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May 2016
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. Solithromycin Compared to Moxifloxacin for the Treatment of Community-Acquired Bacterial Pneumonia 
Reviewed by Zeina Kanafani, MD, MS 
Community-acquired bacterial pneumonia (CABP) is a common and potentially serious infection. Treatment is complicated by the emergence of S. pneumoniae resistance and the difficulty in establishing a microbiological diagnosis in atypical infections. Solithromycin, a fourth-generation macrolide antibiotic under clinical development with activity against extracellular and intracellular organisms, including macrolide-resistant S. pneumoniae and M. pneumoniae, may offer a new treatment option.
The SOLITAIRE-ORAL trial, described in a recent Lancet Infectious Diseases article, was a multi-center, randomized, double-blinded, non-inferiority trial of oral solithromycin (800 mg on day 1, 400 mg on days 2-5, and placebo on days 6-7) versus oral moxifloxacin (400 mg on days 1-7) in patients with CABP. A total of 426 patients were randomized to receive solithromycin and 434 to moxifloxacin. There were no differences in the baseline characteristics between patients in the two study arms. S. pneumoniae and H. influenzae were the most frequently isolated organisms (23 percent and 16 percent, respectively). The prevalence of macrolide resistant S. pneumoniae was low in both arms. 
Early clinical response in the intention-to-treat population was achieved in 78.2 percent of patients receiving solithromycin and in 77.9 percent of those receiving moxifloxacin, which satisfied the non-inferiority assumption of the trial. In the subgroup analysis, patients with Pneumonia Outcomes Research Team (PORT) risk class III and IV, older than 65 years, and those with chronic obstructive pulmonary disease (COPD) or asthma responded better to solithromycin compared to moxifloxacin, but these differences did not reach statistical significance. Treatment failure and mortality rates were similar. In the microbiological intention-to-treat population, early clinical response was lower in the solithromycin vs. moxifloxacin group, although the difference was not significant, and the non-inferiority margin of 15 percent was still met. There was no difference in the proportion of patients developing treatment-emergent adverse events. The main limitation of the study was the relatively short follow-up period (30 days). 
The investigators concluded that solithromycin, which must still meet regulatory approval, is a promising treatment option in patients with CABP. 
Low Yield of Blood Cultures Performed in Response to Fever/Leukocytosis in Inpatients
Reviewed by Christopher J. Graber, MD, MPH, FIDSA

