Genotypic and Phenotypic Study of Antiviral Resistance Mutations in Refractory Cytomegalovirus Infection.

BACKGROUND: This study describes the genotypic and phenotypic characterization of novel human cytomegalovirus (HCMV) genetic variants of a cohort of 94 clinically resistant HCMV patients. METHODS AND RESULTS: Antiviral-resistant mutations were detected in the UL97, UL54, and UL56 target genes of 25 of 94 (26.6%) patients. The genotype-phenotype correlation study resolved the status of 5 uncharacterized UL54 deoxyribonucleic acid polymerase (G441S, A543V, F460S, R512C, A928T) and 2 UL56 terminase (F345L, P800L) mutations found in clinical isolates. A928T conferred high, triple resistance to ganciclovir, foscarnet, and cidofovir, and A543V had 10-fold reduced susceptibility to cidofovir. Viral growth assays showed G441S, A543V, F345L, and P800L impaired viral growth capacities compared with wild-type AD169 HCMV. Three-dimensional modeling predicted A543V and A928T phenotypes but not R512C, reinforcing the need for individual characterization of mutations by recombinant phenotyping. CONCLUSIONS: Extending mutation databases is crucial to optimize treatments and to improve the assessment of patients with resistant/refractory HCMV infection.

Cellular and humoral immune response after mRNA-1273 SARS-CoV-2 vaccine in liver and heart transplant recipients.

Recently published studies have found an impaired immune response after SARS-CoV-2 vaccination in solid organ recipients. However, most of these studies have not assessed immune cellular responses in liver and heart transplant recipients. We prospectively studied heart and liver transplant recipients eligible for SARS-CoV-2 vaccination. Patients with past history of SARS-CoV-2 infection or SARS-CoV-2 detectable antibodies (IgM or IgG) were excluded. We assessed IgM/IgG antibodies and ELISpot against the S protein 4 weeks after receiving the second dose of the mRNA-1273 (Moderna) vaccine. Side effects, troponin I, liver tests and anti-HLA donor-specific antibodies (DSA) were also assessed. A total of 58 liver and 46 heart recipients received two doses of mRNA-1273 vaccine. Median time from transplantation to vaccination was 5.4 years (IQR 0.3-27). Sixty-four percent of the patients developed SARS-CoV-2 IgM/IgG antibodies and 79% S-ELISpot positivity. Ninety percent of recipients developed either humoral or cellular response (87% in heart recipients and 93% in liver recipients). Factors associated with vaccine unresponsiveness were hypogammaglobulinemia and vaccination during the first year after transplantation. Local and systemic side effects were mild or moderate, and none presented DSA or graft dysfunction after vaccination. Ninety percent of our patients did develop humoral or cellular responses to mRNA-1273 vaccine. Factors associated with vaccine unresponsiveness were hypogammaglobulinemia and vaccination during the first year after transplantation, highlighting the need to further protect these patients.

Cellular and humoral response after MRNA-1273 SARS-CoV-2 vaccine in kidney transplant recipients.

According to preliminary data, seroconversion after mRNA SARS-CoV-2 vaccination might be unsatisfactory in Kidney Transplant Recipients (KTRs). However, it is unknown if seronegative patients develop at least a cellular response that could offer a certain grade of protection against SARS-CoV-2. To answer this question, we prospectively studied 148 recipients of either kidney (133) or kidney-pancreas (15) grafts with assessment of IgM/IgG spike (S) antibodies and ELISpot against the nucleocapside (N) and the S protein at baseline and 2 weeks after receiving the second dose of the mRNA-1273 (Moderna) vaccine. At baseline, 31 patients (20.9%) had either IgM/IgG or ELISpot positivity and were considered to be SARS-CoV-2-pre-immunized, while 117 (79.1%) patients had no signs of either cellular or humoral response and were considered SARS-CoV-2-naïve. After vaccination, naïve patients who developed either humoral or cellular response were finally 65.0%, of which 29.9% developed either IgG or IgM and 35.0% S-ELISpot positivity. Factors associated with vaccine unresponsiveness were diabetes and treatment with antithymocytes globulins during the last year. Side effects were consistent with that of the pivotal trial and no DSAs developed after vaccination. In conclusion, mRNA-1273 SARS-CoV-2 vaccine elicits either cellular or humoral response in almost two thirds of KTRs.

