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Predictors of insufficient amikacin peak concentration in critically ill
patients receiving a 25mg/kg total body weight regimen
Etienne de Montmollin, MD1; Lila Bouadma, MD, PhD1; Nathalie Gault, MD2, 3, 4; Bruno Mourvillier, MD1;
Eric Mariotte, MD1; Sarah Chemam, MD1; Laurent Massias, PharmD5; Emmanuelle Papy, PharmD5;
Florence Tubach, MD, PhD2, 3, 4; Michel Wolff, MD1; Romain Sonneville, MD1
1
Service de Réanimation Médicale et des Maladies infectieuse, Hôpital Bichat–Claude-Bernard, Assistance
Publique–Hôpitaux de Paris, Université Paris Diderot, PRES Sorbonne Paris Cité, Paris, France
2
Département d'Epidémiologie et Recherche Clinique, Hôpital Bichat–Claude-Bernard, Assistance Publique–
Hôpitaux de Paris, 75018 Paris, France
3
INSERM CIC 1425-EC, UMR 1123 ECEVE, 75018 Paris, France
4
Université Paris Diderot, PRES Sorbonne Paris Cité, UMR 1123 ECEVE, 75018 Paris, France
5
Pharmacie, Hôpital Bichat-Claude Bernard, Assistance Publique-Hôpitaux de Paris, Université Paris Diderot,
PRES Sorbonne Paris cité, Paris, France.
Table 1s: Microbiological characteristics of the 181 episodes of amikacin initiation
Variable
Reason for antibiotherapy initiation
Severe sepsis/Septic shock
Acute respiratory failure
Others
Site of infection (n=181)
Pulmonary
Intra-abdominal
Urinary tract
Primary blood stream infection
Mediastinal
Skin and soft tissue
Others
Identified pathogens (n=114)*
Gram positive cocci
Staphylococcus aureus
Enterococcus sp
Streptococcus sp
Enterobacteriacae
Escherichia coli
Klebsiella sp
Enterobacter sp
Proteus sp
Serratia sp
Citrobacter sp
Morganella sp
Non-fermentive gram-negative bacilli
Pseudomonas aeruginosa
Acinetobacter sp
Stenotrophomonas maltophilia
Other pathogens
Duration of antibiotic therapy (days)
Number of amikacin infusions
Treatment failure (n=116)
n (%) or median [IQR]
111 (61.3)
33 (18.2)
37 (20.4)
120 (66.3)
10 (5.5)
11 (6.1)
8 (4.4)
2 (1.1)
5 (2.8)
3 (1.7)
23 (20.2)
8
12
3
67 (58.8)
19
12
17
6
6
4
3
35 (30.7)
28
4
3
12 (10.5)
8 [3 – 8]
1 [1 – 1]
7 (6.0)
* Total is more than 100% since more than one pathogen could be identified for a single patient.
Abbreviations: IQR, interquartile range
Table 2s: Univariate analysis of predictive factors of amikacin Cmax<60mg/L
Variable
n (%) or median [IQR]
Demographic data at ICU admission
Male gender
Age (years)
BMI (kg/m2)
Inclusion period, by quarter
1st
2nd
3rd
4th
Type of patient
Medical
Scheduled surgery
Unscheduled surgery
Reason for admission
Severe sepsis/septic shock
Cardiogenic shock
Acute respiratory distress
Cardiac surgery
Cardiac arrest
Acute renal failure
Comorbidities†
Chronic heart failure
Diabetes
Cirrhosis
Terminal renal failure
COPD
HIV positive
Ongoing cancer
Chronic health status (Knaus scale)
Normal health status
Mild limitation
Important limitation
Major restriction
SAPS II
Cmax<60mg/L
n=60
Cmax≥60mg/L
n=121
44 (73.3)
61.5 [49.8-67.3]
22.8 [20.3-26.5]
87 (71.9)
62 [51-72]
25.1 [23.1-30.1]
30 (50)
11 (18.3)
6 (10)
13 (21.7)
24 (19.8)
31 (25.6)
28 (23.1)
38 (31.4)
p
0.84
0.60
0.02*
<0.001*
0.44
48 (80)
5 (8.3)
7 (11.7)
90 (74.4)
8 (6.6)
23 (19)
0.40
17 (28.3)
13 (21.7)
18 (30)
10 (16.7)
1 (1.7)
0
29 (24)
16 (13.2)
37 (30.6)
24 (19.8)
5 (4.1)
5 (4.1)
24 (40)
9 (15)
8 (13.3)
5 (8.3)
8 (13.3)
7 (11.7)
7 (11.7)
44 (36.4)
31 (25.6)
4 (3.3)
10 (8.3)
11 (9.1)
9 (7.4)
8 (6.6)
13 (21.7)
28 (46.7)
19 (31.7)
0
52 [37-66.3]
36 (29.8)
51 (42.1)
33 (27.3)
1 (0.8)
51 [41-68]
*: p<0.1.
