June 30, 2008

IDSA Journal Club, June 2008

In this new 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.

For more from Clinical Infectious Diseases and The Journal of Infectious Diseases, see the "In the IDSA Journals" section of IDSA News.

 Adding Rifampin Helps Treat Staph Infections…Maybe

Sara E. Cosgrove, MD, MS

Addition of rifampin to other antistaphylococcal antibiotics may be useful in the treatment of S. aureus infections involving hardware or bone, although the currently available literature provides only limited supporting data, according to a systematic review in the April 28 edition of Archives of Internal Medicine

The authors performed an extensive review of in vitro, animal, and human studies published between 1966 and 2006 that compared the use of a single antibiotic to that antibiotic in combination with rifampin for therapy of S. aureus.  The in vitro studies were heterogeneous, with a wide range of different methods and results; most studies did not demonstrate antagonism between rifampin and other antibiotics.  Several animal studies, but not all, demonstrated a benefit to combination therapy with rifampin in sterilizing bone, decreasing bacterial counts and improving cure rates.  Seven human studies including six prospective, randomized trials were evaluated.  Generally, the studies were of sub-optimal quality and small.  Three studies evaluating patients with orthopedic hardware infections (n = 1) and mixed infections including osteomyelitis (n = 2) showed a modest potential benefit associated with addition of rifampin. 

This review provides a complete reference for the available data regarding use of rifampin in the treatment of S. aureus infections, but it also highlights the limitations of our current knowledge in the area. (Perlroth et al., Arch Intern Med. 2008;168:805-819.)

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 Cancer Rates Higher Among HIV-infected Patients

Khalil G. Ghanem, MD

A study in the Annals of Internal Medicine found that the incidence of some non-AIDS-defining cancers was higher than in the general population.

The investigators compared the incidence of cancers in two large cohorts, followed between 1992 and 2003 and totaling 54,780 HIV-infected patients, to the population enrolled in 13 central cancer registries (covering 14 percent of the general population). They found an increased incidence of the following malignancies among HIV-infected patients: anal, vaginal, Hodgkin’s lymphoma, liver, lung, melanoma, oropharyngeal, leukemia, colorectal, and renal. The incidence of prostate cancer was lower in the HIV-infected cohort. The latter finding may be related to lower screening rates for prostate cancer among HIV-infected patients.

In the HAART era, rates of AIDS-defining malignancies such as Kaposi’s sarcoma and non-Hodgkin’s lymphoma decreased dramatically, whereas rates of cervical cancer remained high. None of the rates for non-AIDS-defining cancers decreased after the introduction of HAART: some remained stable (liver, lung, oropharyngeal, and breast) while others increased (anal, Hodgkin’s lymphoma, melanoma, colorectal, and prostate cancer).

The authors hypothesize that immune dysfunction, concomitant infection with oncogenic viruses, and lifestyle factors such as smoking may have lead to the increased rates of cancers seen among the HIV-positive group. An important limitation of the study was the lack of tobacco use data.

Given the survival benefits of HAART in our HIV-infected patients, and given the increased incidence of these malignancies, providers need to be vigilant in searching for and recognizing signs of non-AIDS-related cancers. (Patel et al., Ann Intern Med. 2008;148:728-36.)

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 Corticosteroids: Helpful for Some Infections, Harmful for Others

Khalil G. Ghanem, MD

A literature review in the May 28 issue of Archives of Internal Medicine found mixed results in the use of corticosteroids for the treatment of infections.

The authors performed a Medline search through July 2007 for randomized controlled trials of corticosteroid use (mostly in conjunction with antibiotics, when appropriate) for a variety of infectious diseases.

Infections where there was clear a survival advantage to using corticosteroids included tuberculous meningitis and pericarditis, severe typhoid fever, tetanus, and moderate to severe cases of pneumocystis pneumonia in HIV-infected patients. On the other hand, steroids were harmful in the setting of cerebral malaria and viral hepatitis. The authors also list a variety of infections where steroids appeared to confer symptomatic relief (e.g. cellulitis, pneumonia, zoster, infectious mononucleosis).

The use of steroids in these infections, however, must be tempered by the limited data available for many of these conditions, and the observation that most would have resolved even without the use of steroids. Most studies did not report any major adverse events when using steroids, at least not in the short-term.

