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Original Research: CRITICAL CARE |

Effect of Antibiotic Diversity on Ventilator-Associated Pneumonia Caused by ESKAPE OrganismsVentilator-Associated Pneumonia and Pathogens FREE TO VIEW

Alberto Sandiumenge, MD, PhD; Thiago Lisboa, MD; Frederic Gomez, MD; Pilar Hernandez; Laura Canadell, PharmD; Jordi Rello, MD, PhD
Author and Funding Information

From the Critical Care Department (Dr Sandiumenge), Epidemiology Department (Ms Hernandez), and Pharmacology Department (Dr Canadell), IISPV, and Microbiology Department (Dr Gomez), CIBERES, Joan XXIII University Hospital, Tarragona, Spain; Critical Care Department (Dr Lisboa), Hospital de Clinicas, Porto Alegre, Brazil; and Critical Care Department (Dr Rello), Vall d’Hebron University Hospital, Institut de Recerca Vall d’Hebron, CIBERES, Universitat Autonoma de Barcelona, Spain.

Correspondence to: Alberto Sandiumenge, MD, PhD, Critical Care Department, Joan XXIII University Hospital, Carrer Dr Mallafre Guasch 4, 43007 Tarragona, Spain; e-mail: asandiumenge@yahoo.com


Funding/Support: This work was supported by Centro de Investigación Biomedica en Red Enfermedades Respiratorias (CIBERES) (06/06/36).

Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (http://www.chestpubs.org/site/misc/reprints.xhtml).


© 2011 American College of Chest Physicians


Chest. 2011;140(3):643-651. doi:10.1378/chest.11-0462
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Background:  The aim of this study was to test in the clinic whether antimicrobial diversity affects resistance of Enterococcus faecium, Staphylococcus aureus, Klebsiella species, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter species (ESKAPE) pathogens in ventilator-associated pneumonia (VAP).

Methods:  Three different strategies of empirical antimicrobial prescription for VAP were consecutively implemented in an ICU: patient specific (10 months); scheduling, including sequential quarterly prioritization (12 months) and restriction (12 months) of antimicrobials; and mixing (10 months). Periods were compared, measuring the antimicrobial heterogeneity index (AHI). Incidence and resistance patterns of VAP caused by ESKAPE were compared.

Results:  Overall, 127 microbiologic VAP episodes were documented. ESKAPE VAP increased significantly during scheduling (AHI, 0.65) compared with patient-specific (AHI, 0.88) and mixing (AHI, 0.87) periods (relative risk, 2.67 and 3.84, respectively). This finding was associated with a significant (P < .05) increase of carbapenem-resistant A baumannii during the scheduling period (15.0%) compared with the patient-specific (2.4%) and mixing (0%) periods. ICU mortality of resistant patients with ESKAPE VAP was doubled that of patients without ESKAPE VAP (relative risk, 2.25; 95% CI, 1.67-9.48). Thirty-day mechanical ventilation-free days was significantly increased (5 days) in patients with resistant ESKAPE VAP.

Conclusions:  Antibiotic strategies promoting diversity may prevent the emergence of resistance of ESKAPE organisms, improving use of health-care resources.

Figures in this Article

Antimicrobial resistance increases mortality, morbidity, and social and economic costs.1 Recently, Enterococcus faecium, Staphylococcus aureus, Klebsiella species, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter species (ESKAPE) pathogens have been reported by Rice2 as the top six “bugs” for their wide distribution and ability to escape the effects of antibacterial drugs. Stewardship programs have been proposed as structured ways to prolong antibiotic effective life and prevent resistance,3,4 although their use remains controversial.5 Mathematical models using theoretical scenarios have predicted the superiority of antibiotic strategies promoting diversity to prevent antimicrobial resistance.68 However in the clinic, there is no consensus on the best strategy to guarantee antimicrobial diversity. Our group recently proposed the antibiotic heterogeneity index (AHI)9 to quantify diversity of antimicrobial use. Using the AHI, we reported the influence of several antimicrobial strategies on the colonization patterns of resistant pathogens in an ICU.9 The present study evaluates the clinical impact of antimicrobial diversity on the incidence, etiology, and outcome of ventilator-associated pneumonia (VAP) due to ESKAPE.

