Accepted Manuscript Risk Factors of Multidrug-Resistant, Extensively Drug-Resistant and PandrugResistant Acinetobacter baumannii Ventilator-Associated Pneumonia in a Medical Intensive Care Unit of University Hospital in Thailand Juthamas Inchai, Chalerm Liwsrisakun, Theerakorn Theerakittikul, Romanee Chaiwarith, Weerayut Khositsakulchai, Chaicharn Pothirat PII:
S1341-321X(15)00103-8
DOI:
10.1016/j.jiac.2015.04.010
Reference:
JIC 286
To appear in:
Journal of Infection and Chemotherapy
Received Date: 2 November 2014 Revised Date:
22 April 2015
Accepted Date: 23 April 2015
Please cite this article as: Inchai J, Liwsrisakun C, Theerakittikul T, Chaiwarith R, Khositsakulchai W, Pothirat C, Risk Factors of Multidrug-Resistant, Extensively Drug-Resistant and Pandrug-Resistant Acinetobacter baumannii Ventilator-Associated Pneumonia in a Medical Intensive Care Unit of University Hospital in Thailand, Journal of Infection and Chemotherapy (2015), doi: 10.1016/j.jiac.2015.04.010. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
1
ACCEPTED MANUSCRIPT 1
Risk Factors of Multidrug-Resistant, Extensively Drug-Resistant and Pandrug-
2
Resistant Acinetobacter baumannii Ventilator-Associated Pneumonia in a Medical
3
Intensive Care Unit of University Hospital in Thailand Juthamas Inchaia, Chalerm Liwsrisakun a, Theerakorn Theerakittikula,
4
RI PT
Romanee Chaiwarithb, Weerayut Khositsakulchai c, Chaicharn Pothirat a*
5 6
a
7
Division of Pulmonary, Critical Care and Allergy, Department of Medicine, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand b
10
Division of Infectious Disease, Department of Medicine,
M AN U
9
SC
8
Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand c
11
Department of Medicine, Nakornping Hospital, Chiang Mai, Thailand
12
*
Corresponding author: Mailing address: Division of
TE D
13
Pulmonary, Critical Care and Allergy, Department of Internal Medicine,
15
Faculty of Medicine, Chiang Mai University, Chiang Mai 50200,Thailand.
16
Tel: ＋66-5394-6396, Fax: ＋66-5328-9344,
EP
14
18
E-mail: cpothira＠gmail.com
AC C
17
19
Abstract
20
Ventilator-associated pneumonia (VAP) caused by Acinetobacter baumannii remains a
21
significant cause of morbidity and mortality. Increasing antimicrobial resistance influences
22
the selection of antibiotic treatment especially pandrug-resistant A. baumannii. A
23
retrospective cohort study was conducted in the Medical Intensive Care Unit to identify the
24
risk factors of VAP caused by multidrug-resistant A. baumannii (MDR-AB), extensively
2
ACCEPTED MANUSCRIPT drug-resistant A. baumannii (XDR-AB) and pandrug-resistant A. baumannii (PDR-AB). All
26
337 adult patients with confirmed A. baumannii VAP were included. The incidence of MDR-
27
AB, XDR-AB and PDR-AB were 72 (21.4%), 220 (65.3%) and 12 (3.6%), respectively. The
28
risk factor for MDR-AB was prior use of carbapenems (OR 5.20; 95%CI 1.41-19.17). Risk
29
factors for XDR-AB were the prior use of carbapenems (OR, 6.30; 95% CI, 1.80- 21.97) and
30
a high Sequential Organ Failure Assessment (SOFA) score (OR 1.35; 95% CI 1.07 -1.71). In
31
PDR-AB, the risk factors were the prior use of colistin (OR, 155.95; 95% CI, 8.00-3041.98),
32
carbapenems (OR, 12.84; 95% CI, 1.60-103.20) and a high Simplified Acute Physiology
33
Score (SAPS II) (OR 1.10; 95% CI 1.01-1.22). In conclusion, previous exposure to
34
antibiotics and severity of VAP were risk factors of drug-resistant A.baumannii. Judicious use
35
of carbapenems and colistin is recommended to prevent the antimicrobial-resistant strains of
36
this organism.
