AAC Accepts, published online ahead of print on 29 September 2014 Antimicrob. Agents Chemother. doi:10.1128/AAC.03510-14 Copyright © 2014, American Society for Microbiology. All Rights Reserved.
1
Comparison of intra-pulmonary and systemic pharmacokinetics of
2
colistinmethansulphonate (CMS) and colistin after aerosol delivery and intravenous
3
administration of CMS in critically ill patients
4 5 6
Matthieu Boisson1,2*, Matthieu Jacobs2,3*, Nicolas Grégoire2,3, Patrice Gobin1,2, Sandrine Marchand1,2,3, William Couet1,2,3#, Olivier Mimoz1,2,3
7 8
* Matthieu Boisson and Matthieu Jacobs contributed equally to this paper
9
1
CHU Poitiers, Poitiers, France.
10
2
INSERM U1070, Poitiers, France.
11
3
Université de Poitiers, Poitiers, France.
12 13 14
Key words:colistin, pharmacokinetics, aerosol delivery, critical care patients
15 16
Running title: Pharmacokinetics of nebulized colistin in critical care patients
17
18
# Corresponding author.W Couet. Mailing address: INSERM U1070, Pôle Biologie Santé
19
(PBS), Médecine-Sud, Niveau 1, 40 Avenue du Recteur Pineau, 86022 Poitiers Cedex,
20
France. Phone : 33- 5-49-45-43-79 Email : [email protected]
21 22 23
24
Abstract :
25
Colistin is an old antibiotic that has recently gained a considerable renew of interest for the
26
treatment of pulmonary infections due to Multi Drug Resistant Gram-negative bacteria.
27
Nebulization seems promising for this application but colistin is administered as an inactive
28
prodrug, colistin methanesulfonate (CMS), but differences between intrapulmonary
29
concentrations of the active moiety as a function of the route of administration in critically ill
30
patients, have not been precisely documented. CMS and colistin concentrations were
31
measured on two separate occasions within plasma and epithelial lining fluid (ELF) of
32
critically ill patients (n=12) who had received 2 MIU of CMS by aerosol delivery and then
33
intravenous administration. The pharmacokinetic analysis was conducted using a population
34
approach and completed by pharmacokinetic-pharmacodynamic(PK-PD) modelling and
35
simulations. ELF colistin concentrations varied considerably (9.53 - 1137 mg/L) but
36
were much higher than in plasma (0.15 - 0.73 mg/L) after aerosol delivery, but not after
37
intravenous administrationof CMS.Following CMS aerosol delivery, typically 9% of the
38
CMS dose reached the ELF, and only 1.4 % was converted into colistin pre-systemically.
39
PK-PD analysis concluded to a much higher antimicrobial efficacy after CMS aerosol
40
delivery than intravenous administration. These new data seem to support the use of
41
CMS aerosol delivery for the treatment of pulmonary infections in critical care patients.
42 43
Introduction:
44 45
Aerosol delivery of antibiotics for the treatment of pulmonary infections has recently gained
46
considerable attention and approval have been obtained worldwide for several compounds including
47
tobramycin (1, 2), aztreonam (3) and colistin (4, 5). Dry powders formulas have been optimized and at
48
the same time new generation of pocket nebulizers were developed to favor antibiotics aerosol
49
delivery in ambulatory patients such as cystic fibrosis patient in order to improve their quality of life.
