Prospective study of risk factors for ventilator-associatedpneumonia caused by Acinetobacter species

Julio Medina MDa,*, Carlos Formento MDb, Julio Pontet MDb,c, Andrea Curbelo MDd,Cristina Bazet MDe,f, Jorge Gerez MDd, Eduardo Larranaga MDd

aCatedra de Enfermedades Infecciosas, Instituto de Higiene, Facultad de Medicina, Universidad de la Republica,

Montevideo CP 11600, UruguaybUnidad Cuidados Intensivos del Hospital Pasteur, Montevideo, UruguaycPhysiology Department, Facultad de Medicina, Universidad de la Republica, Montevideo, UruguaydUnidad Cuidados Intensivos del Hospital Policial, Montevideo, UruguayeLaboratorio Clınico, Departamento de Microbiologıa, Hospital de Clınicas, Facultad de Medicina,

Universidad de la Republica, Montevideo, UruguayfLaboratorio de Microbiologıa, Hospital Pasteur, Montevideo, Uruguay

0883-9441/$ – see front matter D 2007

doi:10.1016/j.jcrc.2006.06.010

* Corresponding author. Tel.: +598

E-mail address: jcmedina@hc.edu.u

Keywords:Ventilator-associated

pneumonia;

Acinetobacter spp;

Intensive care unit;

Antibiotics;

Specific risk factors;

Prospective cohort study

AbstractSummary: The incidence of ventilator-associated pneumonia (VAP) by Acinetobacter spp (VAPA) is

increasing and has high morbidity and mortality. It is imperative to identify risk factors to be able to use

prevention policies.

Objective: The aim of this study was to identify specific risk factors for VAPA.

Design: Prospective cohort study.

Interventions: None.Setting: Two medical-surgical intensive care units.

Measurements: During a period of 36 months, all patients with more than 48 hours on mechanical

ventilation and suspected of having a VAP were enrolled. Only VAP with microbiological confirmation

was analyzed.

Results: Two hundred eighteen consecutive patients with clinical suspicion of VAP were enrolled.

One hundred twenty-five VAPs were confirmed by culture—46 by Acinetobacter spp and 79 by

other pathogens.

The 36 potential risk factors for Acinetobacter spp were analyzed by univariate analysis.

Logistic regression identified previous use of ceftriaxone (relative risk, 5.1; 95% confidence interval,

1.47-17.82) and previous use of ciprofloxacin (relative risk, 9.1; 95% confidence interval, 2.29-36.63)

as significant independent predictors for the development of VAPA.

Conclusions: Previous use of ceftriaxone and ciprofloxacin are independent risk factors for the

development of VAPA.

D 2007 Elsevier Inc. All rights reserved.

Journal of Critical Care (2007) 22, 18–27

Elsevier Inc. All rights reserved.

2 4876981; fax: +598 2 4876981.

y (J. Medina).

Prospective study of risk factors for VAP caused by Acinetobacter species 19

1. Introduction

Although there are various studies evaluating risk factors

associated to ventilator-associated pneumonia (VAP) by

Acinetobacter spp (VAPA), only a few are prospective or

case-control. The number of enrolled patients with VAPA is

also small in some studies [1-4].

With respect to mortality, there are authors that still

question the attributable mortality due to VAPA [5].

Although, some studies have showed increased mortality

[6] and even a 5-fold increase in mortality risk [7].

Infections by Acinetobacter spp determine new resis-

tance patterns forcing the use of broad-spectrum antibiotics,

which, in turn, increases economic costs and helps the

emergency of new multiresistant pathogens [8,9].

Acinetobacter spp is a nonfermentative, oxidase-

negative, aerobic, Gram-negative coccobacilli. It is an

ubiquitous resident, which grows preferably in moist

environment and has been isolated in food and inanimate

objects such as tap water faucets, sinks, bedside urinals,

hospital air, andmedical equipment. Little is known regarding

the pathogenesis of Acinetobacter spp infection [10,11].

To be able to develop prevention strategies, risk factors

related to VAPAwere sought: head trauma, acute respiratory

distress syndrome (ARDS), neurosurgery, copious pulmo-

nary aspiration, Glasgow Coma Scale (GCS) score of 9 or

lower, previous infection, severity of illness, previous use of

antibiotics (especially ceftazidime), and intravenous use

of fluorquinolones [1-4,12,13]. The emergency and spread

of Acinetobacter spp vary in each hospital, depending on

these factors.

However, there was a progressive increase of the

incidence of VAPA in our intensive care unit (ICU) without

a clear relation to the classic risk factors. Our aim was to

prospectively identify other specific risk factors for VAPA.

