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January 2017
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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.

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, in each issue of Clinical Infectious Diseases.

Integrase Inhibitor Regimen Superior in Antiretroviral-Naive Women with HIV?

Reviewed by Lauren Richey, MD, MPH

Worldwide, half of HIV infections occur in women, but women are routinely under-represented in clinical trials assessing antiretroviral therapy (ART). Current guidelines are derived from studies that include predominately men and do not address potential sex biases in efficacy, tolerability, and safety of different ART regimens.

The Women AntiretroViral Efficacy and Safety (WAVES) Study, a randomized, double-blind, phase 3 study recently published in Lancet HIV, included only women. The study assessed safety and efficacy of two ART regimens: an integrase inhibitor regimen (elvitegravir, cobicistat, emtricitabine, and tenofovir disoproxil fumarate) versus a protease inhibitor regimen (ritonavir boosted atazanavir, emtricitabine, and tenofovir disoproxil fumarate) in treatment-naive women living with HIV. Gilead Sciences provided funding and participated in data analysis and manuscript preparation.

In 11 different countries, 575 adult women were randomly assigned to either the integrase or protease regimen. Pregnancy, breast feeding, and creatinine clearance of less than 70 ml/minute at enrollment were exclusion criteria. Participants had an average age of 35 and were racially diverse. The primary endpoint, 48 week viral loads of less than 50 copies, was met by 87 percent of the women in the integrase inhibitor group and 81 percent of the women in the protease inhibitor group, meeting the predefined criteria for superiority. The difference was more striking in Russia for integrase inhibitor versus protease inhibitor regimen (89 percent versus 74 percent, respectively) and in the non-black subgroup (89 percent versus 78 percent, respectively). In the U.S., the results for the primary endpoint were much lower and slightly better for the protease inhibitor regimen versus the integrase inhibitor regimen (70 percent versus 68 percent, respectively). Discontinuation was higher in the protease inhibitor group (45 versus 29 women, respectively) driven predominately by adverse events (19 versus 5, respectively) related to rash and bilirubin-associated complications.

Geographically and ethnically diverse ART trials among women living with HIV are feasible. Previous trials among men showed protease inhibitor regimens to be non-inferior, with lower discontinuation rates for adverse events; this study shows integrase inhibitor regimens may be superior for women due to increased tolerability. Further studies to delineate sex-based differences in ART safety and efficacy are needed.

( Squires et al.Lancet HIV.2016 Sep;3(9):e410-20.)


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Early Removal of Central Venous Catheters and Mortality Impact in Children with Candidemia

Reviewed by Terri Stillwell, MD

Bloodstream infections due to Candida species remain a common health care-associated infection in hospitalized children, leading to significant morbidity and mortality. Oftentimes risk factors for candidemia are inherent to being severely ill and less likely modifiable. However, early central venous catheter (CVC) removal may be an impactful intervention. A recent Journal of the Pediatric Infectious Diseases Society article evaluated the association between CVC retention and 30-day all-cause inpatient mortality.

This retrospective, observational study assessed 285 pediatric patients (<19 years of age) with candidemia from 2000 through 2012. Patients had to have at least one CVC in place at the time the blood culture was drawn and survive for at least one day after the blood culture became positive with a CVC present. The number of days from the blood culture turning positive for yeast to the day of line removal was evaluated in relation to all-cause inpatient mortality within 30 days of the blood culture turning positive for yeast. Potential confounders also assessed included: parenteral nutrition, immunosuppressive medications, recent surgery, dialysis, intensive care unit (ICU) admission, and time to initiation of antifungal therapy. In the final analysis, a composite variable for clinical complexity, incorporating immunosuppressive medications, parenteral nutrition, and ICU admission, was used. Patients were followed until 30 days from positive culture result, hospital discharge, or death.

In this study, the most frequently isolated Candida species was C. albicans (50 percent), followed by C. parapsilosis (25 percent), with various other Candida species compromising the remainder of the cohort. Thirty-day all-cause inpatient mortality was 10.5 percent. CVC retention had a statistically significant association with an increased risk of death on any given day (OR: 3.59). This association remained significant even when adjusting for age and clinical complexity (OR: 2.50).

Despite limitations of potential confounders, this study provides additional data that early removal of CVCs impacts overall mortality in candidemic pediatric patients.

( Fisher et al.J Ped Infect Dis. 2016;5(4):403-408.)