Study Design and Intervention

A prospective interventional study was conducted during 44 months in all nonneutropenic patients admitted for > 48 h in a 14-bed medical-surgical ICU. Three different antimicrobial strategies for the empirical treatment of VAP were consecutively implemented.9 A patient-specific period in which antimicrobials were prescribed according to each patient’s comorbidities and previous antibiotic exposure and hospitalization time was compared with a 24-month scheduling period in which antipseudomonal β-lactams were prioritized quarterly during the first 12 months (prioritization periods) and restricted during the next 12 months (restriction periods) while following a predefined sequence. During the last 10 months, a mixing strategy in which the target agents were prescribed in a preestablished order was implemented in consecutive patients (mixing period) (Fig 1).

Figure Jump LinkFigure 1. Study schedule. CB = carbapenem; CBP = antipseudomonal carbapenem prioritization schedule; CE = antipseudomonal cephalosporine; CEP = antipseudomonal cephalosporins prioritization schedule; NO = antipseudomonal cephalosporine restriction schedule; P/T = piperacillin/tazobactam; P/TP = piperacillin/tazobactam prioritization schedule; Q = quinolone.Grahic Jump Location

Infection control practices implemented throughout the study as well as diagnostic and clinical approaches to patients with suspected VAP have been described elsewhere.10 In 2002, during the course of the study, an update in the protocol for the management of central venous catheters was implemented.11 Antibiotic prescription patterns of each period were categorized as homogeneous or diverse according to the patient’s AHI. The study was approved by the institutional ethics board (number 07p/2004), and informed consent was waived.

Definitions

Antimicrobial use in each period was expressed as the proportion of patients with suspected VAP receiving empirical treatment with any given agent. Adherence to the preestablished empirical antimicrobial regimen was defined as the percentage of patients receiving the predetermined agent for that period. During the prioritization and mixing periods, protocol violation was defined as the administration of a different agent from the predefined one. The administration of any of the restricted agents during the restriction period was considered a protocol violation. Acceptable protocol deviation was defined when allergy or previous exposure to the scheduled agent led to a protocol violation. Prescription philosophy during the patient-specific period precluded the determination of protocol adherence.

The definition of VAP has been reported elsewhere.12 Center for Disease Control and Prevention criteria13 were used to define other nosocomial infectious events. Only documented microbiologic VAP was included in the study. VAP was considered to be nosocomial in origin if not present or suspected on admission. VAP episodes in the same patient were analyzed as independent events when caused by different pathogens or were separated by at least 6 days.

Bacterial susceptibility testing was recorded only in the first clinical culture that tested positive for the targeted microorganisms using a semiautomated Wider I system (Francisco Soria de Melguizo SA; Madrid, Spain) following standards recommended by National Committee on Clinical Laboratory Standards 2000 as described elsewhere.9 Intermediate susceptibility isolates to the antimicrobials analyzed were considered as nonsusceptible for statistical purposes. Table 1 details criteria used for resistant strains of ESKAPE pathogens.

Table Graphic Jump Location
Table 1 —Resistance Definition Criteria for ESKAPE Pathogens

ESBL = extended-spectrum β-lactamase; ESKAPE = Enterococcus faecium, Staphylococcus aureus, Klebsiella species, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter species.

a 

According to synergic double-diffusion disks, ceftazidime/ceftazidime clavulanic and cefotaxime/cefotaxime clavulanic epsilometer tests were used to confirm ESBL presence in selected cases.

Study Variables

For all patients presenting with VAP, age, sex, APACHE (Acute Physiology and Chronic Health Evaluation) II, and diagnostic category (surgical, trauma, and medical) were recorded at admission. Days on mechanical ventilation (MV) and to and from VAP diagnosis also were prospectively recorded. As a way of adjusting for nonsurvival, we calculated the MV-free days as the number of days during the 30 days after VAP diagnosis that the patients remained off the ventilator. Details on the AHI have been reported elsewhere.9

Statistical Analysis

Continuous variables with normal distribution are expressed as mean ± SD; those with a nonnormal distribution were expressed as median and interquartile range. Proportions were compared using the χ2 test, with Yates correction of Fisher exact test when necessary. Means were compared using the Student t test or Kruskal-Wallis test, as appropriate. No parametric variables were compared using the Mann-Whitney test.

