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September 2010
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IDSA 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.

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.

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Cellulitis in the Time of MRSA
Reviewed by Jonathan Li, MD

Non-culturable cellulitis, defined as cellulitis without abscess, wounds, or ulcers, was historically attributed mainly to streptococcal infection. In a study published in the July 2010 issue of Medicine, the authors investigate whether this still holds true in a time of increasing methicillin-resistant staphylococcal aureus (MRSA) skin and soft-tissue infections and the need for empiric MRSA antibiotic coverage.   

The authors conducted a prospective evaluation of 179 patients admitted with non-culturable cellulitis between 2004 and 2007. Using anti-streptolysin-O (ASO) and Anti-DNase-B (ADB) antibody titers, an estimated 73 percent of individuals with non-culturable cellulitis had an infection by a β-hemolytic streptococci. These individuals had a 97 percent response rate to β-lactam antibiotic treatment. Of the 82 patients who received blood cultures prior to antibiotics, cultures were positive in eight patients with only one showing MRSA. Interestingly, of the 48 individuals without antibody evidence of streptococci infection, 23 were treated with a β-lactam regimen that did not cover MRSA. The vast majority of those individuals (91 percent) had a good clinical response. 

The results suggest that almost three-quarters of non-culturable cellulitis are caused by a streptococcal infection. Even in those without evidence of streptococcal infection by ASO and ADB serologies, β-lactam antibiotics alone appear to be quite effective. This suggests that the remainder of infections are likely attributable to either Group B streptococci, which does not induce ASO or ADB antibodies, or methicillin-susceptible staphylococcal aureus (MSSA). The empiric choice of antibiotics for cellulitis is increasingly complicated by the perceived need for MRSA coverage. However, this entails prescribing additional antibiotics or using broad-spectrum agents, which increases costs and the risk of side effects. This study provides some reassurance that MRSA appears to play a very minor role in non-culturable cellulitis and that empiric treatment with β-lactam agents with close clinical follow-up remains a reasonable option.

(Jeng et al.  Medicine.  2010; 89:217-226.)

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Ceftaroline versus Vancomycin plus Aztreonam in the Treatment of cSSSI
Reviewed by George R. Thompson III, MD

Methicillin-resistant Staphylococcus aureus (MRSA) and Streptococcus pyogenes are the most frequent pathogens associated with complicated skin and skin-structure infections (cSSSI).  Currently available antimicrobials, however, can be limited by their narrow spectrum of activity, resistance, and the need for therapeutic drug monitoring. New treatment options that are both safe and effective are urgently needed. 

In the Sept. 15 issue of Clinical Infectious Diseases, investigators describe the results of a phase III, international, multicenter, randomized, double-blind trial comparing ceftaroline  (a fifth generation cephalosporin with activity against MRSA)  (600mg every 12 hours) to vancomycin plus aztreonam (1gm every 12 hours) in the treatment of cSSSI.  

This study included 1,378 patients with cSSSI randomly assigned to one of the above treatment arms. Cellulitis, cutaneous abscesses, and infected wounds were the most common types of infection and did not differ by treatment group. Diabetes mellitus and peripheral vascular disease were the most common underlying comorbidities in both groups. Clinical cure rates were high in both groups and similar for ceftaroline compared to vancomycin plus aztreonam in the clinically evaluable and modified intention-to-treat populations and in patients infected with MRSA.  Adverse event rates, drug discontinuation, serious adverse events, and death were also similar between treatment groups. 

Vancomycin plus aztreonam demonstrated a higher microbiologic response rate than ceftaroline against gram-negative infections. Although this difference was not statistically significant, prior in vitro studies have suggested decreased efficacy of ceftaroline against Pseudomonas aeruoginosa and Proteus mirabilis isolates. Additionally, there was a trend towards a higher clinical cure rate in patients with bacteremia treated with vancomycin plus aztreonam than those treated with ceftaroline. Further study will undoubtedly clarify the role of this new agent in bacteremia.

These findings support the notion that ceftaroline monotherapy is safe, well tolerated, and associated with high clinical cure rates in the treatment of cSSSI, and has the potential to provide a monotherapy alternative. 

(Corey et al.  Clin Infect Dis.  2010;51(6):641-650.)

