Infectious Disease

Van Der Pol, B., K. B. Waites, L. Xiao, S. N. Taylor, A. Rao, M. Nye, S. Chavoustie, A. Ermel, C. Kaplan, D. Eisenberg, P. A. Chan, L. Mena, S. Pacheco, S. Krishnamurthy, R. Mohan, R. Bertuzis, C. L. McGowin, R. Arcenas and E. M. Marlowe (2020). “Mycoplasma genitalium Detection in Urogenital Specimens from Symptomatic and Asymptomatic Men and Women by Use of the cobas TV/MG Test.” J Clin Microbiol 58(6).

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Mycoplasma genitalium (MG) infections are a growing concern within the field of sexually transmitted infections. However, diagnostic assays for M. genitalium have been limited in the United States. As most infections are asymptomatic, individuals can unknowingly pass the infection on, and the prevalence is likely to be underestimated. Diagnosis of M. genitalium infection is recommended using a nucleic acid test. This multicenter study assessed the performance of the cobas Trichomonas vaginalis (TV)/MG assay (cobas) for the detection of M. genitalium, using 22,150 urogenital specimens from both symptomatic and asymptomatic men and women collected at geographically diverse sites across the United States. The performance was compared to a reference standard of three laboratory-developed tests (LDTs). The specificity of the cobas assay for M. genitalium ranged from 96.0% to 99.8% across symptomatic and asymptomatic men and women. The sensitivities in female vaginal swabs and urine samples were 96.6% (95% confidence interval [CI], 88.5 to 99.1%) and 86.4% (95% CI, 75.5 to 93.0%), respectively. The sensitivities in male urine and meatal swab samples were 100% (95% CI, 94.0 to 100%) and 85.0% (95% CI, 73.9 to 91.9%), respectively. This study demonstrated that the cobas assay was highly sensitive and specific in all relevant clinical samples for the detection of M. genitalium.

Tenforde, M. W., J. Chung, E. R. Smith, H. K. Talbot, C. H. Trabue, R. K. Zimmerman, F. P. Silveira, M. Gaglani, K. Murthy, A. S. Monto, E. T. Martin, H. Q. McLean, E. A. Belongia, L. A. Jackson, M. L. Jackson, J. M. Ferdinands, B. Flannery and M. M. Patel (2020). “Influenza vaccine effectiveness in inpatient and outpatient settings in the United States, 2015 – 2018.” Clin Infect Dis Apr 9. pii: ciaa407. [Epub ahead of print].

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BACKGROUND: Demonstration of influenza vaccine effectiveness (VE) against hospitalization for severe illness in addition to milder outpatient illness may strengthen vaccination messaging and improve suboptimal uptake in the U.S. Our objective was to compare patient characteristics and VE between U.S. inpatient and outpatient VE networks. METHODS: We tested adults >/=18-years with acute respiratory illness (ARI) for influenza within two VE networks, one outpatient- and the other hospital-based, from 2015-2018. We compared age, sex, and chronic high-risk conditions between populations. The test-negative design was used to compare vaccination odds in influenza-positive cases versus influenza-negative controls. We estimated VE using logistic regression adjusting for site, age, sex, race/ethnicity, peak influenza activity, time-to-testing from symptom-onset, season (overall VE) and underlying conditions. VE differences (DeltaVE) were assessed with 95% confidence intervals (CI) determined through bootstrapping with significance defined as excluding the null. RESULTS: The VE networks enrolled 14,573 (4144 influenza-positive) outpatients and 6769 (1452 influenza-positive) inpatients. Inpatients were older (median 62-years vs. 49-years) and had more high-risk conditions (median 4 vs. 1). Overall influenza VE across seasons was 31% (95%CI:26%-37%) among outpatients and 36% (27%-44%) among inpatients. Strain-specific VE among outpatients versus inpatients was 37% (25%-47%) vs. 53% (37%-64%) against H1N1pdm09, 19% (9%-27%) vs. 23% (8%-35%) against H3N2, and 46% (38%-53%) vs. 46% (31%-58%) against B-viruses. DeltaVE was not significant for any comparison across all sites. CONCLUSIONS: Inpatients and outpatients with ARI represent distinct populations. Despite comparatively poor health status among inpatients, influenza vaccination was effective in preventing hospitalizations associated with influenza.

Shealy, S. C., M. M. Brigmon, J. A. Justo, P. B. Bookstaver, J. Kohn and M. N. Al-Hasan (2020). “Impact of Reappraisal of Fluoroquinolone Minimum Inhibitory Concentration Susceptibility Breakpoints in Gram-Negative Bloodstream Isolates.” Antibiotics (Basel) 9(4).

