Cutibacterium species valvular and cardiac device-related infective endocarditis: contemporary data from the GAMES prospective cohort (2008-2023).

BACKGROUND: Information on infective endocarditis (IE) caused by Cutibacterium spp. is limited and new Duke-ISCVID criteria have not yet been properly assessed. We examined clinical characteristics, outcomes and performance of diagnostic tests for Cutibacterium valvular and cardiac implantable electronic device-related IE (CIED-IE). METHODS: Data corresponding to all episodes of Cutibacterium IE recorded from 2008 to 2023 in a prospective national cohort including 46 Spanish hospitals were examined. Possible IE cases were reassessed using the new criteria. The sensitivity of blood cultures, valvular and CIED cultures, and PCR of the 16SrRNA gene and sequencing (16SPCR) was evaluated. RESULTS: There were 67/6,692 (1%) episodes of IE caused by Cutibacterium spp., 85% affecting men. Of these, 50 were valve-related (45 prosthetic, 5 native) and 17 CIED-related. The new criteria identified 8 additional cases and reclassified 15 as definite IE. Intracardiac complications (abscess, pseudoaneurysm, perforation or intracardiac fistula) occurred in 23/50 (46%) valvular IE episodes, leading to 18% mortality, and up to 40% mortality if surgery was indicated but could not be performed. All CIED-IE cases underwent device removal and no deaths were recorded. Positive diagnosis rates for blood cultures, valve/device cultures and 16SPCR were 52%, 70% and 82%, respectively. CONCLUSION: Cutibacterium IE is a rare yet potentially life-threatening condition that warrants a high index of suspicion in men with endovascular prosthetic material. The new Duke-ISCVID criteria and molecular techniques are useful for its diagnosis. Considering a significant complication rate, cardiac surgery and removal of CIEDs play a key role in reducing mortality.

Cloxacillin plus fosfomycin versus cloxacillin alone for methicillin-susceptible Staphylococcus aureus bacteremia: a randomized trial.

Treatment failure occurs in about 25% of patients with methicillin-susceptible Staphylococcus aureus (MSSA) bacteremia. We assessed whether cloxacillin plus fosfomycin achieves better treatment success than cloxacillin alone in hospitalized adults with MSSA bacteremia. We conducted a multicenter, open-label, phase III-IV superiority randomized clinical trial. We randomly assigned patients (1:1) to receive 2 g of intravenous cloxacillin alone every 4 h or with 3 g of intravenous fosfomycin every 6 h for the initial 7 days. The primary endpoint was treatment success at day 7, a composite endpoint with the following criteria: patient alive, stable or with improved quick Sequential Organ Failure Assessment score, afebrile and with negative blood cultures for MSSA, adjudicated by an independent committee blinded to treatment allocation. We randomized 215 patients, of whom 105 received cloxacillin plus fosfomycin and 110 received cloxacillin alone. We analyzed the primary endpoint with the intention-to-treat approach in 214 patients who received at least 1 day of treatment. Treatment success at day 7 after randomization was achieved in 83 (79.8%) of 104 patients receiving combination treatment versus 82 (74.5%) of 110 patients receiving monotherapy (risk difference 5.3%; 95% confidence interval (CI), -5.95-16.48). Secondary endpoints, including mortality and adverse events, were similar in the two groups except for persistent bacteremia at day 3, which was less common in the combination arm. In a prespecified interim analysis, the independent committee recommended stopping recruitment for futility prior to meeting the planned randomization of 366 patients. Cloxacillin plus fosfomycin did not achieve better treatment success at day 7 of therapy than cloxacillin alone in MSSA bacteremia. Further trials should consider the intrinsic heterogeneity of the infection by using a more personalized approach. ClinicalTrials.gov registration: NCT03959345 .

Molecular Epidemiology, Antimicrobial Susceptibility, and Clinical Features of Methicillin-Resistant Staphylococcus aureus Bloodstream Infections over 30 Years in Barcelona, Spain (1990-2019).

