Infectious Disease

Smith, E.R., Fry, A.M., Hicks, L.A., Fleming-Dutra, K.E., Flannery, B., Ferdinands, J., Rolfes, M.A., Martin, E.T., Monto, A.S., Zimmerman, R.K., Nowalk, M.P., Jackson, M.L., McLean, H.Q., Olson, S.C., Gaglani, M. and Patel, M.M. (2020). “Reducing Antibiotic Use in Ambulatory Care Through Influenza Vaccination.” Clin Infect Dis 71(11): e726-e734.

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BACKGROUND: Improving appropriate antibiotic use is crucial for combating antibiotic resistance and unnecessary adverse drug reactions. Acute respiratory illness (ARI) commonly causes outpatient visits and accounts for ~41% of antibiotics used in the United States. We examined the influence of influenza vaccination on reducing antibiotic prescriptions among outpatients with ARI. METHODS: We enrolled outpatients aged ≥6 months with ARI from 50-60 US clinics during 5 winters (2013-2018) and tested for influenza with RT-PCR; results were unavailable for clinical decision making and clinical influenza testing was infrequent. We collected antibiotic prescriptions and diagnosis codes for ARI syndromes. We calculated vaccine effectiveness (VE) by comparing vaccination odds among influenza-positive cases with test-negative controls. We estimated ARI visits and antibiotic prescriptions averted by influenza vaccination using estimates of VE, coverage, and prevalence of antibiotic prescriptions and influenza. RESULTS: Among 37 487 ARI outpatients, 9659 (26%) were influenza positive. Overall, 36% of ARI and 26% of influenza-positive patients were prescribed antibiotics. The top 3 prevalent ARI syndromes included: viral upper respiratory tract infection (47%), pharyngitis (18%), and allergy or asthma (11%). Among patients testing positive for influenza, 77% did not receive an ICD-CM diagnostic code for influenza. Overall, VE against influenza-associated ARI was 35% (95% CI, 32-39%). Vaccination prevented 5.6% of all ARI syndromes, ranging from 2.8% (sinusitis) to 11% (clinical influenza). Influenza vaccination averted 1 in 25 (3.8%; 95% CI, 3.6-4.1%) antibiotic prescriptions among ARI outpatients during influenza seasons. CONCLUSIONS: Vaccination and accurate influenza diagnosis may curb unnecessary antibiotic use and reduce the global threat of antibiotic resistance.

McCullough, P.A., Alexander, P.E., Armstrong, R., Arvinte, C., Bain, A.F., Bartlett, R.P., Berkowitz, R.L., Berry, A.C., Borody, T.J., Brewer, J.H., Brufsky, A.M., Clarke, T., Derwand, R., Eck, A., Eck, J., Eisner, R.A., Fareed, G.C., Farella, A., Fonseca, S.N.S., Geyer, C.E., Jr., Gonnering, R.S., Graves, K.E., Gross, K.B.V., Hazan, S., Held, K.S., Hight, H.T., Immanuel, S., Jacobs, M.M., Ladapo, J.A., Lee, L.H., Littell, J., Lozano, I., Mangat, H.S., Marble, B., McKinnon, J.E., Merritt, L.D., Orient, J.M., Oskoui, R., Pompan, D.C., Procter, B.C., Prodromos, C., Rajter, J.C., Rajter, J.J., Ram, C.V.S., Rios, S.S., Risch, H.A., Robb, M.J.A., Rutherford, M., Scholz, M., Singleton, M.M., Tumlin, J.A., Tyson, B.M., Urso, R.G., Victory, K., Vliet, E.L., Wax, C.M., Wolkoff, A.G., Wooll, V. and Zelenko, V. (2020). “Multifaceted highly targeted sequential multidrug treatment of early ambulatory high-risk SARS-CoV-2 infection (COVID-19).” Rev Cardiovasc Med 21(4): 517-530.