Table 1 Criteria for the diagnosis of VAP

1. New and persistent infiltrate in CXR

2. 2 or more of the following criteria:

Rectal temperature z 38.58C or b368CLeucocytosis z12 � 103 /mm3 or V4 � 103/mm3

Purulent respiratory secretions

3. 1 or more of the following:

BAL z104 CFU/mL

Positive tracheal aspirates plus CPIS N6

Microorganism isolated in z2 blood cultures with

identical sensitivity to tracheal secretions and in absence of

other possible infection

Positive culture of pleural fluid in absence of previous

pleural instrumentation

VAP was considered suspected when I and II were positive. VAP was

considered confirmed when 1, 2, and 3 were positive. BAL,

bronchoalveolar lavage; CXR, chest x-ray.

2. Materials and methods

2.1. Study design

Prospective cohort study.

2.2. Patient selection

This study was conducted during a 36-month

period (from May 2000 to May 2003) in 2 ICUs at Hospital

Pasteur and Hospital Policial in Montevideo, Uruguay.

Hospital Pasteur is a 23-bed medical-surgical ICU with

10 ventilated beds. Hospital Policial is a 14-bed medical-

surgical ICU with 8 ventilated beds. Hospital Pasteur is a

general surgical ICU but differing from Hospital Policial; it

does not include neurosurgery.

2.3. Inclusion criteria

All successive patients with 48 hours or more on

mechanical ventilation and suspected of having a VAP were

enrolled [14].

Only VAP with microbiological confirmation were

analyzed and divided into 2 sets—VAPA and VAP by

other pathogens.

Only the first episode of VAP was considered to avoid

the wrong diagnosis of VAP with a previous radio-

logic image.

2.4. Exclusion criteria

All nonconfirmed VAP and VAP developed within

48 hours of admission in patients transferred from other

centers were excluded.

2.5. Diagnosis of VAP

The diagnostic criteria for VAP used in this study were

modified from those established by the American College of

Chest Physicians [24] and the ones used by Ibrahim et al

[15,16]. These criteria are presented on Table 1.

The most common diagnostic criteria were bronchoal-

veolar lavage of 104 CFU/mL or higher and a positive

tracheal aspirate plus clinical pulmonary infection score

(CPIS) higher than 6, adapted by Flanagan et al [17].

For processing endotracheal aspirates, we used a

semiquantitative culture method. For semiquantitative

analysis, purulent aspirate was inoculated in conventional

agar media. The number of colony forming units (CFU)

was determined by the 4-quadrant method and classified

as follows: no growth, 1+, 2+, 3+, or 4+ [18]. The bacterial

growth in 1, 2, or 3 quadrants of the culture dishes was not

taken into account. Only the 4-quadrant growth was

considered because it had a good correlation with

quantitative methods and was equivalent to 106 CFU or

higher [19].

Patients with bronchoalveolar lavage below 10 4 CFU/

mL were not included.

When it was not possible to perform a bronchoalveolar

lavage, the diagnosis of VAP was done with tracheal

aspirate plus CPIS higher than 6.

J. Medina et al.20

2.6. Definitions

Consensus definitions for ARDS, severe sepsis, and

septic shock were used [20,21]. Community-acquired

pneumonia (CAP) was considered severe, using criteria

described by Ewig et al [22]. Patients with CAP and

multiple organ dysfunction syndrome (MODS) were con-

sidered to have severe respiratory sepsis.

Previous antibiotic use was considered if the patient had

received 48 hours or more of intravenous antibiotics within

the previous 2 weeks. So, patients who received antibiotics

as preoperation prophylaxis therapy were not taken into

account. In no case was the use of selective digestive

decontamination performed. We did not use any specific

oral care agents to decontaminate oropharyngeal cavity.

We considered VAP cured if the leukocyte count

decreased to below 10000/mm3, temperature was below

388C, Pa/Fio2 was below 250, and if there was a decrease

of purulent tracheal secretions and decrease or disappear-

ance of the etiologic microorganism from the cultures of

tracheal aspirates or nonbronchoscopic bronchoalveolar

lavage. We did not take into account the chest radiographs

for assessing the resolution of the VAP [23] We assessed

the resolution of the VAP between the sixth day from the

beginning of the antimicrobial treatment and 72 hours after

completion of therapy.

Crude mortality was considered as total number of deaths

with VAP. Related VAP mortality was defined as death by

VAP or deaths that could not be attributed to other causes.

