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February 2012
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IDSA Journal Club
February 2012

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.

Linezolid Versus Dose-Optimized Vancomycin for MRSA Nosocomial Pneumonia
Reviewed by Ed Dominguez, MD

A decade ago, two large, prospective trials found that linezolid was non-inferior to fixed-dose vancomycin for the treatment of nosocomial pneumonia. However, post hoc analysis revealed that nosocomial pneumonia from methicillin-resistant Staphylococcus aureus (MRSA) responded “significantly” better in linezolid recipients. In the March 1 issue of Clinical Infectious Diseases, researchers describe the first randomized clinical trial exclusively designed to compare the efficacy and mortality of linezolid versus dose-optimized vancomycin for MRSA nosocomial pneumonia.

From October 2004 to January 2010, 1,184 intent-to-treat patients were enrolled in the study; 348 comprised the per protocol population (172 linezolid and 176 vancomycin recipients). The two study groups were demographically similar. Ventilator-associated pneumonia was present in over 60 percent of patients; the remainder had either hospital-acquired or health care-associated pneumonia. Cure at the end of study (EOS) was found in 57.6 percent of linezolid and 46.6 percent of vancomycin recipients (P=.042). Ironically, the difference lost significance if each clinical entity was evaluated independently. Microbiologic success was similar at EOS: 58.1 percent in linezolid and 47.1 percent in vancomycin recipients. Importantly, while bacteremia was present in 5.2 percent of linezolid and 10.8 percent of vancomycin recipients, all bacteremic patients were cured.

In the modified intent-to-treat population (448 patients), nephrotoxicity was seen in 8.4 percent of linezolid and 18.2 percent of vancomycin recipients. In the vancomycin group, nephrotoxicity correlated with higher vancomycin troughs on day three of study. Anemia was more common in the vancomycin group (19.3 percent vs. 18.1 percent) and thrombocytopenia in the linezolid group (16.3 percent vs. 13.2 percent). Finally, all-cause 60-day mortality in this same population was 28.1 percent in linezolid and 26.3 percent in vancomycin recipients.

Is this the end of the controversy? Hardly. While an accompanying editorial touts the merits of this much anticipated study, it also urges caution, citing a recent outbreak of linezolid-resistant S. aureus in an ICU.

(Wunderink et al. Clin Infect Dis. 2012;54 (5): 621-629 and Torres, Antoni. Clin Infect Dis. 2012;54 (5): 630-632.)

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Preventing CMV Infection in Transplant Recipients and the Incidence of Antiviral Resistance
Reviewed by Sheila Mitsuma, MD

Cytomegalovirus (CMV) infection is one of the most commons complications of solid-organ transplantation. Seronegative patients who receive organs from seropositive donors (D+/R-) are at highest risk for developing CMV viremia as well as antiviral resistance. In the January 2012 issue of the American Journal of Transplantation, researchers analyzed 112 D+/R- renal transplant recipients who received either prophylactic or preemptive therapy, the two most commonly used approaches for preventing CMV following organ transplantation.

Thirty-two were treated prophylactically with valganciclovir for three months following transplantation, and 80 were monitored for the emergence of CMV viremia at regular intervals for the first year following transplant. The latter were treated with either ganciclovir or valganciclovir when CMV was detected at a level of 2,000 copies/ml or greater.

Consistent with prior studies, the incidence of CMV viremia was higher in the preemptive group (60 percent v. 34 percent, p = 0.02), though rates of symptomatic viremia and tissue-invasive disease did not differ significantly. Treatment failure, defined as continued viremia eight weeks following the start of therapy, was higher in the preemptive group (31 percent v. 3 percent, p = 0.001). Notably, rates of antiviral drug resistance were higher in the preemptive group (16 percent v. 3 percent, p = 0.05). The only risk factor associated with resistance was peak viral load; 75 percent of patients with a peak viral load over 180,000 copies/ml developed resistance. Rates of graft survival and acute rejection were not associated with resistance; however, the one-year estimated glomerular filtration rate (eGFR) was lower in those with resistant CMV.

