Large numbers of melanoma lesions develop resistance to targeted inhibition of mutant BRAF or fail to respond to checkpoint blockade. We explored whether modulation of intratumoral antigen presenting cells (APCs) could increase responses to these therapies. Using mouse melanoma models, we found that CD103+ dendritic cells (DCs) were the only APCs transporting intact antigens to the lymph nodes and priming tumor-specific CD8+ T cells. CD103+ DCs were required to promote anti-tumoral effects upon blockade of the checkpoint ligand PDL1; however, PD-L1 inhibition only led to partial responses. Systemic administration of the cytokine Flt3L followed by intratumoral poly I:C injections expanded and activated CD103+ DC progenitors in the tumor, enhancing responses to BRAF and PD-L1 blockade and protecting mice from tumor rechallenge. Thus, the paucity of activated CD103+ DCs in tumors limits checkpoint blockade efficacy and Flt3L-poly I:C therapy can enhance tumor responses to checkpoint and BRAF blockade.

Non-tuberculous mycobacteria (NTM) is a collective name given to a group of more than 190 species of Mycobacterium . The clinical presentation for most NTM infections is non-specific, often resulting in delayed diagnosis. Further complicating matters is that NTM organisms can be difficult to isolate. Medications used to treat NTM infection can be difficult for patients to tolerate, and prolonged courses of anti-mycobacterial therapy are often required for adequate suppression or eradication. Herein, we review different NTM syndromes, appropriate diagnostic tests, and treatment regimens.

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We did not identify an association between posaconazole serum concentrations and LFT elevations or QTc prolongation. However, some LFTs were found to increase with more hepatotoxic medications administered.

Contemporary antiretroviral agents afford enhanced potency and safety for patients living with HIV. Newer antiretroviral drugs are often better tolerated than those initially approved in the early stages of the HIV epidemic. While the safety profile has improved, adverse drug reactions still occur. We have segregated the antiretroviral agents used in contemporary practice into class groupings based on their mechanism of antiviral activity (non-nucleoside reverse transcriptase inhibitors, nucleoside reverse transcriptase inhibitors, integrase inhibitors, protease inhibitors, and entry inhibitors) while providing a review and discussion of the hepatoxicity seen in the most relevant clinical literature published to date. Clinical literature for individual agents is discussed and agent comparisons afforded within each group in tabular format. Our review will provide a summative overview of the incidence and medications associated with hepatic adverse reactions linked to the use of contemporary antiretroviral drugs.

Itraconazole is well known for carrying a black-box warning for new or worsening congestive heart failure. Single cases of other cardiac-and fluid-related disturbances have been reported periodically since its issuance. We describe a large cohort of patients on itraconazole experiencing a breadth of cardiac-and fluid-related toxicities, ranging from new-onset hypertension to cardiac arrest. A retrospective, singlecenter, large case series at a large tertiary medical center was conducted. Patients with itraconazole and cardiac toxicitydincluding hypertension, cardiomyopathy, reduced ejection fraction, and edemadin medical record between January 1, 1999, and May 21, 2019, were identified and assigned a Naranjo score; 31 patients were included with a Naranjo score of 5 or higher. There were slightly more male subjects than female subjects, average age was 66, and all subjects were Caucasian. Median time until presentation of adverse effects was 4 weeks (range: 0.3 to 104 weeks). Most common symptom was edema (74% of patients), followed by heart failure without and with preserved ejection fraction (19.4% and 22.6% of patients, respectively). Worsening or new hypertension was also common (25.8% of patients). Rarer were pulmonary edema, pericardial effusion, and cardiac arrest that occurred in 1 patient. In most cases, clinicians stopped itraconazole (74%) or decreased itraconazole dose (19%), resulting in improvement or resolution of symptoms. In 4 cases, the adverse effect did not resolve. Itraconazole can cause a range of possible serious cardiac and fluid-associated adverse events. Dose decrease or cessation usually resulted in symptomatic improvement or reversal.