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The SARS-CoV-2 virus spreading across the world has led to surges of COVID-19 illness, hospitalizations, and death. The complex and multifaceted pathophysiology of life-threatening COVID-19 illness including viral mediated organ damage, cytokine storm, and thrombosis warrants early interventions to address all components of the devastating illness. In countries where therapeutic nihilism is prevalent, patients endure escalating symptoms and without early treatment can succumb to delayed in-hospital care and death. Prompt early initiation of sequenced multidrug therapy (SMDT) is a widely and currently available solution to stem the tide of hospitalizations and death. A multipronged therapeutic approach includes 1) adjuvant nutraceuticals, 2) combination intracellular anti-infective therapy, 3) inhaled/oral corticosteroids, 4) antiplatelet agents/anticoagulants, 5) supportive care including supplemental oxygen, monitoring, and telemedicine. Randomized trials of individual, novel oral therapies have not delivered tools for physicians to combat the pandemic in practice. No single therapeutic option thus far has been entirely effective and therefore a combination is required at this time. An urgent immediate pivot from single drug to SMDT regimens should be employed as a critical strategy to deal with the large numbers of acute COVID-19 patients with the aim of reducing the intensity and duration of symptoms and avoiding hospitalization and death.

Lundgren, J.D., Grund, B., Barkauskas, C.E., Holland, T.L., Gottlieb, R.L., Sandkovsky, U., Brown, S.M., Knowlton, K.U., Self, W.H., Files, D.C., Jain, M.K., Benfield, T., Bowdish, M.E., Leshnower, B.G., Baker, J.V., Jensen, J.U., Gardner, E.M., Ginde, A.A., Harris, E.S., Johansen, I.S., Markowitz, N., Matthay, M.A., Østergaard, L., Chang, C.C., Davey, V.J., Goodman, A., Higgs, E.S., Murray, D.D., Murray, T.A., Paredes, R., Parmar, M.K.B., Phillips, A.N., Reilly, C., Sharma, S., Dewar, R.L., Teitelbaum, M., Wentworth, D., Cao, H., Klekotka, P., Babiker, A.G., Gelijns, A.C., Kan, V.L., Polizzotto, M.N., Thompson, B.T., Lane, H.C. and Neaton, J.D. (2020). “A Neutralizing Monoclonal Antibody for Hospitalized Patients with Covid-19.” N Engl J Med Dec 22;NEJMoa2033130. [Epub ahead of print].

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BACKGROUND: LY-CoV555, a neutralizing monoclonal antibody, has been associated with a decrease in viral load and the frequency of hospitalizations or emergency department visits among outpatients with coronavirus disease 2019 (Covid-19). Data are needed on the effect of this antibody in patients who are hospitalized with Covid-19. METHODS: In this platform trial of therapeutic agents, we randomly assigned hospitalized patients who had Covid-19 without end-organ failure in a 1:1 ratio to receive either LY-CoV555 or matching placebo. In addition, all the patients received high-quality supportive care as background therapy, including the antiviral drug remdesivir and, when indicated, supplemental oxygen and glucocorticoids. LY-CoV555 (at a dose of 7000 mg) or placebo was administered as a single intravenous infusion over a 1-hour period. The primary outcome was a sustained recovery during a 90-day period, as assessed in a time-to-event analysis. An interim futility assessment was performed on the basis of a seven-category ordinal scale for pulmonary function on day 5. RESULTS: On October 26, 2020, the data and safety monitoring board recommended stopping enrollment for futility after 314 patients (163 in the LY-CoV555 group and 151 in the placebo group) had undergone randomization and infusion. The median interval since the onset of symptoms was 7 days (interquartile range, 5 to 9). At day 5, a total of 81 patients (50%) in the LY-CoV555 group and 81 (54%) in the placebo group were in one of the two most favorable categories of the pulmonary outcome. Across the seven categories, the odds ratio of being in a more favorable category in the LY-CoV555 group than in the placebo group was 0.85 (95% confidence interval [CI], 0.56 to 1.29; P = 0.45). The percentage of patients with the primary safety outcome (a composite of death, serious adverse events, or clinical grade 3 or 4 adverse events through day 5) was similar in the LY-CoV555 group and the placebo group (19% and 14%, respectively; odds ratio, 1.56; 95% CI, 0.78 to 3.10; P = 0.20). The rate ratio for a sustained recovery was 1.06 (95% CI, 0.77 to 1.47). CONCLUSIONS: Monoclonal antibody LY-CoV555, when coadministered with remdesivir, did not demonstrate efficacy among hospitalized patients who had Covid-19 without end-organ failure. (Funded by Operation Warp Speed and others; TICO ClinicalTrials.gov number, NCT04501978.).

