Ventilator-associated Pneumonia Caused by ESKAPE Organisms
Ventilator-associated Pneumonia Caused by ESKAPE Organisms
According to the 2004–2008 SENTRY Antimicrobial Surveillance Program, with the exception of E. faecium, ESKAPE pathogens were among the top six causative agents of VAP, representing overall 80% of episodes. Similar results can be seen in several large multinational studies, as well as other national and local clinical trials (Table 1).
The clinical importance of ESKAPE pathogens relies on their virulence and ability to develop mechanisms to decrease susceptibility to antimicrobials, increasing inappropriate therapy (Table 2). The SENTRY Antimicrobial Surveillance Program reported a yearly 1% generalized decrease in drug susceptibility in hospital-acquired pneumonia (HAP) and VAP isolates of the top six pathogens. Geographic differences were also noted in the type of antimicrobial resistance as shown in Table 3. Our group prospectively studied 129 VAP episodes, reporting that 65.6% of all VAP isolates were ESKAPE organisms, almost 20% being resistant.
The prognostic impact of specific microorganisms on patient outcome has been widely debated. Some authors state that VAP morbidity and mortality is related to the presence of resistant pathogens through the higher proportion of inadequate treatment reported for these pathogens. Although appropriateness of the initial treatment was not evaluated in the above-mentioned work, VAP caused by resistant ESKAPE pathogens doubled mortality compared with that in patients with VAP caused by other pathogens [relative risk 2.25; 95% confidence interval (CI) 1.67–9.48], and prolonged mechanical ventilation. In contrast, Damas et al. did not identify infection by any particular group of organisms to be a risk factor for ICU mortality in a large series of ICU-acquired pneumonias.
E. faecium has been consistently identified as the third most frequent cause of nosocomial bloodstream infection in the USA. However, its role in VAP has been only described in testimonial case reports.
S aureus has been for decades one of the main causative agents of nosocomial pneumonia worldwide. This pathogen has shown a trend to rapidly developing resistance to new antibiotic classes as they have been introduced into clinical use. Such was the case of the first oxacillin/methicillin- resistant strains of Staphylococcus aureus (MRSA) that emerged only a few years after these agents were commercialized in the 1960s. Since then MRSA has globally disseminated, and now approximately 60% of S. aureus isolates are resistant to methicillin in some areas of the USA. Current data from the ENVIN Study, a Spanish yearly ICU infection surveillance study, reported that 25% of all ICU pneumonias due to S. aureus were caused by methicillin- resistant strains, suggesting a trend to decreasing incidence. However, this rate was higher (45.4 vs. 33.3%) in the Latin VAP study when compared with the EU-VAP study. Interestingly, this new study suggests that variables associated with empirical anti-MRSA therapy for pneumonia are different from classical risk factors. Although VAP due to MRSA may have similar chest radiograph patterns and clinical course than that casued by methicillinsusceptible S. aureus, it may produce alpha-toxin, suggesting opportunities to improve outcomes with immunotherapy. In a systematic review, Athanassa et al. confirmed that both in-hospital and ICU mortality of patients with VAP due to S. aureus were higher in the presence of methicillin resistance. Moreover, the European Prevalence of Infection in Intensive Care (EPIC) II study investigators confirmed these findings in a subanalysis of MRSA episodes. Interestingly, MRSA pneumonia is associated with significantly higher ICU mortality in Latin America. Overall, treatment failure rates as high as 40% have been reported and attributed to inadequate duration of therapy. MRSA VAP is a difficult-to-treat infection with longer times to clinical resolution and duration of mechanical ventilation when compared with other pathogens, even if appropriate therapy is delivered. Therefore, duration of therapy should be based on individualized follow-up for resolution of signs and symptoms of infection. A meta-analysis compared clinical success in patients with or without culturepositive MRSA pneumonia.
The cost–benefit ratio of strategies aimed to maintain serum concentration of vancomycin at high levels is still under discussion. In addition, the association of a combination of two agents may be considered in patients with poor resolution. Randomized controlled trials with linezolid have been criticized due to possible underdosage of vancomycin when administered at recommended dosages. Data on its potential superiority of clinical response even when vancomycin dosage was modified according to blood levels, in a population with MRSA pneumonia with low risk of death (overall 17%), will represent an important new contribution. Agents such as quinuspristin–dalfpristin, daptomycin or tigecycline have been associated with disappointing results in pulmonary infections. The contribution of potential newer agents, such as todazolid, ceftaroline or telavancin still has to be determined.