Methicillin-resistant Staphylococcus aureus bloodstream infections (MRSA-BSI) are a significant cause of mortality. We analysed the evolution of the molecular and clinical epidemiology of MRSA-BSI (n = 784) in adult patients (Barcelona, 1990−2019). Isolates were tested for antimicrobial susceptibility and genotyped (PFGE), and a selection was sequenced (WGS) to characterise the pangenome and mechanisms underlying antimicrobial resistance. Increases in patient age (60 to 71 years), comorbidities (Charlson's index > 2, 10% to 94%), community-onset healthcare-associated acquisition (9% to 60%), and 30-day mortality (28% to 36%) were observed during the 1990−1995 and 2014−2019 periods. The proportion of catheter-related BSIs fell from 57% to 20%. Current MRSA-BSIs are caused by CC5-IV and an upward trend of CC8-IV and CC22-IV clones. CC5 and CC8 had the lowest core genome proportions. Antimicrobial resistance rates fell, and only ciprofloxacin, tobramycin, and erythromycin remained high (>50%) due to GyrA/GrlA changes, the presence of aminoglycoside-modifying enzymes (AAC(6')-Ie-APH(2″)-Ia and ANT(4')-Ia), and mph(C)/msr(A) or erm (C) genes. Two CC22-IV strains showed daptomycin resistance (MprF substitutions). MRSA-BSI has become healthcare-associated, affecting elderly patients with comorbidities and causing high mortality rates. Clonal replacement with CC5-IV and CC8-IV clones resulted in lower antimicrobial resistance rates. The increased frequency of the successful CC22-IV, associated with daptomycin resistance, should be monitored.

The Effectiveness of Combination Therapy for Treating Methicillin-Susceptible Staphylococcus aureus Bacteremia: A Systematic Literature Review and a Meta-Analysis.

BACKGROUND: This meta-analysis aims to evaluate the effectiveness of combination therapy for treating MSSA bacteremia. METHODS: We searched Ovid MEDLINE, EMBASE, Cochrane CENTRAL, and clinicaltrials.gov for studies including adults with MSSA bacteremia. The monotherapy group used a first-line antibiotic active against MSSA and the combination group used a first-line antibiotic plus additional antibiotic/s. The primary outcome was all-cause mortality. Secondary outcomes included persistent bacteremia, duration of bacteremia, relapse, and adverse events. Random-effects models with inverse variance weighting were used to estimate pooled risk ratios (pRR). Heterogeneity was assessed using the I2 value and the Cochrane's Q statistic. RESULTS: A total of 12 studies (6 randomized controlled trials [RCTs]) were included. Combination therapy did not significantly reduce 30-day mortality (pRR 0.92, 95% CI, 0.70-1.20), 90-day mortality (pRR 0.89, 95% CI, 0.74-1.06), or any-time mortality (pRR 0.91, 95% CI, 0.76-1.08). Among patients with deep-seated infections, adjunctive rifampicin may reduce 90-day mortality (3 studies with moderate-high risk of bias; pRR 0.62, 95% CI, 0.42-0.92). For secondary outcomes, combination therapy decreased the risk of relapse (pRR 0.38, 95% CI, 0.22-0.66), but this benefit was not maintained when pooling RCTs (pRR 0.54, 95% CI, 0.12-2.51). Combination therapy was associated with an increased risk of adverse events (pRR 1.74, 95% CI, 1.31-2.31). CONCLUSIONS: Combination therapy not only did not decrease mortality in patients with MSSA bacteremia, but also increased the risk of adverse events. Combination therapy may reduce the risk of relapse, but additional high-quality studies are needed.

Bloodstream Infection and Endocarditis Caused by Staphylococcus aureus in Patients with Cancer: A Multicenter Cohort Study.

