Carlos A. DiazGranados

Comparison of Mortality Associated with Vancomycin-Resistant and Vancomycin-Susceptible Enterococcal Bloodstream Infections: A Meta-analysis

BACKGROUND Whether vancomycin resistance is independently associated with mortality among patients with enterococcal bloodstream infection (BSI) is controversial. To address this issue, we performed a systematic literature review with meta-analysis. METHODS Data sources were studies identified using the MEDLINE database (for articles from 1988 through March 2003), the Cochrane Library (for articles published up to March 2003), and bibliographies of identified articles. Inclusion criteria were that the study assessed mortality after enterococcal BSI, compared mortality after vancomycin-resistant enterococci (VRE) BSI with that after vancomycin-susceptible enterococci (VSE) BSI, and adjusted for severity of illness. Study exclusion criteria were as follows: no report of the adjusted measure of effect (adjusted odds ratio [OR], adjusted hazard ratio, or adjusted relative risk) of vancomycin resistance on mortality available and/or its adjusted 95% confidence interval (95% CI). Data in the tables, figures, or text were independently extracted by 2 of the authors. Individual weights were calculated using the 95% CI of the adjusted measures of effect performing both fixed-effect and random-effects models. RESULTS Nine studies were eligible (11 studies met the inclusion criteria, and 2 were excluded), with a total of 1614 enterococcal BSI episodes (683 VRE episodes and 931 VSE episodes). Patients with bacteremia caused by VRE were more likely to die than were those with VSE bacteremia (summary OR, 2.52; 95% CI, 1.9-3.4). CONCLUSIONS Vancomycin resistance is independently associated with increased mortality among patients with enterococcal bloodstream infection.

Efficacy of high-dose versus standard-dose influenza vaccine in older adults.

BACKGROUND As compared with a standard-dose vaccine, a high-dose, trivalent, inactivated influenza vaccine (IIV3-HD) improves antibody responses to influenza among adults 65 years of age or older. This study evaluated whether IIV3-HD also improves protection against laboratory-confirmed influenza illness. METHODS We conducted a phase IIIb-IV, multicenter, randomized, double-blind, active-controlled trial to compare IIV3-HD (60 μg of hemagglutinin per strain) with standard-dose trivalent, inactivated influenza vaccine (IIV3-SD [15 μg of hemagglutinin per strain]) in adults 65 years of age or older. Assessments of relative efficacy, effectiveness, safety (serious adverse events), and immunogenicity (hemagglutination-inhibition [HAI] titers) were performed during the 2011-2012 (year 1) and the 2012-2013 (year 2) northern-hemisphere influenza seasons. RESULTS A total of 31,989 participants were enrolled from 126 research centers in the United States and Canada (15,991 were randomly assigned to receive IIV3-HD, and 15,998 to receive IIV3-SD). In the intention-to-treat analysis, 228 participants in the IIV3-HD group (1.4%) and 301 participants in the IIV3-SD group (1.9%) had laboratory-confirmed influenza caused by any viral type or subtype associated with a protocol-defined influenza-like illness (relative efficacy, 24.2%; 95% confidence interval [CI], 9.7 to 36.5). At least one serious adverse event during the safety surveillance period was reported by 1323 (8.3%) of the participants in the IIV3-HD group, as compared with 1442 (9.0%) of the participants in the IIV3-SD group (relative risk, 0.92; 95% CI, 0.85 to 0.99). After vaccination, HAI titers and seroprotection rates (the percentage of participants with HAI titers ≥ 1:40) were significantly higher in the IIV3-HD group. Conclusions: Among persons 65 years of age or older, IIV3-HD induced significantly higher antibody responses and provided better protection against laboratory-confirmed influenza illness than did IIV3-SD. (Funded by Sanofi Pasteur; ClinicalTrials.gov number, NCT01427309.).

Seasonal influenza vaccine efficacy and its determinants in children and non-elderly adults: a systematic review with meta-analyses of controlled trials.