Hughes, K., Middleton, D.B., Nowalk, M.P., Balasubramani, G.K., Martin, E.T., Gaglani, M., Talbot, H.K., Patel, M.M., Ferdinands, J.M., Zimmerman, R.K. and Silveira, F.P. (2021). “Effectiveness of Influenza Vaccine for Preventing Laboratory-Confirmed Influenza Hospitalizations in Immunocompromised Adults.” Clin Infect Dis Jan 3;ciaa1927. [Epub ahead of print].

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BACKGROUND: Yearly influenza immunization is recommended for immunocompromised (IC) individuals, although immune responses are lower than that for the non-immunocompromised and the data on vaccine effectiveness (VE) in the IC is scarce. We evaluated VE against influenza-associated hospitalization among IC adults. METHODS: We analyzed data from adults ≥ 18 years hospitalized with acute respiratory illness (ARI) during the 2017-2018 influenza season at 10 hospitals in the United States. IC adults were identified using pre-specified case-definitions, utilizing electronic medical record data. VE was evaluated with a test-negative case-control design using multivariable logistic regression with PCR-confirmed influenza as the outcome and vaccination status as the exposure, adjusting for age, enrolling site, illness onset date, race, days from onset to specimen collection, self-reported health, and self-reported hospitalizations. RESULTS: Of 3,524 adults hospitalized with ARI, 1,210 (34.3%) had an immunocompromising condition. IC adults were more likely to be vaccinated than non-IC (69.5% vs 65.2%), and less likely to have influenza (22% vs 27.8%). The mean age did not differ among IC and non-IC (61.4 vs 60.8 years old). The overall VE against influenza hospitalization, including immunocompetent adults, was 33% (95% CI, 21% to 44%). VE among IC vs non-IC adults was lower at 5% (-29% to 31%) vs. 41% (27% to 52%) (p<0.05 for interaction term). CONCLUSIONS: VE in one influenza season was very low among IC individuals. Future efforts should include evaluation of VE among the different immunocompromising conditions and whether enhanced vaccines improve the suboptimal effectiveness among the immunocompromised.

Ferdinands, J.M., Gaglani, M., Ghamande, S., Martin, E.T., Middleton, D., Monto, A.S., Silveira, F., Talbot, H.K., Zimmerman, R., Smith, E.R. and Patel, M. (2020). “Vaccine effectiveness against influenza-associated hospitalizations among adults, 2018-2019, US Hospitalized Adult Influenza Vaccine Effectiveness Network.” J Infect Dis Dec 18;jiaa772. [Epub ahead of print].

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We estimated vaccine effectiveness for prevention of influenza-associated hospitalizations among adults during the 2018-2019 influenza season. Adults admitted with acute respiratory illness to 14 hospitals of the US Hospitalized Adult Influenza Vaccine Effectiveness Network and testing positive for influenza were cases; patients testing negative were controls. Vaccine effectiveness was estimated using logistic regression and inverse probability of treatment weighting. We analyzed data from 2863 patients with mean age of 63 years. Adjusted VE against influenza A(H1N1)pdm09-associated hospitalization was 51% (95%CI 25, 68). Adjusted VE against influenza A(H3N2) virus-associated hospitalization was -2% (95%CI -65, 37) and differed significantly by age, with VE of -130% (95% CI -374, -27) among adults 18 to ≤56 years of age. Although vaccination halved the risk of influenza-A(H1N1)pdm09-associated hospitalizations, it conferred no protection against influenza A(H3N2)-associated hospitalizations. We observed negative VE for young-and middle-aged adults but cannot exclude residual confounding as a potential explanation.