Efficacy and safety of a structured de-escalation from antipseudomonal ß-lactams in bloodstream infections due to Enterobacterales (SIMPLIFY): an open-label, multicentre, randomised trial.

BACKGROUND: De-escalation from broad-spectrum to narrow-spectrum antibiotics is considered an important measure to reduce the selective pressure of antibiotics, but a scarcity of adequate evidence is a barrier to its implementation. We aimed to determine whether de-escalation from an antipseudomonal ß-lactam to a narrower-spectrum drug was non-inferior to continuing the antipseudomonal drug in patients with Enterobacterales bacteraemia. METHODS: An open-label, pragmatic, randomised trial was performed in 21 Spanish hospitals. Patients with bacteraemia caused by Enterobacterales susceptible to one of the de-escalation options and treated empirically with an antipseudomonal ß-lactam were eligible. Patients were randomly assigned (1:1; stratified by urinary source) to de-escalate to ampicillin, trimethoprim-sulfamethoxazole (urinary tract infections only), cefuroxime, cefotaxime or ceftriaxone, amoxicillin-clavulanic acid, ciprofloxacin, or ertapenem in that order according to susceptibility (de-escalation group), or to continue with the empiric antipseudomonal ß-lactam (control group). Oral switching was allowed in both groups. The primary outcome was clinical cure 3-5 days after end of treatment in the modified intention-to-treat (mITT) population, formed of patients who received at least one dose of study drug. Safety was assessed in all participants. Non-inferiority was declared when the lower bound of the 95% CI of the absolute difference in cure rate was above the -10% non-inferiority margin. This trial is registered with EudraCT (2015-004219-19) and ClinicalTrials.gov (NCT02795949) and is complete. FINDINGS: 2030 patients were screened between Oct 5, 2016, and Jan 23, 2020, of whom 171 were randomly assigned to the de-escalation group and 173 to the control group. 164 (50%) patients in the de-escalation group and 167 (50%) in the control group were included in the mITT population. 148 (90%) patients in the de-escalation group and 148 (89%) in the control group had clinical cure (risk difference 1·6 percentage points, 95% CI -5·0 to 8·2). The number of adverse events reported was 219 in the de-escalation group and 175 in the control group, of these, 53 (24%) in the de-escalation group and 56 (32%) in the control group were considered severe. Seven (5%) of 164 patients in the de-escalation group and nine (6%) of 167 patients in the control group died during the 60-day follow-up. There were no treatment-related deaths. INTERPRETATION: De-escalation from an antipseudomonal ß-lactam in Enterobacterales bacteraemia following a predefined rule was non-inferior to continuing the empiric antipseudomonal drug. These results support de-escalation in this setting. FUNDING: Plan Nacional de I+D+i 2013-2016 and Instituto de Salud Carlos III, Subdirección General de Redes y Centros de Investigación Cooperativa, Ministerio de Ciencia, Innovación y Universidades, Spanish Network for Research in Infectious Diseases; Spanish Clinical Research and Clinical Trials Platform, co-financed by the EU; European Development Regional Fund "A way to achieve Europe", Operative Program Intelligence Growth 2014-2020.

"A contemporary description of staphylococcus aureus prosthetic valve endocarditis. Differences according to the time elapsed from surgery".