To compare the AHI value of two different periods, sets of 100 AHI values for each period x were generated, considering the number of patients nx and the prescribed daily dose proportion of each antibiotic for every x period pxi. New values were obtained after computing the AHI for nx patients and a random assignment of antibiotic following pxi as a proportion of the observed prescribed antibiotic i. An unpaired t test was used to compare AHI values of different periods. Bonferroni correction was used to adjust for multiple comparisons, and corrected P values were taken. Incidence of ESKAPE microorganisms in VAP were compared among periods using the relative risk (RR) ratio with 95% CI.

Study Population

A total of 3,007 patients were admitted to the ICU during the study period, 2,621 of whom were included in the study (Fig 2). The mean age of admitted patients was 58 ± 16.1 years and APACHE II score was 13.0 ± 2.4. Men comprised 71.1% of the sample. One-half of the included patients (50.2%) were on MV for a median of 4 days (interquartile range, 1-13 days) and a total of 10,491 MV days. Mean ICU length of stay (LOS) was 7.4 ± 3.4 days, with a global mortality of 17.9%.

Figure Jump LinkFigure 2. Patients (number and cause) excluded from the different study periods. y/o = years old.Grahic Jump Location
Antimicrobial Use

Seventy-one percent of the global antimicrobial use was prescribed to treat VAP. Table 2 details the number and percentage of patients receiving a particular empirical antimicrobial treatment of VAP in each period. Of the VAP episodes, 45.7% were empirically treated with combination antimicrobial regimens without differences among periods. The antibiotic use pattern varied significantly during the study periods according to the strategy implemented. Overall, cephalosporins were the most-prescribed antimicrobials, representing 36.4% of the total empirical antimicrobial treatment of patients with VAP, followed by carbapenems (29.7%), piperacillin/tazobactam (18.9%), and quinolones (11.1%). All together, these four agents represented 77.9% of the total empirical antimicrobial prescription for patients with VAP. Adherence to the different antimicrobial strategies was 81.3%, without significant differences among periods. Protocol violations ranged from 25.6% to 29.9% during the mixing and patient-specific periods, of which 7% and 13.6% were considered acceptable protocol deviations. The patient-specific (AHI, 0.88) and mixing (AHI, 0.87) periods attained a significantly more diverse pattern of antimicrobials than the prioritization (AHI, 0.78) or restriction (AHI, 0.52) periods whether individually or grouped as the scheduling period (AHI, 0.65) (P < .01) (Fig 3).

Table Graphic Jump Location
Table 2 —Patients Receiving Empirical Antimicrobial Treatment of VAP During the Study Periods

Data are presented as No. (%). CBP = antipseudomonal carbapenem prioritization schedule; CEP = antipseudomonal cephalosporine prioritization schedule; MP = mixing period; NO CB = antipseudomonal carbapenem restriction schedule; NO CE = antipseudomonal cephalosporine restriction schedule; NO P/T = piperacillin/tazobactam restriction schedule; P-SP = patient-specific period; P/TP = piperacillin/tazobactam prioritization schedule; VAP = ventilator-associated pneumonia.

Figure Jump LinkFigure 3. Empirical antimicrobial use (in percentages) during the different study periods. *P < .05 with respect to patient-specific period. AHI = antimicrobial heterogeneity index. See Figure 1 legend for expansion of other abbreviations.Grahic Jump Location
Ventilator-Associated Pneumonia

Demographic characteristics of patients with VAP are detailed in Table 3. A total of 127 episodes of VAP were observed in 119 patients (VAP episodes per 100 ICU admissions, 4.8; VAP episodes per 1,000 MV days, 12.1). No differences were observed in VAP incidence among study periods. Seven patients had more than one episode of VAP, with a mean delay of 22.2 days (range, 6-56 days) after onset (Table 4).