INTRODUCTION: In a large cohort of patients with Staphylococcus aureus bloodstream infection (SABSI), we aimed to analyze the incidence and risk factors for infective endocarditis (IE) among patients with active cancer (PAC) in comparison with those without cancer (PWC). METHODS: Multicenter cohort study of patients with SABSI admitted to two tertiary care hospitals, from 2011 to 2019. PAC were defined as those with an active solid organ cancer or hematological malignancies. SABSI and S. aureus IE were compared between PAC and PWC. RESULTS: Among 978 episodes of SABSI, 217 (22.2%) occurred in PAC. PAC were younger, had fewer comorbidities, carried cardiac devices less often, and had less community-acquired SABSI than PWC. Compared to PWC, PAC more frequently had catheter-related SABSI, less IE (2.8% vs 10.9%, p < 0.001) and osteoarticular infection (2.3% vs 14.3%, p < 0.001). Independent risk factors for IE were cardiopathy (aOR 4.392, 95% CI 2.719-7.094) and persistent bacteremia (aOR 3.545, 95% CI 2.159-5.820). Thirty-day mortality was high, and similar between groups (24.2% vs 25.5%, p = 0.282). CONCLUSIONS: PAC with SABSI developed IE less frequently than PWC did. This finding seems related to the differences in baseline characteristics and may have significant clinical implications, such as transesophageal echocardiography in PAC without cardiopathy or persistent bacteremia.

Multicentre, randomised, open-label, phase IV-III study to evaluate the efficacy of cloxacillin plus fosfomycin versus cloxacillin alone in adult patients with methicillin-susceptible Staphylococcus aureus bacteraemia: study protocol for the SAFO trial.

INTRODUCTION: Methicillin-susceptible Staphylococcus aureus (MSSA) bacteraemia is a frequent condition, with high mortality rates. There is a growing interest in identifying new therapeutic regimens able to reduce therapeutic failure and mortality observed with the standard of care of beta-lactam monotherapy. In vitro and small-scale studies have found synergy between cloxacillin and fosfomycin against S. aureus. Our aim is to test the hypothesis that cloxacillin plus fosfomycin achieves higher treatment success than cloxacillin alone in patients with MSSA bacteraemia. METHODS: We will perform a superiority, randomised, open-label, phase IV-III, two-armed parallel group (1:1) clinical trial at 20 Spanish tertiary hospitals. Adults (≥18 years) with isolation of MSSA from at least one blood culture ≤72 hours before inclusion with evidence of infection, will be randomly allocated to receive either cloxacillin 2 g/4-hour intravenous plus fosfomycin 3 g/6-hour intravenous or cloxacillin 2 g/4-hour intravenous alone for 7 days. After the first week, sequential treatment and total duration of antibiotic therapy will be determined according to clinical criteria by the attending physician.Primary endpoints: (1) Treatment success at day 7, a composite endpoint comprising all the following criteria: patient alive, stable or with improved quick-Sequential Organ Failure Assessment score, afebrile and with negative blood cultures for MSSA at day 7. (2) Treatment success at test of cure (TOC) visit: patient alive and no isolation of MSSA in blood culture or at another sterile site from day 8 until TOC (12 weeks after randomisation).We assume a rate of treatment success of 74% in the cloxacillin group. Accepting alpha risk of 0.05 and beta risk of 0.2 in a two-sided test, 183 subjects will be required in each of the control and experimental groups to obtain statistically significant difference of 12% (considered clinically significant). ETHICS AND DISSEMINATION: Ethical approval has been obtained from the Ethics Committee of Bellvitge University Hospital (AC069/18) and from the Spanish Medicines and Healthcare Product Regulatory Agency (AEMPS, AC069/18), and is valid for all participating centres under existing Spanish legislation. The results will be presented at international meetings and will be made available to patients and funders. TRIAL REGISTRATION NUMBER: The protocol has been approved by AEMPS with the Trial Registration Number EudraCT 2018-001207-37. ClinicalTrials.gov Identifier: NCT03959345; Pre-results.

Characteristics and Outcomes of Staphylococcus aureus Bloodstream Infection Originating From the Urinary Tract: A Multicenter Cohort Study.