Nosocomial pneumonia caused by A. baumannii represented almost 20% of all episodes of ICU nosocomial pneumonia in Europe. However, important variability has been reported among countries ( Table 1 ). Risk factors for VAP due to this organism are different from those of P. aeruginosa and include previous neurosurgery, head trauma or large-volume aspiration as well as prolonged hospital stay and mechanical ventilation, prior episodes of sepsis, reintubation and prior antibiotic use.
A unique feature of A. baumannii is its rapid acquisition of multiple antibiotic-resistance mechanisms and the ability to coexist in the environment. Carbapenems have been considered the treatment of choice. Unfortunately, resistance is rapidly increasing and previous exposure to imipenem has been associated with VAP due to imipenem-resistant A. baumannii (odds ratio 4.0; 95% CI 1.1–29.8). For this reason, minimum inhibitory concentration (MIC) determination is highly recommended in order to optimize antibiotic treatment. Doripenem, although theoretically less active in vitro, has been reported to be superior to imipenem and meropenem in 87 A. baumannii clinical isolates. The extended infusion or highdose carbapenems, and association with other antibiotics could improve their therapeutic effects against multidrug-resistant (MDR) A. baumannii. Sulbactam at high dosage has shown good clinical and bacteriological cure rates in the treatment of MDR A. baumannii VAP patients whether alone or in combination with colistin. Unfortunately, a steady increase in the resistance to sulbactam has been observed in the last decade and its use is mainly recommended for catheterrelated bacteremia. Rifampicin maintains a high level of activity both in vitro and in vivo against A. baumannii even in carbapenem-resistant strains, but its use in monotherapy is not recommended due to the rapid emergence of strains resistant to this antimicrobial. Colistin retains a high in-vitro activity against A. baumannii and does not promote cross-resistance. Clinical data reveals that colistin is similar to imipenem in the treatment of VAP caused by A. baumannii susceptible to imipenem as well as effective when administered alone or combined with rifampicin for the treatment of VAP caused by MDR strains. The use of aerosolized colistin for A. baumannii VAP should be as adjunctive therapy to intravenous antibiotics.
P. aeruginosa VAP has been associated with high mortality and costs even among patients receiving appropriate antimicrobial therapy. El Solh et al. confirmed previous studies in P. aeruginosa VAP patients stating that expression of genes encoding type III secretory proteins were associated with lower survival rates and that its eradication was not achieved after a 7-day course of antibiotics.
The contribution to tracheobronchitis is controversial and some authors suggest that commonly accepted clinical criteria used to diagnose VAP do not readily identify all patients with P. aeruginosa infection.
P. aeruginosa is notorious for its ability to acquire antibiotic resistance, especially in cases of previous colonization or infection by MDR P. aeruginosa or previous exposure to antibiotics during the ICU stay. Resistance emergence may occur as early as 10 days after initiation of antipseudomonal antibiotics in ventilated patients, increasing mortality and prolonging length of stay and a rise in costs. Emergence of resistance in P. aeruginosa is rapidly increasing for most antimicrobials. Two systematic reviews confirm clinical experience reporting that many P. aeruginosa isolates are resistant to imipenem at the initiation of treatment and, importantly, are likely to develop treatmentemergent resistance to this agent. According to these findings and despite controversial results on the efficacy of combination therapy vs. monotherapy, early initiation of combination therapy with an antipseudomonal b-lactam agent and aminoglycoside or quinolone should be recommended as soon as P. aeruginosa pneumonia is suspected. Emergence of MDR and pan-resistant strains is a real concern, particularly in lung transplant patients or respiratory chronic diseases. When treated with high doses of b-lactams in combination with aminoglycosides, 78% of patients with VAP survived to discharge and only one death was attributable to VAP in a small trial. Colistin may be used instead of aminoglycosides (10MU loading dose, followed by 4.5MU b.i.d) when MIC of tobramycin is higher than 8.
In 2010, these pathogens were responsible for over 40% of VAP reported in the ENVIN study,E. coli and Klebsiella being the most prevalent ones. Approximately 20% of K. pneumoniae infections and 31% of Enterobacter spp infections in ICUs in the United States now involve strains not susceptible to third-generation cephalosporins due to extended spectrum betalactamases (ESBLs). Similar features were reported in a recently published study in which 30% of Klebsiella spp VAPs were ESBL producing. Damas et al. reported a lower rate of ESBL-producing Enterobacteriaceae (36/198) in a 4-year prospective study of 453 patients with ICU-acquired pneumonia in France. Infections with ESBL-producing Enterobacteriaceae have significantly adverse impact on clinical outcomes.
Carbapenems have been considered the most effective drugs against lung infections caused by ESBL-producing Enterobacteriaceae, including pneumonia. However, carbapenem-resistant Enterobacteriaceae have been described as constituting a threat in countries like Greece and Turkey, but only a few are associated with VAP.