CONTEXT The true level of influenza vaccine efficacy is controversial and many factors may influence its estimation. OBJECTIVES To estimate the efficacy of vaccination of children and non-elderly adults for the prevention of influenza and to explore the impact of type of vaccine, age, degree of strain matching, influenza type and case ascertainment methods on vaccine efficacy estimates. DATA SOURCES Medline and EmBase databases until October 2011. References of relevant articles were also reviewed. STUDY SELECTION Controlled trials evaluating seasonal influenza vaccines and presenting incidence of laboratory-confirmed influenza illness were eligible. Studies exploring efficacy after experimental challenge, presenting duplicate data, employing group randomization, or focusing on special populations were excluded. DATA EXTRACTION The vaccine effect on influenza prevention was evaluated by calculating Mantel-Haenszel risk ratios (RR) and using random-effects models. Vaccine efficacies were calculated for each comparison as (1-RR)×100. RESULTS Thirty studies were included in one or more of a total of 101 analyses, comprising 88.468 study participants. There was evidence of heterogeneity in 49% of the analyses. Summary vaccine efficacy was 65% against any strain, 78% against matched strains and 55% against not-matched strains. Both live-attenuated and inactivated vaccines showed similar levels of protection against not-matched strains (60% and 55%, respectively). Live-attenuated vaccines performed better than inactivated vaccines in children (80% versus 48%), whereas inactivated vaccines performed better than live-attenuated vaccines in adults (59% versus 39%). There was a large difference (20%) in efficacy against influenza A (69%) and influenza B (49%) types for not-matched strains. Summary estimates of vaccine efficacy were highest when ascertainment was based on culture confirmation. CONCLUSION Influenza vaccines are efficacious, but efficacy estimates depend on many variables including type of vaccine and age of vaccinees, degree of matching of the circulating strains to the vaccine, influenza type, and methods of case ascertainment.

Chagasic encephalitis in HIV patients: common presentation of an evolving epidemiological and clinical association

We present a case of chagasic meningoencephalitis reactivation in an HIV-infected woman with advanced immunosuppression. Prolonged survival was attained with antiparasitic therapy and secondary prophylaxis, in conjunction with the use of highly-active antiretroviral therapy. The geographic expansion of the HIV epidemic around the world coupled with global migration and international travel have created a favourable situation for Trypanosoma cruzi and HIV coinfection. The clinical manifestations of Chagas disease in HIV-positive people usually represent reactivation and not acute infection with T cruzi (coinfection). Symptomatic reactivation of chronic latent T cruzi infection can be triggered by severe immunosuppression associated with HIV infection. In this setting, Chagas disease reactivation often presents as meningoencephalitis resembling toxoplasma encephalitis. We review, in this Grand Round, the clinical manifestations, diagnostic approach, pathogenesis, natural history, treatment, prognosis, and prevention of Chagas disease reactivation among HIV-infected people with an emphasis on CNS manifestations.

High-dose trivalent influenza vaccine compared to standard dose vaccine in elderly adults: safety, immunogenicity and relative efficacy during the 2009-2010 season.

BACKGROUND High-dose trivalent influenza vaccine was developed to improve antibody responses to influenza vaccine in the elderly and hence potentially impact favorably on influenza-associated morbidity and mortality in this population. METHODS A phase IIIb, multicenter, randomized, double-blind, controlled trial was conducted to compare High-Dose (HD) trivalent inactivated influenza vaccine (60μg of hemagglutinin [HA] per strain) to standard dose (SD) vaccine (15μg of HA per strain) in adults ≥65 years of age. Assessments of safety (serious adverse events [SAE]), immunogenicity (hemagglutination inhibition [HAI] titers) and relative efficacy were performed during the 2009-2010 influenza season, which coincided with the H1N1 pandemic. RESULTS A total of 9172 participants were enrolled in 99 research centers in the US (6117 and 3055 randomized to the HD and SD groups, respectively). Within 180 days after vaccination, 6.7% and 6.5% of participants in the HD and SD vaccine groups, respectively, experienced at least one SAE, of which 0.4% and 0.3% had a fatal outcome. A total of 0.5% of participants in both groups discontinued the study due to a SAE. Post-vaccination HAI titers and rate of post-vaccination HAI titer ≥1:40 were significantly higher in the HD group. No cases of influenza caused by viral types/subtypes similar to those in the vaccines were observed. All cases genetically or antigenically characterized were classified as similar to influenza A/California/7/2009 (H1N1), the pandemic strain. The vaccine efficacy of HD vaccine relative to SD vaccine against any influenza viral type/subtype was 12.6% (95% CI -140.5; 65.8) in the intent-to-treat analysis. CONCLUSION High-dose trivalent inactivated influenza vaccine is safe and well tolerated and provides superior immune responses compared to standard dose vaccine. Demonstration of a superior vaccine efficacy requires a separate large randomized, controlled trial.