Background Fluoroquinolones (FQs) are known to be accompanied by significant risks. However, the incidence of adverse events (ADE) resulting in unplanned drug discontinuation when used for periprosthetic joint infections (PJI) is currently unknown. Methods This study included 156 patients over the age of 18 treated for staphylococcal PJI with debridement, antibiotics, and implant retention (DAIR), between January 1, 2007 and November 21, 2019. Of the 156 patients, 64 had total hip arthroplasty (THA) and 92 had total knee arthroplasty (TKA) infections. The primary outcome was rate of unplanned drug discontinuation. Secondary outcomes included incidence of severe ADE, unplanned rifamycin discontinuation, mean time to unplanned regimen discontinuation, and all-cause mortality. Results Overall, unplanned drug discontinuation occurred in 35.6% of patients in the FQ group and 3% of patients in the non-FQ group. The rate of unplanned discontinuation of FQ regimens as compared to non-FQ regimens was 27.5% vs 4.2% (p=0.021) in THA infections and 42% vs 2.4% (p<0.001) in TKA infections. There was no significant difference in severe ADEs between FQ and non-FQ regimens in both THA and TKA infections. The overall rate of non-severe ADEs in FQ compared to non-FQ regimens was 43.3% vs 6.1% (p<0.001). FQs were associated with tendinopathy, myalgia, arthralgia, and nausea. Conclusions A significantly higher rate of unplanned drug discontinuation was associated with FQ as compared to non-FQ regimens. This provides a real-world view of the implications of FQ related adverse events on unplanned discontinuation when used in prolonged durations for the management of staphylococcal PJIs.

Specific attention was focused on the common ASP infrastructures of prospective audit, existing partnerships with microbiology laboratories, and experience in stewarding medication resources as justification for ASP involvement. We leveraged our existing Enterprise ASP prospective audit platform to contribute to the response. Here we describe the logic and development of COVID-19 ASP flags, which were rapidly operationalized in the enterprise electronic medical record (EMR). Our prospective audit system utilizes a longstanding, homegrown flagging system that was converted to function within the EMR (Epic Systems, Verona, WI). 2-4 It generates a patient list based on a series of "rules" with complex logic incorporating medications and order elements, laboratory values, and microbiology, etc. The system also allows for the documentation of actions taken and provider response. Interventions deemed complete can be dismissed (ie, removed), and those requiring follow-up can be deferred for later review.As the burden of COVID-19 patients began to increase, and amid concerns regarding medication shortages, our ASP needed a mechanism to identify patients with a SARS-CoV-2 polymerase chain reaction (PCR) testing performed and/or patients receiving medications in need of careful stewardship. We elected to incorporate both the PCR result and potential COVID-19 therapies into the rule logic because flagging the medications alone would not filter out non-COVID-19 indications, leading to the addition of low value flags or "noise" into the system. We considered flagging only PCR-positive patients, but this approach would fail to identify pending testing or PCR-negative patients who remained on potentially inappropriate medications. Conversely, incorporation of all ordered PCRs would also have contributed a great deal of noise. We developed a hybrid approach by designing 2 flags that identify opportunities for stewardship of medications and confirm infectious diseases (ID) consultation.The first rule (ASP COVID-19 rule 1) uses logic that identifies inpatients with a negative SARS-CoV-2 PCR test, collected within the previous 7 days, who also have a medication order that may represent "active therapy" (Table 1). Despite the 2 studies by Gautret et al 5,6 claiming the benefit of the combination of hydroxychloroquine and azithromycin, we deliberately omitted azithromycin from the "active therapy" list. 5,6 We recognized that despite significant weaknesses in this literature, providers may still order the combination; however, including azithromycin would have introduced flags for appropriately prescribed azithromycin for non-COVID-19 indications. Additionally, patients prescribed the combination of hydroxychloroquine and azithromycin would be flagged by the hydroxychloroquine order, thus making azithromycin inclusion unnecessary.The second rule (ASP COVID-19 rule 2) is triggered by 2 criteria. The first is an inpatient with a positive PCR result irrespective of active medication orders. Our Enterprise team felt that review of all PC...