Ventilator-associated Pneumonia Due to ESKAPE Pathogens
According to the 2004–2008 SENTRY Antimicrobial Surveillance Program, with the exception of E. faecium, ESKAPE pathogens were among the top six causative agents of VAP, representing overall 80% of episodes. Similar results can be seen in several large multinational studies, as well as other national and local clinical trials (Table 1).
The clinical importance of ESKAPE pathogens relies on their virulence and ability to develop mechanisms to decrease susceptibility to antimicrobials, increasing inappropriate therapy (Table 2). The SENTRY Antimicrobial Surveillance Program reported a yearly 1% generalized decrease in drug susceptibility in hospital-acquired pneumonia (HAP) and VAP isolates of the top six pathogens. Geographic differences were also noted in the type of antimicrobial resistance as shown in Table 3. Our group prospectively studied 129 VAP episodes, reporting that 65.6% of all VAP isolates were ESKAPE organisms, almost 20% being resistant.
The prognostic impact of specific microorganisms on patient outcome has been widely debated. Some authors state that VAP morbidity and mortality is related to the presence of resistant pathogens through the higher proportion of inadequate treatment reported for these pathogens. Although appropriateness of the initial treatment was not evaluated in the above-mentioned work, VAP caused by resistant ESKAPE pathogens doubled mortality compared with that in patients with VAP caused by other pathogens [relative risk 2.25; 95% confidence interval (CI) 1.67–9.48], and prolonged mechanical ventilation. In contrast, Damas et al. did not identify infection by any particular group of organisms to be a risk factor for ICU mortality in a large series of ICU-acquired pneumonias.
Enterococcus Faecium
E. faecium has been consistently identified as the third most frequent cause of nosocomial bloodstream infection in the USA. However, its role in VAP has been only described in testimonial case reports.
Staphylococcus Aureus
S aureus has been for decades one of the main causative agents of nosocomial pneumonia worldwide. This pathogen has shown a trend to rapidly developing resistance to new antibiotic classes as they have been introduced into clinical use. Such was the case of the first oxacillin/methicillin- resistant strains of Staphylococcus aureus (MRSA) that emerged only a few years after these agents were commercialized in the 1960s. Since then MRSA has globally disseminated, and now approximately 60% of S. aureus isolates are resistant to methicillin in some areas of the USA. Current data from the ENVIN Study, a Spanish yearly ICU infection surveillance study, reported that 25% of all ICU pneumonias due to S. aureus were caused by methicillin- resistant strains, suggesting a trend to decreasing incidence. However, this rate was higher (45.4 vs. 33.3%) in the Latin VAP study when compared with the EU-VAP study. Interestingly, this new study suggests that variables associated with empirical anti-MRSA therapy for pneumonia are different from classical risk factors. Although VAP due to MRSA may have similar chest radiograph patterns and clinical course than that casued by methicillinsusceptible S. aureus, it may produce alpha-toxin, suggesting opportunities to improve outcomes with immunotherapy. In a systematic review, Athanassa et al. confirmed that both in-hospital and ICU mortality of patients with VAP due to S. aureus were higher in the presence of methicillin resistance. Moreover, the European Prevalence of Infection in Intensive Care (EPIC) II study investigators confirmed these findings in a subanalysis of MRSA episodes. Interestingly, MRSA pneumonia is associated with significantly higher ICU mortality in Latin America. Overall, treatment failure rates as high as 40% have been reported and attributed to inadequate duration of therapy. MRSA VAP is a difficult-to-treat infection with longer times to clinical resolution and duration of mechanical ventilation when compared with other pathogens, even if appropriate therapy is delivered. Therefore, duration of therapy should be based on individualized follow-up for resolution of signs and symptoms of infection. A meta-analysis compared clinical success in patients with or without culturepositive MRSA pneumonia.
The cost–benefit ratio of strategies aimed to maintain serum concentration of vancomycin at high levels is still under discussion. In addition, the association of a combination of two agents may be considered in patients with poor resolution. Randomized controlled trials with linezolid have been criticized due to possible underdosage of vancomycin when administered at recommended dosages. Data on its potential superiority of clinical response even when vancomycin dosage was modified according to blood levels, in a population with MRSA pneumonia with low risk of death (overall 17%), will represent an important new contribution. Agents such as quinuspristin–dalfpristin, daptomycin or tigecycline have been associated with disappointing results in pulmonary infections. The contribution of potential newer agents, such as todazolid, ceftaroline or telavancin still has to be determined.
Acinetobacter Baumannii
Nosocomial pneumonia caused by A. baumannii represented almost 20% of all episodes of ICU nosocomial pneumonia in Europe. However, important variability has been reported among countries ( Table 1 ). Risk factors for VAP due to this organism are different from those of P. aeruginosa and include previous neurosurgery, head trauma or large-volume aspiration as well as prolonged hospital stay and mechanical ventilation, prior episodes of sepsis, reintubation and prior antibiotic use.