M AN U
SC
RI PT
25
37
Keywords: Risk factor; Multidrug-resistant; Extensively drug-resistant; Pandrug-resistant;
39
Acinetobacter baumannii; Ventilator-associated pneumonia (VAP)
40 41
1. Introduction
EP
TE D
38
A. baumannii is a significant cause of nosocomial infections especially ventilator-
43
associated pneumonia (VAP) in critically ill patients. VAP caused by multidrug-resistant
44
A.baumannii (MDR-AB) is shown to be related to high morbidity and mortality in health care
45
settings [1, 2]. In a previous report, A. baumannii was associated with a rapid development
46
of resistance to commonly used antimicrobial agents[3]. The inappropriate use of antibiotics
47
is a major cause of resistance development leading to poor outcomes [4]. Previous studies
48
have shown that longer periods of hospitalization, longer time on mechanical ventilation,
49
prior use of antibiotics, invasive procedures, severity of illness and underlying diseases are
AC C
42
3
ACCEPTED MANUSCRIPT 50
recognized risk factors of VAP caused by MDR-AB and extensively drug-resistant A.
51
baumannii (XDR-AB) infection [1, 3, 5-10]. Some studies reported that A. baumannii has
52
emerged as an XDR organism before moving toward pandrug-resistant A. baumannii (PDR-
53
AB) strains [9, 11, 12] . Although, many previous studies have reported substantial data regarding the risk
RI PT
54
factors of XDR-AB among patients with VAP; reported data from patients in Thailand was
56
limited, especially the risk factors for VAP caused by PDR-AB. Therefore, we conducted this
57
study to identify the risk factors of drug-resistant A.baumannii, particularly PDR-AB in
58
critically ill VAP patients in a university hospital in Thailand.
SC
55
60
2. Patients and methods
61
2.1 study designs
M AN U
59
A retrospective cohort study was conducted in the 40-bed medical ICU at Chiang Mai
63
University Hospital. This is a 1400-bed, tertiary-care, hospital in Northern Thailand. All
64
patients with VAP caused by A. baumannii from January 2005 to December 2011 were
65
selected from an ICU infection control surveillance database. Non-mechanically ventilated
66
hospital-acquired pneumonia and colonization of A. baumannii were excluded from this
67
study.
69 70
EP
AC C
68
TE D
62
The study was approved by the Ethics Committee of the Faculty of Medicine, Chiang
Mai University.
71
2.2 Definitions
72
VAP is defined, according to ATS/IDSA 2005 criteria, as “a new or progressive pulmonary
73
infiltration occurring more than 48 hours after receiving invasive mechanical ventilation or
4
ACCEPTED MANUSCRIPT within 48 hours after extubation, plus at least two of the following: 1) temperature > 38.0๐C
75
or < 36.0๐C; 2) leukocytosis or leukopenia or 3) purulent tracheal secretions or sputum”
76
VAP is classified to be early-onset and late-onset VAP which has onset within the first four
77
days and more than four days after receiving mechanical ventilation (MV), respectively [13].
RI PT
74
78
80
MDR, XDR and PDR A. baumannii
According to the new definition of drug resistance A. baumannii by the European
SC
79
Centre for Disease Prevention and Control (ECDC) and the Center for Disease Control and
82
Prevention (CDC), 2011, MDR-AB is defined as resistance to at least three classes of the
83
following antibiotics: all cephalosporins, aminoglycosides, fluoroquinolones, carbapenems
84
and beta-lactam/beta-lactamase inhibitors; XDR-AB as resistance to all standard
85
antimicrobial agents except colistin or tigecycline; and PDR-AB as resistance to all
86
categories of antimicrobial agents [14].