Staphylococcus aureus prosthetic valve endocarditis (SAPVE) has a poor prognosis. There are no large series that accurately describe this entity.This is a retrospective observational study on a prospective cohort from 3 Spanish reference hospitals for cardiac surgery, including 78 definitive episodes of left SAPVE between 1996 and 2016.Fifty percent had a Charlson Index score >5; 53% were health care-related. Twenty percent did not present fever. Complications at diagnosis included: severe heart failure (HF, 29%), septic shock (SS, 17.9%), central nervous system abnormalities (19%), septic metastasis (4%). Hemorrhagic stroke was not higher in anticoagulated patients. Twenty-seven percent were methicilin-resistant SA (MRSA). Fifteen of 31 had positive valve culture; it was related to surgery within first 24 hours. At diagnosis, 69% had vegetation (>10 mm in 75%), 21.8% perianular extension, and 20% prosthetic dehiscence. Forty-eight percent had persistent bacteremia, related to nonsurgical treatment. Perianular extension progressed in 18%. Surgery was performed in 35 episodes (12 with stroke). Eleven uncomplicated episodes were managed with medical therapy, 8 survived. In-hospital mortality was 55%, higher in episodes with hemorrhagic stroke (77.8% vs 52.2%, odds ratio 3.2 [0.62-16.55]). Early SAPVE was nosocomial (92%), presented as severe HF (54%), patients were diagnosed and operated on early, 38% died. In intermediate SAPVE (9 weeks-1 year) diagnosis was delayed (24%), patients presented with constitutional syndrome (18%), renal failure (41%), and underwent surgery >72 hours after indication; 53% died. Late SAPVE (>1 year) was related with health care, diagnosis delay, and 60% of deceases.Left SAPVE frequently affected patients with comorbidity and health care contact. Complications at diagnosis and absence of fever were frequent. Presence of MRSA was high. Positive valve culture was related to early surgery. Paravalvular extension was frequent; vegetations were large, but its absence at diagnosis was common. Some uncomplicated SAPVE episodes were safety treated with medical therapy. Surgery was feasible in patients with stroke. Mortality was high. There were differences in some clinical characteristics and in evolution according to the time elapsed from valve replacement. Prognosis was better in early SAPVE.

[Pneumococcal bacteremia in adult patients at a hospital in Madrid: serotypes and susceptibility]. / Bacteriemia neumocócica en pacientes adultos de un hospital de Madrid: serotipos y sensibilidad antibiótica.

INTRODUCTION: The aim of this study is to describe the distribution of Streptococcus pneumoniae serotypes, its antimicrobial susceptibility profiles and the relation with vaccines in pneumococcal invasive strains isolated from blood cultures of adult patients. METHODS: All pneumococci isolated (67 strains) from blood cultures were serotyped by latex agglutination (Pneumotest latex) and Quellung reaction (Statens Serum Institut, Denmark). Antimicrobial susceptibility testing to penicillin (PEN), cefotaxime (CT), erythromycin (ERY) and levofloxacin (LEV) was performed by the E-test method (Biomèrieux, France). RESULTS: Among the 67 strains isolated, the most prevalent serotypes were 22F (11.9%) and 3 (11.9%), the second most frequent were 7F (7.5%) and 19A (7.5%). The coverage of the strains by the pneumococcal 7-valent conjugate vaccine (VNC7V), pneumococcal 13-valent conjugate vaccine (VNC13V) and pneumococcal 23-valent polysaccharide (VNP23V) were 16, 49 and 82%, respectively. Serotypes 22F and 3 were responsible for 14 of the 48 episodes of pneumonia with bacteremia (29.2%) and only 2 of the 19 episodes (10.5%) of bacteremia without pneumonia. According to the 2007 CLSI criteria, 12 strains (17.9%) were non-susceptible to penicillin. Eleven of this 12 strains (91.7%) were resistant to erythromycin, simultaneously. CONCLUSIONS: The most common serotypes were 22F, 3, 7F y 19A. Three of them (3, 7F y 19A) are serotypes that are covered by the new VNC13V but not by VNC7V. Serotype 22F is a serotype emergent that is not covered by the VNC7V. The percentage of non-susceptibility to penicillin and resistance to erythromycin was comparable to the percentage reported in our country.

Relevance of clinical presentation and period of diagnosis in prosthetic valve endocarditis.

