Infectious Disease

Block, T. M., H. Alter, N. Brown, A. Brownstein, C. Brosgart, K. M. Chang, P. J. Chen, C. Cohen, H. El-Serag, J. Feld, R. Gish, J. Glenn, T. F. Greten, J. T. Guo, Y. Hoshida, K. V. Kowdley, W. Li, A. S. Lok, B. McMahon, A. Mehta, R. Perrillo, C. M. Rice, J. Rinaudo, R. F. Schinazi and K. Shetty (2017). “Research priorities for the discovery of a cure for chronic hepatitis B: Report of a workshop.” Antiviral Res 150: 93-100.

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In early 2017, the Hepatitis B Foundation invited 30 experts in the fields of hepatitis B and liver cancer research to identify projects they deemed important to the goal of finding a cure for chronic hepatitis B and D and the diseases with which these viral infections are associated. They were also asked to identify general categories of research and to prioritize sub-project topics within those areas. The experts generally agreed on broadly defined areas of research, but there was usually little difference between the highest and lowest scoring projects; for the most part, all programs described in this document were considered valuable and necessary. An executive summary of this discussion was recently published (Alter et al., Hepatology 2017). The present manuscript reports the areas of research identified by the workshop participants, provides a brief rationale for their selection, and attempts to express differences among the priorities assigned to each area of research, when such distinctions were expressed.

Deshpande, D., S. Srivastava, P. Bendet, K. R. Martin, K. N. Cirrincione, P. S. Lee, J. G. Pasipanodya, K. Dheda and T. Gumbo (2017). “On the antibacterial and sterilizing effect of benzylpenicillin in tuberculosis.” Antimicrob Agents Chemother: 2017 Nov [Epub ahead of print].

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The modern chemotherapy era started with Fleming’s discovery of benzylpenicillin. He demonstrated that benzylpenicillin did not kill Mycobacterium tuberculosis (Mtb) Here, we found that >64 mg/L of static benzylpenicillin concentrations killed 1.16-1.43 log10 CFU/mL below starting inoculum of extracellular and intracellular Mtb over 7 days. When we added the beta-lactamase-inhibitor avibactam, benzylpenicillin maximal kill (Emax) of either extracellular log-phase growth Mtb was 6.80+/-0.45 log10 CFU/mL at an EC50 of 15.11+/-5.2.32 mg/L, while for intracellular Mtb was 2.42+/-0.14 log10 CFU/mL at an EC50 of 6.70+/-0.56 mg/L. The median penicillin (plus avibactam) MIC against South African clinical Mtb strains (80% either multi- or extensively drug-resistant) was 2 mg/L. We mimicked human-like benzylpenicillin and avibactam concentration-time profiles in the hollow fiber model of tuberculosis (HFS-TB). The percentage time above MIC was linked to effect, with an optimal exposure of >/=65%. At optimal exposure in the HFS-TB, the bactericidal activity in log-phase growth Mtb was 1.44 log10 CFU/mL/day, while 3.28 log10 CFU/mL of intracellular Mtb was killed over 3 weeks. In an 8 week HFS-TB study of non-replicating persistent Mtb, penicillin-avibactam alone versus the drug combination of isoniazid, rifampin, and pyrazinamide, both killed >7.0 log10 CFU/mL. Monte Carlo simulations of 10,000 pre-term infants with disseminated disease identified an optimal dose of 10,000 U/kg/hr, while for pregnant women or non-pregnant adults with pulmonary tuberculosis optima dose was 25,000 U/kg/hr, by continuous intravenous infusion. Penicillin-avibactam should be examined for effect in pregnant women and infants with drug-resistant tuberculosis, to replace injectable ototoxic and teratogenic second-line drugs.

Stewart, R. J., B. Flannery, J. R. Chung, M. Gaglani, M. Reis, R. K. Zimmerman, M. P. Nowalk, L. Jackson, M. Jackson, A. S. Monto, E. T. Martin, E. A. Belongia, H. McLean, A. M. Fry and F. Havers (2017). “Influenza antiviral prescribing for outpatients with an acute respiratory illness and at high risk for influenza-associated complications during five influenza seasons-united states, 2011-2016.” Clin Infect Dis: 1-20.

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Background: Influenza causes millions of illnesses annually; certain groups are at higher risk for influenza-associated complications. Early antiviral treatment can reduce the risk of complications and is recommended for outpatients at increased risk. We describe antiviral prescribing among high-risk outpatients for 5 influenza seasons and explore factors that may influence prescribing. Methods: We analyzed antiviral prescription and clinical data for high-risk outpatients aged >/= 6 months with an acute respiratory illness (ARI) and enrolled in the US Influenza Vaccine Effectiveness Network during the 2011-2012 to 2015-2016 influenza seasons. We obtained clinical information from interviews and electronic medical records and tested all enrollees for influenza with rRT-PCR. We calculated the number of patients with ARI that must be treated to treat 1 patient with laboratory-confirmed influenza. Results: Among high-risk outpatients with ARI who presented to care within two days of symptom onset (early), 15% (718/4861) were prescribed an antiviral medication, including 472/1292 (37%) of those with rRT-PCR-confirmed influenza. Less than half (40%) of high-risk outpatients with influenza presented to care early. Earlier presentation to care was associated with antiviral treatment (OR: 4.1, CI: 3.5-4.8), as was fever (OR: 3.2, CI: 2.7-3.8), although 25% of high-risk outpatients with influenza were afebrile. Empiric treatment of 4 high-risk outpatients with ARI was needed to treat 1 patient with laboratory-confirmed influenza. Conclusion: Influenza antiviral medications were infrequently prescribed for high-risk outpatients with ARI who would benefit most from treatment. Efforts to increase appropriate antiviral prescribing are needed to reduce influenza-associated complications.

