ABSTRACT
Lewis basic substrates, such as vinylphosphines and enamines, can be problematic for transition-metal catalysed hydrofunctionalization reactions due to their propensity to ligate and deactivate transition-metal catalysts as well as form direct Lewis adducts with reaction partners. While exploring rhodium-catalyzed hydroboration of diphenylvinylphosphine with pinacolborane, we found that a high degree of regiocontrol could be achieved without the need to diminish the Lewis basicity of the phosphine by oxidation or prior-protection. At slightly elevated temperature, a high yield of the previously unreported branched regioisomer, 1-pinacolatoborono-1-diphenylphosphinoethane, was achieved with regioselectivity greater than 10 : 1 using [Rh(COD)Cl]2 as the catalyst and AgOTf as a catalytic additive. Inversion of regioselectivity occurred at low temperature and high yield of the linear regioisomer was observed. Subsequent functionalization of the new branched phosphine-boronic ester and its coordination to rhodium were also investigated.
ABSTRACT
BACKGROUND: Uncomplicated urinary tract infection (uUTI) typically affects immunocompetent, anatomically normal women. Escherichia coli (E. coli) accounts for approximately 80% of cases. Given increased E. coli-trimethoprimsulfamethoxazole (TMP-SMX) resistance, practice guidelines advocate first-line alternatives based on local resistance rates above 10%. This paper provides a model incorporating use of a new extended-release formulation of ciprofloxacin, used once daily, to facilitate revision of uUTI treatment policies by managed care organizations (MCOs) and practitioners. METHODS: A cost-minimization model was designed from the MCO perspective, assuming an initial office visit with a urinalysis and empiric, 3-day treatment (TMP-SMX 800/160 mg twice daily or ciprofloxacin XR 500 mg once daily). Persistent infections were assumed to require a second visit. Costs were provided by a major employee health and benefit plan provider; clinical data were based on published information. Five case scenarios were used to compare average treatment costs based on varying E. coli resistance rates to therapy and to identify rates of TMP-SMX resistance where total treatment costs are equal. RESULTS: Using national surveillance resistance data, Case 1 demonstrated average cost savings of 9.59 dollars to 10.21 dollars with ciprofloxacin XR. In Case 2, treatment costs (49.19 dollars) were equal at an E. coli resistance rate of 4.3% for TMP-SMX and 1.0% for ciprofloxacin. Case 3 assumed empiric telephone prescribing, demonstrating that, at 4.3% TMP-SMX resistance, costs are equal for both treatments (4.19 dollars). Case 4 used real-world data on therapy duration, demonstrating that, at 2.8% TMP-SMX resistance, costs are equal for both treatments (54.87 dollars). Case 5 assumed 10% ciprofloxacin-E. coli resistance; at 13.3% TMP-SMX resistance, treatment costs were equal (57.50 dollars). Results from all cases demonstrate that while the per-dose cost of ciprofloxacin XR far exceeds TMP-SMX, average total treatment costs are lower for ciprofloxacin XR at expected local levels of E. coli resistance to TMP-SMX. CONCLUSIONS: The results suggest that in areas where local TMP-SMX E. coli resistance exceeds 10% and resistance to ciprofloxacin remains low, (0.5% to 6%) ciprofloxacin XR is an appropriate alternative to standard empiric treatment. The data provide evidence to MCOs that switching to a more expensive per-dose alternative will not necessarily increase total costs when guideline recommendations are followed. Responsible use of antibiotics for uUTI requires selection and administration of the right dosage of the most suitable antibiotic for an appropriate time period to eliminate pathogens quickly and successfully. The decision to use an alternative first-line therapy for uUTI should be driven by local resistance and susceptibility data--not simply per-dose drug acquisition costs.
