Research Spotlight

Gumbo, T., K. Cirrincione and S. Srivastava (2020). “Repurposing drugs for treatment of Mycobacterium abscessus: a view to a kill.” J Antimicrob Chemother Feb 4. [Epub ahead of print].

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BACKGROUND: The current treatment regimens recommended for Mycobacterium abscessus subspecies abscessus (Mab) pulmonary disease are not effective. We identified 16 drugs with potential to build new regimens, translating to 560 possible three-drug combination regimens. OBJECTIVES: To determine MICs and efficacy of drugs from different antibiotic classes for treatment against Mab, in order to winnow down the potential drugs for combination therapy to tractable numbers, for future use in hollow-fibre studies. METHODS: The MICs of levofloxacin, minocycline, meropenem, imipenem, tedizolid, bedaquiline, azithromycin, clarithromycin, amikacin, vancomycin, delafloxacin, tebipenem/avibactam and omadacycline were determined for 20 Mab isolates. In addition, concentration-response studies with tedizolid, bedaquiline, clarithromycin, amikacin, tebipenem/avibactam, cefdinir, faropenem, omadacycline and daunorubicin were performed and data were fitted to the inhibitory sigmoid Emax model. Efficacy was defined as maximal kill, expressed as cfu/mL kill below day 0 burden. RESULTS: The lowest MICs among the 13 antibiotics were of bedaquiline, tebipenem/avibactam and omadacycline. The antibiotics that killed Mab below the day 0 burden were the anticancer agent daunorubicin (3.36 log10 cfu/mL), cefdinir (1.85 log10 cfu/mL), faropenem (2.48 log10 cfu/mL) and tebipenem/avibactam (1.71 log10 cfu/mL kill). The EC50 values of these drugs were 11.67, 9.52, 48.2 and 0.33 mg/L, respectively, below peak concentrations of these drugs. CONCLUSIONS: The low MICs and efficacy at clinically achievable concentrations mean that tebipenem/avibactam, daunorubicin, omadacycline and bedaquiline give a view of components of a three-drug regimen likely to effectively kill Mab. We propose pharmacokinetic/pharmacodynamic studies to identify such a regimen and the doses to be combined.

Grace, E., O. Goldblum, L. Renda, N. Agada, K. See, C. Leonardi and A. Menter (2020). “Injection Site Reactions in the Federal Adverse Event Reporting System (FAERS) Post-Marketing Database Vary Among Biologics Approved to Treat Moderate-To-Severe Psoriasis.” Dermatol Ther (Heidelb) 10(1): 99-106.

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INTRODUCTION: Biologics used to treat moderate-to-severe plaque psoriasis may cause injection site reactions (ISRs) characterized by erythema, edema, itch, and sometimes pain. The Federal Adverse Event Reporting System (FAERS) is a repository of spontaneous post-marketing reports of adverse events (AEs) that are reported to the US Food and Drug Administration (FDA). Our objective was to perform a pharmacovigilance analysis of FAERS reports of ISRs associated with the use of subcutaneously administered biologic products approved to treat moderate-to-severe plaque psoriasis. METHODS: The products included in our assessment were adalimumab, etanercept, ixekizumab, secukinumab, and ustekinumab. Reports from the date of US approval for each biologic as treatment for plaque psoriasis through 2 years were included using the search term “injection site.” RESULTS: The results show that the FAERS database contained reports of ISRs for all of the included biologics during the 2 years following FDA approval. The most common reports on ISRs were on pain, irritation, and erythema for adalimumab; reaction, pain, and erythema for etanercept; erythema, pain, and reaction for ixekizumab; bruising, pain, hemorrhage for secukinumab; and pain, induration, and swelling for ustekinumab. FAERS does not include data on total patient exposure; therefore, ISR rates could not be calculated. CONCLUSIONS: Specific ISRs varied among the biologic therapies assessed. The findings presented could be helpful when patients consider switching therapies due to ISRs. FUNDING: Eli Lilly and Company.

Garg, A., E. Neuren, D. Cha, J. S. Kirby, J. R. Ingram, G. B. E. Jemec, S. Esmann, L. Thorlacius, B. Villumsen, V. D. Marmol, A. Nassif, M. Delage, T. Tzellos, D. Moseng, O. Grimstad, H. Naik, R. Micheletti, S. Guilbault, A. P. Miller, I. Hamzavi, H. van der Zee, E. Prens, N. Kappe, C. Ardon, B. Kirby, R. Hughes, C. C. Zouboulis, G. Nikolakis, F. G. Bechara, L. Matusiak, J. Szepietowski, A. Glowaczewska, S. D. Smith, N. Goldfarb, S. Daveluy, C. Avgoustou, E. Giamarellos-Bourboulis, S. Cohen, Y. Soliman, E. G. Brant, O. Akilov, C. Sayed, J. Tan, A. Alavi, M. A. Lowes, J. C. Pascual, H. Riad, S. Fisher, A. Cohen, S. Y. Paek, B. Resnik, Q. Ju, L. Wang and A. Strunk (2020). “Evaluating patients’ unmet needs in hidradenitis suppurativa: Results from the Global Survey Of Impact and Healthcare Needs (VOICE) Project.” J Am Acad Dermatol 82(2): 366-376.