Development of High-Level Daptomycin Resistance in Abiotrophia and Granulicatella Species Isolates from Patients with Infective Endocarditis.

Abiotrophia and Granulicatella species are fastidious organisms, representing the causative agents of ∼1% to 3% of cases of infective endocarditis (IE). Little is known about the optimal antibiotic treatment for these species, and daptomycin has been suggested as a therapeutic option. We describe the antimicrobial profiles of Abiotrophia and Granulicatella IE isolates, investigate high-level daptomycin resistance (HLDR) development, and evaluate daptomycin activity in combination therapy. In vitro studies with 16 IE strains (6 Abiotrophia defectiva strains, 9 Granulicatella adiacens strains, and 1 G. elegans strain) were performed using microdilution to determine MICs and time-kill methodology to evaluate combination therapy. Daptomycin nonsusceptibility (DNS) (MIC ≥ 2 mg/liter) and HLDR (MIC ≥ 256 mg/liter) were based on existing Clinical and Laboratory Standards Institute (CLSI) breakpoints for viridans group streptococci. All isolates were susceptible to vancomycin: G. adiacens was more susceptible to penicillin and ampicillin than A. defectiva (22% versus 0% and 67% versus 33%) but less susceptible to ceftriaxone and daptomycin (56% versus 83% and 11% versus 50%). HLDR developed in both A. defectiva (33%) and G. adiacens (78%) after 24 h of exposure to daptomycin. Combination therapy did not prevent the development of daptomycin resistance with ampicillin (2/3 strains), gentamicin (2/3 strains), ceftriaxone (2/3 strains), or ceftaroline (2/3 strains). Once developed, HLDR was stable for a prolonged time (>3 weeks) in G. adiacens, whereas in A. defectiva, HLDR reversed to the baseline MIC at day 10. This study is the first to demonstrate rapid HLDR development in Abiotrophia and Granulicatella species in vitro. Resistance was stable, and most combination therapies did not prevent it.

Effectiveness of vancomycin plus cloxacillin compared with vancomycin, cloxacillin and daptomycin single therapies in the treatment of methicillin-resistant and methicillin-susceptible Staphylococcus aureus in a rabbit model of experimental endocarditis.

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.

Mucormycosis associated with COVID-19 in two kidney transplant patients.

Coronavirus disease 2019 (COVID-19) predisposes patients to bacterial and fungal superinfections due to the impairment of the immunological system. Among the associated opportunistic fungal infections, mucormycosis is one of the least frequent but with the highest mortality. We describe two cases of mucormycosis in two kidney transplant recipients, while they were hospitalized for SARS-CoV-2 pneumonia, with rhinosinusal and musculoskeletal involvement, respectively.

Invasive aspergillosis in solid organ transplantation: Diagnostic challenges and differences in outcome in a Spanish national cohort (Diaspersot study).

BACKGROUND: The diagnosis of invasive aspergillosis (IA) can be problematic in solid organ transplantation (SOT). The prognosis greatly varies according to the type of transplant, and the impact of prophylaxis is not well defined. PATIENTS AND METHODS: The Diaspersot cohort analyses the impact of IA in SOT in Spain during the last 10 years. Proven and probable/putative IA was included. RESULTS: We analysed 126 cases of IA. The incidences of IA were as follows: 6.5%, 2.9%, 1.8% and 0.6% for lung, heart, liver and kidney transplantation, respectively. EORTC/MSG criteria confirmed only 49.7% of episodes. Tree-in-bud sign or ground-glass infiltrates were present in 56.3% of patients, while serum galactomannan (optical density index >0.5) was positive in 50.6%. A total of 41.3% received combined antifungal therapy. Overall mortality at 3 months was significantly lower (p < 0.001) in lung transplant recipients (14.8%) than in all other transplants [globally: 48.6%; kidney 52.0%, liver 58.3%, heart 31.2%, and combined 42.9%]. Fifty-four percent of episodes occurred despite the receipt of antifungal prophylaxis, and in 10%, IA occurred during prophylaxis (breakthrough infection), with both nebulised amphotericin (in lung transplant recipients) and candins (in the rest). CONCLUSIONS: Invasive aspergillosis diagnostic criteria, applied to SOT patients, may differ from those established for haematological patients. IA in lung transplants has a higher incidence, but is associated with a better prognosis than other transplants. Combination therapy is frequently used for IA in SOT. Prophylactic measures require optimisation of its use within this population.

