2, the bronchial secretion AUC-to-serum
AUC ratio appeared more important for the od treatment
group than it did for the bid treatment group, but the results
did not reach statistical significance.
Individual variations in concentrations in bronchial secretions were very important. These variations may be explained
by large interindividual variations in peak concentrations in
serum. Many factors contribute to these variations in the case
of critically ill patients, including hemodynamic instability,
variations in the volume of distribution, and age (2, 13).
Other patient-related factors may enhance or reduce bloodbronchioalveolar transport, such as pulmonary perfusion, local
inflammation, paO2 and pH, protein binding, and concentrations of protein and cells in bronchial secretions (5, 17). Moreover, certain sampling method could affect the results, including intrabronchial hemorrhages due to excessive aspiration of
samples.
In summary, many published reports have documented the
fact that conventional twice-daily amikacin administration provides inadequate bronchial concentrations to inhibit gram-negative strains of Acinetobacter spp. and P. aeruginosa for which
MICs are above 6 mg/liter. Our study reveals that therapeutic
concentrations in bronchial secretions are obtained with once-
NOTES