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September 2011
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IDSA Journal Club
September 2011

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.

Outcomes of C. difficile-Associated Diarrhea in Patients using Concomitant Antibiotics
Reviewed by Khalil Ghanem, MD, PhD

A secondary analysis from two trials demonstrated that concomitant antibiotic use during or shortly after Clostridium difficile-associated diarrhea (CDAD) treatment resulted in lower cure rates and longer duration of symptoms, and suggested that participants treated with fidaxomicin had fewer recurrences than those treated with vancomycin. The findings are published in the Sept. 1 issue of Clinical Infectious Diseases.

Thirty percent (N=275) of participants enrolled in the two randomized controlled trials (N=999), which compared efficacy of 10 days of oral fidaxomicin (200 mg orally twice daily) with oral vancomycin (125 mg orally four times daily) in the treatment of CDAD, received concomitant antibiotics (CA). Patients were assessed and compared to participants who did not receive CA. The investigators’ goal was to describe the impact of CA use during or shortly after CDAD therapy and compare cure rates in participants receiving oral vancomycin vs. fidaxomicin. Participants were followed up for 40 days after CDAD treatment completion.

Overall, clinical cure was achieved in 93 percent of participants who did not receive CA vs. 84 percent of those who did. Median time to resolution of diarrhea was longer in participants who received CA (97 hours vs. 54 hours). There was a statistical trend for increased probability of recurrence among patients who received CA (23 percent vs. 17.6 percent). Among participants who received CA, the cure rate for fidaxomicin was 90 percent vs. 79.4 percent for vancomicin. 

This study provides clinicians with useful estimates of recurrence risk, cure rates, and duration of symptoms in CDAD, particularly among persons who use CA during CDAD therapy, a not uncommon occurrence among hospitalized patients. Clinicians must weigh costs and benefits when deciding to use fidaxomicin over vancomycin. The question of extending the duration of CDAD therapy in participants who were receiving CA was not addressed in the study.

(Mullane et al. Clin Inf Dis. 2011;53(5):440-7.)    

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Promising Early Look at a Possible Broad-Spectrum Antiviral
Reviewed by Jason Weinberg, MD

A novel class of compounds that induces cell death only in virus-infected cells may one day serve as a broad-spectrum antiviral strategy, according to an article published online on July 27 in PLoS One.

To specifically target cells that are infected by a virus, the investigators took advantage of a naturally occurring intracellular immune process that recognizes double-stranded RNA, a product produced in virus-infected cells during the course of virus replication.  The investigators synthesized compounds that coupled domains that recognize double-stranded RNA to domains capable of triggering apoptotic cell death. The compounds were nontoxic and effective in a variety of cell types.

 In a series of in vitro experiments, the compounds induced the death of virus-infected cells, thereby limiting ongoing viral replication and preserving the viability of uninfected cells. This strategy was successful when cells were infected with rhinovirus, influenza, and several other RNA and DNA viruses. No obvious toxicities were documented when mice were treated with the compounds, and treatment of mice infected with H1N1 influenza decreased viral replication and increased survival.

Established and emerging viruses continue to cause substantial disease. There have been important successes with vaccines to prevent virus infection and associated disease, but the repertoire of effective antiviral drugs is still very small. The successes with the novel antiviral strategy described in this report were confined to the laboratory, but the strategy is very appealing. The compounds used by the investigators are very specific, because double-stranded RNA is produced only in virus-infected cells. They are also broad-spectrum, because double-stranded RNA is produced during the replication of both RNA and DNA viruses. It will be exciting to see if compounds such as these move beyond the proof-of-concept stage and into clinical trials to provide a much-needed new class of antiviral therapeutics.

(Rider et al. PLoS One 2011; 6(7):e22572.)

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Daily Azithromycin for the Prevention of COPD Exacerbations
Reviewed by Kathryn E. Stephenson

Exacerbations of chronic obstructive pulmonary disease (COPD) result in recurrent courses of antibiotics, steroids, and hospitalizations, and are associated with an increased risk of death. In the Aug. 25 issue of the New England Journal of Medicine, investigators tested whether daily azithromycin, when added to the usual care of patients, would decrease the frequency of these exacerbations compared to a placebo.

In a large, multi-center clinical trial, 1,142 patients were randomized to receive azithromycin at 250 mg by mouth daily or an identical placebo for one year. The primary outcome of the study was the time to the first acute exacerbation of COPD, defined as the increase or new onset of cough, sputum, or respiratory difficulty with the initiation of antibiotics or steroids. The authors also investigated changes in quality of life, nasopharyngeal bacterial colonization, and hearing.

An intention-to-treat analysis showed that the risk of acute exacerbations of COPD was reduced among subjects receiving azithromycin (P<0.001), and that the median time to the first exacerbation was 266 days in the azithromycin arm compared to 174 days in the placebo arm (P<0.001). These differences were significant even when controlled for demographics, behaviors, and pulmonary function. The authors calculated that the number needed to treat to prevent one acute exacerbation of COPD was 2.86.

Though there were no significant differences in the frequency of serious adverse events, the authors did report that subjects treated with azithromycin had more pronounced hearing decrements than those who received placebo. In addition, subjects who became colonized with respiratory pathogens during the study were more likely to have macrolide-resistant organisms if they had received azithromycin as opposed to placebo.

In sum, this large, randomized clinical trial demonstrates that azithromycin can be a valuable tool when treating patients suffering from recurrent COPD exacerbations.

(Albert et al. New Eng J Med. 2011;365 (8): 689-97.)

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Absence of Exposure to Varicella Zoster Virus and Risk of Herpes Zoster
Reviewed by George R. Thompson III, MD

Control of varicella zoster virus  (VZV) reactivation and the avoidance of herpes zoster is largely dependent upon effective cell-mediated immunity. However, the relationship between the epidemiology of varicella and zoster remains unclear. Two primary hypotheses have been proposed:  (1) exogenous boosting from exposure to children with varicella, and (2) endogenous boosting from subclinical reactivation of latent VZV within the sensory ganglia. A study published in the Sept. 1 issue of Clinical Infectious Diseases offers some interesting findings on this issue.

Researchers conducted a national, multicenter, observational, comparative study of exposed versus nonexposed subjects. The nonexposed group consisted of members of Roman Catholic monastic orders (monks and nuns), an isolated population in France with little exposure to children. Those who were members for <2 years or had previous zoster were excluded. The exposed group was comprised of members of the general population and matched to members of the monastic order group.

The frequency of zoster in the monastic order group (16.2 percent) did not significantly differ from the frequency in the general population group (15.1 percent) (P=0.27). Additionally, the age of onset was 54.8 years in the monastic order group and 48.6 years in the general population (P=0.06).

The authors’ results are intriguing and challenge prior assumptions that the absence of contact with varicella causes an increased risk of zoster. Additionally, their findings support the assertion that childhood vaccine programs against VZV will not lead to an increasing number of cases of zoster in young adults.

(Gaillat et al. Clin Infect Dis. 2011;53(5):405-410.)

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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:

September 15

  • Prolonged Incubation for Detection of Propionibacterium acnes in Periprosthetic Joint Infections
  • HCV and Ribavirin Resistance—It’s the Host, Not the Virus

September 1

  • Aspergillosis—Avoiding a Return Visit
  • Old World Cutaneous Leishmaiasis—not Always Just Cutaneous
  • Cytopenias and Parvovirus Infection

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