Randomized Controlled Trial of Intensive Versus Conservative Glucose Control in Patients Undergoing Coronary Artery Bypass Graft Surgery: GLUCO-CABG Trial

OBJECTIVE

The optimal level of glycemic control needed to improve outcomes in cardiac surgery patients remains controversial.

RESEARCH DESIGN AND METHODS

We randomized patients with diabetes (n = 152) and without diabetes (n = 150) with hyperglycemia to an intensive glucose target of 100–140 mg/dL (n = 151) or to a conservative target of 141–180 mg/dL (n = 151) after coronary artery bypass surgery (CABG) surgery. After the intensive care unit (ICU), patients received a single treatment regimen in the hospital and 90 days postdischarge. Primary outcome was differences in a composite of complications, including mortality, wound infection, pneumonia, bacteremia, respiratory failure, acute kidney injury, and major cardiovascular events.

RESULTS

Mean glucose in the ICU was 132 ± 14 mg/dL (interquartile range [IQR] 124–139) in the intensive and 154 ± 17 mg/dL (IQR 142–164) in the conservative group (P < 0.001). There were no significant differences in the composite of complications between intensive and conservative groups (42 vs. 52%, P = 0.08). We observed heterogeneity in treatment effect according to diabetes status, with no differences in complications among patients with diabetes treated with intensive or conservative regimens (49 vs. 48%, P = 0.87), but a significant lower rate of complications in patients without diabetes treated with intensive compared with conservative treatment regimen (34 vs. 55%, P = 0.008).

CONCLUSIONS

Intensive insulin therapy to target glucose of 100 and 140 mg/dL in the ICU did not significantly reduce perioperative complications compared with target glucose of 141 and 180 mg/dL after CABG surgery. Subgroup analysis showed a lower number of complications in patients without diabetes, but not in patients with diabetes treated with the intensive regimen. Large prospective randomized studies are needed to confirm these findings.     

Clindamycin-primaquine versus pentamidine for the second-line treatment of pneumocystis pneumonia

There are limited data on the efficacy of alternative regimens for treating patients with pneumocystis pneumonia (PCP). We compared the efficacy of clindamycin-primaquine (C-P) with that of pentamidine as a secondline treatment for PCP. Among 91 patients receiving trimethoprim-sulfamethoxazole (TMP-SMX) as a first-line treatment for PCP, 31 (34%) did not respond and 7 (8%) had adverse reactions. Fourteen patients received C-P and 9 received pentamidine as a second-line regimen because of treatment failure or an adverse reaction to TMP-SMX. The response rate of patients to C-P was higher than the response rate to pentamidine (9/14; 64% vs 1/9; 11%; P = 0.03).     

Infections after the use of alemtuzumab in solid organ transplant recipients: a comparative study

We undertook a retrospective cohort study comparing infection in solid organ transplant recipients receiving alemtuzumab (n = 726) versus basiliximab (n = 215) or antithymocyte globulin (ATG) (n = 85). Eighty-one percent of patients had kidney transplants. Overall, 33% of patients in the alemtuzumab group (240/724) developed infection compared with 40% (87/215) in the basiliximab group (odds ratio [OR], 0.72; 95% confidence interval [CI], 0.53–0.99; P = .04). The frequency of infection was similar in the alemtuzumab and ATG groups (33% versus 36%, respectively, P = .53). The frequency of fungal infections, most caused by Candida spp., was similar in the alemtuzumab and basiliximab groups (10% versus 9%); disseminated fungal infection occurred in 68% of the patients with fungal infection receiving alemtuzumab and in 30% of the patients with fungal infection receiving basiliximab (OR, 4.76; 95% CI, 1.58–14.28; P = .003). Basiliximab posed a higher risk than alemtuzumab for infection. Disseminated candidal infections were more common in patients receiving alemtuzumab.     

