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March 2014
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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.

    An Unexpected Difference Between ATV/r and EFV in Women Starting HIV Therapy
    Reviewed by Manie Beheshti, MD

    Women account for approximately one-quarter of newly diagnosed HIV-1 infections in the U.S. However, data addressing the most appropriate initial therapy for these patients is lacking. The AIDS Clinical Trials Group 5202 study team reported findings addressing this question in a recent issue of Clinical Infectious Diseases.

    The researchers evaluated the differences (time to virologic failure, safety, and tolerability) of various modern antiretroviral regimens by sex. As 322 (17 percent) of the 1,857 total patients were female, analysis of a uniquely large sample size of women was possible. Participants were randomized to receive a nucleoside reverse transcriptase inhibitor (abacavir/lamivudine [ABC/3TC] or tenofovir/emtricitabine [TDF/FTC]) with either atazanavir plus ritonavir (ATV/r) or efavirenz (EFV). Baseline characteristics were largely similar with the exception of women being more likely to have lower creatinine clearance, lower baseline HIV RNA, and be of black race.

    Overall, all regimens had similar virologic efficacy. However, when evaluated by sex, important differences were noted:
      • Among women, risk of virologic failure was higher in those taking ATV/r compared to EFV [with ABV/3TC: HR   2.55 (95 percent CI, 1.20-5.41); with TDF/FTC: HR 2.16 (95 percent CI, 0.97-4.80)]. No such difference was noted among men.

      • When comparing men to women in multivariate models, women taking ATV/r had a higher risk of virologic failure [with ABC/3TC: HR 1.72 (95 percent CI, 0.99-2.99); with TDF/FTC: HR 2.36 (95 percent CI, 1.30-4.26)].
      Further analysis evaluated safety and tolerability. Although there was a trend towards higher rates of gastrointestinal adverse events in women compared to men on ABC/3TC/ATV/r, the authors reported no significant difference comparing ATV/r to EFV between men and women.

      With a uniquely large sample size, this study marks the first randomized trial to report a higher risk of virologic failure in women initiating HIV therapy with a regimen containing ATV/r as opposed to one with EFV. Prior trials addressing similar issues may not be as relevant due to their use of regimens no longer preferred in current guidelines. This latest study adds important data that helps clarify gender-based differences with common first-line regimens.

      (Smith et al. Clin Infect Dis. 2014;58(4):555-563.)


      De-escalation of Empirical Therapy and Lower Mortality in Severe Sepsis Patients
      Reviewed by Zeina A. Kanafani, MD, MS

      A recent observational study in Intensive Care Medicine examined whether de-escalation of broad-spectrum antibiotics affects outcome in patients with severe infections.

      Patients admitted to the ICU at a Spanish university hospital with severe sepsis or septic shock were enrolled prospectively. All initially received empirical broad-spectrum antibiotics. Adequate empirical therapy was defined as the use of at least one antimicrobial agent with activity against the offending organism within 24 hours of ICU admission. After culture results became available, empirical therapy was either left unchanged, escalated, or de-escalated.

      De-escalation was classified into four groups: Group I consisted of withdrawal of one antimicrobial; Group II, withdrawal of two antimicrobials; Group III, a switch to a narrower spectrum antimicrobial; and Group IV, withdrawal of at least one antimicrobial and a switch to a narrower spectrum agent.

      Of 628 patients included, 403 (87.6 percent) received adequate empirical therapy. De-escalation was performed in 219 patients (34.9 percent), distributed across the four strategies: Group I (n=88), Group II (n=20), Group III (n=80), and Group IV (n=31). De-escalation was more often used in medical compared to surgical patients, while escalation was more often employed in patients with high Sequential Organ Failure Assessment (SOFA) scores. Hospital mortality was significantly higher in the escalation group (42.9 percent) compared to the “no change” (32.6 percent) and de-escalation groups (27.4 percent) (p=0.006).

      Mortality at 90 days, evaluated using multivariable analysis, revealed that septic shock, inadequate empirical antimicrobial therapy, and SOFA score on the day of culture results were associated with higher mortality, whereas de-escalation was associated with significantly lower mortality (OR=0.55; 95 percent CI 0.34-0.87; p=0.011). When the analysis was restricted to patients who received adequate empirical therapy (n=403), de-escalation remained an independent factor associated with a reduced risk of death (OR= 0.57; 95 percent CI 0.38-0.94; p=0.019).

      Notwithstanding its obvious limitations, most importantly the lack of randomized intervention, this study provides some evidence that antimicrobial de-escalation is not only safe, but may also be associated with lower mortality in patients with serious infections.

      (Garnacho-Montero et al. Intensive Care Med. 2014;40:32-40.)