Table 2 Characteristics of the patients included in this study

Variables VAPA (n = 46) Other

Age (y)

Mean (SD) 54.5 (19.2)

Median (interquartile range) 56.5 (46.25-69.75)

No. (%) of women 18 (40)

APACHE II at admission

Mean (SD) 21.0 (7.8)

Median (interquartile range) 20 (16-27)

Criteria proposed by McCabe and Jackson [22]

Rapidly fatal disease (n [%]) 0

Ultimately fatal disease (n [%]) 5 (10.8)

Nonfatal disease (n [%]) 41 (89.2)

Diagnosis at admission (n [%])

Nontraumatic ABI (n [%]) 10 (21.7)

Severe CAP (n [%]) 5 (10.8)

COPD exacerbation (n [%]) 4 (8.6)

Severe trauma (n [%]) 5 (10.8)

Severe sepsis (n [%]) 10 (21.8)

Drug overdose (n [%]) 0

Thoracoabdominal surgery (n [%]) 6 (13.0)

Miscellany (n [%]) 6 (13.0)

Day VAP

Mean (SD) 9.9 F 6.2

Median (interquartile range) 8.5 (5.25-12)

ABI, acute brain injury.

2.7. Microbiology

Microbiological sampling processing and identification

of isolated microorganisms were performed by standard

methods [24].

All nonfermentative, oxidase-negative, catalase-positive,

strictly aerobic, motionless, Gram-negative coccobacilli

were considered belonging to Acinetobacter genus [24].

Phenotype identification was completed with API 20 NE

system (Biomerieux, France).

Susceptibility tests were performed following recom-

mendations of the National Committee for Clinical Labo-

ratory Standards [25].

2.8. Data collection

All patients included in the protocol were followed up

daily until discharged from ICU.

The following variables were recorded: sex, age, nutri-

tional status, smoking habits, alcoholism, use of cortico-

steroids, hemodialysis, presence of diabetes, cancer, chronic

obstructive pulmonary disease (COPD), AIDS, heart failure

functional class III to IV, lung aspiration, use of positive

pressure at end of expiration, use of anti-H2, reintubation,

previous surgery, head trauma, neurosurgery, and GCS.

We also recorded the need of mechanical ventilation,

following criteria by Zwillich et al [26]; previous medical

condition by criteria proposed by McCabe and Jackson [27];

days of mechanical ventilation; diagnosis of VAP;

CPIS [17] the day that VAP was diagnosed; responsible

pathogens (n = 79) P Standardized difference [31]

56.1 (17.0) .61 0.09

56 (45-73)

21 (26.6) .16

19.5 (6.8) .26 0.2

19 (14.5-25)

1

10 (12.6)

68 (86.1) 1

26 (32.9) .22

10 (12.6) 1.00

5 (6.3) .72

10 (12.6) 1.00

4 (5.1) .007

5 (6.3) .15

8 (10.1) .76

11 (13.9) 1.00

7.2 F 5.5 .012 0.47

5 (3-9.5)

Table 3 Severity of VAP, morbidity, and mortality

Characteristics VAPA Other pathogens P

CXR multiple lobes

and/or bilateral (n [%])

28 (60.9) 39 (49.3) .26

MODS b9 (n [%]) 33 (71) 67 (84) .10

MODS z9 (n [%]) 13 (29) 12 (16)

SOFA b6 (n [%]) 24 (52) 38 (48) .71

SOFA z6 (n [%]) 22 (48) 41 (52)

APACHE II at admission

(mean F SD)

21.0 F 7.8 19.5 F 6.8 .26

Septic shock (n [%]) 19 (41.3) 19 (24) .06

ARDS (n [%]) 20 (43.8) 25 (31.6) .24

Cured VAP (n [%]) 28 (60.9) 49 (62) 1.0

Crude mortality (n [%]) 20 (43.8) 35 (44.3) 1.0

Prospective study of risk factors for VAP caused by Acinetobacter species 21

microorganism; previous use of antibiotics; and type and

number of antibiotics used.

Severity of underlying illness was evaluated with Acute

Physiology and Chronic Health Evaluation II (APACHE II)

for each patient at the initial 24 hours of admission [28].

Multiple organ dysfunction score [29], sepsis-related

organ failure assessment (SOFA) [30], septic shock, and

ARDS were evaluated when the diagnosis of pneumonia

was established.

2.9. Statistical analysis

Numeric variables were presented with SD. v2 and

Fischer exact tests were used when variables could be

divided into categories or for nominal variables. P b.05 was

considered significant. Relative risks (RR) and 95% confi-

dence intervals (CI) were calculated using standard methods.

Thirty-six risk factors were taken into account, the ones

already identified for VAPA [1-4,12,13] and other potential

risk factors already identified for VAP in general (not

specifically for VAPA).

