Infectious Disease

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.

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.

Flannery, B., R. J. G. Kondor, J. R. Chung, M. Gaglani, M. Reis, R. K. Zimmerman, M. P. Nowalk, M. L. Jackson, L. A. Jackson, A. S. Monto, E. T. Martin, E. A. Belongia, H. Q. McLean, S. S. Kim, L. Blanton, K. Kniss, A. P. Budd, L. Brammer, T. J. Stark, J. R. Barnes, D. E. Wentworth, A. M. Fry and M. Patel (2020). “Spread of Antigenically Drifted Influenza A(H3N2) Viruses and Vaccine Effectiveness in the United States During the 2018-2019 Season.” J Infect Dis 221(1): 8-15.

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BACKGROUND: Increased illness due to antigenically drifted A(H3N2) clade 3C.3a influenza viruses prompted concerns about vaccine effectiveness (VE) and vaccine strain selection. We used US virologic surveillance and US Influenza Vaccine Effectiveness (Flu VE) Network data to evaluate consequences of this clade. METHODS: Distribution of influenza viruses was described using virologic surveillance data. The Flu VE Network enrolled ambulatory care patients aged >/=6 months with acute respiratory illness at 5 sites. Respiratory specimens were tested for influenza by means of reverse-transcriptase polymerase chain reaction and were sequenced. Using a test-negative design, we estimated VE, comparing the odds of influenza among vaccinated versus unvaccinated participants. RESULTS: During the 2018-2019 influenza season, A(H3N2) clade 3C.3a viruses caused an increasing proportion of influenza cases. Among 2763 Flu VE Network case patients, 1325 (48%) were infected with A(H1N1)pdm09 and 1350 (49%) with A(H3N2); clade 3C.3a accounted for 977 (93%) of 1054 sequenced A(H3N2) viruses. VE was 44% (95% confidence interval, 37%-51%) against A(H1N1)pdm09 and 9% (-4% to 20%) against A(H3N2); VE was 5% (-10% to 19%) against A(H3N2) clade 3C.3a viruses. CONCLUSIONS: The predominance of A(H3N2) clade 3C.3a viruses during the latter part of the 2018-2019 season was associated with decreased VE, supporting the A(H3N2) vaccine component update for 2019-2020 northern hemisphere influenza vaccines.

Rolfes, M. A., B. Flannery, J. R. Chung, A. O’Halloran, S. Garg, E. A. Belongia, M. Gaglani, R. K. Zimmerman, M. L. Jackson, A. S. Monto, N. B. Alden, E. Anderson, N. M. Bennett, L. Billing, S. Eckel, P. D. Kirley, R. Lynfield, M. L. Monroe, M. Spencer, N. Spina, H. K. Talbot, A. Thomas, S. M. Torres, K. Yousey-Hindes, J. A. Singleton, M. Patel, C. Reed and A. M. Fry (2019). “Effects of Influenza Vaccination in the United States During the 2017-2018 Influenza Season.” Clin Infect Dis 69(11): 1845-1853.

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BACKGROUND: The severity of the 2017-2018 influenza season in the United States was high, with influenza A(H3N2) viruses predominating. Here, we report influenza vaccine effectiveness (VE) and estimate the number of vaccine-prevented influenza-associated illnesses, medical visits, hospitalizations, and deaths for the 2017-2018 influenza season. METHODS: We used national age-specific estimates of 2017-2018 influenza vaccine coverage and disease burden. We estimated VE against medically attended reverse-transcription polymerase chain reaction-confirmed influenza virus infection in the ambulatory setting using a test-negative design. We used a compartmental model to estimate numbers of influenza-associated outcomes prevented by vaccination. RESULTS: The VE against outpatient, medically attended, laboratory-confirmed influenza was 38% (95% confidence interval [CI], 31%-43%), including 22% (95% CI, 12%-31%) against influenza A(H3N2), 62% (95% CI, 50%-71%) against influenza A(H1N1)pdm09, and 50% (95% CI, 41%-57%) against influenza B. We estimated that influenza vaccination prevented 7.1 million (95% CrI, 5.4 million-9.3 million) illnesses, 3.7 million (95% CrI, 2.8 million-4.9 million) medical visits, 109 000 (95% CrI, 39 000-231 000) hospitalizations, and 8000 (95% credible interval [CrI], 1100-21 000) deaths. Vaccination prevented 10% of expected hospitalizations overall and 41% among young children (6 months-4 years). CONCLUSIONS: Despite 38% VE, influenza vaccination reduced a substantial burden of influenza-associated illness, medical visits, hospitalizations, and deaths in the United States during the 2017-2018 season. Our results demonstrate the benefit of current influenza vaccination and the need for improved vaccines.

Ferdinands, J. M., M. Gaglani, E. T. Martin, D. Middleton, A. S. Monto, K. Murthy, F. P. Silveira, H. K. Talbot, R. Zimmerman, E. Alyanak, C. Strickland, S. Spencer and A. M. Fry (2019). “Prevention of Influenza Hospitalization among Adults in the United States, 2015-2016: Results from the Us Hospitalized Adult Influenza Vaccine Effectiveness Network (Haiven).” J Infect Dis 220(8): 1265-1275.

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BACKGROUND: Evidence establishing effectiveness of influenza vaccination for prevention of severe illness is limited. The US Hospitalized Adult Influenza Vaccine Effectiveness Network (HAIVEN) is a multiyear test-negative case-control study initiated in 2015-2016 to estimate effectiveness of vaccine in preventing influenza hospitalization among adults. METHODS: Adults aged >/=18 years admitted to 8 US hospitals with acute respiratory illness and testing positive for influenza by polymerase chain reaction were cases; those testing negative were controls. Vaccine effectiveness was estimated with logistic regression adjusting for age, comorbidities, and other confounding factors and stratified by frailty, 2-year vaccination history, and clinical presentation. RESULTS: We analyzed data from 236 cases and 1231 controls; mean age was 58 years. More than 90% of patients had >/=1 comorbidity elevating risk of influenza complications. Fifty percent of cases and 70% of controls were vaccinated. Vaccination was 51% (95% confidence interval [CI], 29%-65%) and 53% (95% CI, 11%-76%) effective in preventing hospitalization due to influenza A(H1N1)pdm09 and influenza B virus infection, respectively. Vaccine was protective for all age groups. CONCLUSIONS: During the 2015-2016 US influenza A(H1N1)pdm09-predominant season, we found that vaccination halved the risk of influenza-association hospitalization among adults, most of whom were at increased risk of serious influenza complications due to comorbidity or age.