Aseptic meningitis and optic neuritis preceding varicella-zoster progressive outer retinal necrosis in a patient with AIDS.

Varicella-Zoster Virus (VZV) is the second most common ocular pathogen in patients with HIV infection. VZV retinitis is estimated to occur in 0.6% of patients with HIV infection and may occur in one of two clinical syndromes. The first is the acute retinal necrosis syndrome, which also may be seen in immunocompetent hosts. The second clinical syndrome occurs in patients with CD4 cell counts typically < 50 x 10(6)/l and is termed progressive outer retinal necrosis. VZV retinitis has been reported to occur simultaneously with other VZV central nervous system manifestations such as encephalitis and myelitis in HIV-infected patients. In addition, VZV retrobulbar optic neuritis heralding VZV retinitis has recently been described in HIV-infected patients who had suffered a recent episode of dermatomal herpes zoster. Herein we report the case of an HIV-infected individual who presented with VZV meningitis and retrobulbar optic neuritis that preceded the onset of progressive outer retinal necrosis. We also review of the literature of seven additional reported cases of retrobulbar optic neuritis preceding the onset of VZV retinitis.

Immunogenicity and safety of Fluzone(®) intradermal and high-dose influenza vaccines in older adults ≥65 years of age: a randomized, controlled, phase II trial.

We conducted a randomized, controlled, multicenter, phase II study to evaluate the immunogenicity and safety of an investigational intradermal (ID) trivalent influenza vaccine (TIV) and a high-dose (HD) intramuscular (IM) TIV in older adults (≥65 years of age). Older adult subjects were immunized with ID vaccine containing either 15μg hemagglutinin (HA)/strain (n=636) or 21μg HA/strain (n=634), with HD IM vaccine containing 60μg HA/strain (n=320), or with standard-dose (SD) IM vaccine (Fluzone(®); 15μg HA/strain; n=319). For comparison, younger adults (18-49 years of age) were immunized with SD IM vaccine. In older adults, post-vaccination geometric mean titers induced by the ID vaccines were superior to those induced by the SD IM vaccine for the A/H1N1 and A/H3N2 strains and non-inferior for the B strain. Seroconversion rates induced by the ID vaccines were superior to those induced by the SD IM vaccine in older adults for the A/H1N1 and B strains and non-inferior for the A/H3N2 strain. Results did not differ significantly for the two ID vaccine dosages. Post-vaccination geometric mean titers, seroconversion rates, and most seroprotection rates were significantly higher in HD vaccine recipients than in older adult recipients of the SD IM or ID vaccines and, for most measures, were comparable to those of younger adult SD IM vaccine recipients. Injection-site reactions, but not systemic reactions or unsolicited adverse events, were more common with the ID vaccines than with the IM vaccines. No treatment-related serious adverse events were reported. This study demonstrated that: (1) the ID and HD vaccines were well-tolerated and more immunogenic than the SD IM vaccine in older adults; (2) the HD vaccine was more immunogenic than the ID vaccines in older adults; and (3) the HD vaccine in older adults and the SD IM vaccine in younger adults elicited comparable antibody responses (ClinicalTrials.gov identifier no.: NCT00551031).

Antimicrobial resistance: international control strategies, with a focus on limited-resource settings.

Microorganisms resistant to multiple anti-infective agents have increased worldwide. These organisms threaten both optimal care of patients with infection as well as the viability of current healthcare systems. In addition, antimicrobials are valuable resources that enhance both prevention and treatment of infections. As resistance diminishes this resource, it is a societal goal to minimise resistance and therefore to reduce forces that produce resistance. This review considers strategies for minimising resistance that are needed at several different levels of responsibility, ranging from the patient care provider to international agencies. It then describes responses that might be appropriate according to the resources available for control, focusing on limited-resource settings. Antimicrobial resistance represents an international concern. Response to this problem demands concerted efforts from multiple sectors both in developed and developing countries, as well as the strengthening of multinational/international partnerships and regulations. Both medical and public health agencies should be in the forefront of these efforts.

