Use of Fluoroquinolones or Sulfamethoxazole-Trimethoprim Compared to Β-Lactams for Oral Step-Down Therapy in Hospitalized Patients With Uncomplicated Enterobacterales Bacteremia.

BACKGROUND: Antibiotic therapy for uncomplicated Enterobacterales bacteremia from a urinary source has traditionally consisted of fluoroquinolones (FQs) and sulfamethoxazole-trimethoprim (SXT). However, adverse events associated with FQs and emerging antimicrobial resistance have led to alternative agents, specifically oral Β-lactams (OBLs), being utilized despite concern of subtherapeutic serum concentrations related to their low relative bioavailability. OBJECTIVE: To compare efficacy of antibiotic therapies with bioavailability differences in patients with uncomplicated bacteremia from a urinary source. METHODS: This was a retrospective study comparing clinical efficacy in hospitalized adult patients receiving OBL or FQ/SXT. Patients were required to receive at least 48 hours of appropriate intravenous antibiotic therapy and at least one dose of oral therapy. The primary outcome was all-cause hospital readmission within 30 days of discharge. Secondary outcomes included readmission with recurrent infectious etiology and readmission due to Clostridioides difficile infection. RESULTS: Of 210 eligible patients, 91 received FQ/SXT and 119 received OBL. There was no difference between the groups in all-cause hospital readmission (FQ/SXT: 16.5%; OBL: 14.3%) (P = 0.660 [95% confidence interval, CI = -0.076, 0.120]) or readmission with recurrent bacteremia (FQ/SXT: 0%; OBL: 3.4%) (P = 0.135). There was a significant difference in repeat hospital admission with recurrent urinary tract infection (UTI) (FQ/SXT: 0%, OBL: 5.0%) (P = 0.037). CONCLUSION AND RELEVANCE: OBLs appear to be non-inferior to FQ/SXT in the rate of all-cause hospital readmission within 30 days. However, OBLs may be associated with increased readmissions with recurrent UTI.

Evaluation of a Rapid Fungal Detection Panel for Identification of Candidemia at an Academic Medical Center.

This study was conducted to assess the utility of the T2Candida panel across an academic health center and identify potential areas for diagnostic optimization. A retrospective chart review was conducted on patients with a T2Candida panel and mycolytic/fungal (myco/f lytic) blood culture collected simultaneously during hospitalizations from February 2017 to March 2018. The primary outcome of this study was to determine the sensitivity, specificity, and positive and negative predictive values of the panel compared to myco/f lytic blood culture. Secondary outcomes included Candida species isolated from culture or detected on the panel, source of infection, days of therapy (DOT) of antifungals in patients with discordant results, and overall antifungal DOT/1,000 patient days. A total of 433 paired T2Candida panel and myco/f lytic blood cultures were identified. The pretest likelihood of candidemia was 4.4%. The sensitivity and specificity were 64.7% and 95.6%, respectively. The positive and negative predictive values were 40.7% and 98.5%, respectively. There were 16 patients with T2Candida panel positive and myco/f lytic blood culture negative results, while 6 patients had T2Candida panel negative and myco/f blood culture positive results. The overall antifungal DOT/1,000 patient days was improved after implementation of the T2Candida panel; however, the use of micafungin continued to decline after the panel was removed. We found that the T2Candida panel is a highly specific diagnostic tool; however, the sensitivity and positive predictive value may be lower than previously reported when employed in clinical practice. Clinicians should use this panel as an adjunct to blood cultures when making a definitive diagnosis of candidemia.

Effects of genetic polymorphisms on the pharmacokinetics of calcineurin inhibitors.

PURPOSE: The effects of genetic polymorphisms on the pharmacokinetics of calcineurin inhibitors were examined. SUMMARY: The bioavailability and metabolism of cyclosporine and tacrolimus are primarily controlled by efflux pumps and members of the cytochrome P-450 (CYP) isoenzyme system found in the liver and gastrointestinal tract. The number and severity of adverse effects from these drugs are related to the overall exposure, measured by length of therapy and blood drug concentration. One contributing factor to the inconsistent pharmacokinetics of calcineurin inhibitors may be variable expression of functional CYP3A4, CYP3A5, and P-glycoprotein (PGP) efflux pumps, which may be the result of single-nucleotide polymorphisms found on the genes encoding for CYP3A4, CYP3A5, and PGP. CYP3A5*3 and CYP3A5*6 are the most common polymorphisms of CYP3A5. Using genetic markers to adjust initial doses of cyclosporine or tacrolimus may prove difficult, considering the variety of polymorphism known to affect CYP3A4, CYP3A5, and the multidrug resistance-1 (MDR1) gene (the gene that codes for PGP). Studies have found that carriers of CYP3A5*1 consistently have higher clearance rates of tacrolimus than do CYP3A5*3 homozygotes. The influences of CYP3A5 alleles on cyclosporine metabolism and the MDR1 C3435T polymorphism on tacrolimus metabolism remain controversial. CONCLUSION: For renal transplant recipients receiving tacrolimus as an immunosuppressant, practitioners can expect CYP3A5*1 carriers to have a tacrolimus clearance 25-45% greater than that of CYP3A5*3 homozygotes, with proportional dosing needs to maintain adequate immunosuppression. Since inadequate immunosuppression is linked to graft rejection, evaluation of CYP3A5 polymorphisms may be helpful in determining an appropriate starting dosage, rapidly achieving adequate immunosuppression, and ultimately improving the outcome of renal transplantation.

Role of sunitinib and sorafenib in the treatment of metastatic renal cell carcinoma.

PURPOSE: The role of sunitinib and sorafenib in the treatment of metastatic renal cell carcinoma (mRCC) is reviewed. SUMMARY: Sunitinib malate is a potent inhibitor of vascular endothelial growth factor (VEGF) receptors, FMS-like tyrosine kinase 3 (FLT3), c-KIT, and platelet-derived growth factor (PDGF), which give the drug its direct antitumor and antiangiogenic properties. Sunitinib is currently approved as a second-line treatment of mRCC in patients who have either not responded to or who are not eligible to receive interleukin-2. Clinical trials of sunitinib have found similar rates of partial response, disease stabilization, and progression-free survival. Sorafenib inhibits VEGF receptors, PDGF receptors, FLT3, RAF-1, and BRAF in vitro and has been shown to prevent the growth of tumors but not to reduce tumor size. Sorafenib has been proven to improve survival in a novel randomized discontinuation trial and a Phase III randomized, placebo-controlled trial. No studies have directly compared the effectiveness of sunitinib to sorafenib in the treatment of advanced renal cell carcinoma. Sunitinib and sorafenib share a similar mechanism of action and primarily target tumor angiogenesis by inhibiting a variety of tyrosine kinases; the agents have similar toxicity, with the exception of an increased risk of hypertension associated with the use of sorafenib. Sorafenib does not result in tumor shrinkage, but sunitinib significantly reduces tumor size. CONCLUSION: The tyrosine kinase inhibitors sorafenib and sunitinib offer improved outcomes for patients with mRCC, but they are far short of a cure. Despite the introduction of sorafenib and sunitinib, palliative care is still an acceptable treatment option for mRCC because of the disease's extremely poor prognosis.