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Background Infective endocarditis (IE) caused by viridans and gallolyticus group streptococci (VGS-GGS) resistant to penicillin (PEN-R; minimum inhibitory concentration ≥4 mg/L) is rare but poses therapeutic challenges. Objectives To describe the characteristics of patients with IE caused by PEN-R VGS-GGS, focusing on antimicrobial management. Methods Retrospective analysis of a prospective cohort of definite IE caused by PEN-R VGS-GGS between 2008 and 2023 in 40 Spanish hospitals. We describe clinical characteristics, management and outcome of the cases, and compare them to IE caused by VGS-GGS with susceptibility or susceptibility with increased exposure to penicillin (PEN-I). Results We identified nine cases of PEN-R VGS-GGS IE in a cohort of 1563 streptococcal IE (0.58%). All isolates belonged to S. mitis group. Three cases died during hospitalization and no relapse occurred at 3 months of follow-up. Compared to cases with susceptibility or PEN-I, PEN-R showed a higher rate of mitral location (78% versus 51%), surgical indication (67% versus 51%), and in-hospital mortality (33% versus 12%). Most cases (86%) showed resistance to third-generation cephalosporins. The preferred antibiotic regimen was beta-lactam-based: ceftriaxone plus gentamicin, penicillin plus gentamicin, ceftriaxone plus levofloxacin, and ceftaroline plus daptomycin. Two cases received a combination of vancomycin plus gentamicin. Levofloxacin was used in two cases in combination with ceftriaxone or daptomycin. All patients that received cardiac surgery were cured at the end of follow-up. Conclusions IE caused by PEN-R VGS-GGS was rare and only affected mitis group streptococci. Antibiotic combination including a beta-lactam seems to be effective in its management. [ABSTRACT FROM AUTHOR]

Background Limited data exist examining the association between incident cancer and cumulative integrase inhibitor (INSTI) exposure. Methods Participants were followed from baseline (latest of local cohort enrollment or January 1, 2012) until the earliest of first cancer, final follow-up, or December 31, 2019. Negative binomial regression was used to assess associations between cancer incidence and time-updated cumulative INSTI exposure, lagged by 6 months. Results Of 29 340 individuals, 74% were male, 24% were antiretroviral treatment (ART)-naive, and median baseline age was 44 years (interquartile range [IQR], 36–51). Overall, 13 950 (48%) individuals started an INSTI during follow-up. During 160 657 person-years of follow-up ([PYFU] median 6.2; IQR, 3.9–7.5), there were 1078 cancers (incidence rate [IR] 6.7/1000 PYFU; 95% confidence interval [CI], 6.3–7.1). The commonest cancers were non-Hodgkin lymphoma (n = 113), lung cancer (112), Kaposi's sarcoma (106), and anal cancer (103). After adjusting for potential confounders, there was no association between cancer risk and INSTI exposure (≤6 months vs no exposure IR ratio: 1.15 [95% CI, 0.89–1.49], >6–12 months; 0.97 [95% CI, 0.71–1.32], >12–24 months; 0.84 [95% CI, 0.64–1.11], >24–36 months; 1.10 [95% CI, 0.82–1.47], >36 months; 0.90 [95% CI, 0.65–1.26] [ P  = .60]). In ART-naive participants, cancer incidence decreased with increasing INSTI exposure, mainly driven by a decreasing incidence of acquired immune deficiency syndrome cancers; however, there was no association between INSTI exposure and cancer for those ART-experienced (interaction P  < .0001). Conclusions Cancer incidence in each INSTI exposure group was similar, despite relatively wide CIs, providing reassuring early findings that increasing INSTI exposure is unlikely to be associated with an increased cancer risk, although longer follow-up is needed to confirm this finding. [ABSTRACT FROM AUTHOR]

Background Limited data exist that compare clinical outcomes of 2-drug regimens (2DRs) and 3-drug regimens (3DRs) in people living with human immunodeficiency virus. Methods Antiretroviral treatment–experienced individuals in the International Cohort Consortium of Infectious Diseases (RESPOND) who switched to a new 2DR or 3DR from 1 January 2012–1 October 2018 were included. The incidence of clinical events (AIDS, non-AIDS cancer, cardiovascular disease, end-stage liver and renal disease, death) was compared between regimens using Poisson regression. Results Of 9791 individuals included, 1088 (11.1%) started 2DRs and 8703 (88.9%) started 3DRs. The most common 2DRs were dolutegravir plus lamivudine (22.8%) and raltegravir plus boosted darunavir (19.8%); the most common 3DR was dolutegravir plus 2 nucleoside reverse transcriptase inhibitors (46.9%). Individuals on 2DRs were older (median, 52.6 years [interquartile range, 46.7–59.0] vs 47.7 [39.7–54.3]), and a higher proportion had ≥1 comorbidity (81.6% vs 73.9%). There were 619 events during 27 159 person-years of follow-up (PYFU): 540 (incidence rate [IR] 22.5/1000 PYFU; 95% confidence interval [CI]: 20.7–24.5) on 3DRs and 79 (30.9/1000 PYFU; 95% CI: 24.8–38.5) on 2DRs. The most common events were death (7.5/1000 PYFU; 95% CI: 6.5–8.6) and non-AIDS cancer (5.8/1000 PYFU; 95% CI: 4.9–6.8). After adjustment for baseline demographic and clinical characteristics, there was a similar incidence of events on both regimen types (2DRs vs 3DRs IR ratio, 0.92; 95% CI:.72–1.19; P  = .53). Conclusions This is the first large, international cohort to assess clinical outcomes on 2DRs. After accounting for baseline characteristics, there was a similar incidence of events on 2DRs and 3DRs. 2DRs appear to be a viable treatment option with regard to clinical outcomes. Further research on resistance barriers and long-term durability of 2DRs is needed. [ABSTRACT FROM AUTHOR]