The authors conclude that post-transplant prophylaxis with valganciclovir for CMV prevention is not associated with an increased risk of antiviral drug resistance. The increased rates of antiviral resistance found in the preemptive group may be due to suboptimal levels of the drug during periods of rapid viral replication, the authors note. Though a single-center retrospective study, this work reminds us that antiviral exposure is not the sole determinant in the development of resistance and that the kinetics of viral replication also plays a critical role.

(Couzi  et al. Am J Transplantation 2012;12: 202–209.)

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Anti-NMDAR Encephalitis: The Most-Diagnosed Cause of Encephalitis among Young Individuals in the California Encephalitis Project
Reviewed by Christopher J. Graber, MD, MPH

An article recently published online in Clinical Infectious Diseases summarizes the experience of the California Encephalitis Project (CEP) in diagnosing previously undiagnosed encephalitis among those aged 30 and younger in California and concludes that the CEP’s most common encephalitis diagnosis was in fact a non-infectious entity: autoimmune anti-N-methyl-D-aspartate receptor (anti-NMDAR) encephalitis.

The CEP accepts blood and cerebrospinal fluid (CSF) samples from immunocompetent patients hospitalized for encephalopathy with at least one clinical or diagnostic finding of fever, seizure, focal neurologic finding, CSF pleocytosis, electroencephalographic (EEG) alteration, or neuroimaging abnormality. From 2007 to 2011, the CEP was referred 761 cases among patients aged 30 and younger. A diagnosis was made by the CEP in 79 cases: anti-NMDAR in 32, enterovirus in 30, herpes simplex type 1 in seven, varicella zoster virus in five, and West Nile virus in five. Patients diagnosed with anti-NMDAR encephalitis were typically ≤18 years of age (65 percent), female (75 percent), and more likely to have a movement disorder, seizures, language dysfunction, psychosis, and EEG alterations than those diagnosed with viral etiologies. Autonomic instability was exclusively seen in 47 percent of anti-NMDAR encephalitis patients.

Anti-NMDAR encephalitis, first recognized in 2007, was thought to target primarily young adult females, often with associated ovarian teratomas, but it has also been described in men or children who typically present without any identifiable tumor. Death is uncommon, and while approximately 75 percent of patients will respond completely to tumor removal and/or immunotherapy (corticosteroids, intravenous immunoglobulin, plasmapheresis, rituximab, and/or cyclophosphamide), approximately 25 percent may have residual cognitive and motor deficits. Relapses can occur in 25 percent of patients, typically those without tumors or those who are suboptimally treated with immunotherapy. Diagnosis can be made via detection of antibodies specific to the NR2B- and NR2A-containing heteromers of the N-methyl-D-aspartate receptor in the serum or cerebrospinal fluid.

Recognition of the clinical and diagnostic findings of this emerging syndrome will be important in determining its true incidence in the population at large and in guiding effective therapy.

(Gable et al. Clin Infect Dis. 2012; doi: 10.1093/cid/cir1038. published online Jan. 26, 2012)

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Reversion of Positive QuantiFERON-TB Results to Negative in Low-Risk HIV-Infected Patients
Reviewed by Nina Kim, MD, MSc

Since its approval in 2007, the use of the interferon-γ release assay for tuberculosis (TB), QuantiFERON-TB Gold (QFT), has become more widespread and has supplanted TB skin testing (TST) for the detection of latent TB in some settings. QFT requires only a single patient visit and provides an objective result. Unfortunately, this result can be subject to poor reproducibility as serial testing in health care workers has shown. A retrospective study in the Feb. 1 issue of Clinical Infectious Diseases suggests this variability in QFT testing may also be seen in a subset of HIV-infected patients, a population at greater risk of TB progression.

