Five-year trends for ventilator-associated pneumonia: Correlation between microbiological findings and antimicrobial drug consumption

doi:10.1016/j.ijantimicag.2015.07.010

International Journal of Antimicrobial Agents

Volume 46, Issue 5, November 2015, Pages 518-525

https://doi.org/10.1016/j.ijantimicag.2015.07.010 Get rights and content

Highlights

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Five-year trends in ventilator-associated pneumonia (VAP) microbial aetiology and antibiotic consumption were analysed.
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Enterobacteriaceae were found to be more often responsible for VAP than Pseudomonas aeruginosa.
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This was the result of a significant increase in AmpC-producing bacteria.
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Concomitantly, third-generation cephalosporin consumption increased over time.
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The incidence of P. aeruginosa and MRSA remained stable.

Abstract

The epidemiology of multidrug-resistant bacteria (MDRB) has changed significantly in European healthcare settings, with a decrease in frequency of meticillin-resistant Staphylococcus aureus and an increase in extended-spectrum β-lactamase (ESBL)-producing Enterobacteriaceae. Little is known about the effects of these changes on ventilator-associated pneumonia (VAP). A retrospective 5-year trend analysis of ICU antibiotic consumption and resistance in bacteria causing VAP was undertaken. Poisson regression analysis between complete microbiological data and antibiotic consumption was performed. In total, 252 episodes of VAP in 184 patients were identified between 2007 and 2011, from which 364 causal bacteria were isolated. Enterobacteriaceae isolation rates increased significantly over this period [from 6.64 to 10.52 isolates/1000 patient-days; P = 0.006], mostly due to an increase in AmpC-producing Enterobacteriaceae (APE) (2.85–4.51 isolates/1000 patient-days; P = 0.013), whereas the number of episodes due to S. aureus and Pseudomonas aeruginosa remained stable. A positive association was found between the increase in APE infections and an increase in past-year antibiotic consumption: amoxicillin/clavulanic acid (P = 0.003), ceftazidime and cefepime (P = 0.007), carbapenems (P = 0.002), fluoroquinolones (P = 0.012), macrolides (P = 0.002) and imidazoles (P = 0.004). No such association was found for the emergence of resistance in P. aeruginosa. These results indicate a change in the epidemiology of VAP, with Enterobacteriaceae exceeding P. aeruginosa and S. aureus. Moreover, a positive correlation was observed between antibiotic consumption and the incidence of potentially MDRB such as APE. No such correlation was found for ESBL-producing Escherichia coli and antibiotic-resistant P. aeruginosa.

Introduction

Ventilator-associated pneumonia (VAP), defined as pneumonia occurring >48 h after the initiation of mechanical ventilation, is the most common life-threatening hospital-acquired infection in the intensive care unit (ICU). This complication affects 8–28% of patients receiving mechanical ventilation [1] and accounts for up to 50% of all antimicrobials prescribed in the ICU. It is associated with increased morbidity, increased costs and increased length of stay in the ICU [2], [3]. In older series, the principal pathogens recovered in bronchoscopy samples were Pseudomonas aeruginosa (24.4%), Staphylococcus aureus (20.4%), Enterobacteriaceae (14.1%) and Haemophilus sp. (9.8%) [1]. Several studies have shown that initial treatment of VAP with inappropriate antimicrobial drugs is associated with a poorer outcome [4]. Knowledge of the epidemiology and resistance trends of the bacteria concerned is therefore of particular importance.

Over the last decade there has been a considerable change in the epidemiology of multidrug-resistant bacteria (MDRB) in Europe [5], [6], particularly in French healthcare settings [7]. In the Assistance Publique–Hôpitaux de Paris (AP-HP), a consortium of Parisian hospitals, the incidence of meticillin-resistant S. aureus (MRSA) was found to have decreased by 43% over a period of 9 years with the implementation of a bundle programme to control cross-transmission [8]. Over the same period, the incidence of extended-spectrum β-lactamase (ESBL)-producing Enterobacteriaceae increased by 182%, mostly due to the emergence of Escherichia coli clones producing CTX-M type ESBL both in the community and in healthcare settings [9].

The relationships between antibiotic use and the emergence of MDRB are complex. Possible or confirmed MDRB infection leads to an increase in antibiotic consumption, which itself increases the selective pressure favouring the most resistant bacteria. Several recent studies have reported an effect of antibiotic use on MDRB emergence both at the national [10] and hospital levels [11], [12]. However, it was not possible to control for differences in prescription habits, the infections treated, infection control measures and epidemic phenomena between participating hospital wards in these studies.