Case report of COVID-19 in a kidney transplant recipient: Does immunosuppression alter the clinical presentation?

COVID-19 is novel infectious disease with an evolving understanding of its epidemiology and clinical manifestations. Immunocompromised patients often present atypical presentations of viral diseases. Herein we report a case of a COVID-19 infection in a solid organ transplant recipient, in which the first clinical symptoms were of gastrointestinal viral disease and fever, which further progressed to respiratory symptoms in 48 hours. In these high risk populations, protocols for screening for SARS-Cov2 may be needed to be re-evaluated.

Relationship between Vancomycin MIC and Virulence Gene Expression in Clonal Complexes of Methicillin-Susceptible Staphylococcus aureus Strains Isolated from Left-Sided Endocarditis.

Higher vancomycin MICs have been associated with more complicated courses and higher mortality rates in patients with Staphylococcus aureus bacteremia and infective endocarditis (IE). The aim of this study was to investigate whether the strains belonging to the cohort of 93 patients from a previously published study in which patients with strains with vancomycin MICs of ≥1.5 µg/ml presented higher mortality rates and systemic emboli than patients with strains with vancomycin MICs of <1.5 µg/ml had specific patterns of virulence factors, clonal complex (CC) types, or the ability to form biofilms. Vancomycin MICs were determined by Etest, and the isolates underwent spa typing to infer the CC, biofilm studies, a thrombin-induced platelet microbicidal assay, and multiplex PCR for the presence of virulence genes. We found no differences in genes encoding adhesins, toxins, or other putative virulence genes according to the vancomycin MIC group. CC30, CC34, and CC45 represented nearly half of the isolates, and there was no association with the vancomycin MIC. agr subgroups I and III predominated, with no association with the vancomycin MIC. Isolates with higher vancomycin MICs exhibited a poorer ability to form biofilms with and without the presence of vancomycin (2.03 versus 2.48 [P < 0.001], respectively, for isolates with higher vancomycin MICs and 2.60 versus 2.87 [P = 0.022], respectively, for isolates with lower vancomycin MICs). In the multivariable analysis, efb and V8 were risk factors for major emboli (adjusted odds ratio [aOR] = 7.5 and 95% confidence interval [CI] = 1.2 to 46.6 for efb, and aOR = 3.9 and 95% CI = 1.1 to 14.1 for V8), whereas no genotypic predictors of in-hospital mortality were found. No clear associations between genes encoding virulence factors, agr type, clonal complexes, mortality, and major embolic events according to vancomycin MIC group were found.

Cloxacillin or fosfomycin plus daptomycin combinations are more active than cloxacillin monotherapy or combined with gentamicin against MSSA in a rabbit model of experimental endocarditis.

