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• W2319627021 abstract "The members of the Enterococcus species may be not the most frequent but, without any doubts, among the most problematic human pathogens in terms of antimicrobial therapy.1 Despite the availability of a number of antimicrobial agents, a substantial proportion of patients do not achieve adequate outcomes, in part because of an increase in the proportion of enterococcal strains that are resistant to 1 or more of these agents.2–4 Enterococci can cause a variety of infections. However, for many of these, other pathogens are also frequently isolated from the same site. In such situations, it is often difficult to interpret whether the clinical manifestations of infection are the result of enterococci or whether these low-virulence bacteria are not playing a significant role in the infection. However, for some types of infections, most notably bloodstream infections and urinary tract infections (EUTIs), enterococci can clearly cause serious disease that needs administration of specific antienterococcal therapies.3 In this issue of the journal, Taimur et al4 reviewed retrospective data on patients hospitalized with enterococcal bloodstream infections (EBSIs) and EUTIs during 2008 to 2009 in a single 508-bed academic Boston medical center. Their results demonstrated that vancomycin was commonly used for both empiric and targeted therapy; vancomycin-resistant enterococci were frequent and empiric therapy was inadequate in most of those cases. At the same time, targeted therapy for both EBSI and EUTI was often not tailored to more appropriate agents. The authors concluded that, in such situation, there are many stewardship opportunities to improve prescribing for enterococcal treatment (mainly by using linezolid or daptomycin instead of vancomycin). When we are thinking about antimicrobial stewardship in the case of infection caused by a particular pathogen, we need to know the answers on the following questions: 1. What is the role of the pathogen in the particular infection (in our case, EBSI and EUTI)? In the past decade, Enterococcus species has become the third most common etiological agent isolated in nosocomial bloodstream infections in the United States.5 However, the rates of isolation of this pathogen from the blood seem to vary significantly in different countries and hospitals. Regarding EUTIs, in the 7-year (2006–2007) retrospective analysis done by Sorlozano et al,6 enterococci accounted for 18% of 31,758 uropathogens, which were isolated from hospitalized patients in Spain. 2. If there are any significant risk factors for the pathogen? Risk factors for enterococcal infections are not really specific and include the previous use of broad-spectrum antimicrobial, prolonged hospital stay, immunosuppression, serious comorbid conditions, and invasive procedures.7 The same risk factors are common for a variety of other opportunistic pathogens. 3. What are the resistance rates? The main problem that clinicians are facing in the treatment of enterococcal infections is that these bacteria are not only intrinsically nonsusceptible to many classes of antimicrobials but also have the ability to acquire resistance to all antimicrobials available. Notably, there is a substantial difference between the potential to develop resistance between 2 most clinically significant members of the Enterococcus genus—Enterococcus faecalis (E. faecalis) and Enterococcus faecium (E. faecium). The most clinically important fact is that E. faecalis in most cases remains susceptible to ampicillin where E. faecium is usually resistant to β-lactams. This fact could be very useful for early targeting therapy choice on the basis of the result of identification to the species level. For a long time, the main drug for the management of enterococcal infections resistant to β-lactams was vancomycin. However, vancomycin resistance is now widespread in E. faecium, although it remains relatively rare in E. faecalis. In response to the growing problem of resistance in Gram-positive bacteria, the pharmaceutical industry has developed a number of newer agents that have activity against enterococci. However, none of these agents (linezolid, daptomycin, tigecycline, telavancin, oritavancin, tedizolid) have been entirely free of resistance. At the same time, the rates of resistance could vary significantly in different countries and hospitals, especially for vancomycin. For example, according to the data recently published by Jones et al,8 the prevalence of resistance to vancomycin in E. faecium ranged from less than 1% in Sweden, Spain, and Ukraine to 77.7% in the United States. The rates of vancomycin resistance in E. faecalis were substantially lower (from 0% in Belgium, Czech Republic, Greece, Hungary, Russia, Sweden, Turkey, and Ukraine to 3.5% in the United States). Interestingly, the prevalence of resistance did not change within all 5 years of the study. When in some countries, the resistance in enterococci distributed relatively uniform, whereas, in others, it depends on the hospital profile. 4. What is the clinical importance of the antimicrobial resistance? From the first point of view, it seems to be a kind of strange question, but if we closely look to the published data, there will be a number of studies with results showing no or modest influence of resistance on the outcome. We can find such data for enterococcal infections. Just 1 example, in a recent study of Khair et al9 published in the Journal of Hospital Infection, the authors of this 6-month prospective cohort study of hospital patients who were admitted with or who developed enterococcal bacteriuria in a 1250-bed tertiary-care hospital concluded that vancomycin resistance did not affect the clinical presentation or impact patient outcomes in this cohort of inpatients with enterococcal bacteriuria. Vancomycin was not used as a pathogen-directed antibiotic for known cases of infection caused by vancomycin-resistant enterococci (VRE). The results of this study in part may be compromised by the fact that almost half of the patient cohort had enterococcal asymptomatic bacteriuria, with more than 50% of these asymptomatic patients received