The variables with P values lower than .20 in the

univariate analysis were included in the multivariate

Table 4 Previous use of antibiotics

Antibiotics VAPA

(n = 46)

VAP by other

pathogens

(n = 79)

P

Carbapenem 0 6 .08

Ceftriaxone 19 12 .0023

Ceftazidime 1 3 1.0

Cefoperazone-sulbactam 1 3 1.0

Ciprofloxacin 16 8 .0017

Vancomycin 3 1 .14

Aminoglycosides 2 5 1.0

Clarithromycin 4 10 .57

Ampicillin-sulbactam 11 19 1.0

Clindamicin 5 4 .28

Metronidazol 6 6 .35

Penicillin-ampicillin 6 8 .78

analysis. These variables were male sex, multiple organ

dysfunction, day of VAP V4 ,day of VAP b7 , septic shock,

use of positive end-expiratory pressure (PEEP) N5 cm H2O,

MODS N9, previous antibiotic use, previous use of

ceftriaxone, previous use of ciprofloxacin, and severe sepsis

at admission. Other variables also included in the univariate

analysis were omitted in the multivariate because of a

P value higher than .20 (Table 6).

Multivariate analysis was performed using the logistic

regression model of a software package (SPSS 10.1, SPSS

Inc, Chicago, Ill) by an Enter method.

2.10. Interventions

We did not perform interventions. The protocol proce-

dure did not interfere with the usual clinical management of

the patients. There was no protocol of empirical antimicro-

bial therapy. The antibiotic plan was chosen according to the

ecology of the ICU. The sputum Gram stain and detection of

intracellular organisms of the bronchoalveolar lavage and

tracheal aspirates were not always used for guiding the

antimicrobial therapy. When the VAPA diagnosis was done,

the patient was isolated, and the measures to prevent cross

transmission were taken.

2.11. Ethics

The study protocol was approved by the ethical

committee of both hospitals. According to the rules of our

ethics committee, specific consent was not requested.

3. Results

During the period of study, 218 successive patients were

enrolled as having clinical suspicion of VAP. In 125 (57%)

episodes, VAP could be confirmed by bacteriology (VAPA,

n = 46 episodes; other pathogens, n = 79 episodes).

Table 5 Isolates

Microorganisms (n [%]) n (%)

Acinetobacter spp 46 (33.6)

P aeruginosa 16 (11.7)

Serratia marscescens 5 (3.6)

Klebsiella spp 9 (6.6)

Stenotrophomona maltophilia 2 (1.4)

Enterobacter sp 4 (2.9)

Escherichia coli 5 (3.6)

S aureusa 40 (29.2)

Streptococcus pneumoniae 4 (2.9)

Haemophilus influenzae 5 (3.6)

b-hemolytic Streptococcus 1 (0.7)

Total no. of isolates (n) 137

Total no. of monomicrobial VAP 110 (88)

Total no. of polimicrobial VAP 15 (12)a Methicillin-resistant S aureus, n = 14; methicillin-susceptible

S aureus, n = 26.

Table 6 Risk factors by univariate analysis

Variables VAPA

(n = 46)

VAP by other

pathogens

(n = 79)

P RR 95% CI

Male

Yes 28 58 .16 0.70 0.44-1.11

No 18 21

Age z65 y

Yes 16 30 .86 0.91 0.56-1.48

No 30 49

Day of VAP V4Yes 9 35 .0064 0.68 0.53-0.87

No 37 44

Day of VAP V7Yes 20 44 .19 0.73 0.46-1.16

No 26 35

PEEP N5 cm H2O

Yes 32 42 .09 1.57 0.93-2.64

No 14 37

Nonfatal diseasea

Yes 41 68 .82 1.20 0.55-2.59

No 5 11

Alcoholism

Yes 4 7 .97 0.98 0.43-2.23

No 42 72

Diabetes

Yes 3 6 .82 0.89 0.34-2.33

No 43 73

Previous use of corticosteroids

Yes 3 4 .73 1.17 0.48-2.85

No 43 75

Hemodialysis

Yes 1 2 .89 0.90 0.17-4.55

No 45 77

Cancer

Yes 1 1 .69 1.36 0.33-5.57

No 45 78

Heart failure class III-IV

Yes 2 6 .73 0.66 0.19-2.25

No 44 73

Use of anti-H2

Yes 24 40 .86 1.04 0.65-1.64

No 22 39

Use of nasogastric tube

Yes 15 30 .68 0.86 0.52-1.41

No 31 49

Heads at 30-45 grades position

Yes 25 47 .70 0.87 0.55-1.38

No 21 32

MV need (neurologic emergency)

