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April 2009
Vol. 19 No. 4
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IDSA Journal Club
April 2009

In this feature, a panel of IDSA members identifies and critiques important new infectious diseases studies in the current literature that have a significant impact on the practice of infectious diseases medicine.

Catheter-Associated Asymptomatic Bacteriuria Should Not be Treated
Reviewed by Sabrina Kendrick, MD

Many catheterized patients with bacteria in the urine but no symptoms are inappropriately treated with antibiotics, according to a study in the May 1 issue of Clinical Infectious Diseases.

Evidenced-based guidelines distinguish between catheter-associated asymptomatic bacteriuria (CAABU) and catheter-associated urinary tract infection (CAUTI). The authors set out to reveal the extent of inappropriate treatment that results from failure of clinicians to distinguish CAABU from CAUTI. They retrospectively reviewed all urine culture results over a three-month period at a veterans’ affairs hospital. Cultures with >104 colony-forming units/mL of any bacterium or yeast from a hospitalized patient with an indwelling (Foley) or condom catheter in place for at least 24 hours during the preceding seven days prior to admission were included. Excluded patients were those being treated with an antibiotic at the time of hospital admission.

Of the 280 patients who met the inclusion criteria, 164 were considered CAABU. Fifty-three (32 percent) of these asymptomatic patients were treated—inappropriately—with antibiotics. Older age, predominant gram-negative organism, and higher urine white blood cell count were significantly associated with inappropriate treatment of CAABU. Limitations of the study include the retrospective design, possible under-estimation of CAABU and possible over-estimation of and CAUTI.

Recent publications and agencies encourage a national goal of no treatment of asymptomatic bacteriuria. This study documents the poor adherence to guidelines that call for this action and may serve as a platform to develop a strategy to improve adherence to guidelines. Better recognition of the difference between the two conditions may play a key role in the reduction of unneeded antibiotic usage, the authors note.

(Cope et al., CID 2009;48:1182-88.)

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More Debate on When to Begin HAART
Reviewed by Khalil Ghanem, MD

Two recent large observational studies attempted to define the optimal time to start highly active antiretroviral therapy (HAART) in HIV-infected patients. Both studies suggest that earlier initiation of HAART may improve outcomes, but had significant limitations.

The first study, published in The New England Journal of Medicine, included 17,517 U.S. and Canadian asymptomatic HIV-infected patients treated between 1996 and 2005. Patients were stratified into two groups based on CD4 count:  351-500 cells/µl or >500 cells/µl. Both groups were analyzed separately to see if there was a difference in mortality among patients who deferred therapy until their CD4 counts fell below the bottom of the range. Among patients in the first group, there was a 69 percent increased risk of death among patients who deferred therapy until  the CD4 count fell below 350 cells/µl, compared to those who did not defer therapy.  In the analysis of the second group, there was a 94 percent increased risk of death among patients who deferred therapy until  the CD4 count fell below 500 cells/µl, compared to those who did not defer therapy. 

The second study, published in The Lancet, included 24,444 patients enrolled in 18 cohorts and who were followed after the initiation of antiretroviral therapy. The combined primary outcome included death or the development of an AIDS-related condition.  The investigators calculated the risk of adverse outcomes based on data from 21,247 patients who were followed in the pre-HAART era. Deferring the initiation of HAART until the CD4 count was between 251 and 350 cells/µl increased the risk of death or an AIDS-related condition by 28 percent  compared to starting therapy when the CD4 count was between 351 and 450 cells/µl. The effect on mortality alone was not significant.

Both studies suggest that the initiation of HAART before the CD4 count falls below 350 cells/µl may improve outcomes. Whether initiating HAART at a CD4 count of ≥500 cells/µl improves outcome is still unclear. Both studies had significant limitations, including the lack of clarity regarding the causes of death and the reasons for starting therapy.. Moreover, neither study evaluated the side effects of earlier initiation of therapy. 

The question of when to start HAART has been debated for many years. The pendulum appears to be swinging towards earlier initiation of HAART. The ideal time, however, is still unclear.  A randomized controlled trial would be expensive and resource-intensive, but may provide less-biased data to guide clinical practice.

(Kitahata et al, N Engl J Med 2009;360:1815-26, Sterne JA and the When to Start Consortium, Lancet 2009;373:1314-16.)

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Widespread Circulation of Oseltamivir-Resistant Seasonal Influenza Viruses
Reviewed by Melinda Pettigrew, PhD

The 2007-2008 influenza season was the first to demonstrate that highly transmissible oseltamivir resistant strains can develop and spread without extensive oseltamivir usage, according to a study in the March 11, 2009 issue of The Journal of the American Medical Association.

