Anidulafungin compared with fluconazole for treatment of candidemia and other forms of invasive candidiasis caused by Candida albicans: a multivariate analysis of factors associated with improved outcome

<p>Abstract</p> <p>Background</p> <p><it>Candida albicans </it>is the most common cause of candidemia and other forms of invasive candidiasis. Systemic infections due to <it>C. albicans </it>exhibit good susceptibility to fluconazole and echinocandins. However, the echinocandin anidulafungin was recently demonstrated to be more effective than fluconazole for systemic <it>Candida </it>infections in a randomized, double-blind trial among 245 patients. In that trial, most infections were caused by <it>C. albicans</it>, and all respective isolates were susceptible to randomized study drug. We sought to better understand the factors associated with the enhanced efficacy of anidulafungin and hypothesized that intrinsic properties of the antifungal agents contributed to the treatment differences.</p> <p>Methods</p> <p>Global responses at end of intravenous study treatment in patients with <it>C. albicans </it>infection were compared post-hoc. Multivariate logistic regression analyses were performed to predict response and to adjust for differences in independent baseline characteristics. Analyses focused on time to negative blood cultures, persistent infection at end of intravenous study treatment, and 6-week survival.</p> <p>Results</p> <p>In total, 135 patients with <it>C. albicans </it>infections were identified. Among these, baseline APACHE II scores were similar between treatment arms. In these patients, global response was significantly better for anidulafungin than fluconazole (81.1% vs 62.3%; 95% confidence interval [CI] for difference, 3.7-33.9). After adjusting for baseline characteristics, the odds ratio for global response was 2.36 (95% CI, 1.06-5.25). Study treatment and APACHE II score were significant predictors of outcome. The most predictive logistic regression model found that the odds ratio for study treatment was 2.60 (95% CI, 1.14-5.91) in favor of anidulafungin, and the odds ratio for APACHE II score was 0.935 (95% CI, 0.885-0.987), with poorer responses associated with higher baseline APACHE II scores. Anidulafungin was associated with significantly faster clearance of blood cultures (log-rank <it>p </it>< 0.05) and significantly fewer persistent infections (2.7% vs 13.1%; <it>p </it>< 0.05). Survival through 6 weeks did not differ between treatment groups.</p> <p>Conclusions</p> <p>In patients with <it>C. albicans </it>infection, anidulafungin was more effective than fluconazole, with more rapid clearance of positive blood cultures. This suggests that the fungicidal activity of echinocandins may have important clinical implications.</p> <p>Trial registration</p> <p>ClinicalTrials.gov: <a href="http://www.clinicaltrials.gov/ct2/show/NCT00058682">NCT00058682</a></p

Management of invasive candidiasis and candidemia in adult non-neutropenic intensive care unit patients: Part I. Epidemiology and diagnosis

Background Invasive candidiasis and candidemia are frequently encountered in the nosocomial setting, particularly in the intensive care unit (ICU)

Management of invasive candidiasis and candidemia in adult non-neutropenic intensive care unit patients: Part II. Treatment

Background Invasive candidiasis and candidemia are frequently encountered in the nosocomial setting particularly in the intensive care unit (ICU)

Structure of the Dead Sea Pull-Apart Basin From Gravity Analyses

Analyses and modeling of gravity data in the Dead Sea pull-apart basin reveal the geometry of the basin and constrain models for its evolution. The basin is located within a valley which defines the Dead Sea transform plate boundary between Africa and Arabia. Three hundred kilometers of continuous marine gravity data, collected in a lake occupying the northern part of the basin, were integrated with land gravity data from Israel and Jordan to provide coverage to 30 km either side of the basin. Free-air and variable-density Bouguer anomaly maps, a horizontal first derivative map of the Bouguer anomaly, and gravity models of profiles across and along the basin were used with existing geological and geophysical information to infer the structure of the basin. The basin is a long (132 km), narrow (7-10 km), and deep (≤10 km) full graben which is bounded by subvertical faults along its long sides. The Bouguer anomaly along the axis of the basin decreases gradually from both the northern and southern ends, suggesting that the basin sags toward the center and is not bounded by faults at its narrow ends. The surface expression of the basin is wider at its center (≤16 km) and covers the entire width of the transform valley due to the presence of shallower blocks that dip toward the basin. These blocks are interpreted to represent the widening of the basin by a passive collapse of the valley floor as the full graben deepened. The collapse was probably facilitated by movement along the normal faults that bound the transform valley. We present a model in which the geometry of the Dead Sea basin (i.e., full graben with relative along-axis symmetry) may be controlled by stretching of the entire (brittle and ductile) crust along its long axis. There is no evidence for the participation of the upper mantle in the deformation of the basin, and the Moho is not significantly elevated. The basin is probably close to being isostatically uncompensated, and thermal effects related to stretching are expected to be minimal. The amount of crustal stretching calculated from this model is 21 km and the stretching factor is 1.19. If the rate of crustal stretching is similar to the rate of relative plate motion (6 mm/yr), the basin should be ~3.5 m.y. old, in accord with geological evidence

A dissection of SARS‑CoV2 with clinical implications (Review)

We are being confronted with the most consequential pandemic since the Spanish flu of 1918‑1920 to the extent that never before have 4 billion people quarantined simultaneously; to address this global challenge we bring to the forefront the options for medical treatment and summarize SARS‑CoV2 structure and functions, immune responses and known treatments. Based on literature and our own experience we propose new interventions, including the use of amiodarone, simvastatin, pioglitazone and curcumin. In mild infections (sore throat, cough) we advocate prompt local treatment for the naso‑pharynx (inhalations; aerosols; nebulizers); for moderate to severe infections we propose a tried‑and‑true treatment: the combination of arginine and ascorbate, administered orally or intravenously. The material is organized in three sections: i) Clinical aspects of COVID‑19; acute respiratory distress syndrome (ARDS); known treatments; ii) Structure and functions of SARS‑CoV2 and proposed antiviral drugs; iii) The combination of arginine‑ascorbate