BACKGROUND: Staphylococcus aureus bloodstream infection (SABSI) arising from a urinary tract source (UTS) is poorly understood. METHODS: We conducted a retrospective analysis in 3 major teaching hospitals in Spain of prospectively collected data of hospitalized patients with SABSI. SABSI-UTS was diagnosed in patients with urinary tract symptoms and/or signs, no evidence of an extra-urinary source of infection, and a urinary S. aureus count of ≥105 cfu/mL. Susceptibility of S. aureus strains and patient mortality were compared between SABSI from UTS (SABSI-UTS) and other sources (SABSI-other). RESULTS: Of 4181 episodes of SABSI, we identified 132 (3.16%) cases of SABSI-UTS that occurred predominantly in patients who were male, had high Charlson comorbidity scores, were dependent for daily life activities, and who had undergone urinary catheterization and/or urinary manipulation before the infection. SABSI-UTS was more often caused by MRSA strains compared with SABSI-other (40.9% vs 17.5%; P < .001). Patients with SABSI-UTS caused by MRSA more often received inadequate empirical treatment compared with those caused by susceptible strains (59.7% vs 23.1%; P < .001). The 30-day case fatality rate was lower in patients with SABSI-UTS than in those with SABSI-other (14.4% vs 23.8%; P = .02). Factors independently associated with mortality were dependence for daily activities (aOR, 3.877; 95% CI, 1.08-13.8; P = .037) and persistent bacteremia (aOR, 7.88; 95% CI, 1.57-39.46; P = .012). CONCLUSIONS: SABSI-UTS occurs predominantly in patients with severe underlying conditions and in those who have undergone urinary tract manipulation. Moreover, it is frequently due to MRSA strains and causes significant mortality.

Black Hole Superradiant Instability from Ultralight Spin-2 Fields.

Ultralight bosonic fields are compelling dark-matter candidates and arise in a variety of beyond standard model scenarios. These fields can tap energy and angular momentum from spinning black holes through superradiant instabilities, during which a macroscopic bosonic condensate develops around the black hole. Striking features of this phenomenon include gaps in the spin-mass distribution of astrophysical black holes and a continuous gravitational-wave (GW) signal emitted by the condensate. So far these processes have been studied in great detail for scalar fields and, more recently, for vector fields. Here we take an important step forward in the black hole superradiance program by computing, analytically, the instability timescale, direct GW emission, and stochastic background, in the case of massive tensor (i.e., spin-2) fields. Our analysis is valid for any black hole spin and for small boson masses. The instability of massive spin-2 fields shares some properties with the scalar and vector cases, but its phenomenology is much richer, for example, there exist multiple modes with comparable instability timescales, and the dominant GW signal is hexadecapolar rather than quadrupolar. Electromagnetic and GW observations of spinning black holes in the mass range M∈(1,10^{10}) M_{⊙} can constrain the mass of a putative spin-2 field in the range 10^{-22}≲m_{b} c^{2}/eV≲10^{-10} . For 10^{-17}≲m_{b} c^{2}/eV≲10^{-15} , the space mission LISA could detect the continuous GW signal for sources at redshift z=20, or even larger.

Impact of ß-Lactam and Daptomycin Combination Therapy on Clinical Outcomes in Methicillin-susceptible Staphylococcus aureus Bacteremia: A Propensity Score-matched Analysis.

BACKGROUND: Mortality rates from Staphylococcus aureus bacteremia are high and have only modestly improved in recent decades. We compared the efficacies of a ß-lactam in combination with daptomycin (BL/D-C) and ß-lactam monotherapy (BL-M) in improving clinical outcomes in methicillin-susceptible S. aureus (MSSA) bacteremia. METHODS: A retrospective cohort study of MSSA bacteremia was performed in a tertiary hospital from January 2011 to December 2017. Patients receiving BL/D-C and BL-M were compared to assess 7-, 30-, and 90-day mortality rates. A 1:2 propensity score matching analysis was performed. Differences were assessed using Cox regression models. RESULTS: Of the 514 patients with MSSA bacteremia, 164 were excluded as they had received combination therapies other than BL/D-C, had pneumonia, or died within 48 hours of admission. Of the remaining 350 patients, 136 and 214 received BL/D-C and BL-M, respectively. BL/D-C patients had higher Pitt scores and persistent bacteremia more often than BL-M patients. In the raw analysis, there were no differences in mortality rates between groups. After propensity score matching, there were no significant differences between the BL/D-C (110 patients) and BL-M (168 patients) groups for all-cause mortality rates at 7 days (8.18% vs 7.74%; P = 1.000), 30 days (17.3% vs 16.1%; P = .922), and 90 days (22.7% vs 23.2%; P = 1.000), even in a subanalysis of patients with high-risk source of infection and in a subgroup excluding catheter-related bacteremia. CONCLUSIONS: BL/D-C failed to reduce mortality rates in patients with MSSA bacteremia. Treatment strategies to improve survival in MSSA bacteremia are urgently needed.