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Procalcitonin as an Early Marker in Severe Community-Acquired Pneumonia

Reviewed by Kelly Cawcutt, MD

Patients with community-acquired pneumonia (CAP) who require invasive ventilation or vasopressor use have improved outcomes when admitted to the intensive care unit (ICU). Existing guidelines and predictive scoring systems, however, are fraught with inaccuracy in identifying those who need ICU admission. The authors of a recent article published in Chest evaluated the association of procalcitonin (PCT) as a marker for invasive respiratory support or vasopressor support (IRVS) and whether PCT added predictive value to existing pneumonia severity scoring systems.

The nested, prospective cohort study included adult patients hospitalized with CAP in Illinois and Tennessee between January 2010 and June 2012. All patients had sera stored and those with a remaining adequate serum volume for PCT measurement were included. The primary outcome was IRVS within 72 hours of hospital admission. Pneumonia severity scores assessed included the American Thoracic Society minor criteria for severe CAP, Pneumonia Severity Index, and SMART-COP. Each severity score was evaluated with and without PCT inclusion to assess whether PCT rendered a significant additive effect.

Of the 1,770 included patients, 115 (6.5 percent) required IRVS in the first 72 hours. The serum PCT was statistically significantly higher among patients with IRVS than those without. PCT was evaluated as a continuous variable, and between 0.05 ng/mL and 10 ng/mL, there was a 1 to 2 percent increase in risk of IRVS for every ng/mL the PCT increased. The IRVS risk plateaued at PCT concentrations > 10 ng/mL.

This association was then translated into an assessment of the additive value of PCT to the severity scores. PCT increased the area under the ROC curve for all scoring systems. Subgroup analysis between low and high risk groups based on the scoring systems continued to show improved predictive value in statistical models.

PCT alone may not render enough predictive value to determine clinical need for ICU admission based on IRVS. However, further studies incorporating PCT into augmented scoring systems may yield improved patient outcomes via increased accuracy in predicting severity of illness and resultant ICU admissions.

( Self et al.Chest. 2016 Oct;150(4):819-828.)


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Clostridium difficile Risk Increased by Antibiotic Use by Prior Inpatient Bed Occupants

Reviewed by Michael T. Melia, MD

Antibiotic use is associated with increased risk of Clostridium difficile infection (CDI) at individual patient, hospital, and regional levels. Within hospital rooms, a current roommate or prior occupant with CDI also increases CDI risk. Does antibiotic use by a hospital bed's previous occupant - regardless of whether that occupant had CDI - result in increased CDI risk?

A recent article in JAMA Internal Medicine describes a retrospective cohort study of adults who spent at least 48 hours in the bed they initially occupied upon admission to four hospitals in the New York City area. Patients were excluded if they had had CDI within 90 days prior to or 48 hours of admission. Only admissions in which the prior bed occupant had been in the bed for at least 24 hours were included; the duration of bed vacancy was less than one week. The primary exposure was receipt of at least one dose of antibiotics (other than those specifically used to treat CDI) by the prior bed occupant.

Of 100,615 pairs of sequentially-admitted patients, 576 subsequent patients developed CDI within 2-14 days of bed arrival. Subsequent patients diagnosed with CDI were more likely to have traditional CDI risk factors, as were their prior bed occupants. On multivariable analysis, receipt of antibiotics was the prior bed occupants' only characteristic associated with increased CDI risk for subsequent patients.

While traditional CDI risk factors related to the subsequent patient were the most important CDI risk factors in this study, receipt of antibiotics by the prior bed occupant was associated with a 22 percent relative increase in subsequent patients' CDI risk. Although there are limitations of retrospective, observational studies, and while the observed effect size was small, the findings highlight another possible environmental contributor to CDI risk, as well as another possible peril of antibiotic use.

( Freedberg et al.JAMA Intern Med. 2016 Dec 1;176(12):1801-1808.)


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For a review of other recent research in the infectious diseases literature, see "In the Literature," by Stanley Deresinski, MD, in each issue of Clinical Infectious Diseases:

December 15

  • Paradoxical Reactions in Meningitis due to Mycobacterium Tuberculosis
  • Early Source Control, Together With Antifungal Therapy, Is the Key to Management of Intra-abdominal Candida Infection

December 1

  • Vancomycin Minimum Inhibitory Concentration Revisited
  • How to Avoid Human Pentastomiasis: Cook Your Snake Well
  • Case Vignette: Conidiobolomycosis

November 15

  • Neurological Findings in Acute HIV Infection: Frequent, Mild, and Reversible
  • Why Antibiotic Allergy De-labeling Is Important
  • Case Vignette: Lagochilascariasis

November 1

  • Rifampin for Surgically Treated Staphylococcal Endocarditis?
  • Ceftaroline and Neutropenia
  • Case Vignette: Colonic Anisakiasis


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