Feasibility of Simplification From a Basal-Bolus Insulin Regimen to a Fixed-Ratio Formulation of Basal Insulin Plus a GLP-1RA or to Basal Insulin Plus an SGLT2 Inhibitor: BEYOND,a Randomized,Pragmatic Trial

OBJECTIVEBEYOND trial evaluated the feasibility of either basal insulin plus glucagon-like peptide 1 receptor agonist (GLP-1RA) or basal insulin plus sodium–glucose cotransporter 2 inhibitor (SGLT2i) to replace a full basal-bolus insulin (BBI) regimen in participants with type 2 diabetes and inadequate glycemic control.RESEARCH DESIGN AND METHODSParticipants were randomized (1:1:1) to: 1) intensification of the BBI regimen (n = 101), 2) fixed ratio of basal insulin plus GLP-1RA (fixed-combo group; n = 102), and 3) combination of basal insulin plus SGLT2i (gliflo-combo group; n = 102). The primary efficacy outcome was change from baseline in HbA_1c at 6 months.RESULTSBaseline characteristics were similar among the three groups (mean HbA_1c was 8.6% [70 mmol/mol]). At 6 months, patients experienced similar reduction in HbA_1c level (−0.6 ± 0.8, −0.6 ± 0.8, and −0.7 ± 0.9%, mean ± SD, respectively; noninferiority P < 0.001 vs. BBI), and the proportion of patients with HbA_1c ≤7.5% was also similar (34%, 28%, and 27%, respectively; P = 0.489). Total insulin dose increased in the BBI group (62 units/day) and decreased both in the fixed-combo and gliflo-combo groups (27 units/day and 21 units/day, respectively; P < 0.01). The proportion of patients with hypoglycemia was 17.8%, 7.8%, and 5.9%, respectively (P = 0.015). There were 12 dropouts in the fixed-combo group, 9 in the gliflo-combo group, and none in the BBI group.CONCLUSIONSBEYOND provides evidence that it is possible and safe to switch from a BBI regimen to either a once-daily fixed-combo injection or once-daily gliflozin added to basal insulin, with similar glucose control, fewer insulin doses, fewer injections daily, and less hypoglycemia.     

Hypoglycemia Unawareness Is Associated With Reduced Adherence to Therapeutic Decisions in Patients With Type 1 Diabetes: Evidence from a clinical audit

OBJECTIVE

Hypoglycemia unawareness increases severe hypoglycemia risk. Hypoglycemia avoidance restores awareness, but it is difficult to sustain. We compared adherence to treatment changes by awareness status.

RESEARCH DESIGN AND METHODS

Case notes of 90 type 1 diabetic patients were analyzed retrospectively, identifying awareness status and insulin regimens over four visits. The proportion of patients adhering to advice and percent advice taken were calculated.

RESULTS

A total of 31 patients with hypoglycemia awareness and 19 patients with hypoglycemia unawareness were identified, with insulin regimens available in 23 and 13, respectively. Patients with hypoglycemia unawareness were older (P = 0.001) and had longer diabetes duration (P = 0.002) and lower A1C (P = 0.007). More patients with hypoglycemia unawareness reported severe hypoglycemia (P = 0.002) and fewer were adherent (53.8 vs. 87.0%, P = 0.046), with lower adherence scores (42.5 ± 24.7 vs. 75.3 ± 27.5%, P = 0.001).

CONCLUSIONS

Reduced adherence to changes in insulin regimen in hypoglycemia unawareness is compatible with habituation to hypoglycemic stress. Therapies aimed at reversing repetitive harmful behaviors may be useful to restore hypoglycemia awareness and protection from severe hypoglycemia.Hypoglycemia unawareness in type 1 diabetes increases risk of severe hypoglycemia more than fivefold (1). Hypoglycemia awareness can be restored by hypoglycemia avoidance (2–4), which can be difficult. We hypothesized that hypoglycemia unawareness may translate into resistance to changing insulin regimens targeting hypoglycemia avoidance.     