Jackson, M. L., J. R. Chung, L. A. Jackson, C. H. Phillips, J. Benoit, A. S. Monto, E. T. Martin, E. A. Belongia, H. Q. McLean, M. Gaglani, K. Murthy, R. Zimmerman, M. P. Nowalk, A. M. Fry and B. Flannery (2017). “Influenza vaccine effectiveness in the united states during the 2015-2016 season.” N Engl J Med 377(6): 534-543.

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BACKGROUND: The A(H1N1)pdm09 virus strain used in the live attenuated influenza vaccine was changed for the 2015-2016 influenza season because of its lack of effectiveness in young children in 2013-2014. The Influenza Vaccine Effectiveness Network evaluated the effect of this change as part of its estimates of influenza vaccine effectiveness in 2015-2016. METHODS: We enrolled patients 6 months of age or older who presented with acute respiratory illness at ambulatory care clinics in geographically diverse U.S. sites. Using a test-negative design, we estimated vaccine effectiveness as (1-OR)x100, in which OR is the odds ratio for testing positive for influenza virus among vaccinated versus unvaccinated participants. Separate estimates were calculated for the inactivated vaccines and the live attenuated vaccine. RESULTS: Among 6879 eligible participants, 1309 (19%) tested positive for influenza virus, predominantly for A(H1N1)pdm09 (11%) and influenza B (7%). The effectiveness of the influenza vaccine against any influenza illness was 48% (95% confidence interval [CI], 41 to 55; P<0.001). Among children 2 to 17 years of age, the inactivated influenza vaccine was 60% effective (95% CI, 47 to 70; P<0.001), and the live attenuated vaccine was not observed to be effective (vaccine effectiveness, 5%; 95% CI, -47 to 39; P=0.80). Vaccine effectiveness against A(H1N1)pdm09 among children was 63% (95% CI, 45 to 75; P<0.001) for the inactivated vaccine, as compared with -19% (95% CI, -113 to 33; P=0.55) for the live attenuated vaccine. CONCLUSIONS: Influenza vaccines reduced the risk of influenza illness in 2015-2016. However, the live attenuated vaccine was found to be ineffective among children in a year with substantial inactivated vaccine effectiveness. Because the 2016-2017 A(H1N1)pdm09 strain used in the live attenuated vaccine was unchanged from 2015-2016, the Advisory Committee on Immunization Practices made an interim recommendation not to use the live attenuated influenza vaccine for the 2016-2017 influenza season.

Chung, J. R., B. Flannery, R. K. Zimmerman, M. P. Nowalk, M. L. Jackson, L. A. Jackson, J. G. Petrie, E. T. Martin, A. S. Monto, H. Q. McLean, E. A. Belongia, M. Gaglani and A. M. Fry (2017). “Prior season vaccination and risk of influenza during the 2014-2015 season in the U.S.” J Infect Dis: 2017 Jun [Epub ahead of print].

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The US Flu VE Network conducts annual studies of VE using the test-negative study design that is also used in Canada. In the Canadian study, current and prior-season vaccination status is based on a combination of patient self-report and sentinel practitioner documentation. In the US Flu VE Network, current season vaccination status is also based on a combination of patient self-report and electronic immunization records; however, prior-season vaccination is based on immunization records only. Misclassification of vaccine history may result from inaccurate self-report or incomplete immunization records. One study that compared self-reported influenza vaccination to an immunization registry found that patients overreported vaccination by approximately 10% [5]; recall of prior seasons’ vaccination may be less accurate. To minimize misclassification of vaccination history in 2 prior seasons, we considered documented doses only among patients aged ≥9 years with medical records available for at least 2 years prior to enrollment, and excluded patients who reported 2014–2015 influenza vaccination that was not documented. After adjusting for age and other potential confounding variables, we found no statistically significant association between vaccination in 3 consecutive seasons and A(H3N2)-related illness during 2014–2015 (Table 1). However, we observed the highest point estimate among persons vaccinated in 2014–2015 only. A sensitivity analysis restricted to the main genetic group (clade 3C.2a) of antigenically drifted A(H3N2) and influenza negatives resulted in similar estimates (data not shown). Although the higher point estimate for vaccination only in 2014–2015 is consistent with potential negative interference from prior vaccination [1], our results do not support evidence of increased likelihood of influenza due to A(H3N2) viruses among repeatedly vaccinated individuals compared to those unvaccinated in 3 consecutive seasons.