Journal Club

In this feature, a panel of IDSA members identifies and critiques important new studies in the current literature that have a significant impact on the practice of infectious diseases medicine.

• PrEP in the United States, 2014-2016: Trends and Important Gaps
• The Drift in Molecular Testing for Influenza: Mutations Affecting Assay Performance
• Bactericidal Versus Bacteriostatic: What Makes the Biggest Difference in VRE Bacteremia?

Click here for the previous edition of Journal Club. For a review of other recent research in the infectious diseases literature, see “In the Literature,”  by Stanley Deresinski, MD, FIDSA, in each issue of Clinical Infectious Diseases.

PrEP in the United States, 2014-2016: Trends and Important Gaps

Reviewed by Lauren Richey, MD, MPH, FIDSA

In 2012, TDF/FTC (tenofovir disoproxil/emtricitabine) was approved as preexposure prophylaxis (PrEP) for HIV prevention in the United States and clinical guidelines for its use quickly followed. A recent study reported in the Morbidity and Mortality Weekly Report collected data on PrEP uptake in order to monitor trends. Data on prescriptions of antiretroviral drugs dispensed from 2014 to 2016 were extracted from a database representing 92 percent of all retail pharmacies and 60-80 percent of mail order prescriptions in the U.S. Patients with a diagnostic code for hepatitis B or HIV infection were excluded, as were people with prescriptions for TDF/FTC for less than 30 days, as the short duration was considered to be post-exposure prophylaxis. Data on age, race/ethnicity, sex, geographic area, and payer type were also collected.

The number of PrEP users annually increased 470 percent from 13,748 in 2014 to 78,360 in 2016. Males accounted for 95 percent of users. The majority were aged 25 to 34 (40 percent). The region with the highest percentage of PrEP users was the Western U.S. (30 percent) followed by the Southern U.S. (27 percent). Commercial insurance paid for 81 percent of TDF/FTC prescriptions, and Medicaid covered 12 percent of prescriptions. Only 42 percent of the PrEP users had race and ethnicity data available, and 69 percent of these users were white, 11 percent were black, and 13 percent were Hispanic.

Based on the presented data, approximately 7 percent of the estimated 1.1 million persons with indications for PrEP were prescribed PrEP in 2016. Women accounted for 5 percent of PrEP users, which represents about 2 percent of the estimated 176,000 heterosexual women for whom it is indicated, demonstrating a large gap. Additionally, among the estimated 1.1 million adults with PrEP indications 44 percent are black and 25 percent are Hispanic. This does not correlate with the percentages of these groups prescribed PrEP, indicating another gap. Focused public health interventions are needed to expand PrEP to women and racial and ethnic minorities in order to have a more equitable distribution of PrEP prescriptions. 

(Huang et al. Morb Mortal Wkly Rep. 2018;67(41):1147-1150.)

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The Drift in Molecular Testing for Influenza: Mutations Affecting Assay Performance

Reviewed by A. Krishna Rao, MD, MS

Influenza remains a major public health threat worldwide. Early diagnosis can improve outcomes, although diagnosis on clinical grounds alone is unreliable as symptoms vary substantially. Diagnosis by nucleic acid amplification technology (NAAT) is rapid, sensitive, and specific compared to immunoassays or traditional viral culture and is relied upon by many clinicians. However, concerns have been raised over the accuracy of NAAT-based testing given the tendency of influenza to undergo antigenic drift.

With the 2018–2019 influenza season upon us, a review article addressing this concern in the Journal of Clinical Microbiology is timely. For NAAT assays, the World Health Organization (WHO) recommends targeting the M gene region from bases 144–251 as it is highly conserved. However, in addition to affecting vaccine efficacy through mutations in the hemagglutinin, genetic drift has caused mutations even in the conserved WHO target region. Many clinical specimens from the Centers for Disease Control and Prevention (CDC) starting in 2012 had higher to undetectable polymerase chain reaction cycle threshold values. The mechanisms varied but included mismatches in the forward/reverse primers or the probes. Commercial assays also have decreased performance, documented as far back as 2009. While the details are proprietary, most commercial assays are thought to target the WHO region as well. Since 2014, of the eight commercially available NAAT tests for influenza, two saw sensitivities drop to 91–92 percent, while three saw sensitivities drop to only 51–81 percent!

The review suggests ways to move forward. Continuous monitoring of assay performance against commonly circulating strains is essential and is already recommended by the Food and Drug Administration (FDA). However, there is neither a requirement for a minimal performance level nor an obligation to demonstrate performance annually. In contrast to the European Union, U.S. regulations also impede manufacturers’ ability to continually adjust assays based on such surveillance. For now, clinicians should follow CDC guidance regarding rapid influenza tests and consider false negatives, especially in patients at higher risk for complications, such as children under 5, older adults, and the immunocompromised.

(Stellrecht. J Clin Microbiol. 2018;56(3):e01531-17.)

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Bactericidal Versus Bacteriostatic: What Makes the Biggest Difference in VRE Bacteremia?

Reviewed by Kelly Cawcutt, MD, MS

A recent prospective study in Critical Care Medicine aimed to assess all-cause mortality and rate of bloodstream clearance among adult patients in Taiwan enrolled from 2010 to 2015 with vancomycin-resistant enterococci (VRE) treated with daptomycin (bactericidal) versus linezolid (bacteriostatic). Patients were treated with conventional daptomycin (6 to 9 mg/kg actual body weight), high-dose daptomycin ( 9 mg/kg), or linezolid (600 mg intravenously every 12 hours). The initial blood culture bacterial load was determined, followed by blood cultures daily for the first four days and then twice per week for a total of two weeks unless the patient was discharged or therapy was discontinued prior to that. Blood cultures were assessed via traditional blood culture methodology and by a real-time quantitative polymerase chain reaction (PCR) detecting vanA (no vanB documented in the cohort).

In the analysis, 108 patients were included: 63 (58.3 percent) received conventional dose daptomycin, 15 (13.9 percent) received high-dose daptomycin, and 30 (27.8 percent) received linezolid. There was no statistically significant difference between survivors and non-survivors in the initial bacterial load. However, survivors had a statistically significant higher rate of early bacterial clearance (P = 0.02). There was no statistically significant difference in bacterial clearance among those with empiric versus definitive treatment, although clearance was statistically significant in difference among the antimicrobial treatment arms. Early bacterial clearance was faster with high-dose daptomycin (P < 0.001) and linezolid (P =0.043) as compared to conventional daptomycin, with no statistically significant difference between high-dose daptomycin and linezolid. A higher Pitt bacteremia score and slower clearance of bacteremia were independent predictors of mortality. PCR was more sensitive, and equally as specific, compared to traditional blood cultures.

The statistically significant differences in rate of bacterial clearance (and associated survivorship) between high-dose daptomycin and linezolid, compared to conventional daptomycin, suggest that higher doses of daptomycin or use of linezolid should be considered in VRE bloodstream infections. Larger studies are needed to validate the results and to determine clinical impact and optimal dosing.

(Chuang et al. Crit Care Med. 2018;46(10):1634–1642.)

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