Table Graphic Jump Location
Table 3 —Demographic Characteristics of 119 Patients With VAP

Data are presented as mean ± SD, No. (%), or median (interquartile range), unless otherwise indicated. APACHE = Acute Physiology and Chronic Health Evaluation; BPS = brush-protected specimen; MV = mechanical ventilation. See Table 2 legend for expansion of other abbreviation.

a 

P < .05 with respect to patient-specific period.

Table Graphic Jump Location
Table 4 —Characteristics of Patients Suffering More Than One Episode of VAP

CRAB = carbapenem-resistant Acinetobacter baumannii; Dx-day = day to VAP diagnosis; LOS = length of stay; MSSA = methicillin-susceptible Staphylococcus aureus. See Table 1 and 2 legends for expansion of other abbreviations.

Mean age (55.3 ± 15.6 years) and sex (men, 72.1%) of patients with VAP was similar to the ICU general population admitted during the same period. Patients with VAP were more severely ill (APACHE II, 16.2 ± 5.9) at admission than the rest of the ICU population (P < .05). VAP episodes were diagnosed a mean of 7.4 ± 6.3 days after ICU admission, and 41.4% (n = 56) were considered early VAP (< 5 days). Time on MV of patients with VAP was superior (median, 11 days; P < .05) to those without VAP. No significant differences in any of these variables were observed among study periods.

Microbiologic Data

A total of 157 microorganisms were isolated in VAP episodes. In 22.8% of VAP (n = 29), more than one microorganism was isolated. Table 5 details the microbiologic etiology of all VAP episodes. Gram-negative microorganisms represented 61.1% (n = 96) of all isolates, whereas 38.8% (n = 61) were gram-positive rods. No yeasts were identified.

Table Graphic Jump Location
Table 5 —Microbiologic Etiology of All VAP Episodes

Data are presented as No. (%). MRSA = methicillin-resistant Staphylococcus aureus. See Table 1, 2, and 4 legends for expansion of other abbreviations.

ESKAPE organisms represented 65.6% (n = 103) of all isolates from VAP (3.85 episodes per 100 ICU admissions), and 28 (19.4%) isolates (1.07 episodes per 100 ICU admissions) were resistant ESKAPE strains. Although incidence of ESKAPE organisms was similar among periods, resistant ESKAPE strains increased significantly during the scheduling period (1.44 episodes per 100 ICU admissions) compared with the patient-specific (0.66 episodes per 100 ICU admissions; RR, 2.67; 95% CI, 1.01-7.08) and mixing (0.43 episodes per 100 ICU admissions; RR, 3.84; 95% CI, 1.55-12.9) periods.

E faecium isolates were not documented in any VAP episode throughout the study period. S aureus was the most-isolated microorganism responsible for VAP throughout the study period, yet its occurrence as well as the methicillin-resistant S aureus strains were not significantly influenced by the antimicrobial prescription patterns implemented during the different study periods.

The scheduling period started with carbapenem prioritization, leading to an increase of A baumannii VAP compared with the patient-specific period (15.0% vs 7.3%, respectively). Moreover, all A baumannii isolates during the scheduling period were resistant to carbapenems compared with patient-specific period (15.0% vs 2.4%, respectively; P < .05). A diverse use of antibiotics during the mixing period returned global incidence of A baumannii to similar rates as those of the patient-specific period (3.6%), eradicating carbapenems-resistant A baumannii (CRAB) strains (P < .05) (Fig 4). No significant differences were observed in the proportion of VAP episodes due to Klebsiella species, P aeruginosa, and Enterobacter species among periods.

Figure Jump LinkFigure 4. Percentage of isolations from VAP. *P < .05 of scheduling period with respect to patient-specific period. **P < .05 of scheduling period with respect to mixing period. CRAB = carbapenem resistant Acinetobacter baumannii; ESKAPE = Enterococcus faecium, Staphylococcus aureus, Klebsiella species, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter species; ESBL = extended-spectrum β-lactamase; MR PA = multiresistant Pseudomonas aeruginosa; MRSA = methicillin-resistant Staphylococcus aureus; VAP = ventilator-associated pneumonia.Grahic Jump Location
Outcomes

Table 6 details outcome variables. Overall, ICU mortality of patients with VAP (32.7%; n = 39) was higher than that of patients without VAP (P < .05), without differences among study periods. Mortality of ESKAPE VAP was superior to that of patients without ESKAPE VAP (unilateral significance, 0.42). Resistant ESKAPE VAP mortality doubled mortality of the remaining patients with VAP (RR, 2.25; 95% CI, 1.67-9.48). During the mixing period, all patients with resistant ESKAPE VAP died.