89
TE D
88
2.3 Microbiological testing
A. baumannii was confirmed by positive microbial cultures of either bronchoalveolar
EP
87
M AN U
81
lavage (BAL) or tracheal aspirate (TA) using a quantitative and semi-quantitative method,
91
respectively. Routine microscopic gram stain was performed before each culture with
92
squamous epithelial cells < 10 cells/low-power field and polymorphornuclear (PMN)
93
leucocytes > 25 cells/low-power field regarded as an adequate specimen. Antimicrobial
94
susceptibility testing for A. baumannii was performed using disk diffusion with the following
95
antibiotics: gentamicin, netilmycin, amikacin, piperacillin/tazobactam,
96
cefoperazone/sulbactam, ceftazidime, cefpirome, cefepime, imipenem, meropenem,
97
ciprofloxacin, colistin and tigecycline, and was interpreted according to the Clinical and
AC C
90
5
ACCEPTED MANUSCRIPT 98
Laboratory Standards Institute (CLSI)[15]. An intermediate susceptibility was considered as
99
resistant.
100 101
2.4 Data collection Baseline characteristics including sex, age, co-morbidities, presence of severe sepsis or
RI PT
102
septic shock according to the 2012 Surviving Sepsis Campaign criteria [16], were collected.
104
The Clinical Pulmonary Infection Score (CPIS) and disease severity assessment, including
105
the Simplified Acute Physiology Score (SAPS II) and the Sequential Organ Failure
106
Assessment (SOFA) score, at the onset of VAP were collected. The length of hospital stay
107
(LOS), mechanical ventilation (MV) days, and the history of previous antibiotic uses within
108
90 days before VAP onset were also recorded. Data were retrieved from electronic medical
109
records.
M AN U
SC
103
111
2.5 Statistical analysis
112
TE D
110
Comparisons among groups were performed using Fisher’s exact test for categorical variables. Continuous variables were analyzed using a one way ANOVA or Kruskal Wallis as
114
appropriate. The polytomous logistic regression was performed to identify the risk factors of
115
MDR-AB, XDR-AB, and PDR-AB in comparison to the reference group (drug-susceptible A.
116
baumannii, DS-AB). The odds ratio (OR) and 95% confidence intervals (CI) were estimated.
117
Variables with a p-value
S1341-321X(15)00103-8
DOI:
10.1016/j.jiac.2015.04.010
Reference:
JIC 286
To appear in:
Journal of Infection and Chemotherapy
Received Date: 2 November 2014 Revised Date:
22 April 2015
Accepted Date: 23 April 2015
Please cite this article as: Inchai J, Liwsrisakun C, Theerakittikul T, Chaiwarith R, Khositsakulchai W, Pothirat C, Risk Factors of Multidrug-Resistant, Extensively Drug-Resistant and Pandrug-Resistant Acinetobacter baumannii Ventilator-Associated Pneumonia in a Medical Intensive Care Unit of University Hospital in Thailand, Journal of Infection and Chemotherapy (2015), doi: 10.1016/j.jiac.2015.04.010. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
1
ACCEPTED MANUSCRIPT 1
Risk Factors of Multidrug-Resistant, Extensively Drug-Resistant and Pandrug-
2
Resistant Acinetobacter baumannii Ventilator-Associated Pneumonia in a Medical
3
Intensive Care Unit of University Hospital in Thailand Juthamas Inchaia, Chalerm Liwsrisakun a, Theerakorn Theerakittikula,
4
RI PT
Romanee Chaiwarithb, Weerayut Khositsakulchai c, Chaicharn Pothirat a*
5 6
a
7
Division of Pulmonary, Critical Care and Allergy, Department of Medicine, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand b
10
Division of Infectious Disease, Department of Medicine,
M AN U
9
SC
8
Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand c
11
Department of Medicine, Nakornping Hospital, Chiang Mai, Thailand
12
*
Corresponding author: Mailing address: Division of
TE D
13
Pulmonary, Critical Care and Allergy, Department of Internal Medicine,
15
Faculty of Medicine, Chiang Mai University, Chiang Mai 50200,Thailand.