We avoided such biases in this study by focusing on changes in the epidemiological characteristics of bacterial VAP, a typical hospital-acquired infection, within a single ICU department. We also investigated the correlation between ICU antibiotic consumption and antimicrobial resistance of the pathogens recovered in the ICU between 2007 and 2011.

Section snippets

Setting and case definition

Louis Mourier Hospital is a 460-bed, university-affiliated tertiary care institution in Colombes (France), with 600 ICU admissions per year.

All adult patients (≥15 years) presenting at least one episode of VAP at this hospital between January 2007 and December 2011 were included in this observational historical cohort study. The completeness of episode counts was ensured by cross-referencing data from two different and completely independent registries: the files of the microbiology department

Epidemiology of ventilator-associated pneumonia

During the study period, 2783 patients were admitted to the ICU, among which 1133 (40.7%) underwent invasive mechanical ventilation for >48 h. In total, 252 VAP episodes occurred in 184 patients (16.2%). The frequency of early episodes decreased significantly over the study period (from 26% in 2007 to 9% in 2011; P = 0.007). Annual data for ICU activity and patients with at least one VAP diagnosis are summarised in Table 1. Of the VAP episodes, 90% were diagnosed using PTC.

These 252 episodes lead

Discussion

In this study, the change in the epidemiological characteristics of bacterial VAP and the impact of antibiotic use on this epidemiology over a 5-year period were evaluated.

The major findings can be summarised as follows: (i) Enterobacteriaceae have now overtaken P. aeruginosa as the leading pathogens responsible for VAP; (ii) the increase in the incidence of Enterobacteriaceae isolation was the result of a significant increase in the incidence of AmpC-producing bacteria; (iii) the incidence of

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Cited by (33)