Table Graphic Jump Location
Table 6 —Outcome of Patients With VAP

Data are presented as No. cases/No. patients with VAP, unless otherwise indicated. IQR = interquartile range; R = resistant. See Table 1-4 legends for expansion of other abbreviations.

a 

Unilateral significance of .45; ESKAPE VAP vs no ESKAPE VAP.

b 

P < .05 R-ESKAPE VAP vs no R-ESKAPE VAP.

c 

P < .05 Scheduling period vs patient-specific period.

d 

P < .05 Scheduling period vs mixing period.

Patients surviving VAP remained in the ICU 23.9 days longer than those without VAP admitted during the same period (P < .01). The presence of resistant ESKAPE did not affect ICU LOS of surviving patients with VAP. However, LOS of patients surviving VAP during the scheduling period was significantly longer than that of those surviving VAP during the patient-specific and mixing periods, especially in VAP caused by ESKAPE (P < .05).

Total MV time of patients with VAP was 7.3 days longer than that of patients without VAP (P < .05). Total MV time of resistant ESKAPE VAP was superior (median, 28 days; P < .05) to that of the remaining patients with VAP (Table 6). Finally, for 30-day MV-free days, VAP caused by resistant ESKAPE pathogens was significantly higher (5 days) than nonresistant ESKAPE pathogens or non-ESKAPE organisms (Table 6).

To our knowledge, this study is the first to report that strategies favoring homogeneity promote the rise and spread of VAP due ESKAPE microorganisms. This finding is not only of academic interest because it is associated with significant changes in ICU mortality and MV and ICU LOS.

Although alternating different antibiotic classes during predefined time periods initially was proposed as a structured way of attain diversity,1417 other authors have reported that cycling antimicrobials may impose variable homogeneous-selective antimicrobial pressure in the exposed ecology, favoring emergence of resistance.18 Restricting the use of certain antimicrobials has been used to control resistance outbreaks.19 However, although restriction of one antibiotic class may decrease the selective pressure exerted by the withdrawn agent, compensatory increase in the use of other antibiotic classes may be favored.20 In the present study, the quarterly prioritization or restriction of antimicrobials exerted during the scheduling period attained a more homogeneous antimicrobial pattern than prescribing antimicrobials according to patient characteristics (patient-specific period) or following a preestablished order in consecutive patients20 (mixing period) as measured by the AHI.

ESKAPE pathogens have been recently reported2,21 as microorganisms responsible for the majority of nosocomial infections. In the present study, those periods in which greater antimicrobial diversity was attained showed a lower rate of VAP due to resistant ESKAPE pathogens. However, antimicrobial prescription patterns did not influence incidence of VAP caused by resistant gram-positive pathogens. In contrast, gram-negative resistance emergence was affected by antimicrobial prescription patterns probably because the different antimicrobial prescription strategies were focused on those with higher activity against these pathogens.

The increased proportion of patients with head injury admitted during the scheduling and mixing periods could account for the progressive, nonsignificant increase in methicillin-susceptible S aureus. This fact could have altered the microbiologic pattern of nosocomial infections occurring during those periods with S aureus being the leading etiologic agent of VAP episodes in patients in coma.22 However, the rate of methicillin-resistant S aureus was not influenced by antimicrobial prescription patterns. Similarly, no infection by vancomycin-resistant Enterococcus faecium was identified in any of the study periods. These data could be justified in the context of a vancomycin-resistant E faecium incidence as low as 1% reported in Spanish ICUs.23

In Europe, A baumannii accounts for almost 20% of all microorganisms isolated in ICU nosocomial pneumonia.24 Data from 77 Spanish ICUs showed a rise in CRAB nosocomial infections from 28.6% in 2003 to 58.3% in 2005.23

Homogeneous prescription periods started with a quarterly antipseudomonal carbapenem prioritization schedule characterized by a rise in carbapenem use. Similarly, carbapenems were the most-prescribed agents during the restriction of antipseudomonal cephalosporins schedule. Both periods were associated with an increase in CRAB isolations in nosocomial infections. In contrast, periods in which a diverse prescription pattern was implemented had a lower incidence of VAP due to these pathogens, suggesting a protective role of diversity on the emergence and development of CRAB.