As part of ongoing surveillance, the authors tested H1N1 influenza viruses and reviewed cases submitted to the Centers for Disease Control and Prevention (CDC) during the 2007-08 influenza season. Oseltmavir resistance was identified in 12 percent of seasonal H1N1 viruses. (Note: this article does not address H1N1 swine influenza, which is sensitive to oseltamivir.) Overall, 2 percent of circulating influenza viruses were resistant to oseltamivir. Oseltamivir resistant viruses were susceptible to zanamivir and the adamantanes.

Prior to 2007-08, sporadic cases of oseltamivir resistance were limited to treated individuals, person-to-person transmission was rare, and resistant viruses appeared less fit compared to wild type. The current study challenges the notion that resistance arises only under heavy selective pressure and that resistant viruses are less biologically fit. The individuals infected with a resistant strain had not previously taken oseltamivir. There were no differences in demographic and clinical characteristics or disease outcome among those infected with resistant compared to susceptible viruses.

(This year, the trend continued: As of April 11, preliminary CDC data indicated that over 99 percent of seasonal H1N1 influenza viruses were oseltamivir resistant.)

The authors relied on passive surveillance and these data may not be representative of all U.S. infections. Oseltamivir resistance may emerge in other influenza subtypes. These data indicate the critical need for new antiviral drugs, rapid diagnostic tests, and real-time surveillance to inform policy and clinical treatment guidelines.

(Dharan et al. JAMA. 2009;301:1034-41.)

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Tenofovir-associated Kidney Tubular Abnormalities
Reviewed by Sabrina Kendrick, MD

Tenofovir (TDF) exposure is associated with increased risk of kidney tubular abnormalities, often in the absence of renal insufficiency, according to a published report in the March 27 issue of AIDS. Long-term consequences of the tubulopathy are unknown, but the article recommends periodic screening of tubular function parameters for HIV+ patients receiving TDF.

284 HIV+ patients in regular outpatient clinic follow-up were divided into 3 groups: patients receiving highly active antiretroviral therapy (HAART) including TDF for at least 3 months (154 pateints), patients receiving HAART but never exposed to TDF (49); and HIV antiretroviral-naïve individuals (81). Kidney tubular parameters (glucosuria, hyperaminoaciduria, hyperphosphaturia, hyperuricosuria, and β2-microglobinuria) were determined in all patients in this cross-sectional study. Proximal tubular damage was defined as at least two markers repeatedly present with one of them being any of the Fanconi syndrome criteria. Glomerular function was determined using creatinine clearance.

Twenty-two percent of patients receiving HAART containing TDF had tubular damage, compared to 6 percent of those receiving HAART not containing TDF and 12 percent of antiretroviral-naïve patients. Multivariate analysis identified TDF use (OR=21.6) and older age as the only independent predictors of tubular damage. The cross-sectional design of the study limited assessment of time-frames for the TDF-associated tubulopathy development.

The authors recommend periodic measurement of kidney tubular function to assess the toxicities of TDF, particularly in the absence of significant renal insufficiency and accelerated bone loss.

(Labarga et al. AIDS 2009;23:689-696.)

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CMV Vaccine Provides Protection
Reviewed by Jason Weinberg, MD

A recombinant vaccine provided about 50 percent protection against cytomegalovirus (CMV) infection in young women, according to a report in the March 19 issue of The New England Journal of Medicine.

The authors of this study performed a phase 2, placebo-controlled, randomized, double-blind trial to evaluate the efficacy of three doses of a CMV envelope glycoprotein B vaccine. The study was terminated early when an interim analysis determined that women who received the study vaccine were significantly more likely to remain uninfected than women who received placebo.  Rates of CMV infection per 100 person-years were 3.3 in the vaccine group compared to 6.6 in the placebo group, for an overall vaccine efficacy of 50 percent. 

The vaccine was generally well tolerated.  Although more adverse events were associated with vaccine than with placebo, they tended to be mild.

The potential protection afforded to women who received the vaccine in this study is encouraging, but the ultimate goal of maternal vaccination is to prevent congenital CMV infection, a substantial cause of central nervous system impairment in infants.  Specific immunologic correlates of protection against CMV infection are still not completely understood, and it is difficult to predict whether antibody responses induced by maternal vaccination will provide adequate protection against congenital infection. The study was not powered to determine if maternal vaccination provided significant protection against congenital CMV infection.

Other important issues remain undefined.  For instance, when should CMV vaccine be given?  How long will protection last?  Will vaccination provide protection to infants whose mothers have already been infected with CMV?  Although not yet definitive, the results of this study should encourage ongoing efforts to develop a vaccine that will prevent CMV infection in young women and congenital CMV in their infants.

(Pass et al.  N Engl J Med 2009; 360:1191-9.)
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