Prevention of serious events in adults 65 years of age or older: A comparison between high-dose and standard-dose inactivated influenza vaccines

BACKGROUND A recent study showed that a high-dose inactivated influenza vaccine (IIV-HD) was 24.2% more efficacious than a standard-dose inactivated influenza vaccine (IIV-SD) in preventing laboratory-confirmed symptomatic influenza in adults ≥65 years. Here we evaluate the effectiveness of IIV-HD compared to IIV-SD in preventing serious illnesses considered potential sequelae or complications of influenza infection. METHODS The original study was a double-blind, randomized, active-controlled, multicenter trial. Participants were adults ≥65 years randomized to receive IIV-HD or IIV-SD, and followed for 6-8 months post-vaccination for the occurrence of influenza and serious adverse events (SAEs). SAEs were events: leading to death or hospitalization (or its prolongation); considered life-threatening or medically important; or resulting in disability. For the present analysis, reported SAEs were classified as possibly related to influenza by three blinded physicians and rates per 1000 participant-seasons were calculated. Relative vaccine effectiveness (rVE) was estimated as (1-Rate Ratio)×100. RESULTS 31,989 participants were enrolled, with 15,991 and 15,998 randomized to receive IIV-HD and IIV-SD, respectively. IIV-HD was significantly more effective than IIV-SD in preventing SAEs possibly related to influenza overall (rVE, 17.7%; 95% confidence interval [CI], 6.6-27.4%) and serious pneumonia (rVE, 39.8%; 95% CI, 19.3-55.1%). Borderline significance was observed for the efficacy of IIV-HD relative to IIV-SD for the prevention of all-cause hospitalizations (rVE, 6.9%; 95% CI, 0.5-12.8%). CONCLUSIONS Compared to IIV-SD, IIV-HD reduced the risk of SAEs possibly related to influenza. The observed relative effectiveness against serious pneumonia is particularly noteworthy considering the burden of influenza and pneumonia in older adults.

Efficacy and immunogenicity of high-dose influenza vaccine in older adults by age, comorbidities, and frailty.

BACKGROUND A randomized trial demonstrated that a high-dose inactivated influenza vaccine (IIV-HD) was 24.2% more efficacious than a standard-dose vaccine (IIV-SD) against laboratory-confirmed influenza illness in adults ≥65 years. To evaluate the consistency of IIV-HD benefits, supplemental analyses explored efficacy and immunogenicity by baseline characteristics of special interest. METHODS Double-blind, randomized, active-controlled, multicenter trial. Adults ≥65 years were randomized 1:1 to receive IIV-HD or IIV-SD and followed for 6-8 months postvaccination for the occurrence of influenza. One third of participants were randomly selected to provide sera for measurement of hemagglutination inhibition antibody (HAI) titers. Efficacy (IIV-HD vs. IIV-SD) against laboratory-confirmed, protocol-defined influenza-like illness (PD-ILI) and HAI geometric mean titer (GMT) ratios (IIV-HD/IIV-SD) were evaluated by age, and number of high-risk comorbid and frailty conditions. RESULTS Efficacy (95% confidence intervals) of IIV-HD relative to IIV-SD against laboratory-confirmed PD-ILI was 19.7% (0.4%; 35.4%) for participants 65-74 years, 32.4% (8.1%; 50.6%) for those ≥75 years, 22.1% (3.9%; 37.0%) for participants with ≥1 high-risk comorbidity, 23.6% (-3.2%; 43.6%) for those with ≥2 high-risk comorbidities, 27.5% (0.4%; 47.4%) for persons with 1 frailty condition, 23.9% (-9.0%; 47.2%) for those with 2 frailty conditions, and 16.0% (-16.3%; 39.4%) for those with ≥3 frailty conditions. There was no evidence of vaccine efficacy heterogeneity within age, comorbidity, and frailty strata (P-values 0.351, 0.875, and 0.838, respectively). HAI GMT ratios were significantly higher among IIV-HD recipients for all strains and across all subgroups. CONCLUSIONS Estimates of relative efficacy consistently favored IIV-HD over IIV-SD. There was no significant evidence that baseline age, comorbidity, or frailty modified the efficacy of IIV-HD relative to IIV-SD. IIV-HD significantly improved HAI responses for all strains and in all subgroups. IIV-HD is likely to provide benefits beyond IIV-SD for adults ≥65 years, irrespective of age and presence of comorbid or frailty conditions.