Clinicians should keep in mind that the scope of the study did not allow the authors to expand on the many limitations inherent in the reported studies. The utility of this paper is that it provides a fairly comprehensive list of references of well designed studies to guide clinicians when they are entertaining the notion of using steroids in the treatment of infections. (McGee and Hirschmann, Arch Intern Med. 2008;168:1034-1046.)

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 Corticosteroids May Not Be the Answer for Meningitis in Children

Jason B. Weinberg, MD

Adjuvant corticosteroid use did not reduce mortality and did not affect time to hospital discharge in children with meningitis in a study in the May 7 issue of the Journal of the American Medical Association.

The use of adjuvant corticosteroids is associated with decreased mortality in adults with bacterial meningitis, but studies in children have revealed conflicting results for outcomes such as mortality or hearing loss. 

In this large (2,780 patients), multicenter retrospective cohort study, steroid use was not associated with time to death or time to hospital discharge.  These results did not change by age or by organism, although the study was likely underpowered to detect small differences in many of these subgroups.  Overall mortality was low at 4.2 percent, making it difficult to detect small effects of corticosteroids on mortality.

Unfortunately, the current study did not address the effects of corticosteroids on hearing loss or other neurological morbidity in patients with meningitis.  In another shortcoming, the investigators did not determine whether corticosteroids were administered prior to the first dose of antibiotics. 

Despite these issues, the report highlights important differences between the responses of children and adults with bacterial meningitis to adjuvant corticosteroid treatment.  Although this study suggests corticosteroids are not the answer for meningitis in children, a larger, randomized controlled trial would provide more definitive data. (Mongelluzzo et al., JAMA. 2008;299:2048-2055.)

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 Pharmacy Refills as a Predictor of Virologic Failure

Melinda M. Pettigrew, PhD

Pharmacy refill receipts can provide a simple and low -cost method for clinicians in developing countries to monitor adherence to treatment among HIV positive individuals on combination antiretroviral therapy (ART), according to a report in the May 20 issue of PLoS Medicine.

Lack of adherence to treatment is associated with risk of virologic failure and poor health outcomes. Changes in CD4 cell counts are often used to monitor the effectiveness of cART in developing countries. Bisson et al.  followed a South African cohort and used insurance claims for pharmacy refills as a proxy for adherence and compared this to monitoring through changes in CD4 count. Outcomes of interest were high viral load and rebound in viral load after previously low levels. Pharmacy refill data predicted virologic failure more accurately than CD4 counts. Both methods were equally good at predicting rebounds in viral load.

In contrast to changing CD4 counts, which measures virologic failure after it occurs, pharmacy refill records can help predict those at high risk for virologic failure earlier and allow time for interventions. This study was conducted among individuals with private insurance. More research is needed to determine whether similar adherence assessments could be adapted for those who obtain their medication at free clinics. It is also important to keep in mind that virologic failure does occur in patients who adhere to therapy. (Bisson et al., PLoS Medicine. 5: e109 doi:10.1371/journal.pmed.0050109.)

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 Take Your Vitamins: Micronutrient Supplementation for Tuberculosis

Jason B. Weinberg, MD

Micronutrient supplementation significantly decreased the risk of tuberculosis recurrences in patients receiving anti-tuberculosis chemotherapy in a study in the June 1 issue of The Journal of Infectious Diseases.

Nutritional supplementation with vitamins A, B complex, C, and E and selenium was associated with decreased recurrence of pulmonary tuberculosis and decreased risk for extrapulmonary tuberculosis.  Both of these effects were most pronounced in HIV-positive subjects.  In HIV-negative patients there were fewer deaths among patients receiving micronutrients, but this decrease was not statistically significant.  Micronutrient supplementation had no significant effect on treatment failure.

Increases in CD3+ and CD4+ cell counts were seen in HIV-negative but not HIV-positive patients receiving micronutrient supplementation.  HIV viral load and HIV disease progression were not affected by micronutrient supplementation.  In both HIV-negative and HIV-positive patients, micronutrient supplementation decreased the risk for peripheral neuropathy. 

It remains to be seen which micronutrients and which doses will provide the most benefit.  Likewise, the full extent to which patient characteristics such as HIV status, age, sex, or underlying nutritional status determine whether micronutrients provide any clinical benefit.  These questions are worth pursuing, because nutritional support shows promise as a simple and inexpensive adjuvant therapy that could reduce the risk for complications of therapy such as peripheral neuropathy, reduce the incidence of relapse after initial therapy, and potentially increase survival of patients with tuberculosis. (Villamor et al., J Infect Dis 2008;197:1499-1505.)

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