BACKGROUND: In vitro and in vivo activity of daptomycin alone or plus either cloxacillin or fosfomycin compared with cloxacillin alone and cloxacillin plus gentamicin were evaluated in a rabbit model of MSSA experimental endocarditis (EE). METHODS: Five MSSA strains were used in the in vitro time-kill studies at standard (105-106 cfu/mL) and high (108 cfu/mL) inocula. In the in vivo EE model, the following antibiotic combinations were evaluated: cloxacillin (2 g/4 h) alone or combined with gentamicin (1 mg/kg/8 h) or daptomycin (6 mg/kg once daily); and daptomycin (6 mg/kg/day) alone or combined with fosfomycin (2 g/6 h). RESULTS: At standard and high inocula, daptomycin plus fosfomycin or cloxacillin were bactericidal against 4/5 and 5/5 strains, respectively, while cloxacillin plus gentamicin was bactericidal against 3/5 strains at standard inocula but against none at high inocula. Fosfomycin, cloxacillin, gentamicin and daptomycin MIC/MBCs of the MSSA-678 strain used in the EE model were: 8/64, 0.25/0.5, 0.25/0.5 and 1/8 mg/L, respectively. Adding gentamicin to cloxacillin significantly reduced bacterial density in vegetations compared with cloxacillin monotherapy (P = 0.026). Adding fosfomycin or cloxacillin to daptomycin [10/11 (93%) and 8/11 (73%), respectively] significantly improved the efficacy of daptomycin in sterilizing vegetations [0/11 (0%), P < 0.001 for both combinations] and showed better activity than cloxacillin alone [0/10 (0%), P < 0.001 for both combinations] and cloxacillin plus gentamicin [3/10 (30%), P = 0.086 for cloxacillin plus daptomycin and P = 0.008 for fosfomycin plus daptomycin]. No recovered isolates showed increased daptomycin MIC. CONCLUSIONS: The addition of cloxacillin or fosfomycin to daptomycin is synergistic and rapidly bactericidal, showing better activity than cloxacillin plus gentamicin for treating MSSA EE, supporting their clinical use.

Diagnostic yield of 18F-FDG PET/CT in suspected diagnosis of vascular graft infection: A prospective cohort study.

BACKGROUND: Prosthetic vascular graft infection (PVGI) is a severe complication associated with high morbidity and mortality. Clinical diagnosis is complex, requiring image testing such as CT angiography or leukocyte scintigraphy, which has considerable limitations. The aim of this study was to know the diagnostic yield of PET/CT with 18F-Fluorodeoxyglucose (18F-FDG) in patients with suspected PVGI. METHODS: We performed a prospective cohort study including 49 patients with suspected PVGI, median age of 62 ± 14 years. Three uptake patterns were defined following published recommendations: (i) focal, (ii) patched (PVGI criteria), and (iii) diffuse (no PVGI criterion). RESULTS: Sensitivity, specificity, and positive and negative predictive values for 18F-FDG-PET/CT were 88%, 79%, 67%, and 93%, respectively. 18F-FDG-PET/CT identified 14/16 cases of PVGI showing a focal (n = 10) or patched pattern (n = 4), being true negative in 26/33 cases with either a diffuse pattern (n = 16) or without uptake (n = 10). Five of the seven false-positive cases (71%) showed a patched pattern and all coincided with the application of adhesives for PVG placement. CONCLUSIONS: 18F-FDG-PET/CT is a useful technique for the diagnosis of PVGI. A patched pattern on PET/CT in patients in whom adhesives were applied for prosthetic vascular graft placement does not indicate infection.

Endocarditis Caused by Highly Penicillin-Resistant Viridans Group Streptococci: Still Room for Vancomycin-Based Regimens.

Optimal treatment options remain unknown for infective endocarditis (IE) caused by penicillin-resistant (PEN-R) viridans group streptococcal (VGS) strains. The aims of this study were to report two cases of highly PEN-R VGS IE, perform a literature review, and evaluate various antibiotic combinations in vitro and in vivo The following combinations were tested by time-kill studies and in the rabbit experimental endocarditis (EE) model: PEN-gentamicin, ceftriaxone-gentamicin, vancomycin-gentamicin, daptomycin-gentamicin, and daptomycin-ampicillin. Case 1 was caused by Streptococcus parasanguinis (PEN MIC, 4 µg/ml) and was treated with vancomycin plus cardiac surgery. Case 2 was caused by Streptococcus mitis (PEN MIC, 8 µg/ml) and was treated with 4 weeks of vancomycin plus gentamicin, followed by 2 weeks of vancomycin alone. Both patients were alive and relapse-free after ≥6 months follow-up. For the in vitro studies, except for daptomycin-ampicillin, all combinations demonstrated both synergy and bactericidal activity against the S. parasanguinis isolate. Only PEN-gentamicin, daptomycin-gentamicin, and daptomycin-ampicillin demonstrated both synergy and bactericidal activity against the S. mitis strain. Both strains developed high-level daptomycin resistance (HLDR) during daptomycin in vitro passage. In the EE studies, PEN alone failed to clear S. mitis from vegetations, while ceftriaxone and vancomycin were significantly more effective (P < 0.001). The combination of gentamicin with PEN or vancomycin increased bacterial eradication compared to that with the respective monotherapies. In summary, two patients with highly PEN-R VGS IE were cured using vancomycin-based therapy. In vivo, regimens of gentamicin plus either ß-lactams or vancomycin were more active than their respective monotherapies. Further clinical studies are needed to confirm the role of vancomycin-based regimens for highly PEN-R VGS IE. The emergence of HLDR among these strains warrants caution in the use of daptomycin therapy for VGS IE.