Current etiology, clinical features and outcomes of bacteremia in older patients with solid tumors.

PURPOSE: To assess the etiology, clinical features and outcomes of bacteremia in older patients with solid tumors. METHODS: All episodes of bacteremia in hospitalized patients with solid tumors were prospectively collected. Patients aged ≥70 years were compared to patients aged <70 years. Risk factors for case-fatality rates in older patients were identified. RESULTS: We compared 217 episodes of bacteremia involving older patients and 525 occurring in younger patients. Older patients had more frequently other comorbidities, but were less commonly neutropenic and carried less frequently central venous catheters. Bacteremia from an abdominal source was more common in patients ≥70, whereas an endogenous source and catheter-related infection were less frequently observed. Streptococcus bovis group (3.7% vs. 0.8%, p = .01) and Listeria monocytogenes (4.6% vs. 1.9%, p = .04) were more common in older patients, whereas coagulase-negative staphylococci were less frequently found (1.4% vs. 5.3% p = .01). Infection due to multi-drug resistant (MDR) strains was significantly higher in older patients (17.1% vs. 10.9%, p = .02), who in addition, presented higher overall mortality (35.4% vs 27.7%, p = .04). In older patients, lung tumor, neutropenia, and low grade fever were associated with early mortality, whereas comorbidities, corticosteroids, septic shock and inadequate empirical antibiotic therapy were associated with overall mortality. CONCLUSIONS: We identified remarkable differences in the etiology and sources of bacteremia between older and younger cancer patients with bacteremia. Older patients had more frequent infection due to MDR organisms and presented a higher overall mortality. Corticosteroids and inadequate empirical antibiotic therapy are modifiable factors associated with mortality.

Lymphopenia as prognostic factor for mortality and hospital length of stay for elderly hospitalized patients.

BACKGROUND: Lymphopenia is a common finding in elderly patients and its relevance is unknown. AIMS: To evaluate the clinical prognostic value of lymphopenia on the admission of elderly hospitalized patients. METHODS: From 2012 to 2013, all consecutive patients >75 hospitalized because of medical conditions were prospectively included in the study. Sociodemographic, clinical and laboratory data were collected. Lymphopenia was considered by a plasmatic lymphocyte count of <1100 × 10(9)/l. Hospital length of stay, in-hospital mortality and mortality after a 1-year follow-up were assessed. RESULTS: The total sample consisted of 180 patients, 90 of whom were females (50 %). Mean age was 83.8 years (SD 5.4). Lymphopenia was present in 45 patients (25 %) upon admission. When compared, those patients with lymphopenia showed a longer hospital stay (19.9 vs. 15.7 days; p 0.002) and higher in-hospital mortality (26.7 vs 7.7 %; p 0.001). The odds ratio for in-hospital mortality in patients with lymphopenia was 3.9 (p 0.03) and the hazard ratio for 1-year mortality 1.9 (p 0.038). Both groups of elderly patients, with and without lymphopenia on admission, showed no differences related to sociodemographic, clinical, or other laboratory data. The study showed no difference in rate of infections between the groups. CONCLUSION: A quarter of our elderly hospitalized patients had lymphopenia on admission. Furthermore, lymphopenia seemed to constitute as a predictor for bad outcome in terms of a longer hospital stay, in-hospital mortality and 1-year mortality after discharge.