Yes 16 38 .25 0.72 0.44-1.18

No 30 41

Reintubation

Yes 4 8 .79 0.89 0.38-2.06

No 42 71

Lung aspiration

Yes 3 7 .90 0.80 0.30-2.12

No 43 72

Table 6 (continued)

Variables VAPA

(n = 46)

VAP by other

pathogens

(n = 79)

P RR 95% CI

GCS b9

Yes 25 39 .72 1.13 0.71-1.82

No 21 40

Cardiac arrest during ICU stay

Yes 4 6 .82 1.09 0.49-2.42

No 42 73

Previous surgery

Yes 12 22 .99 0.94 0.55-1.60

No 34 57

Severe trauma

Yes 5 10 .99 0.89 0.42-1.90

No 41 69

Neurosurgery

Yes 4 10 .70 0.75 0.31-1.78

No 42 69

Traumatic brain injury

Yes 4 11 .56 0.69 0.29-1.67

No 42 68

Severe sepsis at admission

Yes 10 4 .007 2.2 1.43-3.37

No 36 75

Severe CAP

Yes 5 10 .99 0.89 0.42-1.90

No 41 69

COPD exacerbation

Yes 4 5 .89 1.22 0.56-2.65

No 42 74

APACHE II z15

Yes 37 60 .72 1.18 0.65-2.15

No 9 19

SOFA z6

Yes 22 41 .79 0.90 0.56-1.42

No 24 38

MODS z9

Yes 13 12 .10 1.58 0.98-2.51

No 33 67

Multiple organ dysfunction

Yes 25 28 .06 1.6 1.02-2.56

No 21 51

Septic shock

Yes 19 19 .06 1.61 1.03-2.51

No 27 60

Previous antibiotics

Yes 40 42 b .0001 3.49 1.61-7.58

No 6 37

Previous use of ceftriaxone

Yes 19 12 .0023 2.1 1.39-3.26

No 27 67

Previous use of ciprofloxacin

Yes 16 8 .0017 2.2 1.48-3.39

No 30 71

Previous use of ampicillin-sulbactam

Yes 11 19 1 0.99 0.58-1.70

No 35 60

MV, mechanical ventilation.a Criteria by McCabe and Jackson.

J. Medina et al.22

Table 7 Risk factors for VAPA

Variables Univariate analysis Multivariate analysis

RR (95% CI) P RR (95% CI) P

Male 0.70 (0.44-1.11) .16 1.44 (0.56-3.78) .44

Multiple organ dysfunction 1.6 (1.02-2.56) .06 0.79 (0.18-3.40) .75

Day of VAP V4 0.68 (0.53-0.87) .0064 1.35 (0.39-4.65) .63

Day of VAP V7 0.73 (0.46-1.16) .19 0.29 (0.07-1.12) .73

Septic shock 1.61 (1.03-2.51) .06 2.23 (0.42-11.6) .34

Use of PEEP 1.57 (0.93-2.64) .09 0.36 (0.11-1.12) .08

MODS z9 1.58 (0.98-2.51) .10 2.05 (0.43-9.67) .36

Previous antibiotics 3.49 (1.61-7.58) b.0001 1.89 (0.43-8.16) .39

Previous use of ceftriaxone 2.1 (1.39-3.26) .0023 5.12 (1.47-17.82) .01

Previous use of ciprofloxacin 2.2 (1.48-3.39) .0017 9.15 (2.29-36.63) .002

Severe sepsis at admission 2.2 (1.43-3.37) .007 0.47 (0.11-1.87) .28

Variables were selected at the time the diagnosis of VAP was confirmed. They entered multivariate analysis if P value was below .20 in univariate analysis.

Prospective study of risk factors for VAP caused by Acinetobacter species 23

Diagnosis of VAPA was performed by bronchoalveolar

lavage in 20 patients (43%), tracheal aspirates + CPIS N6 in

24 (53%), and tracheal aspirates + blood cultures in 2 (4%).

In the set, diagnosis of VAP by other pathogens was

performed by bronchoalveolar lavage in 43 patients (55%),

tracheal aspirates +CPISN6 in 30 (38%), and tracheal aspirates

+ blood cultures in 5 (6%) and in pleural fluid in 1 (1%).

APACHE II at admission was z15 in 37 patients and

b15 in 9.

Of 46, 26 (56%) episodes of VAPA developed after 7 days

and 20 (44%) during the first 7 days of mechanical ventilation.

VAP compromised more than 1 lobe or was bilateral in

28 (61%) of 46 cases. Nineteen patients developed sepsis

(41%), and 20 (43.5%) developed ARDS.

