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.

• Reduction in Hospital Stay and Adverse Events in Community-Acquired Pneumonia via a Simple Intervention
• Trial Closes Book on Drotrecogin Alfa for Severe Sepsis
• Is High-Dose, Extended-Interval Colistin Dosing Safe and Effective?
• Azithromycin and Risk of Cardiac Death: Another Reason to Curb Unnecessary Antibiotic Use

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.

Reduction in Hospital Stay and Adverse Events in Community-Acquired Pneumonia via a Simple Intervention
Reviewed by Christopher J. Graber, MD, MPH

A recent article published online in Archives of Internal Medicine describes a randomized controlled trial in which a three-step intervention for patients hospitalized with community-acquired pneumonia reduced hospital stay and medication-related adverse events without an effect on readmission rates and patient satisfaction.

The investigators randomized 401 adults admitted to two hospitals (one 900-bed university public hospital and one 300-bed private hospital) in Barcelona, Spain, to either receive usual care or to have their treating physicians follow a three-step critical pathway consisting of early mobilization, use of objective criteria for switching to oral antibiotic therapy, and use of predefined criteria for hospital discharge. A printed checklist detailing this pathway was placed in the charts of patients assigned to the intervention arm, and each participating attending physician was only assigned patients from a single arm of the study. Patients were seen daily by their attending physicians and by study investigators.

Patients in the intervention arm had a median length of stay of 3.9 days, versus 6.0 days in the usual care arm (p<.001); a similar decrease in duration of intravenous antibiotic therapy was also observed (2 versus 4 days, p<.001). Medication-related adverse events were also less frequently seen in the intervention arm (4.5 percent vs. 15.9 percent, p<.001). Readmission within 30 days and patient satisfaction were similar in the two groups. The overall case-fatality rate within 30 days of admission was low in both groups (2 percent in the intervention arm vs. 1 percent in the control arm).

While the daily presence of study investigators may have influenced the high level of compliance likely achieved in this study (as evidenced by the authors’ report that only 8 of 200 patients in the intervention arm did not receive early mobilization), this study shows that adherence to simple evidence-based guidelines can result in dramatic improvements in efficiency of care.

(Carratala et al. Arch Intern Med 2012; doi:10.1001/archinternmed.2012.1690.)

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Trial Closes Book on Drotrecogin Alfa for Severe Sepsis
Reviewed by Ed Dominguez, MD

In 2001, drotrecogin alfa (activated) (DrotAA) was approved for treatment in patients with severe sepsis. Thus began an 11-year journey from guarded optimism to growing skepticism regarding the role of this agent, culminating in 2008 with the start of Prospective Recombinant Human Activated Protein C Worldwide Evaluation in Severe Sepsis (PROWESS-SHOCK), a trial designed to re-evaluate DrottAA’s role in treating severe sepsis. An article in the May 31, 2012 issue of the New England Journal of Medicine reports the results of this trial.

PROWESS-SHOCK was a randomized, double-blind, placebo-controlled, multicenter trial in adults with infection, systemic inflammation, and shock. Patients were randomized to receive either DrotAA or placebo for 96 hours. The primary outcome was 28-day all-cause mortality. Of the 27,816 patients screened, 1,697 were recruited and 1,680 were evaluable (846 in the DrottAA arm and 834 in the placebo arm). Baseline clinical characteristics were similar although DrottAA patients were more likely to have an identified organism (73.2 percent vs. 68.0 percent, P=0.02). The lungs were the most common primary site of infection followed by the abdomen and the urinary tract.

At day 28, all-cause mortality was 26.4 percent in the DrottAA arm and 24.2 percent in the placebo arm. In patients with severe protein C deficiency at the outset, mortality was slightly higher in the placebo group, 28.7 percent v 30.8 percent. By day 90, mortality had climbed to 34.1 percent and 32.7 percent, respectively. None of the differences reached statistical significance. As expected, bleeding was more often encountered in the DrottAA recipients.

An accompanying editorial notes that the study did not achieve statistical power as hoped. Nonetheless, the design was precise in its clinical definitions, effective at blinding, and successful in randomization. The editorial authors remark that the journey is now over for DrottAA after this study, and now we wait for another sepsis drug to embark on a new journey.

(Ranieri et al. N Engl J Med. 2012; 366:2055-2064.)