Perioperative prophylaxis with ertapenem reduced infections caused by extended-spectrum betalactamase-producting Enterobacteriaceae after kidney transplantation.

BACKGOUND: In recent years we have witnessed an increase in infections due to multidrug-resistant organisms in kidney transplant recipients (KTR). In our setting, we have observed a dramatic increase in infections caused by extended-spectrum betalactamase-producing (ESBL) Enterobacteriaceae in KTR. In 2014 we changed surgical prophylaxis from Cefazolin 2 g to Ertapenem 1 g. METHODS: We compared bacterial infections and their resistance phenotype during the first post-transplant month with an historical cohort collected during 2013 that had received Cefazolin. RESULTS: During the study period 110 patients received prophylaxis with Cefazolin and 113 with Ertapenem. In the Ertapenem cohort we observed a non-statistically significant decrease in the percentage of early bacterial infection from 57 to 47%, with urine being the most frequent source in both. The frequency of infections caused by Enterobacteriaceae spp. decreased from 64% in the Cefazolin cohort to 36% in the Ertapenem cohort (p = 0.005). In addition, percentage of ESBL-producing strains decreased from 21 to 8% of all Enterobacteriaceae isolated (p = 0.015). After adjusted in multivariate Cox regression analysis, male sex (HR 0.16, 95%CI: 0.03-0.75), cefazolin prophylaxis (HR 4.7, 95% CI: 1.1-22.6) and acute rejection (HR 14.5, 95% CI: 1.3-162) were associated to ESBL- producing Enterobacteriaceae infection. CONCLUSIONS: Perioperative antimicrobial prophylaxis with a single dose of Ertapenem in kidney transplant recipients reduced the incidence of early infections due to ESBL-producing Enterobacteriaceae without increasing the incidence of other multidrug-resistant microorganisms or C. difficile.

Community-Acquired Legionella Pneumonia in Human Immunodeficiency Virus-Infected Adult Patients: A Matched Case-Control Study.

We investigate whether the clinical presentations and outcomes of Legionella pneumonia in human immunodeficiency virus (HIV)-infected patients were comparable to those seen in non-HIV-infected patients (case-control design). HIV-infected individuals presented neither a more severe disease nor a worse clinical outcome than matched HIV-negative control patients.

Epidemiology, Clinical Features, and Outcome of Infective Endocarditis due to Abiotrophia Species and Granulicatella Species: Report of 76 Cases, 2000-2015.

Background: Infective endocarditis (IE) caused by Abiotrophia (ABI) and Granulicatella (GRA) species is poorly studied. This work aims to describe and compare the main features of ABI and GRA IE. Methods: We performed a retrospective study of 12 IE institutional cases of GRA or ABI and of 64 cases published in the literature (overall, 38 ABI and 38 GRA IE cases). Results: ABI/GRA IE represented 1.51% of IE cases in our institution between 2000 and 2015, compared to 0.88% of HACEK (Haemophilus, Aggregatibacter, Cardiobacterium, Eikenella, Kingella)-related IE and 16.62% of Viridans group streptococci (VGS) IE. Institutional ABI/GRA IE case characteristics were comparable to that of VGS, but periannular complications were more frequent (P = .008). Congenital heart disease was reported in 4 (10.5%) ABI and in 11 (28.9%) GRA cases (P = .04). Mitral valve was more frequently involved in ABI than in GRA (P < .001). Patient sex, prosthetic IE, aortic involvement, penicillin susceptibility, and surgical treatment were comparable between the genera. New-onset heart failure was the most frequent complication without genera differences (P = .21). Five (13.2%) ABI patients and 2 (5.3%) GRA patients died (P = .23). Factors associated with higher mortality were age (P = .02) and new-onset heart failure (P = .02). The genus (GRA vs ABI) was not associated with higher mortality (P = .23). Conclusions: GRA/ABI IE was more prevalent than HACEK IE and approximately one-tenth as prevalent as VGS; periannular complications were more frequent. GRA and ABI genera IE presented similar clinical features and outcomes. Overall mortality was low, and related to age and development of heart failure.