The cultural norm of inpatient care frequently dictates that an evaluation for fever in a hospitalized patient should automatically prompt a non-evidence-based “full-fever workup” consisting of blood cultures, urinalysis with urine culture, sputum culture, and/or a chest x-ray. This “shotgun” approach is often unnecessary and can drive potentially inappropriate antibiotic use. A recent study published in the Journal of Hospital Medicine specifically examined its most common component, blood cultures, with regard to indications and yield. 
The authors reviewed 576 blood culture orders from 363 patients hospitalized on general medicine or cardiology services over a seven-month period at a Veterans Administration teaching hospital where an indication had to be listed as a part of the order. The rate of “true” blood culture positivity was 3.6 percent; the false-positive rate was 2.3 percent (most typically from coagulase-negative staphylococci). The most common listed indications for blood cultures were fever alone (25.6 percent), fever with an additional indication (22.6 percent), follow-up of positive blood cultures (11.3 percent), fever and leukocytosis (9.4 percent), and leukocytosis alone (9.4 percent), but the only indication associated with true positivity was follow-up of previous positive culture (likelihood ratio [LR] 3.4). Patients already on antibiotics at the time of the culture rarely had true positivity (1.4 percent, LR 0.4), and the only working diagnosis associated with true culture positivity was bacteremia/endocarditis (LR 3.7). 
This study highlights the low utility of the routine “culture if spikes” approach to the care of the febrile hospitalized patient without taking additional clinical information into context, particularly if that patient is already being treated with antibiotic therapy and the culture is not being done to follow up on a prior positive. Attention to clinician behavior in this arena could be a valuable target for intervention by antimicrobial stewardship programs.
Body Fat Distribution Changes with Modern ART
Reviewed by Brian R. Wood, MD
Early antiretrovirals (ARVs) notoriously caused dystrophic changes in body fat, including lipoatrophy (primarily a consequence of mitochondrial toxicity from thymidine analogue nucleoside reverse transcriptase inhibitors) and lipohypertrophy, often attributed to protease inhibitors (PIs). What happens to body fat with modern ARVs? Do integrase inhibitors, which now dominate recommended first-line regimens, cause body fat alterations? 
In a recent open-label, randomized study, treatment-naïve HIV-infected adults with no known cardiovascular disease, diabetes, use of lipid-lowering medications, or uncontrolled thyroid disease were randomized to tenofovir DF-emtricitabine plus either raltegravir, ritonavir-boosted atazanavir, or ritonavir-boosted darunavir. Investigators monitored peripheral and central body fat using abdominal CT and whole-body dual-energy absorptiometry (DXA) scans (at baseline and 96 weeks). 
The 328 persons randomized were predominantly male (90 percent), white non-Hispanic (44 percent), with a median age of 36, CD4 count of 349 cells/ml, and body mass index (BMI) of 25 mg/kg2. Participants experienced similar increases in BMI across study arms (3.8 to 4.7 percent). Significant fat gains were detected in all compartments: limbs (13.4 percent), subcutaneous (19.9 percent), visceral and abdominal (25.8 percent), trunk (18.0 percent), and lean mass (1.8 percent); there was no statistically significant difference in fat gains between the PI groups or comparing raltegravir to the combined PI arms. Greater fat gains occurred in those with higher baseline HIV RNA or IL-6 level.
Notably, the majority of individuals, even those with a baseline BMI in the normal to overweight range, experienced significant fat gains, especially centrally. Raltegravir led to similar fat distribution changes as modern boosted PIs, which challenges the common belief that integrase inhibitors are better than PIs in this regard and suggests that the changes are primarily a result of HIV control and not an ARV class effect.
As the authors note, the long-term clinical consequences of such fat increases, which may surpass “return-to-health” levels, are not well defined, though other recent research suggests that changes in body fat composition with antiretroviral therapy (ART) contribute to elevated rates of hypertension. Anecdotally, I have seen many individuals who initiate ART and, even though wasting was not readily apparent at baseline, gain significant weight over subsequent months, leading to new hypertension, diabetes, or other evidence of metabolic syndrome.
Discussion regarding diet, exercise, potential weight gain, and prevention of complications of excess weight gain should be a part of routine ART counseling.
(McComsey et al. Clin Infect Dis. 2016 Apr 1;62(7):853-62.
Another Opportunity to Vaccinate: Flu Vaccine in the Hospitalized Surgical Patient
Reviewed by Manie Beheshti, MD

Less than half of the U.S. population is vaccinated against influenza annually. Aiming to capitalize on opportunity, the Advisory Committee on Immunization Practices (ACIP) recommends that all eligible hospitalized patients receive the influenza vaccine prior to discharge. This practice is a measured quality metric by the Joint Commission and the Centers for Medicare and Medicaid Services. However, possibly due to lack of safety data evaluating influenza vaccination in this setting, providers may be hesitant to vaccinate hospitalized patients due to concerns about vaccine reactions affecting post-operative care. 
Researchers at Kaiser Permanente Southern California aimed to address this issue in a recent publication in the Annals of Internal Medicine. Spanning three influenza seasons between 2010 and 2013 across 14 hospitals, their study encompassed over 42,000 surgeries in the adjusted analysis. Among these surgical patients, 6,420 were vaccinated during hospitalization. Vaccination was not associated with an increased risk of readmission, emergency department visits, post-discharge fever (defined as a temperature ≥38.0°C), or the need for clinical evaluation for an infection. An increased risk for outpatient visits was detected, but this was marginal (5 percent). Of interest, 34 percent of the study patients were unvaccinated for the duration of influenza season, leaving a large vaccination gap in a population that had multiple health care encounters.
In sum, this data lends support to the practice of vaccinating hospitalized surgical patients, as there was no strong evidence for any increased risk with vaccination in this cohort. Given the missed vaccination opportunities in more than one-third of the study population and the lack of vaccination in such a large portion of the U.S. population, increasing vaccine efforts in this cohort could help reduce a portion of the vulnerable population.

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:

May 15
  • Cerebrospinal Fluid Galactomannan Testing for the Diagnosis of Cerebral Aspergillosis
  • Recurrent Diarrhea After Clostridium difficile Infection (CDI): Not Always CDI Even if Polymerase Chain Reaction Is Positive
May 1
  • Safety of a Single Dose of Gentamicin in Sepsis
  • Bacteriophage and Biofilm

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