Relationship of Sulfamethoxazole Therapeutic Drug Monitoring to Clinical Efficacy and Toxicity: A Retrospective Cohort Study.

BACKGROUND: Trimethoprim/sulfamethoxazole (TMP/SMX) is the treatment of choice for infections caused by Pneumocystis jiroveci, Stenotrophomonas maltophilia, and Nocardia species, but the utility of therapeutic drug monitoring (TDM) is unclear. The objective of this study was to evaluate the association between peak sulfamethoxazole (SMX) serum levels and clinical outcomes to determine the utility of TDM of TMP/SMX. METHODS: This study was conducted in patients receiving treatment with TMP/SMX for culture-positive infection who underwent TDM from 2003 to 2013. Peak SMX levels were classified as below target (<100 mcg/mL), within target (100-150 mcg/mL), or above target (>150 mcg/mL). The effect of initial SMX levels on clinical outcomes was compared using propensity score adjusted multivariable Cox models. RESULTS: A total of 279 patients had SMX monitoring performed. The primary infecting organisms were P. jiroveci (47%) and S. maltophilia (38%). A majority of patients (74%) had an SMX peak level outside of the target range. Using direct regression propensity score adjustment, there was no significant difference between rates of clinical failure and initial peak SMX level (<100 mcg/mL versus 100-150 mcg/mL: hazard ratio 0.92, 95% confidence interval, 0.28-3.07 and >150 mcg/mL versus 100-150 mcg/mL: hazard ratio 1.92, 95% confidence interval, 0.72-5.09). Similarly, there was no relationship between SMX level and toxicity (P = 0.42). CONCLUSIONS: Sulfamethoxazole serum levels outside the target range were not associated with increased rates of clinical failure in patients treated with TMP/SMX. There was also no association found between peak SMX levels and rates of adverse events. Although this study cannot disprove that dose adjustments after the initial SMX peak level may have affected clinical outcomes, the results suggest that the utility of SMX TDM may be limited to a subset of patients and requires further prospective investigation.

Combination pertuzumab, trastuzumab, and taxane for metastatic breast cancer after first progression: a single institution's experience.

BACKGROUND: The addition of pertuzumab to trastuzumab and taxane therapy was shown to be an effective first-line treatment for patients with HER2-positive metastatic breast cancer. OBJECTIVE: Describe the progression-free survival of pertuzumab, trastuzumab, and taxane therapy for previously treated HER2-positive metastatic breast cancer. METHODS: This case-series reviews 19 patients with metastatic breast cancer receiving treatment with pertuzumab, trastuzumab, taxane after progression and exposure to previous lines of HER2-directed therapy. Progression-free survival and adverse effects such as changes in ejection fraction and episodes of neutropenic fever were assessed. RESULTS: The median progression-free survival of pertuzumab, trastuzumab, taxane therapy for previously treated metastatic breast cancer was 4.1 months. The mean baseline left ventricular ejection fraction change experienced by patients was -1%. Neutropenic fever events were not encountered. CONCLUSIONS: Pertuzumab, trastuzumab, and taxane therapy seems to confer progression-free survival benefit for previously treated metastatic breast cancer. The use of the dual anti-HER2 antibodies, pertuzumab and trastuzumab, in addition to cytotoxic chemotherapy agents for previously treated metastatic breast cancer should be further evaluated.

Serum peak sulfamethoxazole concentrations demonstrate difficulty in achieving a target range: a retrospective cohort study.

OBJECTIVES: Trimethoprim (TMP)/sulfamethoxazole (SMX) has consistently demonstrated great interindividual variability. Therapeutic drug monitoring may be used to optimize dosing. Optimal peak SMX concentration has been proposed as 100 to 150 µg/mL. The objective of our work was to determine the success rate of a TMP/SMX dosing guideline in achieving a targeted serum peak SMX concentration range. METHODS: Our retrospective cohort study enrolled 305 adult hospitalized patients who received treatment with TMP/SMX and underwent serum peak SMX concentration monitoring from January 2003 to November 2011. Patients receiving low-dose TMP/SMX therapy (TMP <15 mg/kg/d) were compared with those receiving high-dose therapy (TMP >15 mg/kg/d). RESULTS: Patients were classified into peak and modified peak SMX concentration cohorts based on time between TMP/SMX dose and SMX quantification. The association between dosing group and the outcome of the SMX level within the goal range was measured using logistic regression models. The primary outcome measured was serum peak SMX concentration 100 to 150 µg/mL. Serum peak SMX concentrations were attained within range for the peak and modified peak cohort 29% and 26% of the time, respectively. The median peak SMX concentration was 144 µg/mL (range 25-471 µg/mL). The low daily dose cohort demonstrated a trend toward improvement in the odds of target peak concentration range attainment. The results were similar regardless of the method used to adjust for baseline characteristics. The pure peak and modified peak cohorts had 44% and 46% of patients with above-target SMX peak concentrations, respectively. CONCLUSIONS: Attainment of the intended target concentration range was low with no difference in attainment between the low-dose and high-dose cohorts. Higher proportions of patients had an above-target SMX peak, which may indicate that the dosing algorithm is overly aggressive in obtaining the therapeutic goal.

First-Line Use of Vemurafenib to Enable Thyroidectomy and Radioactive Iodine Ablation for BRAF-Positive Metastatic Papillary Thyroid Carcinoma: A Case Report.

Background. Patients with metastatic or radioactive iodine refractory papillary thyroid carcinoma (PTC) have poor prognosis due to ineffective therapy for this condition beyond surgery and radioactive iodine (RAI or (131)I). BRAF mutation occurs in more than 44% of PCT. Tyrosine kinase inhibitors, the most commonly used agents for these patients, have weak BRAF inhibition activity. BRAF inhibitors have demonstrated promising efficacy in relapsed metastatic PCT after standard treatment, though they are not currently approved for this indication. Case Presentation. We present the case of a 48-year-old Hispanic male who initially presented with columnar-cell variant subtype of PTC and positive BRAFV600E mutation. The patient had widespread bulky metastases to lungs, chest wall, brain, and bone. Discussion. Initial use of vemurafenib demonstrated a 42% cytoreduction of targeted pulmonary metastases and facilitated thyroidectomy and RAI treatment. The patient achieved a durable response over 21 months in the setting of widely metastatic disease. Conclusion. Vemurafenib may be effectively used for cytoreduction in patients with bulky metastatic PTC to bridge them to thyroidectomy and RAI treatment.