16
Tel: ＋66-5394-6396, Fax: ＋66-5328-9344,
EP
14
18
E-mail: cpothira＠gmail.com
AC C
17
19
Abstract
20
Ventilator-associated pneumonia (VAP) caused by Acinetobacter baumannii remains a
21
significant cause of morbidity and mortality. Increasing antimicrobial resistance influences
22
the selection of antibiotic treatment especially pandrug-resistant A. baumannii. A
23
retrospective cohort study was conducted in the Medical Intensive Care Unit to identify the
24
risk factors of VAP caused by multidrug-resistant A. baumannii (MDR-AB), extensively
2
ACCEPTED MANUSCRIPT drug-resistant A. baumannii (XDR-AB) and pandrug-resistant A. baumannii (PDR-AB). All
26
337 adult patients with confirmed A. baumannii VAP were included. The incidence of MDR-
27
AB, XDR-AB and PDR-AB were 72 (21.4%), 220 (65.3%) and 12 (3.6%), respectively. The
28
risk factor for MDR-AB was prior use of carbapenems (OR 5.20; 95%CI 1.41-19.17). Risk
29
factors for XDR-AB were the prior use of carbapenems (OR, 6.30; 95% CI, 1.80- 21.97) and
30
a high Sequential Organ Failure Assessment (SOFA) score (OR 1.35; 95% CI 1.07 -1.71). In
31
PDR-AB, the risk factors were the prior use of colistin (OR, 155.95; 95% CI, 8.00-3041.98),
32
carbapenems (OR, 12.84; 95% CI, 1.60-103.20) and a high Simplified Acute Physiology
33
Score (SAPS II) (OR 1.10; 95% CI 1.01-1.22). In conclusion, previous exposure to
34
antibiotics and severity of VAP were risk factors of drug-resistant A.baumannii. Judicious use
35
of carbapenems and colistin is recommended to prevent the antimicrobial-resistant strains of
36
this organism.
M AN U
SC
RI PT
25
37
Keywords: Risk factor; Multidrug-resistant; Extensively drug-resistant; Pandrug-resistant;
39
Acinetobacter baumannii; Ventilator-associated pneumonia (VAP)
40 41
1. Introduction
EP
TE D
38
A. baumannii is a significant cause of nosocomial infections especially ventilator-
43
associated pneumonia (VAP) in critically ill patients. VAP caused by multidrug-resistant
44
A.baumannii (MDR-AB) is shown to be related to high morbidity and mortality in health care
45
settings [1, 2]. In a previous report, A. baumannii was associated with a rapid development
46
of resistance to commonly used antimicrobial agents[3]. The inappropriate use of antibiotics
47
is a major cause of resistance development leading to poor outcomes [4]. Previous studies
48
have shown that longer periods of hospitalization, longer time on mechanical ventilation,
49
prior use of antibiotics, invasive procedures, severity of illness and underlying diseases are
AC C
42
3
ACCEPTED MANUSCRIPT 50
recognized risk factors of VAP caused by MDR-AB and extensively drug-resistant A.
51
baumannii (XDR-AB) infection [1, 3, 5-10]. Some studies reported that A. baumannii has
52
emerged as an XDR organism before moving toward pandrug-resistant A. baumannii (PDR-
53
AB) strains [9, 11, 12] . Although, many previous studies have reported substantial data regarding the risk
RI PT
54
factors of XDR-AB among patients with VAP; reported data from patients in Thailand was
56
limited, especially the risk factors for VAP caused by PDR-AB. Therefore, we conducted this
57
study to identify the risk factors of drug-resistant A.baumannii, particularly PDR-AB in
58
critically ill VAP patients in a university hospital in Thailand.