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BACKGROUND: A needs assessment for patients with hidradenitis suppurativa (HS) will support advancements in multidisciplinary care, treatment, research, advocacy, and philanthropy. OBJECTIVE: To evaluate unmet needs from the perspective of HS patients. METHODS: Prospective multinational survey of patients between October 2017 and July 2018. RESULTS: Before receiving a formal HS diagnosis, 63.7% (n = 827) of patients visited a physician >/=5 times. Mean delay in diagnosis was 10.2 +/- 8.9 years. Patients experienced flare daily, weekly, or monthly in 23.0%, 29.8%, and 31.1%, respectively. Most (61.4% [n = 798]) rated recent HS-related pain as moderate or higher, and 4.5% described recent pain to be the worst possible. Access to dermatology was rated as difficult by 37.0% (n = 481). Patients reported visiting the emergency department and hospital >/=5 times for symptoms in 18.3% and 12.5%, respectively. An extreme impact on life was reported by 43.3% (n = 563), and 14.5% were disabled due to disease. Patients reported a high frequency of comorbidities, most commonly mood disorders. Patients were dissatisfied with medical or procedural treatments in 45.9% and 34.6%, respectively. LIMITATIONS: Data were self-reported. Patients with more severe disease may have been selected. CONCLUSION: HS patients have identified several critical unmet needs that will require stakeholder collaboration to meaningfully address.

Gaglani, M., A. Vasudevan, C. Raiyani, K. Murthy, W. Chen, M. Reis, E. A. Belongia, H. Q. McLean, M. L. Jackson, L. A. Jackson, R. K. Zimmerman, M. P. Nowalk, A. S. Monto, E. T. Martin, J. R. Chung, S. Spencer, A. M. Fry and B. Flannery (2020). “Effectiveness of Trivalent and Quadrivalent Inactivated Vaccines against Influenza B in the United States, 2011-2012 to 2016-2017.” Clin Infect Dis Feb 1. [Epub ahead of print].

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BACKGROUND: Since 2013, quadrivalent influenza vaccines containing two B viruses gradually replaced trivalent vaccines in the United States. We compared vaccine effectiveness of quadrivalent to trivalent inactivated vaccines (IIV4 to IIV3) against illness due to influenza B during the transition when IIV4 use increased rapidly. METHODS: The US Influenza Vaccine Effectiveness (Flu VE) Network analyzed 25,019 of 42,600 outpatients aged >/=6 months enrolled within 7 days of illness-onset during six seasons from 2011-2012. Upper respiratory specimens were tested for influenza virus type and B-lineage. Using logistic regression, we estimated IIV4 or IIV3 effectiveness by comparing the odds of influenza B infection overall, and by B lineage among vaccinated versus unvaccinated participants. Over four seasons from 2013-2014, we compared relative odds of influenza B infection among IIV4 versus IIV3 recipients. RESULTS: Trivalent vaccines included the predominantly circulating B lineage in four of six seasons. During four influenza seasons when both IIV4 and IIV3 were widely used, overall effectiveness against any influenza B was 53% (95% confidence interval [CI], 45 to 59) for IIV4 versus 45% (95% CI, 34 to 54) for IIV3. IIV4 was more effective than IIV3 against the B lineage not included in IIV3, but comparative effectiveness against illness related to any influenza B favored neither vaccine valency. CONCLUSIONS: Uptake of quadrivalent inactivated influenza vaccines was not associated with increased protection against any influenza B illness, despite higher effectiveness of quadrivalent vaccines against the added B virus lineage. Public health impact and cost-benefit analyses are needed globally.

Farrell, R. M., L. Johannesson, R. Flyckt, E. G. Richards, G. Testa, A. Tzakis and T. Falcone (2020). “Evolving Ethical Issues with Advances in Uterus Transplantation.” Am J Obstet Gynecol Jan 22. [Epub ahead of print].

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While uterus transplantation was once considered only a theoretical possibility for patients with uterine factor infertility, researchers have now developed methods of transplantation that have led to successful pregnancies with multiple children born to date. Because of the unique and significant nature of this type of research, it has been undertaken with collaboration not only with scientists and physicians but also with bioethicists, who paved the initial path for research of uterus transplantation to take place. As the science of uterus transplantation continues to advance, so too must the public dialogue among obstetrician/gynecologists, transplant surgeons, bioethicists, and other key stakeholders in defining the continued direction of research in addition to planning for the clinical implementation of uterus transplantation as a therapeutic option. Given the rapid advances in this field, the time has come to revisit the fundamental questions raised at the inception of uterus transplantation and, looking forward, determine the future of this approach given emerging data on the procedure’s impact on individuals, families, and society.