† Total is more than 100% since patients could have more than one comorbidity
Abbreviations: IQR, Interquartile range; BMI, Body Mass Index; COPD, Chronic Obstructive
Pulmonary Disease; SAPS, Simplified Acute Physiology Score.
0.63
0.11
0.03*
0.79
0.38
0.35
0.38
0.59
0.58
Table 2s (continued): Univariate analysis of predictive factors of amikacin Cmax<60mg/L
Variable
n (%) or median [IQR]
Data at inclusion
Time between ICU admission and Cmax (days)
SOFA score at inclusion ≥ 8
Cmax<60mg/L
n=60
Cmax≥60mg/L
n=121
3 [0.8-15]
35 (58.3)
5 [1-13]
69 (57)
0.59
0.87
Need for catecholamine
44 (73.3)
75 (62)
0.13
ECMO
8 (13.3)
20 (16.5)
0.58
Glasgow score <15
23 (38.3)
52 (43)
0.55
Mechanical ventilation
51 (85)
99 (81.8)
0.59
PEEP (cmH2O)
6 [5-8]
6 [5-8]
0.71
Plateau pressure (cmH2O)
24 [21-28]
22 [19-28]
0.34
DIC
8 (13.3)
11 (9.1)
0.38
GFR (mL/min)
0 [0-35.6]
0 [0-36.4]
0.94
RIFLE
p
0.83
Normal renal function
18 (30)
37 (30.6)
Risk
9 (15)
14 (11.6)
Injury
10 (16.7)
14 (11.6)
Failure
17 (28.3)
41 (33.9)
Loss
2 (3.3)
3 (2.5)
End stage
4 (6.7)
12 (9.9)
8 (13.3)
6 (5)
0.09*
PaO2/FiO2 ratio
215 [134-302]
228 [141-322]
0.60
Albuminemia (g/L)
18.7 [16.2-21.7]
20.2 [16-24.5]
0.57
Lactates (mmol/L)
1.7 [1-2.6]
1.8 [1.2-3.2]
0.78
550 [-450 – 2450]
1550 [500 – 3060]
300 [0 – 1025]
675 [220 – 1100]
-1.74 [-5.9 – 1.1]
-1.6 [-7.3 – 0.8]
-500 [-1600 – 650]
950 [75 – 2000]
200 [-220 – 1000]
500 [0 – 1500]
-1.6 [-6.3 – 1.8]
-1.4[-5.6 – 1.7]
<0.01*
0.03*
0.53
0.45
0.79
0.19
0.23
42 (70)
8 (13.3)
10 (16.7)
69 (57)
25 (20.7)
27 (22.3)
40 (66.7)
4 (6.7)
3 (5)
2 (3.3)
80 (66.7)
6 (5)
8 (6.6)
6 (5)
Ascites
Biology
Hemodilution parameters
24-hour fluid balance (mL)
24-hour fluid intake (mL)
6-hour fluid balance (mL)
6-hour fluid intake (mL)
24-hour hematocrit delta (%)
24-hour proteinemia delta (%)
Reason for antibiotherapy initiation
Severe sepsis/Septic shock
Acute respiratory failure
Others
Site of infection
Lung
Digestive
Urinary tract
Primary bacteremia
0.90
Mediastinum
Skin and soft tissue
Others
1 (1.7)
2 (3.3)
8 (13.3)
1 (0.8)
3 (2.5)
17 (14)
*: p<0.1.
Abbreviations: IQR, Interquartile range; SOFA, Sequential Organ Failure Assessment; ECMO, Extra Corporeal
Membrane Oxygenation; DIC, Disseminated Intravascular Coagulation; GFR, Glomerular Filtration Rate.
Table 3s: Univariate analysis of outcomes at ICU and hospital discharge or death, depending on
Cmax<60mg/L
Variable
n (%) or median [IQR]
Cmax<60mg/L
Cmax≥60mg/L
N=60
N=121
p
Hospital mortality at day 14
16 (26.7)
16 (13.2)
0.03
Patients discharged alive from ICU at day 14
18 (30)
30 (24.8)
0.18
All ICU survivors (n=77)
8.5 [5-41]
13 [8-22.5]
0.49
ICU survivors with confirmed infection (n=54)
9 [5-37]
13 [7.5-22.5]
0.63
All ICU survivors (n=56)
3 [1-36]
6 [1-23]
0.29
ICU survivors with confirmed infection (n=37)
2.5 [1-35]
2 [1-11.5]
0.16
All ICU survivors (n=51)
3.5 [2-34]
10 [5-18]
0.23
ICU survivors with confirmed infection (n=33)
3 [2-34]
10 [5-24]
0.84
12 (42.9)
27 (45.8)
0.80
Duration of mechanical ventilation (days)
Duration of renal replacement therapy (days)
Duration of catecholamine treatment (days)
AKI at ICU discharge
Abbreviations: IQR, Interquartile range; AKI, Acute Kidney Injury
Figure 1s: Graphical representations of identified risk factors for amikacin Cmax<60mg/L, depending
on inclusion period.
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