Combination of in vivo phage therapy data with in silico model highlights key parameters for pneumonia treatment efficacy
2022, Cell Reports
Citation Excerpt :
It is worth noting that until the early 2000s, Enterobacteriaceae were not considered major pathogens responsible for ventilator-associated pneumonia (VAP) (Chastre and Fagon, 2002). However, recent data have consistently shown that Enterobacteriaceae are now frequent etiologic agents of VAP, more frequently encountered than Pseudomonas aeruginosa and Staphylococcus aureus (Fihman et al., 2015; Hamet et al., 2012; Kollef et al., 2017). In particular, several studies have clearly identified specific traits of strains of E. coli responsible for intensive care unit (ICU)-acquired pneumonia (La Combe et al., 2019; Messika et al., 2012).
The clinical (re)development of bacteriophage (phage) therapy to treat antibiotic-resistant infections faces the challenge of understanding the dynamics of phage-bacteria interactions in the in vivo context. Here, we develop a general strategy coupling in vitro and in vivo experiments with a mathematical model to characterize the interplay between phage and bacteria during pneumonia induced by a pathogenic strain of Escherichia coli. The model allows the estimation of several key parameters for phage therapeutic efficacy. In particular, it quantifies the impact of dose and route of phage administration as well as the synergism of phage and the innate immune response on bacterial clearance. Simulations predict a limited impact of the intrinsic phage characteristics in agreement with the current semi-empirical choices of phages for compassionate treatments. Model-based approaches will foster the deployment of future phage-therapy clinical trials.
Effectiveness and safety of adjunctive inhaled antibiotics for ventilator-associated pneumonia: A systematic review and meta-analysis of randomized controlled trials
2021, Journal of Critical Care
The efficacy and safety of adjunctive inhaled antibiotic therapy for ventilator-associated pneumonia (VAP) was systematically reviewed based on updated studies.
We searched four databases and four clinical trial registration platforms to identify relevant studies published prior to May 19, 2020. Randomized controlled trials (RCTs) assessing adjunctive antibiotic inhalation treatment for VAP patients were eligible for this review. Two reviewers independently screened the articles and extracted the data. Information on inhaled therapy and clinical outcomes was collected. Study quality was assessed with the Cochrane risk of bias tool. The meta-analysis was conducted with Review Manager and R software. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) guidelines were used to evaluate the quality of evidence for each pooled outcome.
Eleven RCTs and 1210 patients were included in this analysis after the application of the inclusion and exclusion criteria. Compared with the use of intravenous injection alone, the use of adjunctive inhaled antibiotic therapy improved the rates of clinical cure (relative risk (RR) 1.13, 95% CI [1.02,1.26]) and microbiological eradication (RR 1.45, 95% CI [1.19,1.76]) in VAP patients. However, despite these improvements, mortality was not reduced (RR 1.00, 95% CI [0.82,1.21]). Adjunctive antibiotics delivered through the respiratory tract were not associated with a higher risk of renal impairment but were associated with an increased risk of bronchospasm (RR 2.74, 95% CI [1.31,5.73] during treatment.
Adjunctive inhaled antibiotics improved the clinical outcomes in VAP patients, but the increased rates clinical cure and microbiological eradication were not associated with reduced mortality. The use of nebulized antibiotics is not supported by the currently available evidence as a routine therapeutic strategy for VAP.
CRD42020186970.
Changes of resistance rates in Pseudomonas aeruginosa strains are unrelated to antimicrobial consumption in ICU populations with invasive device-related infection
2020, Medicina Intensiva
Citation Excerpt :
However, cross-correlation coefficients and fitted regression models showed that resistance to antimicrobials during a given quarter depends not only on the consumption of antimicrobials during that quarter, but also on consumption during the previous one combined with the incidence of resistant circulating strains.35 By contrast, Fihman et al.36 did not find a correlation between VAP episodes due to P. aeruginosa and antimicrobial consumption in the ICU. Our results of P. aeruginosa strains isolated in ICU-acquired infections related to the use of invasive devices and consumption of antipseudomonal agents during the ICU stay are consistent with these data.
To evaluate the relationship between antipseudomonal antibiotic consumption and each individual drug resistance rate in Pseudomonas aeruginosa strains causing ICU acquired invasive device-related infections (IDRI).
A post hoc analysis was made of the data collected prospectively from the ENVIN-HELICS registry.
Intensive Care Units participating in the ENVIN-UCI registry between the years 2007 and 2016 (3-month registry each year).
Patients admitted for over 24 h.
Annual linear and nonlinear trends of resistance rates of P. aeruginosa strains identified in IDRI and days of treatment of each antipseudomonal antibiotic family per 1000 occupied ICU bed days (DOT) were calculated.
A total of 15,095 episodes of IDRI were diagnosed in 11,652 patients (6.2% out of a total of 187,100). Pseudomonas aeruginosa was identified in 2095 (13.6%) of 15,432 pathogens causing IDRI. Resistance increased significantly over the study period for piperacillin-tazobactam (P < 0.001), imipenem (P = 0.016), meropenem (P = 0.004), ceftazidime (P = 0.005) and cefepime (P = 0.015), while variations in resistance rates for amikacin, ciprofloxacin, levofloxacin and colistin proved nonsignificant. A significant DOT decrease was observed for aminoglycosides (P < 0.001), cephalosporins (P < 0.001), quinolones (P < 0.001) and carbapenems (P < 0.001).
No significant association was observed between consumption of each antipseudomonal antibiotic family and the respective resistance rates for P. aeruginosa strains identified in IDRI.
Evaluar la relación entre el consumo de antibióticos antipseudomonales y la tasa de resistencia de cada fármaco individual en cepas de Pseudomonas aeruginosa aisladas en infecciones relacionadas con dispositivos invasivos (IDRI, por sus siglas en inglés) adquiridas en la unidad de cuidados intensivos (UCI).
Análisis post-hoc de los datos recopilados prospectivamente del registro ENVIN-HELICS.
Las UCI que participaron en el registro ENVIN-UCI entre los años 2007-2016 (registro de 3 meses cada año).
Pacientes ingresados > 24 h.
Se calcularon las tendencias anuales lineales y no lineales de las tasas de resistencia de las cepas de P. aeruginosa identificadas en IDRI y los días de tratamiento de cada familia de antibióticos antipseudomonales por 1.000 días de cama ocupada en la UCI (DOT).
Se diagnosticaron 15.095 episodios de IDRI en 11.652 pacientes (6,2% de 187.100). Se identificó P. aeruginosa en 2.095 (13,6%) de 15.432 patógenos que causaron IDRI. La resistencia aumentó significativamente durante el período de estudio para piperacilina-tazobactam (p < 0,001), imipenem (p = 0,016), meropenem (p = 0,004), ceftazidima (p = 0,005) y cefepima (p = 0,015), mientras que las variaciones en las tasas de resistencia de amikacina, ciprofloxacina, levofloxacina y colistina no fueron significativas. Se observó una disminución significativa de la DOT para aminoglucósidos (p < 0,001), cefalosporinas (p < 0,001), quinolonas (p < 0,001) y carbapenems (p < 0,001).