A unique feature of A. baumannii is its rapid acquisition of multiple antibiotic-resistance mechanisms and the ability to coexist in the environment. Carbapenems have been considered the treatment of choice. Unfortunately, resistance is rapidly increasing and previous exposure to imipenem has been associated with VAP due to imipenem-resistant A. baumannii (odds ratio 4.0; 95% CI 1.1–29.8). For this reason, minimum inhibitory concentration (MIC) determination is highly recommended in order to optimize antibiotic treatment. Doripenem, although theoretically less active in vitro, has been reported to be superior to imipenem and meropenem in 87 A. baumannii clinical isolates. The extended infusion or highdose carbapenems, and association with other antibiotics could improve their therapeutic effects against multidrug-resistant (MDR) A. baumannii. Sulbactam at high dosage has shown good clinical and bacteriological cure rates in the treatment of MDR A. baumannii VAP patients whether alone or in combination with colistin. Unfortunately, a steady increase in the resistance to sulbactam has been observed in the last decade and its use is mainly recommended for catheterrelated bacteremia. Rifampicin maintains a high level of activity both in vitro and in vivo against A. baumannii even in carbapenem-resistant strains, but its use in monotherapy is not recommended due to the rapid emergence of strains resistant to this antimicrobial. Colistin retains a high in-vitro activity against A. baumannii and does not promote cross-resistance. Clinical data reveals that colistin is similar to imipenem in the treatment of VAP caused by A. baumannii susceptible to imipenem as well as effective when administered alone or combined with rifampicin for the treatment of VAP caused by MDR strains. The use of aerosolized colistin for A. baumannii VAP should be as adjunctive therapy to intravenous antibiotics.
Pseudomonas Aeruginosa
P. aeruginosa VAP has been associated with high mortality and costs even among patients receiving appropriate antimicrobial therapy. El Solh et al. confirmed previous studies in P. aeruginosa VAP patients stating that expression of genes encoding type III secretory proteins were associated with lower survival rates and that its eradication was not achieved after a 7-day course of antibiotics.
The contribution to tracheobronchitis is controversial and some authors suggest that commonly accepted clinical criteria used to diagnose VAP do not readily identify all patients with P. aeruginosa infection.
P. aeruginosa is notorious for its ability to acquire antibiotic resistance, especially in cases of previous colonization or infection by MDR P. aeruginosa or previous exposure to antibiotics during the ICU stay. Resistance emergence may occur as early as 10 days after initiation of antipseudomonal antibiotics in ventilated patients, increasing mortality and prolonging length of stay and a rise in costs. Emergence of resistance in P. aeruginosa is rapidly increasing for most antimicrobials. Two systematic reviews confirm clinical experience reporting that many P. aeruginosa isolates are resistant to imipenem at the initiation of treatment and, importantly, are likely to develop treatmentemergent resistance to this agent. According to these findings and despite controversial results on the efficacy of combination therapy vs. monotherapy, early initiation of combination therapy with an antipseudomonal b-lactam agent and aminoglycoside or quinolone should be recommended as soon as P. aeruginosa pneumonia is suspected. Emergence of MDR and pan-resistant strains is a real concern, particularly in lung transplant patients or respiratory chronic diseases. When treated with high doses of b-lactams in combination with aminoglycosides, 78% of patients with VAP survived to discharge and only one death was attributable to VAP in a small trial. Colistin may be used instead of aminoglycosides (10MU loading dose, followed by 4.5MU b.i.d) when MIC of tobramycin is higher than 8.
Enterobacteriaceae
In 2010, these pathogens were responsible for over 40% of VAP reported in the ENVIN study,E. coli and Klebsiella being the most prevalent ones. Approximately 20% of K. pneumoniae infections and 31% of Enterobacter spp infections in ICUs in the United States now involve strains not susceptible to third-generation cephalosporins due to extended spectrum betalactamases (ESBLs). Similar features were reported in a recently published study in which 30% of Klebsiella spp VAPs were ESBL producing. Damas et al. reported a lower rate of ESBL-producing Enterobacteriaceae (36/198) in a 4-year prospective study of 453 patients with ICU-acquired pneumonia in France. Infections with ESBL-producing Enterobacteriaceae have significantly adverse impact on clinical outcomes.
Carbapenems have been considered the most effective drugs against lung infections caused by ESBL-producing Enterobacteriaceae, including pneumonia. However, carbapenem-resistant Enterobacteriaceae have been described as constituting a threat in countries like Greece and Turkey, but only a few are associated with VAP.
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