Mechanical Thrombectomy for Acute Ischemic Stroke Secondary to Infective Endocarditis.

Intravenous thrombolysis is contraindicated in acute ischemic stroke secondary to infective endocarditis. We report our initial experience in 6 cases of proximal vessel occlusion treated with mechanical thrombectomy, which was safe (no bleeding) and effective (significant early neurological improvement) and might be useful in this clinical setting.

A 5-Year Prospective Multicenter Evaluation of Influenza Infection in Transplant Recipients.

Background: Seasonal influenza infection may cause significant morbidity and mortality in transplant recipients. The purpose of this study was to assess the epidemiology of symptomatic influenza infection posttransplant and determine risk factors for severe disease. Methods: Twenty centers in the United States, Canada, and Spain prospectively enrolled solid organ transplant (SOT) or hematopoietic stem cell transplant (HSCT) recipients with microbiologically confirmed influenza over 5 consecutive years (2010-2015). Demographics, microbiology data, and outcomes were collected. Serial nasopharyngeal swabs were collected at diagnosis and upto 28 days, and quantitative polymerase chain reaction for influenza A was performed. Results: We enrolled 616 patients with confirmed influenza (477 SOT; 139 HSCT). Pneumonia at presentation was in 134 of 606 (22.1%) patients. Antiviral therapy was given to 94.1% for a median of 5 days (range, 1-42 days); 66.5% patients were hospitalized and 11.0% required intensive care unit (ICU) care. The receipt of vaccine in the same influenza season was associated with a decrease in disease severity as determined by the presence of pneumonia (odds ratio [OR], 0.34 [95% confidence interval {CI}, .21-.55], P < .001) and ICU admission (OR, 0.49 [95% CI, .26-.90], P = .023). Similarly, early antiviral treatment (within 48 hours) was associated with improved outcomes. In patients with influenza A, pneumonia, ICU admission, and not being immunized were also associated with higher viral loads at presentation (P = .018, P = .008, and P = .024, respectively). Conclusions: Annual influenza vaccination and early antiviral therapy are associated with a significant reduction in influenza-associated morbidity, and should be emphasized as strategies to improve outcomes of transplant recipients.

Direct-acting antivirals are effective and safe in HCV/HIV-coinfected liver transplant recipients who experience recurrence of hepatitis C: A prospective nationwide cohort study.

Direct-acting antivirals have proved to be highly efficacious and safe in monoinfected liver transplant (LT) recipients who experience recurrence of hepatitis C virus (HCV) infection. However, there is a lack of data on effectiveness and tolerability of these regimens in HCV/HIV-coinfected patients who experience recurrence of HCV infection after LT. In this prospective, multicenter cohort study, the outcomes of 47 HCV/HIV-coinfected LT patients who received DAA therapy (with or without ribavirin [RBV]) were compared with those of a matched cohort of 148 HCV-monoinfected LT recipients who received similar treatment. Baseline characteristics were similar in both groups. HCV/HIV-coinfected patients had a median (IQR) CD4 T-cell count of 366 (256-467) cells/µL. HIV-RNA was <50 copies/mL in 96% of patients. The DAA regimens administered were SOF + LDV ± RBV (34%), SOF + SMV ± RBV (31%), SOF + DCV ± RBV (27%), SMV + DCV ± RBV (5%), and 3D (3%), with no differences between the groups. Treatment was well tolerated in both groups. Rates of SVR (negative serum HCV-RNA at 12 weeks after the end of treatment) were high and similar for coinfected and monoinfected patients (95% and 94%, respectively; P = .239). Albeit not significant, a trend toward lower SVR rates among patients with advanced fibrosis (P = .093) and genotype 4 (P = .088) was observed. In conclusion, interferon-free regimens with DAAs for post-LT recurrence of HCV infection in HIV-infected individuals were highly effective and well tolerated, with results comparable to those of HCV-monoinfected patients.