50
However antibiotics aerosol delivery for the treatment of nosocomial pulmonary infections is also
51
quite popular. Yet there is no general consensus and in practice it is quite difficult to provide clinical
52
evidence demonstrating the superiority of antibiotics aerosol delivery over other routes of
53
administrations in critically ill patients. Therefore comparison of antibiotics concentrations at the site
54
of infection after intravenous administration and aerosol delivery, followed by prediction of the
55
resulting antimicrobial activity using modern pharmacokinetic-pharmacodynamic (PK-PD) modeling
56
approaches may provide valuable information. Numerous physico-chemical parameters including
57
particule size, aerodynamic diameter, density, charge… that are in part determined by the type of
58
aerosol generator, determine how much of the drug may reach the alveolar space after aerosol
59
delivery. However patient physio-pathology, such as impaired expiratory airflow or atelectasis may
60
also have a major impact on antibiotic distribution within the lung after aerosol delivery. Overall only
61
a limited fraction of the inhaled dose is likely to reach the target and then antibiotics characteristics
62
such as solubility, permeability and affinity for efflux transport system present at the blood alveolar
63
barrier will also determine intra-pulmonary concentration versus time profile. Eventually PK-PD
64
characteristics that vary among antibiotics must also been considered for aerosol treatment
65
optimization. Albeit this relative complexity, promising results have been obtained with colistin after
66
nebulization in rats by several groups including our’s (6, 7) and the objective of this new study was to
67
describe the pharmacokinetics of colistin after CMS aerosol delivery for treating pulmonary infections
68
in critically ill patients.
69
70 71
Material and Methods
72
Study population
73
The study was performed in 12 adult patients hospitalized in intensive care unit (ICU) of University
74
Hospital of Poitiers, France, who developed ventilator-associated pneumonia during their stay,
75
between october 2011 and august 2012. Patients were eligible if they were aged between 18 and 85
76
years, were intubated and had a pneumonia caused by gram negative bacteria sensitive to colistin.
77
Patients were not eligible if they had received colistin within 7 days prior to study, had creatinine
78
clearance < 30 ml/min, had personal or family history of myasthenia. At study onset, the following
79
data were collected: age, sex, weight, diagnosis on admission, serum urea, serum creatinine,
80
Simplified Acute Physiology Score (SAPS II), Sequential Organ Failure Assessment score (SOFA).
81
Creatinine clearance was calculated according to the Cockroft-Gault formula (8). The study protocol
82
was approved by the local ethical committee (CPP Ouest III, approval number 2009009578-28). In all
83
patients informed consent was obtained from their nearest relatives prior to initiation of the study. A
84
total of 6 women and 6 men were enrolled. Their demographic, clinical and biological data are shown
85
in Table 1.
86 87
CMS administration
88
Patients were treated with CMS (Colimycine, Sanofi, Paris, France). Treatment was initiated with a 2
89
million International Unit (MIU) dose of CMS corresponding to 160 mg of CMS sulfate or 60 mg of
90
colistin based activity (CBA) (9) dissolved in 10 mL of saline and nebulized over 30 min via a
91
vibrating-mesh nebulizer (Aeroneb Pro, Aerogen, Galway, France).Thus 8h later the same dose of
92
CMS was dissolved in 50 mL of saline and infused intravenously (IV) over 60 min. Intravenous
93
administrations were then repeated every 8 h until the end of treatment or therapeutic de-escalation.
94
CMS solutions were prepared extemporaneously.
95 96
Sampling procedures
97
Blood samples
98
Blood samples were collected immediately before and at 0.33, 0.66, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7 and 8 h
99
after the beginning of aerosol delivery and after starting the first intravenous infusion via a distinct
100
line. Two extra blood samples were collected at steady state, at the same time as the BAL. Blood
101
samples were immediately centrifuged (3 000 g, 10 min) at 4°C and plasma was stored at -80°C until
102
analysis.