20-Year Risks of Breast-Cancer Recurrence after Stopping Endocrine Therapy at 5 Years

The administration of endocrine therapy for 5 years substantially reduces recurrence rates during and after treatment in women with early-stage, estrogen-receptor (ER)-positive breast cancer. Extending such therapy beyond 5 years offers further protection but has additional side effects. Obtaining data on the absolute risk of subsequent distant recurrence if therapy stops at 5 years could help determine whether to extend treatment

Long-term outcomes for neoadjuvant versus adjuvant chemotherapy in early breast cancer: meta-analysis of individual patient data from ten randomised trials

Background Neoadjuvant chemotherapy (NACT) for early breast cancer can make breast-conserving surgery more feasible and might be more likely to eradicate micrometastatic disease than might the same chemotherapy given after surgery. We investigated the long-term benefits and risks of NACT and the influence of tumour characteristics on outcome with a collaborative meta-analysis of individual patient data from relevant randomised trials. Methods We obtained information about prerandomisation tumour characteristics, clinical tumour response, surgery, recurrence, and mortality for 4756 women in ten randomised trials in early breast cancer that began before 2005 and compared NACT with the same chemotherapy given postoperatively. Primary outcomes were tumour response, extent of local therapy, local and distant recurrence, breast cancer death, and overall mortality. Analyses by intention-to-treat used standard regression (for response and frequency of breast-conserving therapy) and log-rank methods (for recurrence and mortality). Findings Patients entered the trials from 1983 to 2002 and median follow-up was 9 years (IQR 5–14), with the last follow-up in 2013. Most chemotherapy was anthracycline based (3838 [81%] of 4756 women). More than two thirds (1349 [69%] of 1947) of women allocated NACT had a complete or partial clinical response. Patients allocated NACT had an increased frequency of breast-conserving therapy (1504 [65%] of 2320 treated with NACT vs 1135 [49%] of 2318 treated with adjuvant chemotherapy). NACT was associated with more frequent local recurrence than was adjuvant chemotherapy: the 15 year local recurrence was 21·4% for NACT versus 15·9% for adjuvant chemotherapy (5·5% increase [95% CI 2·4–8·6]; rate ratio 1·37 [95% CI 1·17–1·61]; p=0·0001). No significant difference between NACT and adjuvant chemotherapy was noted for distant recurrence (15 year risk 38·2% for NACT vs 38·0% for adjuvant chemotherapy; rate ratio 1·02 [95% CI 0·92–1·14]; p=0·66), breast cancer mortality (34·4% vs 33·7%; 1·06 [0·95–1·18]; p=0·31), or death from any cause (40·9% vs 41·2%; 1·04 [0·94–1·15]; p=0·45). Interpretation Tumours downsized by NACT might have higher local recurrence after breast-conserving therapy than might tumours of the same dimensions in women who have not received NACT. Strategies to mitigate the increased local recurrence after breast-conserving therapy in tumours downsized by NACT should be considered—eg, careful tumour localisation, detailed pathological assessment, and appropriate radiotherapy

Hospital-Acquired Methicillin-Resistant Staphylococcus aureus: Epidemiology, Treatment and Control

Antimicrobial-resistant organisms are an expanding problem, resulting in increased morbidity and mortality, prolonged hospital stay, and heightened health care costs for care and antimicrobial management. Methicillin-resistant Staphylococcus aureus (MRSA) has emerged as a major hospital-acquired, antimicrobial-resistant pathogen. MRSA not only colonizes hospitalized patients but has a propensity to produce more serious, life- threatening infection than methicillin-susceptible strains. Numerous risk factors, including antimicrobial use and proximity to a patient harbouring MRSA, have been linked to the acquisition of MRSA. Although vancomycin has been the mainstay of therapy for MRSA, failures have been reported due to reduced susceptibility to this agent. Other available therapeutic agents for MRSA include trimethoprim-sulfamethoxazole, tetracycline, fusidic acid, rifampin (in combination with other effective agents) and linezolid. Potential therapeutic agents that are currently under investigation include daptomycin, dalbavancin, tigecycline, ceftobiprole and iclaprim. Only enhanced infection control practices can halt the progressive transmission of MRSA in the hospital environment. However, such measures have not quite fulfilled their promise in clinical studies. Moreover, eradication of MRSA colonization is controversial and may promote greater resistance. A multidisciplinary approach to the prevention, containment and treatment of MRSA is necessary

Reduction in the nephrotoxicity of amphotericin B when administered in 20% intralipid

The administration of amphotericin B (AmB) is often limited by the development of nephrotoxicity. In a pilot crossover trial, aqueous AmB followed by a new preparation of a mixture of AmB with 20% intralipid (AmB-IL) was administered to 10 immunocompromised patients for systemic fungal infections caused by Candida species. Mean total dose and duration of therapy with AmB-IL exceeded that of aqueous AmB (649±165 mg versus 394±105 mg, P=0.061 and 13.2±2.5 days versus 9±2.1 days, P=0.31). However, mean creatinine clearance of the patients rose during AmB-IL therapy by 10.7±7.7 mL/min (P=0.03). AmB-IL warrants further investigation to assess its stability and efficacy for treating serious fungal infections