Network Theory in Autoimmunity: IN VITRO SUPPRESSION OF SERUM ANTI-DNA ANTIBODY BINDING TO DNA BY ANTI-IDIOTYPIC ANTIBODY IN SYSTEMIC LUPUS ERYTHEMATOSUS

Regulation of serum anti-DNA antibody in systemic lupus erythematosus (SLE) by an antiidiotypic antibody was evaluated. Various sera from SLE patients in active and inactive states of their disease, as well as sera from normal individuals, were first completely depleted of anti-DNA and of DNA by affinity chromatography. The suppressive capacity of equimolar concentrations of the various depleted sera (blocking sera) on target lupus sera were determined. The target sera were from lupus patients with known DNA-binding capacity. Blocking sera from inactive SLE suppressed the binding of autologous anti-DNA antibody to [³H]DNA (n = 19,P < 0.01). Blocking sera from active SLE (n = 19), as well as human serum albumin, did not suppress. Sera from normal donors who had no contact with lupus patients or with lupus sera did not suppress (n = 14, P > 0.5), whereas those from normal donors who had contact with lupus patients or sera did suppress the binding (n = 5,P < 0.02). The anti-anti-DNA antibody suppressive activity in the inactive lupus serum was shown to be localized within the F(ab′)₂ portion of immunoglobulin (Ig)G and could not be removed upon adsorption by normal human gammaglobulin. Furthermore, immune complexes could be detected by a Clq binding assay when the inactive lupus blocking sera were incubated with the anti-DNA antibody containing target sera. The specificity of the suppressive serum factor was shown by its inability to block the binding of tetanus toxoid to antitetanus antibody and its ability to block the binding of DNA to F(ab′)₂ fragments of active lupus IgG.     

New Dosing Strategies for an Old Antibiotic: Pharmacodynamics of Front-Loaded Regimens of Colistin at Simulated Pharmacokinetics in Patients with Kidney or Liver Disease

Increasing evidence suggests that colistin monotherapy is suboptimal at currently recommended doses. We hypothesized that front-loading provides an improved dosing strategy for polymyxin antibiotics to maximize killing and minimize total exposure. Here, we utilized an in vitro pharmacodynamic model to examine the impact of front-loaded colistin regimens against a high bacterial density (10⁸ CFU/ml) of Pseudomonas aeruginosa. The pharmacokinetics were simulated for patients with hepatic (half-life [t_1/2] of 3.2 h) or renal (t_1/2 of 14.8 h) disease. Front-loaded regimens (n = 5) demonstrated improvement in bacterial killing, with reduced overall free drug areas under the concentration-time curve (fAUC) compared to those with traditional dosing regimens (n = 14) with various dosing frequencies (every 12 h [q12h] and q24h). In the renal failure simulations, front-loaded regimens at lower exposures (fAUC of 143 mg · h/liter) obtained killing activity similar to that of traditional regimens (fAUC of 268 mg · h/liter), with an ∼97% reduction in the area under the viable count curve over 48 h. In hepatic failure simulations, front-loaded regimens yielded rapid initial killing by up to 7 log₁₀ within 2 h, but considerable regrowth occurred for both front-loaded and traditional regimens. No regimen eradicated the high bacterial inoculum of P. aeruginosa. The current study, which utilizes an in vitro pharmacodynamic infection model, demonstrates the potential benefits of front-loading strategies for polymyxins simulating differential pharmacokinetics in patients with hepatic and renal failure at a range of doses. Our findings may have important clinical implications, as front-loading polymyxins as a part of a combination regimen may be a viable strategy for aggressive treatment of high-bacterial-burden infections.     