103 104
BAL samples
105
Mini-boncho alveolar lavage (mini-BAL) was performed as previously described (10). Mini-BAL
106
were performed with a 16 Fr diameter double sterile catheter (BAL, KimVent, Kimberly-Clark,
107
Roswell, GA) inserted through the endotracheal tube. Two 20-mL aliquots of saline solution were
108
instilled and then immediately aspirated with a syringe, these two BAL samples were pooled and
109
rapidly centrifuged (3 000 g, 10 min) and supernatants were stored at -80°C until analysis. For Patients
110
1 to 6, mini-BAL was performed at 1 h and 3 h after initiating aerosol delivery and then at steady state,
111
2 to 3 days later, 1 h and 3 h after starting the nth intravenous infusion(7
1
Comparison of intra-pulmonary and systemic pharmacokinetics of
2
colistinmethansulphonate (CMS) and colistin after aerosol delivery and intravenous
3
administration of CMS in critically ill patients
4 5 6
Matthieu Boisson1,2*, Matthieu Jacobs2,3*, Nicolas Grégoire2,3, Patrice Gobin1,2, Sandrine Marchand1,2,3, William Couet1,2,3#, Olivier Mimoz1,2,3
7 8
* Matthieu Boisson and Matthieu Jacobs contributed equally to this paper
9
1
CHU Poitiers, Poitiers, France.
10
2
INSERM U1070, Poitiers, France.
11
3
Université de Poitiers, Poitiers, France.
12 13 14
Key words:colistin, pharmacokinetics, aerosol delivery, critical care patients
15 16
Running title: Pharmacokinetics of nebulized colistin in critical care patients
17
18
# Corresponding author.W Couet. Mailing address: INSERM U1070, Pôle Biologie Santé
19
(PBS), Médecine-Sud, Niveau 1, 40 Avenue du Recteur Pineau, 86022 Poitiers Cedex,
20
France. Phone : 33- 5-49-45-43-79 Email : [email protected]
21 22 23
24
Abstract :
25
Colistin is an old antibiotic that has recently gained a considerable renew of interest for the
26
treatment of pulmonary infections due to Multi Drug Resistant Gram-negative bacteria.
27
Nebulization seems promising for this application but colistin is administered as an inactive
28
prodrug, colistin methanesulfonate (CMS), but differences between intrapulmonary
29
concentrations of the active moiety as a function of the route of administration in critically ill
30
patients, have not been precisely documented. CMS and colistin concentrations were
31
measured on two separate occasions within plasma and epithelial lining fluid (ELF) of
32
critically ill patients (n=12) who had received 2 MIU of CMS by aerosol delivery and then
33
intravenous administration. The pharmacokinetic analysis was conducted using a population
34
approach and completed by pharmacokinetic-pharmacodynamic(PK-PD) modelling and
35
simulations. ELF colistin concentrations varied considerably (9.53 - 1137 mg/L) but
36
were much higher than in plasma (0.15 - 0.73 mg/L) after aerosol delivery, but not after
37
intravenous administrationof CMS.Following CMS aerosol delivery, typically 9% of the
38
CMS dose reached the ELF, and only 1.4 % was converted into colistin pre-systemically.
39
PK-PD analysis concluded to a much higher antimicrobial efficacy after CMS aerosol
40
delivery than intravenous administration. These new data seem to support the use of
41
CMS aerosol delivery for the treatment of pulmonary infections in critical care patients.
42 43
Introduction:
44 45
Aerosol delivery of antibiotics for the treatment of pulmonary infections has recently gained
46
considerable attention and approval have been obtained worldwide for several compounds including
47
tobramycin (1, 2), aztreonam (3) and colistin (4, 5). Dry powders formulas have been optimized and at
48
the same time new generation of pocket nebulizers were developed to favor antibiotics aerosol
49
delivery in ambulatory patients such as cystic fibrosis patient in order to improve their quality of life.
