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Arianna Burton,1 Adam Castaño,1 Marianna Bruno,1 Steve Riley,2 Jennifer Schumacher,1 Marla B Sultan,3 Sandi See Tai,4 Daniel P Judge,5 Jignesh K Patel,6 Jeffery W Kelly7 1Medical Affairs, Pfizer Inc, New York, NY, USA; 2Clinical Pharmacology, Pfizer Inc, Groton, CT, USA; 3Global Product Development, Pfizer Inc, New York, NY, USA; 4Global Product Development, Pfizer Inc, Collegeville, PA, USA; 5Department of Medicine, Medical University of South Carolina, Charleston, SC, USA; 6Department of Cardiology, Cedars-Sinai Smidt Heart Institute, Los Angeles, CA, USA; 7Department of Chemistry, The Scripps Research Institute, La Jolla, CA, USACorrespondence: Adam Castaño Email Adam.Castano@pfizer.comAbstract: Rare diseases are increasingly recognized as a global public health priority. Governments worldwide currently provide important incentives to stimulate the discovery and development of orphan drugs for the treatment of these conditions, but substantial scientific, clinical, and regulatory challenges remain. Tafamidis is a first-in-class, disease-modifying transthyretin (TTR) kinetic stabilizer that represents a major breakthrough in the treatment of transthyretin amyloidosis (ATTR amyloidosis). ATTR amyloidosis is a rare, progressive, and fatal systemic disorder caused by aggregation of misfolded TTR and extracellular deposition of amyloid fibrils in various tissues and organs, including the heart and nervous systems. In this review, we present the successful development of tafamidis spanning 3 decades, marked by meticulous laboratory research into disease mechanisms and natural history, and innovative clinical study design and implementation. These efforts established the safety and efficacy profile of tafamidis, leading to its regulatory approval, and enabled post-approval initiatives that further support patients with ATTR amyloidosis.Keywords: amyloidosis, cardiomyopathy, heart failure, transthyretin, treatment, Vyndaqel/Vyndamax

The Ramco latex agglutination test in the diagnosis of systemic candidiasis was utilized for 11 serum samples from 10 patients with systemic candidiasis, 21 serum samples from patients colonized with Candida species, and 20 control serum samples from patients with stable medical problems and no evidence of Candida albicans infection. This study was double-blind and the results of the latex agglutination test did not influence the decision for antifungal therapy. Nine of 10 patients with systemic candidiasis had positive titers (greater than or equal to 1:4); however, these were determined only 1 to 5 days before culture positivity. Nine of 21 (43%) of colonized patients were falsely positive (greater than or equal to 1:4) and all of the control samples were negative. The Ramco latex agglutination test was unreliable and inconsistent in this small sample group to establish an early diagnosis of systemic candidiasis.

We conducted a randomized, prospective, open comparison to evaluate the efficacy and safety of cefepime and ceftazidime in the treatment of hospitalized patients with suspected gram-negative bacteremia. Twenty-eight patients with signs and symptoms of sepsis were prospectively randomized to receive cefepime (13 patients) or ceftazidime (1 5 patients). Cultures of blood obtained at entry into the study were positive for 24 (85.7%) of 28 patients. Eight patients had two or more positive pretreatment blood cultures, and the remaining 16 had one positive pretreatment blood culture. The most commonly isolated blood pathogen was Escherichia coli. Eleven of 13 patients treated with cefepime and 12 of 15 patients treated with ceftazidime were clinically cured. Adverse effects attributable to therapy with the study drugs were minimal in both groups of patients and included rash, headache, nausea, and diarrhea. Our results suggest that cefepime is as efficacious and well tolerated as is ceftazidime in the treatment of hospitalized patients with documented gram-negative bacteremia

Empyema thoracis is a disease that, despite centuries of study, still causes significant morbidity and mortality. Sixty-five cases were seen at Brooke Army Medical Center over an 8-year period (March 1, 1985, through March 1, 1993). The majority of the patients were men, older than 50 years of age, with significant underlying diseases. Pneumonia remains the most common single proximate cause of empyema. Gram-positive cocci are the most frequently isolated organisms; however, empyemas due to gram-negative organisms and anaerobes are associated with higher mortality. Pleural fluid gram stains proved to be an accurate but neglected diagnostic tool in guiding initial therapy. The choice of antibiotics seemed to have no discernible impact on mortality. Closed tube thoracostomy was the initial method of drainage in most patients and had an overall success rate of 50%. Empyemas that could not be effectively drained by a single chest tube were unlikely to be drained by additional closed maneuvers. There was an overall 22% case-fatality rate with most deaths related to our inability to eradicate the empyema.