Comparative Effectiveness of Single versus Combination Antibiotic Prophylaxis for Infections after Transrectal Prostate Biopsy

An increase in fluoroquinolone resistance and transrectal ultrasound-guided prostate (TRUS) biopsy infections has prompted the need for alternative effective antibiotic prophylaxis. We aimed to compare ciprofloxacin and other single-agent therapies to combination therapy for efficacy and adverse effects. Men who underwent a TRUS biopsy within the VA Boston health care system with documented receipt of prophylactic antibiotics periprocedure were eligible for inclusion. Postprocedure infections within 30 days were ascertained by chart review from electronic records, including any inpatient, outpatient, or urgent-care visits. Among 455 evaluable men over a 3-year period, there were 25 infections (5.49%), with sepsis occurring in 2.4%, urinary tract infections (UTI) in 1.54%, and bacteremia in 0.44% of patients. Escherichia coli was the most common urine (89%) and blood (92%) pathogen, with fluoroquinolone resistance rates of 88% and 91%, respectively. Ciprofloxacin alone was associated with significantly more infections than ciprofloxacin plus an additional agent (P = 0.014). Intramuscular gentamicin alone was also significantly associated with a higher infection rate obtained with all other regimens (P = 0.004). Any single-agent regimen, including ciprofloxacin, ceftriaxone, or gentamicin, was associated with significantly higher infection rates than any combination regimen (odds ratio [OR], 4; 95% confidence interval [CI], 1.47, 10.85; P = 0.004). Diabetes, immunosuppressive condition or medication, hospitalization within the previous year, and UTI within the previous 6 months were not associated with infection risk. Clostridium difficile infections were similar. These findings suggest that ciprofloxacin, ceftriaxone, and gentamicin alone are inferior to a combination regimen. Institutions with high failure rates of prophylaxis for TRUS biopsies should consider combination regimens derived from their local data.     

Prevalence of iron deficiency on ICU discharge and its relation with fatigue: a multicenter prospective study

Introduction

Prevalence of iron deficiency (ID) at intensive care (ICU) admission is around 25 to 40%. Blood losses are important during ICU stay, leading to iron losses, but prevalence of ID at ICU discharge is unknown. ID has been associated with fatigue and muscular weakness, and may thus impair post-ICU rehabilitation. This study assessed ID prevalence at ICU discharge, day 28 (D28) and six months (M6) after and its relation with fatigue.

Methods

We conducted this prospective, multicenter observational study at four University hospitals ICUs. Anemic (hemoglobin (Hb) less than 13 g/dL in male and less than 12 g/dL in female) critically ill adult patients hospitalized for at least five days had an iron profile taken at discharge, D28 and M6. ID was defined as ferritin less than 100 ng/L or less than 300 ng/L together with a transferrin saturation less than 20%. Fatigue was assessed by numerical scale and the Multidimensional Fatigue Inventory-20 questionnaire at D28 and M6 and muscular weakness by a hand grip test at ICU discharge.

Results

Among 107 patients (men 77%, median (IQR) age 63 (48 to 73) years) who had a complete iron profile at ICU discharge, 9 (8.4%) had ID. At ICU discharge, their hemoglobin concentration (9.5 (87.7 to 10.3) versus 10.2 (92.2 to 11.7) g/dL, P =0.09), hand grip strength (52.5 (30 to 65) versus 49.5 (15.5 to 67.7)% of normal value, P =0.61) and visual analog scale fatigue scale (57 (40 to 80) versus 60 (47.5 to 80)/100, P =0.82) were not different from non-ID patients. At D28 (n =80 patients) and M6 (n =78 patients), ID prevalence increased (to 25 and 35% respectively) while anemia prevalence decreased (from 100% to 80 and 25% respectively, P <0.0001). ID was associated with increased fatigue at D28, after adjustment for main confounding factors, including anemia (regression coefficient (95%CI), 3.19 (0.74 to 5.64), P =0.012). At M6, this association disappeared.

Conclusions

The prevalence of ID increases from 8% at discharge to 35% six months after prolonged ICU stay (more than five days). ID was associated with increased fatigue, independently of anemia, at D28.     