50
However antibiotics aerosol delivery for the treatment of nosocomial pulmonary infections is also
51
quite popular. Yet there is no general consensus and in practice it is quite difficult to provide clinical
52
evidence demonstrating the superiority of antibiotics aerosol delivery over other routes of
53
administrations in critically ill patients. Therefore comparison of antibiotics concentrations at the site
54
of infection after intravenous administration and aerosol delivery, followed by prediction of the
55
resulting antimicrobial activity using modern pharmacokinetic-pharmacodynamic (PK-PD) modeling
56
approaches may provide valuable information. Numerous physico-chemical parameters including
57
particule size, aerodynamic diameter, density, charge… that are in part determined by the type of
58
aerosol generator, determine how much of the drug may reach the alveolar space after aerosol
59
delivery. However patient physio-pathology, such as impaired expiratory airflow or atelectasis may
60
also have a major impact on antibiotic distribution within the lung after aerosol delivery. Overall only
61
a limited fraction of the inhaled dose is likely to reach the target and then antibiotics characteristics
62
such as solubility, permeability and affinity for efflux transport system present at the blood alveolar
63
barrier will also determine intra-pulmonary concentration versus time profile. Eventually PK-PD
64
characteristics that vary among antibiotics must also been considered for aerosol treatment
65
optimization. Albeit this relative complexity, promising results have been obtained with colistin after
66
nebulization in rats by several groups including our’s (6, 7) and the objective of this new study was to
67
describe the pharmacokinetics of colistin after CMS aerosol delivery for treating pulmonary infections
68
in critically ill patients.
69
70 71
Material and Methods
72
Study population
73
The study was performed in 12 adult patients hospitalized in intensive care unit (ICU) of University
74
Hospital of Poitiers, France, who developed ventilator-associated pneumonia during their stay,
75
between october 2011 and august 2012. Patients were eligible if they were aged between 18 and 85
76
years, were intubated and had a pneumonia caused by gram negative bacteria sensitive to colistin.
77
Patients were not eligible if they had received colistin within 7 days prior to study, had creatinine
78
clearance < 30 ml/min, had personal or family history of myasthenia. At study onset, the following
79
data were collected: age, sex, weight, diagnosis on admission, serum urea, serum creatinine,
80
Simplified Acute Physiology Score (SAPS II), Sequential Organ Failure Assessment score (SOFA).
81
Creatinine clearance was calculated according to the Cockroft-Gault formula (8). The study protocol
82
was approved by the local ethical committee (CPP Ouest III, approval number 2009009578-28). In all
83
patients informed consent was obtained from their nearest relatives prior to initiation of the study. A
84
total of 6 women and 6 men were enrolled. Their demographic, clinical and biological data are shown
85
in Table 1.
86 87
CMS administration
88
Patients were treated with CMS (Colimycine, Sanofi, Paris, France). Treatment was initiated with a 2
89
million International Unit (MIU) dose of CMS corresponding to 160 mg of CMS sulfate or 60 mg of
90
colistin based activity (CBA) (9) dissolved in 10 mL of saline and nebulized over 30 min via a
91
vibrating-mesh nebulizer (Aeroneb Pro, Aerogen, Galway, France).Thus 8h later the same dose of
92
CMS was dissolved in 50 mL of saline and infused intravenously (IV) over 60 min. Intravenous
93
administrations were then repeated every 8 h until the end of treatment or therapeutic de-escalation.
94
CMS solutions were prepared extemporaneously.
95 96
Sampling procedures
97
Blood samples
98
Blood samples were collected immediately before and at 0.33, 0.66, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7 and 8 h
99
after the beginning of aerosol delivery and after starting the first intravenous infusion via a distinct
100
line. Two extra blood samples were collected at steady state, at the same time as the BAL. Blood
101
samples were immediately centrifuged (3 000 g, 10 min) at 4°C and plasma was stored at -80°C until
102
analysis.
103 104
BAL samples
105
Mini-boncho alveolar lavage (mini-BAL) was performed as previously described (10). Mini-BAL
106
were performed with a 16 Fr diameter double sterile catheter (BAL, KimVent, Kimberly-Clark,
107
Roswell, GA) inserted through the endotracheal tube. Two 20-mL aliquots of saline solution were
108
instilled and then immediately aspirated with a syringe, these two BAL samples were pooled and
109
rapidly centrifuged (3 000 g, 10 min) and supernatants were stored at -80°C until analysis. For Patients
110
1 to 6, mini-BAL was performed at 1 h and 3 h after initiating aerosol delivery and then at steady state,
111
2 to 3 days later, 1 h and 3 h after starting the nth intravenous infusion(7