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Rapid Detection of Tuberculosis and Rifampin Resistance
Reviewed by Jason Weinberg, MD

A molecular assay is a rapid, sensitive, and specific method to both detect Mycobacterium tuberculosis (MTB) and identify rifampin resistance, according to a study published in the Sept. 9, 2010 edition of The New England Journal of Medicine.

The investigators tested the performance of the Xpert MTB/RIF assay, an automated molecular test that integrates sample processing with real-time polymerase chain-reaction amplification and probing of the MTB rpoB gene. Sputum samples were collected from a diverse set of 1,462 HIV-negative and HIV-positive patients with symptoms suggestive of active pulmonary tuberculosis. MTB/RIF assay results were then compared to results from standard techniques for detecting MTB (microscopy, culture, antigen detection, and nucleic acid amplification) and rifampin resistance (culture-based and molecular genotyping).

The overall sensitivity of the MTB/RIF assay in culture-positive patients was 97.6 percent. Importantly, sensitivity in culture-positive patients whose sputum smears were negative was 72.5 percent when a single specimen was tested and 90.2 percent when three specimens were tested. The overall specificity of the MTB/RIF assay was 99.2 percent when a single specimen was tested and 98.1 percent when three specimens were tested. The MTB/RIF assay had a similarly high sensitivity (97.6 percent) and specificity (98.1 percent) for detection of rifampin resistance.

The limited availability of this costly technology, particularly in low-income countries with a high burden of tuberculosis, will likely limit widespread implementation of the assay.  The authors suggest, however, that MTB/RIF testing could ultimately be less costly than standard culture and drug-susceptibility testing in some settings. The assay’s excellent sensitivity and specificity are encouraging. Other clear benefits include the assay’s simplicity and its ability to rapidly (in less than two hours) identify the presence of MTB and provide information about drug resistance. Altogether, this study highlights the potential for a powerful diagnostic tool to improve tuberculosis management.

(Boehme et al. N Eng J Med 2010; 363:1005-1015.)

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Acyclovir, Valacyclovir, and Famciclovir During First Trimester Not Associated with Birth Defects
Reviewed by Sara Cosgrove, MD

Exposure to acyclovir, valacyclovir, and famciclovir during the first trimester of pregnancy does not appear to be associated with birth defects. The findings, from a study evaluating 837,795 live births in Denmark between 1996 and 2008, were published in the Aug. 25 edition of the Journal of the American Medical Association.

Researchers analyzed data from several large national databases, including the Medical Birth Register, which contains information on all deliveries in Denmark; the Prescription Drug Register, which has individual-level data on prescriptions filled at all outpatient pharmacies (but not inpatient prescriptions); and the National Patient Register Data, containing data on inpatient admissions, including ICD-9 codes (but not outpatient data).

Major defects were diagnosed in 19,960 of 837,795 live births (2.4 percent). There was no difference in the percentage of patients who were exposed to acyclovir (n = 1561), valacyclovir (n = 229), or famciclovir (n = 26) in the first trimester and had a major defect (40/1804, 2.2 percent) and the percentage of those who were not exposed (19,920/835,991, 2.4 percent). After adjustment for several potential confounding maternal factors (e.g., smoking, other drug exposure, diabetes), exposure to the above antiviral agents was not associated with an increased risk of major birth defects (POR 0.89; 95 percent CI 0.65-1.22).  Additional analyses evaluating acyclovir and valacyclovir separately, and evaluating 13 different subgroups of birth defects, also showed no associations between antiviral exposure and birth defects.
 
This study provides additional evidence that exposure to antiviral agents during pregnancy is likely of low risk to the developing fetus. It is important to note that acyclovir was by far the most commonly used antiviral; thus, the data are the most robust for this agent. In addition, while the results do not show an increased signal for birth defects across the population, there still may be birth defects associated with antiviral therapy that were not detected because they were very rare or due to limitations in the available data set.

(Pasternak and Hviid. JAMA 2010; 304(8):859-66.)

 

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:

Oct. 15

  • Does Tropheryma whipplei Cause Acute Gastroenteritis?
  • Two More Causes of Travelers’ Diarrhea?
  • Breast Prosthesis Infection

Oct. 1

  • Paranasal Sinus Mycetomas
  • Subversive Antibodies: The Increased Risk of Salmonella Infection in Human Immunodeficiency Virus (HIV)–Infected Patients Is Related to High Serum Concentrations of Ineffective Antibody That Impair the Activity of Bactericidal Antibody
  • Asymptomatic Systemic Leishmanial Infection

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