A Sterilizing Tuberculosis Treatment Regimen Is Associated with Faster Clearance of Bacteria in Cavitary Lesions in Marmosets

Shortening the lengthy treatment duration for tuberculosis patients is a major goal of current drug development efforts. The common marmoset develops human-like disease pathology and offers an attractive model to better understand the basis for relapse and test regimens for effective shorter duration therapy. We treated Mycobacterium tuberculosis-infected marmosets with two drug regimens known to differ in their relapse rates in human clinical trials: the standard four-drug combination of isoniazid, rifampin, pyrazinamide, and ethambutol (HRZE) that has very low relapse rates and the combination of isoniazid and streptomycin that is associated with higher relapse rates. As early as 2 weeks, the more sterilizing regimen significantly reduced the volume of lung disease by computed tomography (P = 0.035) and also significantly reduced uptake of [¹⁸F]-2-fluoro-2-deoxyglucose by positron emission tomography (P = 0.049). After 6 weeks of therapy, both treatments caused similar reductions in granuloma bacterial load, but the more sterilizing, four-drug regimen caused greater reduction in bacterial load in cavitary lesions (P = 0.009). These findings, combined with the association in humans between cavitary disease and relapse, suggest that the basis for improved sterilizing activity of the four-drug combination is both its faster disease volume resolution and its stronger sterilizing effect on cavitary lesions. Definitive data from relapse experiments are needed to support this observation.     

Safety and Efficacy of Moxifloxacin-Dexamethasone Eyedrops as Treatment for Bacterial Ocular Infection Associated with Bacterial Blepharitis

Introduction

Treatments that offer two medications in a fixed combination have the potential to offer efficacious and safe treatment with advantages such as a regimen that is simpler than administering two separate solutions. This study evaluated the safety and efficacy of fixed-combination versus concomitant moxifloxacin 0.5% and dexamethasone 0.1% ocular solutions for the treatment of bacterial ocular inflammation and infection.

Methods

The clinical study design was a randomized, double-masked, active-controlled, parallel-group trial of 102 subjects with bacterial blepharitis in which two patients also had bacterial conjunctivitis. All subjects received two bottles of study medication: either a fixed combination of moxifloxacin 0.5%/dexamethasone 0.1% ophthalmic solution and placebo eye drops (fixed-dose group), or moxifloxacin 0.5% ophthalmic solution and dexamethasone 0.1% (concomitant group). One drop of each study medication was instilled bilaterally four times per day for 7 days. Clinical resolution, signs, symptoms, and safety were assessed. Microbiological specimens were collected from the eyelid margin and conjunctivae of each eye from each patient at the time of enrollment and at the exit visit.

Results

Clinical resolution occurred similarly in both groups (81.6% of eyes, fixed-dose group; 82.3% of eyes, concomitant group). Moreover, the microbiological efficacy of the treatment was also similar for both the fixed-dose group (84%) and the concomitant group (83%). Ocular symptoms and signs improved over time, with no significant differences between groups after 7 days of treatment, except the fixed-dose group had significantly more eyes with clinical resolution in eyelid erythema (100%, n = 98/98, fixed-dose group; 92.7%, n = 89/96, concomitant group; P = 0.0194) and eyelid scaling/crusting (98%, n = 96/98, fixed-dose group; 89.6%; n = 86/96 eyes, concomitant group; P = 0.0337). Both regimens were safe and well tolerated.

Conclusion

The fixed-dose combination of moxifloxacin, 0.5% and dexamethasone, 0.1% was therapeutically equivalent and as well tolerated as the concomitant dosage.     