Twenty-eight patients (60.9%) achieved healing criteria

(cured VAPA) and crude mortality was 43.8% (n = 20)

Tables 2 and 3. The previous use of antimicrobials is

presented in Table 4. Distribution of different pathogens is

seen in Table 5.

One hundred twenty-seven isolates were documented. Of

which, Acinetobacter spp was the most frequent, followed

by Staphylococcus aureus and Pseudomonas aeruginosa.

Four VAPAs had polimicrobial flora associated with

Proteus spp in 1 case, with methicillin-susceptible S aureus

in another, and associated with P aeruginosa in 2 cases

(Table 5).

Apart from that, the onset of 9 of 46 VAPA was before

the fifth day of mechanical ventilation. Of these 9 patients,

5 had been admitted to hospital at least 72 hours before

ICU admission.

Acinetobacter spp was sensitive to carbapenems in 100%

of cases, cefoperazone-sulbactam in 85%, and amikacin

in 52%; less than 10% of the strains were sensitive to

ceftazidime, ciprofloxacin, gentamicin, and ceftriaxone. Forty

percent of the strains were resistant to ampicillin-sulbactam.

In total, 36 potential risk factors were analyzed by

univariate analysis (Table 6).

Previous use of antibiotics was associated with increased

risk to develop a VAPA (P b .0001, RR 3.49, 95% CI

1.61-7.58). Only 6 of 46 episodes of VAPA appeared in

patients who had no prior antibiotic treatment. In VAP

developed in patients previously treated with antibiotics

(82/125), Acinetobacter spp was found in 48.7%.

When VAP developed in patients previously receiving

ceftriaxone, the frequency of Acinetobacter spp was 61%

(19/31) vs 28% (27/94) in patients receiving other anti-

biotics than ceftriaxone.

When VAP developed in patients receiving ciproflox-

acin, the frequency of Acinetobacter spp was 67% (16/24)

vs 29.7% (30/101) in patients receiving other antibiotic

than ciprofloxacin.

Receiving a plan including ceftriaxone on the previous

days was clearly associated in univariate analysis to an

increased risk to develop a VAPA (P = .0023; RR, 2.1; 95%

CI, 1.39-3.26). In addition, previous use of ciprofloxacin

was associated to increased risk for VAPA (P = .0017; RR,

2.2; 95% CI, 1.48-3.39).

Severe sepsis diagnosis at admission was another risk

factor for VAPA (P = .007; RR, 2.2; 95% CI, 1.43-3.37)

(Table 6).

Data were processed in a model of logistic regression

with Acinetobacter spp as dependent variable. Independent

variables were sex, presence of MODS score higher than

9, time of appearance of VAP, multiple organ dysfunction,

septic shock, use of PEEP, previous antibiotics, severe

sepsis at admission, previous use of ceftriaxone, and

previous use of ciprofloxacin.

Logistic regression identified that previous use of

ceftriaxone (RR, 5.1; 95% CI, 1.47-17.82) and previous

use of ciprofloxacin (RR, 9.1; 95% CI, 2.29-36.63)

predicted significantly and independently the development

of VAPA (Table 7).

4. Discussion

Acinetobacter spp is the microorganism most frequently

isolated in our ICU. It represents the 37% of the VAP

J. Medina et al.24

episodes, with similar incidence in both ICU. This problem

is also seen in many South American countries where the

VAPA represents the 14% to 29% of the total VAP [32,33].

The most important findings of this prospective, obser-

vational study are identification of previous use of

ceftriaxone and ciprofloxacin as independent risk factors

for VAPA. It is noteworthy that our population (n = 46) is

bigger than other published series [1-4,34].

VAPA is important because of added morbidity and

mortality; it is also associated with increasing incidence and

resistance, forcing the use of broad-spectrum antibiotics that

generate selection pressure favoring development of new

multiresistant pathogens, which is a major problem in

infection control [6-9,35].

Different authors have documented the impact of

previous antimicrobial agents in the development of VAPA.

Lortholary et al [4] found that 75% patients colonized or

infected by Acinetobacter spp had received antibiotics

previously, whereas in our population the relationship was

40/46 (86.9%).

Fagon et al [12] found that the frequency of VAP due to

species of Pseudomonas and Acinetobacter spp was higher

in patients with previous antibiotic therapy (65% vs 19%).

The antibiotics related to higher risk differed; in a

retrospective study of 15 episodes of VAP by Acinetobacter

baumannii in mechanical ventilation for at least a week,

univariate analysis found that the previous use of ceftazi-

dime was a risk factor for VAP [3]. This was not found in

our study. The infrequent use of ceftazidime in our ICU was

the difference between the 2 studies.