No se encontró asociación significativa del consumo de cada familia de antibióticos antipseudomonales con sus respectivas tasas de resistencia para las cepas de P. aeruginosa identificadas en IDRI.
Data on antibiotic use for detecting clusters of healthcare-associated infection caused by multidrug-resistant organisms in a hospital in China, 2014 to 2017
2019, Journal of Hospital Infection
Citation Excerpt :
According to Joseph et al., a significant positive correlation was observed between unit- or physician-specific infection rate and antibiotic use [11]. Similarly, a positive association was found between an increase in AmpC-producing Enterobacteriaceae infections and an increase in the consumption of antibiotics, such as amoxicillin/clavulanic acid, ceftazidime and cefepime, carbapenems, fluoroquinolones, macrolides, and imidazoles, based on a five-year study [8]. In China, the association between resistance in Pseudomonas aeruginosa to ciprofloxacin and fluoroquinolone consumption as well as resistance of P. aeruginosa to ceftazidime and third-generation cephalosporin consumption was identified in patients admitted at Changhai Hospital from 2008 to 2013 [10].
Detection of healthcare-associated infection (HCAI) clusters is crucial in limiting disease transmission.
To investigate whether data on antibiotic use can be an alternative indicator for the identification of HCAI clusters caused by multidrug-resistant organisms (MDROs).
We retrospectively analysed MDRO-related HCAIs and the 10 indicators of antibiotic use from four independent high-risk units at a tertiary hospital in China from January 2014 to January 2017. Spearman's correlation test was used to evaluate the correlations between the variables, and Shewhart chart algorithm was used to evaluate the performances of cluster identification.
We identified 856 MDRO-related HCAI cases. All indicators of antibiotic use were positively correlated with the incidence of MDRO-related HCAIs (r = 0.2–0.5; P < 0.05), except for the antibiotics utilization rate (AUR) for single-agent use (r = –0.191; P = 0.017) and the AUR of unrestricted drugs (r = –0.042, P = 0.601). Shewhart chart algorithm identified 22 clusters of MDRO-related HCAI. The AUR of special-grade antibiotics, the AUR for three agents used in combination, and the number of antibiotic varieties per patient displayed the optimal predictive values for detecting these 22 MDRO-related HCAI clusters. At an acceptable specific level of 75%, these three indicators were considered as the optimal surveillance indicators for detecting MDRO-related HCAI clusters, with sensitivities from 80.00% to 95.00%, and positive predictive values from 71.05% to 77.50%.
The use of data on antibiotic use is a sensitive method for identifying clusters of MDRO-related HCAIs in high-risk units and may be a useful adjunctive method for HCAI surveillance.
Pathophysiology of Escherichia coli pneumonia: Respective contribution of pathogenicity islands to virulence
2018, International Journal of Medical Microbiology
Citation Excerpt :
Gram-negative bacteria (GNB) predominate in hospital-acquired pneumonias (Chastre and Fagon, 2002; Peleg and Hooper, 2010). In the past, Pseudomonas aeruginosa was the most frequent GNB involved in VAP; however, recent data indicate that Enterobacteriaceae, and specifically E. coli, are more frequently responsible for VAP (Fihman et al., 2015; Hamet et al., 2012; Kollef et al., 2017; Ricard et al., 2012). Surprisingly, little is known about the epidemiology and pathophysiology of E. coli pneumonia.
Ventilator-associated pneumonia (VAP) remains the most frequent life-threatening nosocomial infection. Enterobacteriaceae including Escherichia coli are increasingly involved. If a cumulative effect of pathogenicity islands (PAIs) has been shown for E. coli virulence in urinary tract or systemic infections, very little is known regarding pathophysiology of E. coli pneumonia. This study aimed to determine the role of each of the 7 PAIs present in pathogenic E. coli strain 536 in pneumonia pathophysiology.
We used mutant strains to screen pathophysiological role of PAI in a rat pneumonia model. We also test individual gene mutants within PAI identified to be involved in pneumonia pathogenesis. Finally, we determined the prevalence of these genes of interest in E. coli isolates from feces and airways of ventilated patients.
Only PAIs I and III were significantly associated with rat pneumonia pathogenicity. Only the antigen-43 (Ag43) gene in PAI III was significantly associated with bacterial pathogenicity. The prevalence of tested genes in fecal and airway isolates of ventilated patients did not differ between isolates. In contrast, genes encoding Ag43, the F17-fimbriae subunits, HmuR and SepA were more prevalent in VAP isolates with statistical significance for hmuR when compared to airway colonizing isolates.
The E. coli PAIs involved in lung pathogenicity differed from those involved in urinary tract and bloodstream infections. Overall, extraintestinal E. coli virulence seems to rely on a combination of numerous virulence genes that have a cumulative effect depending on the infection site.
A Randomized Trial of the Amikacin Fosfomycin Inhalation System for the Adjunctive Therapy of Gram-Negative Ventilator-Associated Pneumonia: IASIS Trial
2017, Chest
Citation Excerpt :
The microbiology results in this multinational trial illustrate the daunting task of developing novel antibiotics for gram-negative bacterial infections. Interestingly, Enterobacteriaceae were the leading VAP pathogens in this study, confirming 2015 epidemiologic findings.22 In addition, > 30 different bacterial species were collected in baseline BAL samples, with multiple different mechanisms of resistance.
Clinical failures in ventilator-associated pneumonia (VAP) caused by gram-negative bacteria are common and associated with substantial morbidity, mortality, and resource utilization.
We assessed the safety and efficacy of the amikacin fosfomycin inhalation system (AFIS) for the treatment of gram-negative bacterial VAP in a randomized double-blind, placebo-controlled, parallel group, phase 2 study between May 2013 and March 2016. We compared standard of care in each arm plus 300 mg amikacin/120 mg fosfomycin or placebo (saline), delivered by aerosol twice daily for 10 days (or to extubation if < 10 days) via the investigational eFlow Inline System (PARI GmbH). The primary efficacy end point was change from baseline in the Clinical Pulmonary Infection Score (CPIS) during the randomized course of AFIS/placebo, using the subset of patients with microbiologically proven baseline infections with gram-negative bacteria.
There were 143 patients randomized: 71 to the AFIS group, and 72 to the placebo group. Comparison of CPIS change from baseline between treatment groups was not different (P = .70). The secondary hierarchical end point of no mortality and clinical cure at day 14 or earlier was also not significant (P = .68) nor was the hierarchical end point of no mortality and ventilator-free days (P = .06). The number of deaths in the AFIS group was 17 (24%) and 12 (17%) in the placebo group (P = .32). The AFIS group had significantly fewer positive tracheal cultures on days 3 and 7 than placebo.
In this trial of adjunctive aerosol therapy compared with standard of care IV antibiotics in patients with gram-negative VAP, the AFIS was ineffective in improving clinical outcomes despite reducing bacterial burden.
ClinicalTrials.gov; No.: NCT01969799; URL: www.clinicaltrials.gov

