This is the first Brazilian series describing the characteristics and risk factors associated with mortality of patients affected by IE due to NGNB. Due to its infrequent occurrence, estimates of NGNB IE prevalence are variable and depend on the study period. Such population selection bias also restricted earlier studies to large metropolitan cities. The earliest systematic review of NGNB IE conducted from 1945 to 1977, concentrated on intravenous drug users (17).
The incidence of IE cases due to NGNB varies in the literature, ranging from 2–6%, with recent series showing higher incidences. These growing numbers are probably related to the presence of cardiac and vascular devices, invasive medical procedures, recurrent hospitalisation and immunosuppression [1, 8–13]. Previous studies showed that IE due to NGNB was predominantly on the right side of the heart, especially in cases associated with the use of injectable drugs . Over the decades with the increase of IE caused by NGNB, the pattern of the infection also has changed, with the left side of the heart being the most affected nowadays. IE data with involvement of the left side of the heart show that the course of the disease has a median onset of symptoms of 15 days and high rates of complications, including congestive heart failure, perivalvular abscesses, and peripheral, splenic and nervous system central embolization [6, 11, 26]. Although investigators from the ICE group showed that most cases of IE due to NGNB had a subacute diagnosis , our data show that in 84.2% of the cases the diagnosis was made within 30 days of the onset of symptoms. In our study the left side of the heart was the most affected.
There are few case series reporting IE due to NGNB and table 7 summarizes the main findings from them.
The incidence of NGNB endocarditis in our study was 3.29% and was similar to the incidence in a large international series previously published. The main clinical findings were HF in 19 (50%), CKD in 17 (44.7%), ACD in 10 (26.3%) and haemodialysis in 10 (26.3%) patients. Male sex was the most affected (65.8%) with a median age of 57 years (IIQ 43-69). Age and gender have been reported as important risk factors in IE due to NGNB. Historically, men and elderly are the most affected population [1, 10–12].
Non-fermenting bacteria is the main group of NGNB reported in the literature as causing IE. This group includes species as Pseudomonas aeruginosa, Acinetobacter sp., Burkholderia cepacia and Stenotrophomonas malthophilia [6, 7, 18]. In a recent epidemiological study in the United States, this bacterial group corresponded to 70% of IE due to NGNB and Pseudomonas aeruginosa (68%) was the main etiological agent . Among the group of fermenting GNBN that causes IE, the Enterobacteriaceae family is the most relevant, and Klebsiella spp. and Enterobacter cloacae were the most common agents. The International Collaboration on Endocarditis (ICE) study , and more recently an Argentine case series  and an Italian cohort  showed that Escherichia coli was the main microbiological agent of IE due to NGNB; in their studies, this probably related to high rates of urinary bacteraemia and high rates of use of urinary catheters. In our series, Enterobacteria were most frequent etiologies as a group. This relates to their frequency as etiologies of nosocomial infection. Klebsiella sp. accounted for 21% and Serratia marcescens (6%). P.aeruginosa, a non-fermenter, accounted for 21%.These etiological agents are the main NGNB identified in central venous-catheter related bacteraemia in Brazil, which is consistent with the main risk factors to IE due to NGNB acquisition found in this study, the presence of a central venous catheter (34.2%) and patients undergoing haemodialysis (26.3%). This probably indicates a problem with infection control. The NGNB, except for Salmonella spp. and Pseudomonas aeruginosa, have limited capacity for biofilm formation and low capacity for adhesion to the endocardium . However, the presence of prosthesis and of intracardiac devices facilitate adherence and the formation of vegetations. The structures most affected in the 38 cases of IE due to NGNB were prosthetic valves (50%). The incidence of NGNB endocarditis in CDEI and prosthetic valves has increased over the years due to previous health care contact and permanence of these patients in hospital institutions [1, 20].
Fever (81.6%) was the most common clinical finding and is described as one of the first signs/symptoms in IE due to NGNB . Of the other minor Duke criteria  we found pre-existing valve disease in 63.2% of cases. Among the findings that can increase the sensitivity of the diagnosis of IE , our study showed elevated CRP in 76.3%, elevated ESR in 21.1%, hematuria in 13.2% and indwelling CVC in 34.2% of cases of NGNB endocarditis.
Historically, beta-lactams with or without aminoglycosides regimes, whether or not associated with fluoroquinolone are the drugs of choice for the treatment of endocarditis caused by NGNB. Current guidelines recommend the use for 6 weeks [20–22]. Mechanisms of antimicrobial resistance in NGNB have increased dramatically across the planet [23, 24], making this a public health issue . Due to the varied profile of possible etiologic agents and drug resistance, indications for the treatment of IE due to MDR NGNB are still debated, because of the high risk of clinical failure. In these cases, antibiotic therapy should be individualized, combination therapy should be provided if possible, and a consultation for the evolution of a prompt surgical removal if infected valves should be performed. Despite all, MDR in NGNB was not related to mortality and was not carbapenem including regimes.
Surgical intervention in previous cohorts varies from 23 to 58% [1, 9, 10]. Although previous studies have shown benefits in combined clinical and surgical treatment, some authors reported no significant difference in outcome between clinical treatment alone versus combined medical and surgical intervention [6, 29]. This could perhaps be explained by introduction of new antimicrobial medications against NGNB. in the last decades
Previous data on IE mortality due to NGNB show rates between 8 and 47% [1, 9–11]. In our study mortality due to NGNB endocarditis was significantly high (50%, 19/38). Of interest, MDR etiology was not a risk factor associated to mortality. On the other hand, chronic kidney disease, indwelling CVC and patients undergoing haemodialysis were associated to mortality among patients affected by NGNB endocarditis.
Our study has some limitations. First, because of the rarity of infection, we were able to investigate only a small number of patients overall. Moreover, the study was conducted at a quaternary care centers, where the complicated cases of IE might be overrepresented. The major strength of our study is that it represents the first Brazilian contemporary study describing IE due to NGNB. This is a multicenter prospective study, what increases the value of the results obtained.