Nosocomial infections due to resistant strains (extended-spectrum β-lactamase [ESBL]) of Klebsiella species and Enterobacter species did not show significant variations among study periods. The same pattern was observed for ESBL stains of Escherichia coli. Takesue et al25 also observed no changes in ESBL-producing organisms after promoting diverse hospital-wide antibiotic use (as measured by the AHI) by the implementation of a periodic antimicrobial monitoring and supervision strategy.

The present study has several limitations. It was a long-term, single-center study. Our findings may be attributed to institution-specific variables, such as the low incidence of resistance and VAP episodes in the study ICU that may have lessened the impact of antimicrobial intervention strategies. The before-and-after design may have allowed temporal confounding variables, diluting the impact of the antimicrobial pressure on infection and clinical outcome. However, the prolonged study time and limited resources available made impractical the use of more-reliable designs, such as cluster randomized controlled or interrupted series. Provided that ICU LOS during the study period was 8 days and in order to minimize the sequential design of the study, a 30-day gap was allowed between initiation/finalization and the recording of the clinical impact for each period to fit mathematical modeling predictions stating that resistance dynamics are driven by the replacement of resistant strains by new admissions.24

In summary, this study suggests that strategies promoting antimicrobial diversity may prevent the emergence and spread of resistance among ESKAPE microorganisms. Intervention in the current study focused on agents with activity against gram-negative bacteria. Further studies should evaluate the effect of diversity with agents active against gram-positive bacteria.

Author contributions: Dr Sandiumenge had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Dr Sandiumenge: contributed to the conception and design of the study; patient recruitment; data acquisition, analysis, and interpretation; discussion and writing of the manuscript; and approval of the final version of the manuscript to be published.

Dr Lisboa: contributed to the data acquisition, analysis, and interpretation; statistical analysis; discussion and writing of the manuscript; and approval of the final version of the manuscript to be published.

Dr Gomez: contributed to the data acquisition, analysis, and interpretation; analysis and reporting of microbiologic cultures obtained during the study period; discussion and writing of the manuscript; and approval of the final version of the manuscript to be published.

Ms Hernandez: contributed to the data acquisition, analysis, and interpretation; statistical analysis; discussion and writing of the manuscript; and approval of the final version of the manuscript to be published.

Dr Canadell: contributed to the data acquisition, analysis, and interpretation; recording of the antimicrobial use during the study period; provision of monthly antibiotic reports; discussion and writing of the manuscript; and approval of the final version of the manuscript to be published.

Dr Rello: contributed to the conception and design of the study; patient recruitment; data acquisition, analysis, and interpretation; discussion and writing of the manuscript; and approval for the final version of the manuscript to be published.

Financial/nonfinancial disclosures: The authors have reported to CHEST the following conflicts of interest: Dr Rello belongs to the advisory board and speakers bureau of Pfizer Inc. Drs Sandiumenge, Lisboa, Gomez, Canadell, and Ms Hernandez have reported that no potential conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article.

Role of sponsor: The sponsor had no role in the design of the study, the collection and analysis of the data, or in the preparation of the manuscript.

Other contributions: We thank Ignacio Martin-Loeches, MD, PhD, for his valuable assistance in the statistical analysis.