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Five-year trends for ventilator-associated pneumonia: Correlation between microbiological findings and antimicrobial drug consumption

Highlights

Abstract

Introduction

Section snippets

Setting and case definition

Epidemiology of ventilator-associated pneumonia

Discussion

Lancet Infect Dis

J Crit Care

Clin Microbiol Infect

Curr Opin Microbiol

Am J Infect Control

Lancet Infect Dis

Am J Infect Control

J Hosp Infect

Ventilator-associated pneumonia

Am J Respir Crit Care Med

Attributable mortality of ventilator-associated pneumonia: a reappraisal using causal analysis

Am J Respir Crit Care Med

Antimicrobial resistance surveillance in Europe. Annual report of the European Antimicrobial Resistance Surveillance Network (EARS-Net)

National multidrug-resistant bacteria (MDRB) surveillance in France through the RAISIN network: a 9 year experience

J Antimicrob Chemother

Curbing methicillin-resistant Staphylococcus aureus in 38 French hospitals through a 15-year institutional control program

Arch Intern Med

Antibiotics involved in the occurrence of antibiotic-resistant bacteria: a nationwide multilevel study suggests differences within antibiotic classes

J Antimicrob Chemother

Trend analysis of antimicrobial consumption and development of resistance in non-fermenters in a tertiary care hospital in Delhi, India

J Antimicrob Chemother