Propensity Score Analysis of the Role of Initial Antifungal Therapy in the Outcome of Candida glabrata Bloodstream Infections

Candida glabrata isolates have reduced in vitro susceptibility to azoles, which raises concerns about the clinical effectiveness of fluconazole for treating bloodstream infection (BSI) by this Candida species. We aimed to evaluate whether the choice of initial antifungal treatment (fluconazole versus echinocandins or liposomal amphotericin B [L-AmB]-based regimens) has an impact on the outcome of C. glabrata BSI. We analyzed data from a prospective, multicenter, population-based surveillance program on candidemia conducted in 5 metropolitan areas of Spain (May 2010 to April 2011). Adult patients with an episode of C. glabrata BSI were included. The main outcomes were 14-day mortality and treatment failure (14-day mortality and/or persistent C. glabrata BSI for ≥48 h despite antifungal initiation). The impact of using fluconazole as initial antifungal treatment on the patients'' prognosis was assessed by logistic regression analysis with the addition of a propensity score approach. A total of 94 patients with C. glabrata BSI were identified. Of these, 34 had received fluconazole and 35 had received an echinocandin/L-AmB-based regimen. Patients in the echinocandin/L-AmB group had poorer baseline clinical status than did those in the fluconazole group. Patients in the fluconazole group were more frequently (55.9% versus 28.6%) and much earlier (median time, 3 versus 7 days) switched to another antifungal regimen. Overall, 14-day mortality was 13% (9/69) and treatment failure 34.8% (24/69), with no significant differences between the groups. On multivariate analysis, after adjusting for baseline characteristics by propensity score, fluconazole use was not associated with an unfavorable evolution (adjusted odds ratio [OR] for 14-day mortality, 1.16, with 95% confidence interval [CI] of 0.22 to 6.17; adjusted OR for treatment failure, 0.83, with 95% CI of 0.27 to 2.61). In conclusion, initial fluconazole treatment was not associated with a poorer outcome than that obtained with echinocandins/L-AmB regimens in patients with C. glabrata BSI. (This study has been registered at ClinicalTrials.gov under registration no. {"type":"clinical-trial","attrs":{"text":"NCT01236261","term_id":"NCT01236261"}}NCT01236261.)     

Prognostic significance of miR-34 rs4938723 T > C polymorphism in triple negative breast cancer patients

ObjectivesThe aim of this was the assessment of the prognostic role of the rs4938723 C > T polymorphism of the miR-34 in triple negative breast cancer patients.MethodsTherefore formalin fixed paraffin embedded tissue samples from 114 triple negative breast cancer patients and blood samples from 124 healthy donors were genotyped and subsequently extensive statistical analysis was performed in order to investigate the clinical value of this polymorphism in triple negative breast cancer.ResultsOur statistical analysis disclosed that the majority of patients harboring ductal breast carcinoma (69.4%) have the TC or CC genotypes (P = .020). Moreover the survival of the patients was significantly correlated with the occurrence of the TC or CC alleles (P < .001). Regarding the correlation of miR-34 polymorphisms with patients' survival we found that women with TC or CC single nucleotide polymorphisms were characterized by shorter disease free survival intervals (P = .05). Furthermore triple negative breast cancer patients with TC/CC genotype exhibited shorter overall survival intervals as disclosed by Kaplan Meier analysis (P < .001) and Cox regression analysis (HR = 3.2, %95 CI = 2.0–5.5, P = .008). Stratified Kaplan-Meier analysis showed that the women harboring the TC or CC genotype along with the ductal histology had significantly shorter survival (P < .001). This result was also confirmed by Univariate Cox regression analysis, which showed that women ductal breast cancer and TC or CC genotype are of worse prognosis (HR = 2.35, %95 CI = 2.1–4.65, P = .003).ConclusionsIn conclusion, we found that the TC and CC alleles are associated with unfavorable prognosis in triple negative breast cancer patients.     

Palonosetron in combination with 1-day versus 3-day dexamethasone for prevention of nausea and vomiting following moderately emetogenic chemotherapy: a randomized, multicenter, phase III trial

Purpose

A phase III trial assessed the efficacy of palonosetron plus dexamethasone given once in preventing acute and delayed chemotherapy-induced nausea and vomiting (CINV) following a broad range of moderately emetogenic chemotherapy (MEC) regimens.