antibiotics. In contrast, there are not a lot of concerns about the significance of resistance in enterococcal bacteremia. When the studies comparing the mortality of vancomycin-resistant and vancomycin-susceptible EBSI were incorporated into meta-analyses, vancomycin resistance was found to be an independent factor for both morbidity and mortality after controlling for disease severity and other factors.10 However, most of these studies were conducted before the availability of newer antimicrobials with activity against VRE. Therefore, it is possible that use of newer agents to treat VRE bacteremia might alter the observed association between vancomycin resistance and mortality. Interesting observation was made by Australian scientists.11 According to the results of their study on 724 patients with enterococcal bacteremia treated during 2002 to 2010, VRE bacteremia was not associated with increased mortality but was independently associated with prolonged length of stay and higher hospitalization costs. The authors proposed the idea that the absence of correlation between vancomycin resistance and mortality in their study was not caused by VanA but VanB genotype prevalence in Australia in contrast with other studies where VanA genotype was prevalent. 5. Do we have the possibilities to improve the timing of targeted antimicrobial therapy? Modern molecular technologies allow to significantly shorten the time to detection, identification, and susceptibility testing at least for some pathogens. Enterococcus in this field is one of the best targets. Just identification to the species level (E. faecalis or not E. faecalis) is already giving us the answer on rationale of ampicillin use, which is still the best and cheapest option for the treatment of E. faecalis infections. High level of vancomycin resistance in enterococci could be easily predicted by detecting vanA and vanB genes. Therefore, using molecular techniques at the moment, we already might have enough information to perform pathogen-targeted therapy within few hours after clinical sample collection. 6. Which of the in vitro active antimicrobials will be optimal? As far as the ampicillin resistance continues to be uncommon in clinical isolates of E. faecalis, this antimicrobial is still the first choice in E. faecalis infections. Vancomycin and other antimicrobials (linezolid, daptomycin) are usually reserved for cases of E. faecalis infections in which ampicillin cannot be used because of a β-lactam allergy. Addition of gentamicin, if strain susceptible, should be considered for achieving bactericidal effect in a case of deep-seated infections, such as endocarditis. One of the important clinical challenges in the treatment of E. faecalis bloodstream infections is the emergence of resistance to gentamicin. Clinical studies and animal models have shown that the combination of ampicillin with cephalosporins (such as ceftriaxone or cefotaxime) is synergistic and bactericidal against strains of E. faecalis that are fully susceptible to ampicillin. Treatment of infection caused by multidrug-resistant E. faecium strains is a much more challenging task. Only 2 compounds are currently approved for the treatment of vancomycin-resistant E. faecium infections: linezolid and quinupristin/dalfopristin. The later one is not available in a number of countries and has a nonfavorable safety profile. The main alternative to linezolid for treatment of VRE infections is a lipopeptide antimicrobial daptomycin. Daptomycin is Food and Drug Administration approved for the treatment of vancomycin-susceptible enterococcal skin and soft tissue infections but not for VRE infection or for E. faecium. However, clinicians often use this compound in the treatment of severe VRE infections because of a lack of other bactericidal options. Daptomycin demonstrated excellent in vitro activity against enterococcal isolates recovered from patients at high risk for developing infections caused by antibiotic-resistant bacteria, such as patients with cancer or in intensive care units. Studies have also shown that other enterococcal species, including Enterococcus durans, Enterococcus avium, Enterococcus casseliflavus, Enterococcus gallinarum, and Enterococcus raffinosus, are susceptible to daptomycin. Overall, there were 8 comparative retrospective cohort studies, 2 meta-analyses of daptomycin and linezolid, as well as 3 retrospective comparisons of linezolid and quinupristin/dalfopristin.10,12,13 Mortality associated with VRE bloodstream infections was high across studies, and the ability to determine differences in outcomes between agents was confounded by the complex nature of the patients included. Two meta-analyses comparing daptomycin with linezolid for VRE bloodstream infections found modest advantages for linezolid, but these conclusions may be hampered by heterogeneity within the included studies. In most of these clinical failures and emergence of resistance during therapy, a lack of a clinical cure has been correlated with the use of dosing regimens of 4 and 6 mg/kg per day, which were approved for the treatment of staphylococcal skin/soft tissue infection and bloodstream infections, respectively. At the same time, minimal inhibitory concentration breakpoint for enterococci is substantially higher than that of staphylococci (4 mg/L versus 1 mg/L).14,15 That suggests that higher doses of daptomycin (≥8 mg/kg) are needed for the treatment of enterococcal infections. Tigecycline also has good in vitro activity against enterococci, but the blood and urine levels achieved by tigecycline are low, making the use of this antibiotic as monotherapy questionable for EBSI and EUTI. Nonetheless, the combination of tigecycline with daptomycin may be an option for the treatment of multidrug-resistant EBSI. For the nonsevere uncomplicated lower EUTI, agents such as fosfomycin, nitrofurantoin, and fluoroquinolones should be considered." @default.
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• W2319627021 modified "2023-09-26" @default.
• W2319627021 title "Antimicrobial Stewardship for the Treatment of Enterococcal Bloodstream and Urinary Tract Infections" @default.
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