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The Clinical Laboratory Standards Institute lowered the fluoroquinolone minimum inhibitory concentration (MIC) susceptibility breakpoints for Enterobacteriaceae and glucose non-fermenting Gram-negative bacilli in January 2019. This retrospective cohort study describes the impact of this reappraisal on ciprofloxacin susceptibility overall and in patients with risk factors for antimicrobial resistance. Gram-negative bloodstream isolates collected from hospitalized adults at Prisma Health-Midlands hospitals in South Carolina, USA, from January 2010 to December 2014 were included. Matched pairs mean difference (MD) with 95% confidence intervals (CI) were calculated to examine the change in ciprofloxacin susceptibility after MIC breakpoint reappraisal. Susceptibility of Enterobacteriaceae to ciprofloxacin declined by 5.2% (95% CI: -6.6, -3.8; p < 0.001) after reappraisal. The largest impact was demonstrated among Pseudomonas aeruginosa bloodstream isolates (MD -7.8, 95% CI: -14.6, -1.1; p = 0.02) despite more conservative revision in ciprofloxacin MIC breakpoints. Among antimicrobial resistance risk factors, fluoroquinolone exposure within the previous 90 days was associated with the largest change in ciprofloxacin susceptibility (MD -9.3, 95% CI: -16.1, -2.6; p = 0.007). Reappraisal of fluoroquinolone MIC breakpoints has a variable impact on the susceptibility of bloodstream isolates by microbiology and patient population. Healthcare systems should be vigilant to systematically adopt this updated recommendation in order to optimize antimicrobial therapy in patients with bloodstream and other serious infections.

Ordonez, A. A., H. Wang, G. Magombedze, C. A. Ruiz-Bedoya, S. Srivastava, A. Chen, E. W. Tucker, M. E. Urbanowski, L. Pieterse, E. Fabian Cardozo, M. A. Lodge, M. R. Shah, D. P. Holt, W. B. Mathews, R. F. Dannals, J. V. S. Gobburu, C. A. Peloquin, S. P. Rowe, T. Gumbo, V. D. Ivaturi and S. K. Jain (2020). “Dynamic imaging in patients with tuberculosis reveals heterogeneous drug exposures in pulmonary lesions.” Natture Medicine Feb 17. [Epub ahead of print].

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Tuberculosis (TB) is the leading cause of death from a single infectious agent, requiring at least 6 months of multidrug treatment to achieve cure. However, the lack of reliable data on antimicrobial pharmacokinetics (PK) at infection sites hinders efforts to optimize antimicrobial dosing and shorten TB treatments. In this study, we applied a new tool to perform unbiased, noninvasive and multicompartment measurements of antimicrobial concentration-time profiles in humans. Newly identified patients with rifampin-susceptible pulmonary TB were enrolled in a first-in-human study using dynamic [(11)C]rifampin (administered as a microdose) positron emission tomography (PET) and computed tomography (CT). [(11)C]rifampin PET-CT was safe and demonstrated spatially compartmentalized rifampin exposures in pathologically distinct TB lesions within the same patients, with low cavity wall rifampin exposures. Repeat PET-CT measurements demonstrated independent temporal evolution of rifampin exposure trajectories in different lesions within the same patients. Similar findings were recapitulated by PET-CT in experimentally infected rabbits with cavitary TB and confirmed using postmortem mass spectrometry. Integrated modeling of the PET-captured concentration-time profiles in hollow-fiber bacterial kill curve experiments provided estimates on the rifampin dosing required to achieve cure in 4 months. These data, capturing the spatial and temporal heterogeneity of intralesional drug PK, have major implications for antimicrobial drug development.

Srivastava, S., D. Deshpande, G. Magombedze, J. van Zyl, K. Cirrincione, K. Martin, P. Bendet, A. Berg, D. Hanna, K. Romero, D. Hermann and T. Gumbo (2020). “Duration of pretomanid/moxifloxacin/pyrazinamide therapy compared with standard therapy based on time-to-extinction mathematics.” J Antimicrob Chemother 75(2): 392-399.

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OBJECTIVES: Animal models have suggested that the combination of pretomanid with pyrazinamide and moxifloxacin (PaMZ) may shorten TB therapy duration to 3-4 months. Here, we tested that in the hollow-fibre system model of TB (HFS-TB). METHODS: A series of HFS-TB experiments were performed to compare the kill rates of the PaMZ regimen with the standard three-drug combination therapy. HFS-TB experiments were performed with bacilli in log-phase growth treated for 28 days, intracellular bacilli treated daily for 28 days and semi-dormant Mycobacterium tuberculosis treated with daily therapy for 56 days for sterilizing effect. Next, time-to-extinction equations were employed, followed by morphism transformation and Latin hypercube sampling, to determine the proportion of patients who achieved a time to extinction of 3, 4 or 6 months with each regimen. RESULTS: Using linear regression, the HFS-TB sterilizing effect rates of the PaMZ regimen versus the standard-therapy regimen during the 56 days were 0.18 (95% credible interval=0.13-0.23) versus 0.15 (95% credible interval=0.08-0.21) log10 cfu/mL/day, compared with 0.16 (95% credible interval=0.13-0.18) versus 0.11 (95% credible interval=0.09-0.13) log10 cfu/mL/day in the Phase II clinical trial, respectively. Using time-to-extinction and Latin hypercube sampling modelling, the expected percentages of patients in which the PaMZ regimen would achieve sterilization were 40.37% (95% credible interval=39.1-41.34) and 72.30% (95% credible interval=71.41-73.17) at 3 and 4 months duration of therapy, respectively, versus 93.67% (95% credible interval=93.18-94.13) at 6 months for standard therapy. CONCLUSIONS: The kill rates of the PaMZ regimen were predicted to be insufficient to achieve cure in less than 6 months in most patients.