SC
55
60
2. Patients and methods
61
2.1 study designs
M AN U
59
A retrospective cohort study was conducted in the 40-bed medical ICU at Chiang Mai
63
University Hospital. This is a 1400-bed, tertiary-care, hospital in Northern Thailand. All
64
patients with VAP caused by A. baumannii from January 2005 to December 2011 were
65
selected from an ICU infection control surveillance database. Non-mechanically ventilated
66
hospital-acquired pneumonia and colonization of A. baumannii were excluded from this
67
study.
69 70
EP
AC C
68
TE D
62
The study was approved by the Ethics Committee of the Faculty of Medicine, Chiang
Mai University.
71
2.2 Definitions
72
VAP is defined, according to ATS/IDSA 2005 criteria, as “a new or progressive pulmonary
73
infiltration occurring more than 48 hours after receiving invasive mechanical ventilation or
4
ACCEPTED MANUSCRIPT within 48 hours after extubation, plus at least two of the following: 1) temperature > 38.0๐C
75
or < 36.0๐C; 2) leukocytosis or leukopenia or 3) purulent tracheal secretions or sputum”
76
VAP is classified to be early-onset and late-onset VAP which has onset within the first four
77
days and more than four days after receiving mechanical ventilation (MV), respectively [13].
RI PT
74
78
80
MDR, XDR and PDR A. baumannii
According to the new definition of drug resistance A. baumannii by the European
SC
79
Centre for Disease Prevention and Control (ECDC) and the Center for Disease Control and
82
Prevention (CDC), 2011, MDR-AB is defined as resistance to at least three classes of the
83
following antibiotics: all cephalosporins, aminoglycosides, fluoroquinolones, carbapenems
84
and beta-lactam/beta-lactamase inhibitors; XDR-AB as resistance to all standard
85
antimicrobial agents except colistin or tigecycline; and PDR-AB as resistance to all
86
categories of antimicrobial agents [14].
89
TE D
88
2.3 Microbiological testing
A. baumannii was confirmed by positive microbial cultures of either bronchoalveolar
EP
87
M AN U
81
lavage (BAL) or tracheal aspirate (TA) using a quantitative and semi-quantitative method,
91
respectively. Routine microscopic gram stain was performed before each culture with
92
squamous epithelial cells < 10 cells/low-power field and polymorphornuclear (PMN)
93
leucocytes > 25 cells/low-power field regarded as an adequate specimen. Antimicrobial
94
susceptibility testing for A. baumannii was performed using disk diffusion with the following
95
antibiotics: gentamicin, netilmycin, amikacin, piperacillin/tazobactam,
96
cefoperazone/sulbactam, ceftazidime, cefpirome, cefepime, imipenem, meropenem,
97
ciprofloxacin, colistin and tigecycline, and was interpreted according to the Clinical and
AC C
90
5
ACCEPTED MANUSCRIPT 98
Laboratory Standards Institute (CLSI)[15]. An intermediate susceptibility was considered as
99
resistant.
100 101
2.4 Data collection Baseline characteristics including sex, age, co-morbidities, presence of severe sepsis or
RI PT
102
septic shock according to the 2012 Surviving Sepsis Campaign criteria [16], were collected.
104
The Clinical Pulmonary Infection Score (CPIS) and disease severity assessment, including
105
the Simplified Acute Physiology Score (SAPS II) and the Sequential Organ Failure
106
Assessment (SOFA) score, at the onset of VAP were collected. The length of hospital stay
107
(LOS), mechanical ventilation (MV) days, and the history of previous antibiotic uses within
108
90 days before VAP onset were also recorded. Data were retrieved from electronic medical
109
records.
M AN U
SC
103
111
2.5 Statistical analysis
112
TE D
110
Comparisons among groups were performed using Fisher’s exact test for categorical variables. Continuous variables were analyzed using a one way ANOVA or Kruskal Wallis as
114
appropriate. The polytomous logistic regression was performed to identify the risk factors of
115
MDR-AB, XDR-AB, and PDR-AB in comparison to the reference group (drug-susceptible A.
116
baumannii, DS-AB). The odds ratio (OR) and 95% confidence intervals (CI) were estimated.
117
Variables with a p-value