Similar to the findings of Villers et al [13], we found that

the previous use of fluorquinolones (in our case, ciproflox-

acin) was associated with an increased risk of developing

VAPA. These authors recommend caution in the use of

fluorquinolones and that its use should be discontinued in

units with high resistance to this antibiotic and with high

prevalence of nonfermentative Gram-negative bacilli, as is

the case of the 2 ICUs analyzed in this article.

Trouillet et al [34] found that the previous use of broad-

spectrum antibiotics (including third-generation cephalospo-

rin, fluoroquinolone, and carbapenem) was an independent

risk factor for VAP caused by potentially resistant bacteria.

The resistant bacteria most frequently isolated in this study

were P aeruginosa and methicillin-resistant S aureus.

Contrary to the findings of Lortholary et al [4], previous

infection and severity of illness were not statistically

significant risk factors in our population. Other authors

have identified other risk factors different from the previous

use of antibiotics for VAPA. Baraibar et al [1] found, in a

logistic regression analysis of 12 VAP by A baumannii, that

head trauma, ARDS, neurosurgery, and large-volume

pulmonary aspiration were independent risk factors for

VAP by this microorganism.

This work analyzed VAP in ICUs both in Europe and

Uruguay. In our work, these risk factors were not found, but

the populations analyzed are not comparable because

Baraibar et al [1] had higher number of patients with

myocardial infarction, severe trauma, and severe head

injuries, whereas our population had more patients with

severe sepsis, postoperative abdominal surgery, and non-

traumatic acute brain injury. We included patients from

2 different ICUs because in 1, there were no neurosurgical

patients that are a known risk factor.

Akca et al [2] analyzed 9 pneumonias by Acinetobacter

spp, identifying pulmonary aspiration and a GCS of 9 or

lower as risk factors, which were not found in this work.

Comorbidity, general characteristics of the population,

severity scores, diagnosis at admission, nor interventions

such as PEEP, reintubation, use of anti-H2, and nasogastric

tubes were not associated with increased risk of infection by

this pathogen.

Forty-three percent of VAPA developed before day 7 of

mechanical ventilation, explaining why, in endemic situa-

tion, this pathogen quickly colonizes and infects the

patients. Critically ill patients are the reservoir of multi-

resistant microorganisms, and the documented infection is

only the tip of the iceberg of the relation between

colonization infections. Therefore, emphasis should be

placed in trying to decrease selective pressure by ceftriaxone

and ciprofloxacin.

To decrease the increasing incidence of Acinetobacter

spp, restriction or rotation with similar molecules policies

for this antimicrobial agents should be applied. This has

shown benefit in decreasing incidence of VAP [36,37].

Of nineteen patients, 8 had received ceftriaxone and had

a severe CAP either as severe respiratory sepsis. Therefore,

emphasis should be placed in reevaluation of the empirical

use of ceftriaxone for CAP in the ICU. Alternative plans of

restriction and or rotation with aminopenicillins plus

b-lactam antibiotics could be proposed.

The acquisition and dissemination of Acinetobacter spp

varies in each ICU, depending on multiple factors, as

mentioned above.

This leads us to hypothesize that risk factors for VAPA

are characteristic of each ICU, and thus, each ICU must

know their own ecology and also those specific risk factors

for the acquisition of VAPA. The growth of a subpopulation

of microorganisms in previously colonized patients could be

favored by previous use of some antimicrobial agents and

produce infection [38].

Especially, ceftriaxone and ciprofloxacin have high

digestive elimination, approximately 40% to 50% for both,

and this could favor digestive colonization and ulterior

development of VAPA via an endogenous mechanism.

Future studies are needed to confirm this hypothesis.

According to our study, the 3 antibiotics most frequently

prescribed were ceftriaxone, ciprofloxacin, and ampicillin-

sulbactam. The different use of antibiotics in each ICU

could determine different risk factors.

Furthermore, because Acinetobacter spp is an endemic

pathogen in Uruguay and the rest of Latin America, this

could determine different risk factors.

Prospective study of risk factors for VAP caused by Acinetobacter species 25

We suggest that restriction of these antibiotics accompa-

nied by rotation with other molecules of similar spectrum is

a valid strategy of infection control and, thus, decrease the

incidence of VAPA. Each ICU should know its own specific

risk factors for acquiring VAPA.

Limitations of the present study are that we have done

the typification of genus but not the species identification,

and no molecular typification was performed.