The HIV clinics at Denver Health and University of Colorado switched from TST to QFT testing in 2009. With routine testing of 1,364 HIV-infected patients during their first year, 94 (6.9 percent) had positive QFT results. Of these, 36 (38.3 percent) had risk factors for TB – 34 were born outside the U.S. Of the remainder, repeat QFTs were sent on 49 patients a median of 40.5 days after the first test. Of these 49 positives, 35 (71.4 percent) reverted to negative on repeat testing. Reversion occurred across all strata of initial interferon-γ response, although fewer reversions were seen in higher levels further from the cutoff value. Reversions were much more likely to occur in those patients who were born in low TB-endemic countries (odds ratio 7) and those with no identifiable risk of TB exposure (33 of 41 patients retested). None of the 35 who retested negative were offered isoniazid prophylaxis and none developed TB over a cumulative follow-up of 41 patient-years.

While much of the literature has focused on the problem of false-negative results in QFT testing of HIV-infected patients, this report cautions us about the possibility of false positives whenever we test low-prevalence populations. Unfortunately the lack of a reference standard leaves both the prognosis of positive-to-negative QFT reversion and the merits of repeat testing in HIV-infected patients unclear, particularly in those who have advanced HIV despite their lack of epidemiologic risk factors for TB.

(Gray et al. Clin Infect Dis 2012;54:e20-e23.)

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PFC Exposure and Childhood Antibody Response: A Concerning Association
Reviewed by Christian B. Ramers, MD, MPH

Perfluorinated compounds (PFCs) are widely used in manufacturing, industrial, food packaging, and textile applications. Recent studies in rodents have shown that the humoral immune system is highly sensitive to perfluorooctanoic acid (PFOA) at comparable levels of exposure in humans. A study in the Jan. 25 issue of The Journal of the American Medical Association investigates this concerning relationship in children.

Investigators conducted a prospective cohort study in the Faroe Islands, enrolling 656 consecutive singleton births from 1999 to 2001 and following 587 of these children through 2008. PFC exposure was determined both pre-natally (maternal serum levels at 32 weeks gestation) and post-natally at 5 years of age. All children received immunizations against tetanus, diphtheria, polio, pertussis, and Haemophilus influenza type B at 3, 5, and 12 months and at 5 years. The primary study endpoints were serum antibody concentrations at age 5 (both pre- and post-vaccination) and 7 years. 

Exposure to PFCs—particularly PFOA and perfluorooctane sulfonic acid (PFOS)—was significantly negatively correlated with serum antibody response. A two-fold increase in pre-natal exposure to PFOS was associated with a 39 percent lower anti-diphtheria antibody titer (95 percent CI 17-55 percent decrease) at the 5-year pre-booster visit. Similarly, a two-fold increase in post-natal (5 year old) PFOA exposure was associated with a 36 percent lower anti-tetanus antibody titer (95 percent CI 14-52 percent) and a 25 percent lower anti-diphtheria antibody titer at 7 years (95 percent CI 2-43 percent). The odds ratio of anti-diphtheria antibody concentrations falling below the protective level of 0.1 IU/mL was 2.48 at 5 years (95 percent CI 1.55-3.97) for pre-natal PFOS concentrations and 3.27 at 7 years (95 percent CI 1.43-7.51) for post-natal PFOS concentrations. 

If these associations are causal, the clinical implications are alarming: PFC exposure may decrease a child’s likelihood of being protected from vaccine-preventable diseases, despite receiving a full vaccine series. Although the Faroe Islands were chosen because of an expected higher level of exposure to PFCs through a diet rich in seafood, both the pre-natal and post-natal serum levels found were lower than those found in surveys of American pregnant women and children in recent studies.  

 (Grandjean et al. JAMA 2012;307(4): 391-397.)

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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:

February 15

  • Malaria Prevention With Ivermectin
  • Sarcocystosis
  • Paracoccidioidomycosis in Brazil

February 1

  • Progressive Multifocal Leukoencephalopathy; Variable Presentations and Clinical Course: AIDS, Organ Transplantation, Natalizumab
  • Periscapular Abscess

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