AHI

antibiotic heterogeneity index

APACHE

Acute Physiology and Chronic Health Evaluation

CRAB

carbapenem-resistant Acinetobacter baumannii

ESKAPE

Enterococcus faecium, Staphylococcus aureus, Klebsiella species, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter species

LOS

length of stay

MV

mechanical ventilation

RR

relative risk

VAP

ventilator-associated pneumonia

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Figures

Figure Jump LinkFigure 1. Study schedule. CB = carbapenem; CBP = antipseudomonal carbapenem prioritization schedule; CE = antipseudomonal cephalosporine; CEP = antipseudomonal cephalosporins prioritization schedule; NO = antipseudomonal cephalosporine restriction schedule; P/T = piperacillin/tazobactam; P/TP = piperacillin/tazobactam prioritization schedule; Q = quinolone.Grahic Jump Location
Figure Jump LinkFigure 2. Patients (number and cause) excluded from the different study periods. y/o = years old.Grahic Jump Location
Figure Jump LinkFigure 3. Empirical antimicrobial use (in percentages) during the different study periods. *P < .05 with respect to patient-specific period. AHI = antimicrobial heterogeneity index. See Figure 1 legend for expansion of other abbreviations.Grahic Jump Location
Figure Jump LinkFigure 4. Percentage of isolations from VAP. *P < .05 of scheduling period with respect to patient-specific period. **P < .05 of scheduling period with respect to mixing period. CRAB = carbapenem resistant Acinetobacter baumannii; ESKAPE = Enterococcus faecium, Staphylococcus aureus, Klebsiella species, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter species; ESBL = extended-spectrum β-lactamase; MR PA = multiresistant Pseudomonas aeruginosa; MRSA = methicillin-resistant Staphylococcus aureus; VAP = ventilator-associated pneumonia.Grahic Jump Location

Tables

Table Graphic Jump Location
Table 1 —Resistance Definition Criteria for ESKAPE Pathogens

ESBL = extended-spectrum β-lactamase; ESKAPE = Enterococcus faecium, Staphylococcus aureus, Klebsiella species, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter species.

a 

According to synergic double-diffusion disks, ceftazidime/ceftazidime clavulanic and cefotaxime/cefotaxime clavulanic epsilometer tests were used to confirm ESBL presence in selected cases.

Table Graphic Jump Location
Table 2 —Patients Receiving Empirical Antimicrobial Treatment of VAP During the Study Periods

Data are presented as No. (%). CBP = antipseudomonal carbapenem prioritization schedule; CEP = antipseudomonal cephalosporine prioritization schedule; MP = mixing period; NO CB = antipseudomonal carbapenem restriction schedule; NO CE = antipseudomonal cephalosporine restriction schedule; NO P/T = piperacillin/tazobactam restriction schedule; P-SP = patient-specific period; P/TP = piperacillin/tazobactam prioritization schedule; VAP = ventilator-associated pneumonia.

Table Graphic Jump Location
Table 3 —Demographic Characteristics of 119 Patients With VAP

Data are presented as mean ± SD, No. (%), or median (interquartile range), unless otherwise indicated. APACHE = Acute Physiology and Chronic Health Evaluation; BPS = brush-protected specimen; MV = mechanical ventilation. See Table 2 legend for expansion of other abbreviation.

a 

P < .05 with respect to patient-specific period.

Table Graphic Jump Location
Table 4 —Characteristics of Patients Suffering More Than One Episode of VAP

CRAB = carbapenem-resistant Acinetobacter baumannii; Dx-day = day to VAP diagnosis; LOS = length of stay; MSSA = methicillin-susceptible Staphylococcus aureus. See Table 1 and 2 legends for expansion of other abbreviations.

Table Graphic Jump Location
Table 5 —Microbiologic Etiology of All VAP Episodes

Data are presented as No. (%). MRSA = methicillin-resistant Staphylococcus aureus. See Table 1, 2, and 4 legends for expansion of other abbreviations.

Table Graphic Jump Location
Table 6 —Outcome of Patients With VAP

Data are presented as No. cases/No. patients with VAP, unless otherwise indicated. IQR = interquartile range; R = resistant. See Table 1-4 legends for expansion of other abbreviations.

a 

Unilateral significance of .45; ESKAPE VAP vs no ESKAPE VAP.

b 

P < .05 R-ESKAPE VAP vs no R-ESKAPE VAP.

c 

P < .05 Scheduling period vs patient-specific period.

d 

P < .05 Scheduling period vs mixing period.

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