Background Studies investigating the impact of cardiogenic shock (CS) on endocarditis are lacking. Methods Prospectively collected cohort from 35 Spanish centers (2008-2018). Logistic regression analyses were performed to identify risk factors for developing CS and predictors of mortality. Results Among 4856 endocarditis patients, 1652 (34%) had acute heart failure (AHF) and 244 (5%) CS. Compared with patients without AHF and AHF but no CS, patients with CS presented higher rates of surgery (40.5%, 52.5%, and 68%; P <.001) and in-hospital mortality (16.3%, 39.1%, and 52.5%). Compared with patients with septic shock, CS patients presented higher rates of surgery (42.5% vs 68%; P <.001) and lower rates of in-hospital and 1-year mortality (62.3% vs 52.5%, P =.008, and 65.3% vs 57.4%, P =.030). Severe aortic and mitral regurgitation (OR [95% CI], 2.47 [1.82-3.35] and 3.03 [2.26-4.07]; both P <.001), left-ventricle ejection fraction <60% (1.72; 1.22-2.40; P =.002), heart block (2.22; 1.41-3.47; P =.001), tachyarrhythmias (5.07; 3.13-8.19; P <.001), and acute kidney failure (2.29; 1.73-3.03; P <.001) were associated with higher likelihood of developing CS. Prosthetic endocarditis (2.03; 1.06 -3.88; P =.032), Staphylococcus aureus (3.10; 1.16 -8.30; P =.024), tachyarrhythmias (3.09; 1.50-10.13; P =.005), and not performing cardiac surgery (11.40; 4.83-26.90; P <.001) were associated with a higher risk of mortality. Conclusions AHF is common among patients with endocarditis. CS is associated with high mortality and should be promptly identified and assessed for cardiac surgery. [ABSTRACT FROM AUTHOR]

Objectives: To investigate if the addition of cloxacillin to vancomycin enhances the activity of both monotherapies for treating MSSA and MRSA experimental endocarditis (EE) in rabbits.Methods: Vancomycin plus cloxacillin was compared with the respective monotherapies and daptomycin. In vitro time-kill studies were performed using standard (105 cfu) and high (108 cfu) inocula of five MRSA, one glycopeptide-intermediate (GISA) and five MSSA strains. One MSSA (MSSA-678) and one MRSA (MRSA-277) strain were selected to be used in the in vivo model. A human-like pharmacokinetics model was applied and the equivalents of cloxacillin 2 g/4 h IV and daptomycin 6 mg/kg/day IV were administered. To optimize vancomycin activity, dosage was adjusted to achieve an AUC/MIC ≥400.Results: Daptomycin sterilized significantly more vegetations than cloxacillin (13/13, 100% versus 9/15, 60%; P = 0.02) and showed a trend of better activity than vancomycin (10/14, 71%; P = 0.09) and vancomycin plus cloxacillin (10/14, 71%; P = 0.09) against MSSA-678. Addition of cloxacillin to vancomycin (13/15, 87%) was significantly more effective than vancomycin (8/16, 50%; P = 0.05) and showed similar activity to daptomycin (13/18, 72%; P = 0.6) against MRSA-277. In all treatment arms, the bacterial isolates recovered from vegetations were re-tested and showed the same daptomycin susceptibility as the original strains.Conclusions: Vancomycin plus cloxacillin proved synergistic and bactericidal activity against MRSA. Daptomycin was the most efficacious option against MSSA and similar to vancomycin plus cloxacillin against MRSA. In settings with high MRSA prevalence, vancomycin plus cloxacillin might be a good alternative for empirical therapy of S. aureus IE. [ABSTRACT FROM AUTHOR]

Objectives: To develop a population pharmacokinetic model for romidepsin given as an HIV latency reversing agent (LRA) and to explore the relationship between romidepsin exposure and its in vivo effects on viral gene expression and antiviral immunity.Methods: A population pharmacokinetic analysis was performed in 15 HIV-1-infected patients who received three weekly infusions of romidepsin (5 mg/m2) within the BCN02 clinical trial. A full pharmacokinetic profile was obtained for each participant at the first dose, and additional samples thereafter. A population pharmacokinetic model was developed. Bayesian estimates of the individual pharmacokinetic parameters of romidepsin were used to simulate individual time-concentration curves on each occasion. The relationship between romidepsin AUC0-∞ and its in vivo effects was assessed.Results: Romidepsin pharmacokinetics were best described by a three-compartment model with linear kinetics. Body weight influenced romidepsin disposition. A significant relationship was observed between romidepsin AUC0-∞ and increases in expression of exhaustion markers by CD4+ and CD8+ T cells and apoptosis markers in CD4+, but not with histone acetylation levels or HIV-1 cell-associated RNA in CD4+ T cells. For each increase of 100 ng·h/mL in romidepsin AUC0-∞, CD4+ counts decreased by a mean (95% CI) of 74 (42-94) cells/mm3 after dosing.Conclusions: A population model describing the pharmacokinetics of romidepsin as an HIV LRA was developed. Higher exposure to romidepsin resulted in higher expression of apoptosis markers and declines in CD4+ count but did not increase viral reactivation levels. These observations have important implications for the optimization of effective kick-and-kill strategies for an HIV-1 cure. [ABSTRACT FROM AUTHOR]