The Combination of Daptomycin and Fosfomycin Has Synergistic, Potent, and Rapid Bactericidal Activity against Methicillin-Resistant Staphylococcus aureus in a Rabbit Model of Experimental Endocarditis.

We investigated whether the addition of fosfomycin or cloxacillin to daptomycin provides better outcomes in the treatment of methicillin-resistant Staphylococcus aureus (MRSA) experimental aortic endocarditis in rabbits. Five MRSA strains were used to perform in vitro time-kill studies using standard (106) and high (108) inocula. Combined therapy was compared to daptomycin monotherapy treatment in the MRSA experimental endocarditis model. A human-like pharmacokinetics model was applied, and the equivalents of cloxacillin at 2 g/4 h, fosfomycin at 2 g/6 h, and daptomycin at 6 to 10 mg/kg/day were administered intravenously. A combination of daptomycin and either fosfomycin or cloxacillin was synergistic in the five strains tested at both inocula. A bactericidal effect was detected in four of five strains tested with both combinations. The MRSA-277 strain (vancomycin MIC, 2 µg/ml) was used for the experimental endocarditis model. Daptomycin plus fosfomycin significantly improved the efficacy of daptomycin monotherapy at 6 mg/kg/day in terms of both the proportion of sterile vegetations (100% versus 72%, P = 0.046) and the decrease in the density of bacteria within the vegetations (P = 0.025). Daptomycin plus fosfomycin was as effective as daptomycin monotherapy at 10 mg/kg/day (100% versus 93%, P = 1.00) and had activity similar to that of daptomycin plus cloxacillin when daptomycin was administered at 6 mg/kg/day (100% versus 88%, P = 0.48). Daptomycin nonsusceptibility was not detected in any of the isolates recovered from vegetations. In conclusion, for the treatment of MRSA experimental endocarditis, the combination of daptomycin plus fosfomycin showed synergistic and bactericidal activity.

B-cell non-Hodgkin lymphoma linked to Coxiella burnetii.

Bacteria can induce human lymphomas, whereas lymphoproliferative disorders have been described in patients with Q fever. We observed a lymphoma in a patient with Q fever that prompted us to investigate the association between the 2 diseases. We screened 1468 consecutive patients of the 2004 to 2014 French National Referral Center for Q fever database. The standardized incidence ratios (SIRs) of diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL) were calculated comparatively to the 2012 Francim Registry. The presence of Coxiella burnetii was tested using immunofluorescence and fluorescence in situ hybridization using a specific 16S ribosomal RNA probe and genomic DNA probe. Seven patients (0.48%) presented mature B-cell lymphoma consisting of 6 DLBCL and 1 FL. An excess risk of DLBCL and FL was found in Q fever patients compared with the general population (SIR [95% confidence interval], 25.4 [11.4-56.4] and 6.7 [0.9-47.9], respectively). C burnetii was detected in CD68(+) macrophages within both lymphoma and lymphadenitis tissues but localization in CD123(+) plasmacytoid dendritic cells (pDCs) was found only in lymphoma tissues. Q fever patients with persistent focalized infection were found more at risk of lymphoma (hazard ratio, 9.35 [1.10-79.4]). Interleukin-10 (IL10) overproduction (P = .0003) was found in patients developing lymphoma. These results suggest that C burnetii should be added to the list of bacteria that promote human B-cell non-Hodgkin lymphoma, possibly by the infection of pDCs and IL10 overproduction. Screening for early lymphoma diagnosis should be considered in the management of patients with Q fever, especially those with persistent focalized infections.