Methods

This multicentre, randomized, open-label, non-inferiority trial evaluated two different treatment groups. One group received palonosetron (0.25?mg intravenously) and dexamethasone (8?mg intravenously) before chemotherapy, while the other was administered the same regimen on day?1 followed by dexamethasone 8?mg orally on days?2 and 3. The primary endpoint was complete response (CR; defined as no emetic episodes and no rescue medication) during the overall phase (days?1?C5 after chemotherapy initiation). The non-inferiority margin was predefined as a 15% difference between groups in the primary endpoint.

Results

Of 332 chemotherapy-na?ve patients included in the intention-to-treat analysis, 65.1% were female, and 35.2% received anthracycline plus cyclophosphamide (AC)-based regimens. Overall CR rates were 67.5% for those administered dexamethasone only on day?1 (n?=?166), and 71.1% for those also administered dexamethasone on days?2 and 3 (n?=?166; difference ?3.6% (95% confidence interval, ?13.5 to 6.3)). CR rates were not significantly different between groups during the acute (0?C24?h post-chemotherapy; 88.6% versus 84.3%; P?=?0.262) and delayed phases (days?2?C5; 68.7% versus 77.7%; P?=?0.116).

Conclusions

Palonosetron plus single-dose dexamethasone administered before common MEC regimens provide protection against acute and delayed CINV which is non-inferior to that of palonosetron plus dexamethasone for 3?days. However, the major benefit of the single-day regimen occurs in patients receiving non-AC MEC regimens.     

β-Lactams Enhance Vancomycin Activity against Methicillin-Resistant Staphylococcus aureus Bacteremia Compared to Vancomycin Alone

Vancomycin (VAN) is often used to treat methicillin-resistant Staphylococcus aureus (MRSA) bacteremia despite a high incidence of microbiological failure. Recent in vitro analyses of β-lactams in combination with VAN demonstrated synergistic activity against MRSA. The goal of this study was to examine the impact of combination therapy with VAN and a β-lactam (Combo) on the microbiological eradication of MRSA bacteremia compared to VAN alone. This was a retrospective cohort study of patients with MRSA bacteremia who received Combo therapy or VAN alone. Microbiological eradication of MRSA, defined as a negative blood culture obtained after initiation of therapy, was used to evaluate the efficacy of each regimen. A total of 80 patients were included: 50 patients in the Combo group and 30 patients in the VAN-alone group. Microbiological eradication was achieved in 48 patients (96%) in the Combo group compared to 24 patients (80%) in the VAN-alone group (P = 0.021). In a multivariable model, the Combo treatment had a higher likelihood of achieving microbiological eradication (adjusted odds ratio, 11.24; 95% confidence interval, 1.7 to 144.3; P = 0.01). In patients with infective endocarditis (n = 22), 11/11 (100%) who received Combo therapy achieved microbiological eradication compared to 9/11 (81.8%) treated with VAN alone, but the difference was not statistically significant (P = 0.20). Patients with MRSA bacteremia who received Combo therapy were more likely to experience microbiological eradication of MRSA than patients who received VAN alone.     

Prior Exposure to Lamivudine Increases Entecavir Resistance Risk in Chronic Hepatitis B Patients without Detectable Lamivudine Resistance