       

      Snapshot of Antimicrobial Usage in U.S. Hospitals: Opportunities for Improvement
      Reviewed by Christopher J. Graber, MD, MPH, FIDSA

      A recent article in the Morbidity and Mortality Weekly Report used a variety of data sources to provide a valuable snapshot of antimicrobial usage in United States hospitals that shows ample opportunities to improve antimicrobial prescribing and reduce Clostridium difficile  infection (CDI). Key highlights include:
      • A review of a proprietary database that aggregates claims data from 323 U.S. hospitals determined that in 2010, 55.7 percent of inpatients received antibiotics during their hospitalization and that 29.8 percent received broad-spectrum therapy.
      • A point prevalence survey of 183 hospitals associated with the Emerging Infections Program (EIP) determined that on any certain day in 2011, 37.1 percent of patients were receiving at least one antibiotic to treat active infection, half of which were for either lower respiratory tract infection, urinary tract infection (UTI), or presumed resistant Gram-positive infections. 
      • A review of 296 records of patients admitted to 36 EIP hospitals in 2011 with two specific conditions, either urinary tract infection present on admission without indwelling catheter (n=111), or patients treated with intravenous vancomycin (n=185), determined that antibiotic usage could be improved in 37.2 percent of episodes. The most common opportunities for improvement in UTI prescribing were ordering of urine cultures prior to treatment (not done in 16 percent of episodes) and documentation that UTI symptoms were actually present (not present in 21 percent). The most common opportunity for improvement in vancomycin prescribing was that in 22 percent of episodes, patients who did not have presumed skin-soft tissue infection received at least three days of therapy despite no diagnostic cultures positive for Gram-positive bacteria.
      • A review of antibiotic use data reported to the National Healthcare Safety Network from October 2012 to June 2013 determined that on 26 combined medical-surgical wards at 19 hospitals, there was up to eight-fold variation in fluoroquinolone usage, six-fold variation in antipseudomonal agents, and three-fold variation in vancomycin and broad-spectrum agents in general.
      Subsequent modeling using data from two academic centers and CDI surveillance data from EIP determined an adjusted relative risk of CDI of 2.9 for patients exposed to broad-spectrum antibiotics within the prior 180 days and that a 30 percent reduction in broad-spectrum antibiotic usage would result in a 26 percent reduction in CDI.

      Overall, these data support that there is tremendous potential for antimicrobial stewardship to reduce inappropriate broad-spectrum antimicrobial usage and that such reductions can be associated with tangible benefit, at least with respect to CDI.

      (Fridkin et al. MMWR. March 7, 2014 / 63(09);194-200.)


      An Emerging Disease: Microsporidiosis Acquired Through Solid Organ Transplantation
      Reviewed by Ed Dominguez, MD, FIDSA

      Microsporidia comprise a group of organisms closely related to fungi. Seroprevalence of 10 percent is present in healthy blood donors; rates exceeding 30 percent are seen in animal handlers. Despite such high exposure, clinical disease is uncommon, and transmission via organ donation has not been previously reported. However, in the Feb. 18 issue of Annals of Internal Medicine, researchers described donor transmission of Encephalitozoon cuniculi, a species of microsporidia, to three recipients.

      In the fall of 2011, a young woman who recently immigrated from Mexico suffered a catastrophic subarachnoid hemorrhage. She donated both of her kidneys and lungs, which were transplanted into three recipients. Seven weeks after the transplant, the bilateral lung recipient developed a febrile illness; the left kidney recipient became febrile at week 10, and the right recipient at week 12. The lung and left kidney recipients were found to have serology positive for acute brucellosis, for which they were treated. Neither the donor nor the right kidney recipient were positive, however. The left kidney recipient died at week 21.

      Autopsy studies of the renal allograft by the Centers for Disease Control and Prevention identified Encephalitozoon cuniculi genotype III. The other recipients were then evaluated and found to have serologic and histologic evidence of the same microsporidium. Look back serologic testing of donor serum revealed an antibody titer of 1:4,096 to Encephalitozoon. Although the lung and right kidney recipient received anti-microsporidial therapy, only the kidney recipient survived. The lung recipient expired from an unrelated malignancy.

      Although microsporidial infection has been reported in solid organ and bone marrow transplant recipients, donor transmission was not evaluated or implicated in those patients. Given the high seroprevalence in the general population, however, it should be considered in febrile organ recipients from a common donor when more common pathogens have been excluded and response to usual antimicrobial therapy has been unsuccessful.

      (Hocevar et al. Ann Intern Med. 2014;160(4):213-220-220.)


      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:

      March 15

      • Enhanced Bacterial Fitness in Association With Antibiotic Resistance
      • The Microbiology of Drowning

      March 1

      • Severe Sepsis and Septic Shock and Mycobacterium tuberculosis Infection
      • Stopping Empiric Anti–Methicillin-Resistant Staphylococcus aureus Antibiotics in Patients With Pneumonia



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