We also ignore if during this period, there was an

outbreak of a monoclonal strain in units having Acineto-

bacter spp as an endemic agent, and thus, other risk factors

different from the ones analyzed could not be found. We

emphasize that our population consists of 46 prospectively

collected VAPA, which represents a high number of cases,

and that a strict methodology was used for the diagnosis of

VAP. This gives us a high clinical significance to the risk

factors found in our study.

5. Conclusions

In summary, previous use of ceftriaxone and ciproflox-

acin are independent risk factors for the development

of VAPA.

Acknowledgments

The authors thank Alejandro Arroliga MD, FCCS, for his

exhaustive revision of the manuscript and his suggestions,

and Stella M. Calvo, MD, and Graciela Perez, MD, for

translating and designing this manuscript.

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Commentary

Ventilator-associated pneumonia by multidrug-resistantbacteria: Pathogen-specific risks versuscare-related risks

biotics. However, they found out that antibiotic resistance

consistently caused an increase in hospital stay [15,16].

Within the Gram-negative bacteria identified as patho-

gens causing ventilator-associated pneumonia (VAP), mul-

tidrug-resistant ones, especially Acinetobacter species,

present specific challenges for the caregivers in intensive

care units (ICUs). Acinetobacter species consist of strictly

aerobic, Gram-negative, oxidase-negative cocobasillary

organisms. The DNA/DNA hybridization studies have

revealed 25 genomic species of Acinetobacter, 17 of which

have been confirmed and 10 of which have been named [1].

In clinical practice, because most species cannot reliably be

separated by phenotypic testing, the genospecies 1 (Acine-

tobacter calcoaceticus), 2 (Acinetobacter baumannii), 3,

and 13 are grouped together under the name A baumannii-

calcoaceticus complex (ABC). The ABC is the source of

approximately 80% of Acinetobacter infections [2-4].

Traditionally, ABC was considered a low-virulence

microorganism given that most clinical isolates reflected

colonization rather than significant infection [5,6]. Howev-

er, recent experience suggests that members of ABC can

cause outbreaks of hospital-acquired infections (including

multifacility outbreaks) [7]. Although there is controversy in

the reported mortality attributed to ABC, it is associated

with an elevated crude mortality in a subset of high-risk

patients [8,9]. The unique characteristics of ABC, such as

diversity of reservoirs, tolerance to desiccation—hence

survival in hospital conditions—and the capacity to acquire

antimicrobial-resistant genes leading to multidrug resistance

are the reasons why it is an emerging cause of health care–

associated infections.

In this issue, Dr Medina and colleagues conducted

a prospective study to identify specific risk factors for

VAP caused by Acinetobacter species [10]. Similar to

previous studies [11-13], this study confirmed that the use

of broad-spectrum antibiotics—namely ceftriaxone and

ciprofloxacin—is associated with increased incidence of

Acinetobacter VAP by creating an environment favoring

multidrug-resistant pathogens.

Although intensivists have an increased awareness about

pneumonia induced by multidrug-resistant pathogens, in the

light of current evidence-based medicine, it is hard to con-

clude whether these pathogens play a definite role in in-

creasing morbidity or mortality. In addition, there is no clear

evidence that a more resistant bacterial strain is more

virulent than its susceptible counterpart. Therefore, the

outcome differences between the 2 strains [14,15] are often

suggested to relate to patient characteristics at baseline or at

time of infection onset and to the effect of empirical

antibiotic use and a longer time of hospitalization. In 2 large

series of severe Staphylococcus aureus and Pseudomonas

aeruginosa VAP outbreaks, Combes et al [16] showed that

antibiotic resistance did not significantly affect ICU

mortality of patients receiving appropriate initial anti-

Similarly, we found increased length of stay in the ICU, but

no difference in mortality with VAP as a result of multidrug-

resistant pathogens [17].

With the findings somewhat similar to previous studies,

the real importance of this study is that it raises awareness

about the severity of the patient’s status and the importance of

preventive measures instead of specific risks for resistant

pathogens as they relate to causes of VAP. Assessment of

severity of status, clinical suspicion and diagnosis of

pneumonia, appropriate empiric antibiotherapy, and deesca-

lation approach are the key elements in managing pneumonia

in the ICU. The management of VAP in the ICU requires

knowledge of when to start the antibiotic, the dose and

duration needed, and most importantly, institution-specific

empiric coverage [18]. Healthcare facilities are recommen-

ded to provide their own preventive pathways according to

their own epidemiological and surveillance data [19].

Another important issue is how to handle the endemic of

multidrug-resistant species in the ICU. Multidrug-resistant

pathogens including Acinetobacter species usually cause

pneumonia in the late phase (N5-7 days) and possibly in