The efficacy of entecavir (ETV) treatment in chronic hepatitis B (CHB) patients who were exposed to lamivudine (LAM) but had no detectable LAM resistance (LAM-R) is not well evaluated. In this study, we aimed to evaluate whether the probability of developing genotypic resistance to ETV in LAM-exposed patients with or without LAM-R is comparable to that in antiviral-naive patients. This retrospective cohort study included 500 consecutive patients with CHB who started ETV monotherapy at a single tertiary hospital in Korea. The patients were divided into three groups: nucleos(t)ide analogue (NA)-naive patients (group 1, n = 142), patients who were previously exposed to LAM and had no currently or previously detected LAM-R (group 2, n = 233), and patients with LAM-R when starting ETV (group 3, n = 125). The overall median ETV treatment duration was 48.7 months. The probabilities of virologic breakthrough were significantly increased not only in group 3 (hazard ratio [HR] = 14.4, P < 0.001) but also in group 2 (HR = 5.0, P < 0.001) compared to group 1. Genotypic ETV resistance (ETV-R) developed more frequently in group 2 (HR = 13.0, P = 0.013) as well as group 3 (HR = 43.9, P < 0.001) than in group 1: the probabilities of developing ETV-R in groups 1, 2, and 3 were <1.0%, 8.0%, and 28.2%, respectively, at month 48. The results of this study indicate that ETV-R occurred more frequently in LAM-exposed patients, even though they had no detectable LAM-R, than in NA-naive patients. Therefore, LAM-exposed CHB patients, regardless of the presence or absence of LAM-R, should be monitored more cautiously for the development of ETV-R during ETV monotherapy.     

A Phase 2, Randomized,Double-Blind,Multicenter Trial To Evaluate the Safety and Efficacy of Three Dosing Regimens of Isavuconazole Compared with Fluconazole in Patients with Uncomplicated Esophageal Candidiasis

Esophageal candidiasis is a frequent cause of morbidity in immunocompromised patients. Isavuconazole is a novel, broad-spectrum antifungal developed for the treatment of opportunistic fungal infections. This phase 2 trial compared the efficacy and safety of three oral dosing regimens of isavuconazole with an oral fluconazole regimen in the primary treatment of uncomplicated esophageal candidiasis. The isavuconazole regimens were as follows: 200 mg on day 1 and then 50 mg once daily (arm A), 400 mg on day 1 and then 400 mg once-weekly (arm B), and 400 mg on day 1 and then 100 mg once daily (arm C). Patients in arm D received fluconazole at 200 mg on day 1 and then 100 mg once daily. The minimum treatment duration was 14 days. The primary endpoint was the rate of endoscopically confirmed clinical response at end of therapy. Safety and tolerability were also assessed. Efficacy was evaluated in 153 of 160 enrolled patients. Overall, 146 (95.4%) achieved endoscopically confirmed clinical success. Each of the isavuconazole regimens was shown to be not inferior to fluconazole, i.e., arm A versus D, −0.5% (95% confidence interval [CI] −10.0 to 9.4), arm B versus D, 3.5% (95% CI, −5.6 to 12.7), and arm C versus D, −0.2% (95% CI, −9.8 to 9.4). The frequency of adverse events was similar in arm A (n = 22; 55%), arm B (n = 18; 45%), and arm D (n = 22; 58%), but higher in arm C (n = 29; 71%). In summary, efficacy and safety of once-daily and once-weekly isavuconazole were comparable with once-daily fluconazole in the primary treatment of uncomplicated esophageal candidiasis.     

三阴乳腺癌与非三阴乳腺癌X线及病理特征分析

目的 与非三阴乳腺癌(non-TNBC)比较,探讨三阴乳腺癌(TNBC)的X线表现及病理特征.方法 回顾性分析经病理证实的574例乳腺癌患者资料,对比分析81例TNBC(TNBC组)与493例non-TNBC患者(non-TNBC组)的临床、病理特征及X线表现.结果 TNBC组织学分级以中、高级别为主,其中53.09％(43/81)发生腋窝淋巴结转移,高于non-TNBC组(39.96％,197/493,P＜0.05).与non-TNBC组相比,TNBC病变体积较大,多为单纯肿块型,少见钙化(P＜0.05),肿块型TNBC瘤体多为类圆形,边缘光滑,较少见不规则形及毛刺(P＜0.05).结论 TNBC与non-TNBC在X线表现及病理特征方面存在一定差异,了解其特征有助于诊断TNBC.