BACKGROUND AND AIM OF THE STUDY: The study aim was to describe the characteristics of prosthetic valve endocarditis (PVE) and the clinical presentation in relation to the period of diagnosis. METHODS: In this observational, prospective, multicenter study, data acquired from 100 consecutive cases of PVE were recorded. The period of diagnosis was defined as the time elapsed from valve implantation surgery to the PVE diagnosis. PVE was classified as early (EPVE) if diagnosed during the first eight weeks, intermediate (IPVE) from nine weeks to one year, and late (LVPE) if diagnosed after one year. Variables related to the period of diagnosis and causal microorganisms were compared using a chi-square test. A logistic regression analysis was made for any diagnosis delay greater than 15 days from the first symptoms, periannular extension, surgery, and death during hospitalization. RESULTS: In total, data were collected from 24 patients with EPVE, 29 with IPVE, and 47 with LPVE. Some 59% of the IPVE episodes were caused by low-virulence microorganisms, compared to 29% of the EPVE episodes and 28% of the LPVE episodes (p = 0.017). Similarly, 66% of the IPVE episodes had a diagnosis delay longer than 15 days compared to 50% for LPVE and 20% for EPVE (p = 0.034), while 38% of the EPVE cases presented with fever and severe dyspnea compared to 10% of IPVE and 4% of LPVE cases (p = 0.001). In addition, 24% of the IPVE cases presented as fever and cardiac conduction disturbances, versus 4% for EPVE and 11% for LPVE (p = 0.08). When comparing EPVE with IPVE, the latter had a 69% periannular extension versus 38% for EPVE (p = 0.02) and 48% mortality versus 25%, respectively (p = 0.082). In a multivariate analysis, IPVE was related to the periannular extension of infection compared to EPVE (OR 3.4, 95% CI 0.98-12.1, p = 0.054). Death depended on the periannular extension of infection (OR 3.4, 95% CI 1.3-8.8, p = 0.011) and septic shock during hospitalization (OR 6.9, 95% CI 2.0-23.7, p = 0.002). CONCLUSION: When diagnosed between nine weeks and one year after valve implantation, IPVE presented with low-grade clinical manifestations, a greater delay in diagnosis, a longer periannular extension and a poorer prognosis than did EPVE.

Chronic prosthetic valve endocarditis due to Propionibacterium acnes: an unexpected cause of prosthetic valve dysfunction.

INTRODUCTION AND OBJECTIVES: To determine the characteristics of Propionibacterium acnes prosthetic valve endocarditis (PAPVE). METHODS: Prospective descriptive study of 16 consecutive cases of PAPVE. RESULTS: Seven patients developed PAPVE early and 9 developed it late. In all those who developed PAPVE late, there was a history of mucocutaneous barrier manipulation. The delay in diagnosis was >3 months in 75%. The clinical presentation was asymptomatic prosthetic valve dysfunction in 31%, heart failure in 19%, coronary syndrome in 12.5%, fever in 25%, and neurological deficits in 19%. At diagnosis, 62.5% had heart failure and 44% had fever. The predominant echocardiographic finding was prosthesis dysfunction due to dehiscence of metallic aortic valves (6 out of 7) or stenosis of metallic mitral valves (4 out of 7). In 2 of the 3 biological aortic prostheses, dysfunction was due to leaflet distortion. Blood cultures and surgical specimens tested positive after a mean of 11.6 and 12.2 days, respectively. In 2 cases, the diagnosis was confirmed by PCR. The principle intraoperative finding was the presence of abundant grayish pannus. Histology demonstrated the absence of acute inflammatory features. Twelve patients received antibiotic treatment with valve replacement: 7 were cured, 4 experienced early prosthesis dehiscence and 1 relapsed. All 3 patients who were initially treated with antibiotics alone suffered relapses. CONCLUSIONS: Generally, PAPVE presents as prosthetic valve dysfunction with few symptoms of infection. Prolonged incubation of cultures is essential for diagnosis. Antibiotic treatment provides clinical control but does not eradicate the infection, and valve replacement is necessary for a cure. The postoperative course can be complicated by prosthesis dehiscence.