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Is High-Dose, Extended-Interval Colistin Dosing Safe and Effective?

Reviewed by Shireesha Dhanireddy, MD

Colistin has been used to treat severe multidrug-resistant (MDR) Gram-negative infections, but efficacy widely varies, possibly due to suboptimal dosing regimens, as colistin exhibits concentration-dependent bactericidal activity. In the June 15 issue of Clinical Infectious Diseases, the authors of a study argue that current dosing regimens lead to subtherapeutic peak concentrations and prolonged time to steady state.

The researchers conducted a prospective, observational, cohort study to assess the efficacy and toxicity of a high-dose and extended-interval dosing regimen of colistin in critically ill patients with colistin-sensitive MDR Gram-negative bloodstream infections or ventilator-associated pneumonia. Patients received a loading dose of colistin 9 million units (MU) followed by 4.5 MU every 12 hours for maintenance. Doses were adjusted for impaired creatinine clearance. A total of 28 patients were prescribed colistin but three were excluded as they were either discharged or died within 72 hours of treatment. Three patients developed infections with another pathogen and were included for each infection. Acinetobacter baumannii and Klebsiella pneumoniae accounted for the majority of infections, 46.4 percent for each, and Pseudomonas aeruginosa (7.2 percent) for the remainder.

Half of patients received colistin as monotherapy, and the other half received it either in combination with either an aminoglycoside or a carbapenem. Serum concentrations of colistin were not measured. Eighty-two percent of patients achieved clinical cure. Acute kidney injury occurred in 5/28 of the treatment courses, with increases in creatinine from normal baseline to 2.09-5.85 mg/dL, which occurred within two to five days of therapy. Renal function improved by 10 days of discontinuation of therapy in all patients. Renal toxicity that did occur was not associated with duration of treatment or cumulative doses of colistin.

The study authors conclude that high-dose, extended interval dosing of colistin is effective without leading to significant renal toxicity in critically ill patients with serious MDR Gram-negative infections. A larger, multicenter study is needed to confirm these findings.

(Dalfino et al. Clin Infect Dis. 2012;54:1720-6.)

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Azithromycin and Risk of Cardiac Death: Another Reason to Curb Unnecessary Antibiotic Use
Reviewed by Rachel Simmons, MD

A study in the May 17 issue of theNew England Journal of Medicine should lend more weight to public health campaigns to curb the use of unnecessary antibiotics.

Researchers used data from Tennessee Medicaid enrollees to estimate the risk of cardiovascular death during a five-day day course of azithromycin compared to no antibiotics and compared to a course of amoxicillin, ciprofloxacin, or levofloxacin. The study included 347,795 prescriptions for azithromycin, 1,391,180 non-prescription periods, 1,348,672 prescriptions for amoxicillin, 264,626 prescriptions for ciprofloxacin, and 193,906 prescriptions for levofloxacin. The most common indications for azithromycin and amoxicillin prescriptions were ear, nose, and throat infections and bronchitis.

During a five-day course of azithromycin, 29 cardiovascular deaths (85.2 deaths per million courses) and 22 (64.6 per million courses) sudden cardiac deaths occurred. In the matched periods where no antibiotics were prescribed, 41 (29.8 deaths per million periods) cardiovascular deaths and 33 (24 deaths per million periods) sudden deaths occurred. Compared to no antibiotics, azithromycin was associated with an increased risk of cardiovascular death (HR 2.88, p <0.001), sudden cardiac death, and death from any cause.

Compared to amoxicillin and ciprofloxacin, azithromycin was also associated with higher rates of cardiovascular death with hazard ratios of 2.49 (p 0.002) and HR 3.49 (p 0.01), respectively. Patients who took azithromycin had an estimated 47 additional cardiovascular deaths per 1 million courses compared to those who took amoxicillin. The risk of cardiovascular death associated with azithromycin also varied according to overall risk of cardiovascular disease. Those in the highest decile of cardiac risk scores had the highest risk of death while taking azithromycin, with an estimated additional 245 cardiovascular deaths for every 1 million five-day courses of azithromycin.

This study indicates that azithromycin, like other macrolide antibiotics, has serious cardiac effects and is associated with an increased risk of cardiovascular death, especially in patients at greatest risk of cardiovascular disease

(Ray et al. N Engl J Med. 2012; 366:1881-1890.)

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