Immunogenicity of a two-dose investigational hepatitis B vaccine, HBsAg-1018, using a toll-like receptor 9 agonist adjuvant compared with a licensed hepatitis B vaccine in adults.

BACKGROUND: Hepatitis B virus infection remains an important public health problem in the United States. Currently approved alum-adjuvanted vaccines require three doses and have reduced immunogenicity in adults, particularly in those who have diabetes mellitus, or are older, male, obese, or who smoke. METHODS: Phase 3 observer-blinded, randomized (2:1 HBsAg-1018 [HEPLISAV-B™]:HBsAg-Eng [Engerix-B®]), active-controlled trial in adults 18-70 years of age. HBsAg-1018 was administered intramuscularly at weeks 0 and 4 and placebo at week 24 and HBsAg-Eng at weeks 0, 4, and 24. The primary immunogenicity endpoint assessed the noninferiority of the seroprotection rate at week 28 in participants with type 2 diabetes mellitus. Secondary endpoints included seroprotection rates in the total trial population and by age, sex, body mass index, and smoking status. RESULTS: Among 8374 participants randomized, 961 participants in the per-protocol population had type 2 diabetes mellitus. In diabetes participants, the seroprotection rate in the HBsAg-1018 group at week 28 was 90.0%, compared with 65.1% in the HBsAg-Eng group, with a difference of 24.9% (95% CI: 19.3%, 30.7%), which met the prospectively-defined criteria for noninferiority and statistical significance. In the total study per-protocol population (N = 6826) and each pre-specified subpopulation, the seroprotection rate in the HBsAg-1018 group was statistically significantly higher than in the HBsAg-Eng group. CONCLUSION: Two doses of HBsAg-1018, administered over 4 weeks, induced significantly higher seroprotection rates than three doses of HBsAg-Eng, given over 24 weeks, in adults with factors known to reduce the immune response to hepatitis B vaccines as well as in those without those factors. With fewer doses in a shorter time, and greater immunogenicity, HBsAg-1018 has the potential to significantly improve protection against hepatitis B in adults at risk for hepatitis B infection. Trial Registration clinicaltrials.gov Identifier: NCT02117934.

Benefits and harms of doxycycline treatment for Gulf War veterans' illnesses: a randomized, double-blind, placebo-controlled trial.

BACKGROUND: It has been hypothesized that certain Mycoplasma species may cause Gulf War veterans' illnesses (GWVIs), chronic diseases characterized by pain, fatigue, and cognitive symptoms, and that affected patients may benefit from doxycycline treatment. OBJECTIVE: To determine whether a 12-month course of doxycycline improves functional status in Gulf War veterans with GWVIs. DESIGN: A randomized, double-blind, placebo-controlled clinical trial with 12 months of treatment and 6 additional months of follow-up. SETTING: 26 U.S. Department of Veterans Affairs and 2 U.S. Department of Defense medical centers. PARTICIPANTS: 491 deployed Gulf War veterans with GWVIs and detectable Mycoplasma DNA in the blood. INTERVENTION: Doxycycline, 200 mg, or matching placebo daily for 12 months. MEASUREMENTS: The primary outcome was the proportion of participants who improved more than 7 units on the Physical Component Summary score of the Veterans Short Form-36 General Health Survey 12 months after randomization. Secondary outcomes were measures of pain, fatigue, and cognitive function and change in positivity for Mycoplasma species at 6, 12, and 18 months after randomization. RESULTS: No statistically significant differences were found between the doxycycline and placebo groups for the primary outcome measure (43 of 238 participants [18.1%] vs. 42 of 243 participants [17.3%]; difference, 0.8 percentage point [95% CI, -6.5 to 8.0 percentage points]; P > 0.2) or for secondary outcome measures at 1 year. In addition, possible differences in outcomes at 3 and 6 months were not apparent at 9 or 18 months. Participants in the doxycycline group had a higher incidence of nausea and photosensitivity. LIMITATIONS: Adherence to treatment after 6 months was poor. CONCLUSION: Long-term treatment with doxycycline did not improve outcomes of GWVIs at 1 year.

Prosthetic joint infections: bane of orthopedists, challenge for infectious disease specialists.

Prosthetic joint infections (PJIs) occur in approximately 1.5%-2.5% of all primary hip or knee arthroplasties. The mortality rate attributed to PJIs may be as high as 2.5%. Substantial morbidity is associated with a loss of mobility, although this is temporary. The costs associated with a single episode of PJI are approximately $50,000 per episode, exclusive of lost wages. Risk factors that increase the occurrence of PJI include revision arthroplasty, time in the operating room, postoperative surgical site infection, and malignancy. Pain is the most consistent symptom. Staphylococcus species are the most common organisms isolated from PJI sites. Two-stage revision is superior to single-stage revision or to debridement with prosthesis retention. Long-term antibiotic suppression and/or arthrodesis are useful for patients too frail to undergo extensive surgery. Using an optimal approach, recurrent infection occurs in <10% of previously infected joints.

Association between initial empirical therapy and decreased length of stay among veteran patients hospitalized with community acquired pneumonia.

This investigation assessed the impact of initial empirical antimicrobial therapy on the outcome of therapy for community acquired pneumonia (CAP) patients and on patients' length of stay (LOS) in the hospital. Hospital records for 165 patients with pneumonia admitted to the Edward Hines, Jr. VA Hospital between 1 October 1997, and 31 March 2000, were reviewed. Criteria for CAP were met for 92 of 165 patients. Comparisons were made between patients treated with azithromycin and with other parenteral antibiotics (the reference group). No statistical differences were observed between the treatment groups for the risk factors. The azithromycin group patients were slightly older with a mean age of 69 years versus 66 years (P=0.23). Patients treated with parenteral azithromycin had on average, a shorter length of hospitalization namely 4.6 days compared with 9.7 days for patients treated with the other antibiotics (log-rank test, P=0.0001). In order to make the two groups of patients more alike we considered patients' data set without intensive care unit (ICU) admissions. The conclusion was the same namely azithromycin monotherapy was associated with a decreased duration of hospital stay.

Risk factors and mortality associated with Clostridium difficile-associated diarrhoea at a VA hospital.

The objective of this study was to evaluate the risk of certain patient co-morbidities and antibiotics in the development of Clostridium difficile-associated diarrhoea (CDAD). Hospitalized patients developing CDAD during a specified period were compared with a cohort of patients, matched by age, without a diagnosis of CDAD, who were hospitalized during the same time period. Data collection included demographics, hospital ward, co-morbid conditions, antibiotics received, and mortality. Gender and age were similar in both groups. Co-morbid conditions significantly associated with the case group included cancer and COPD. The most commonly prescribed antibiotics in the case versus control group included levofloxacin, intravenous vancomycin, clindamycin, and piperacillin/tazobactam. The case group was associated with a higher mortality rate.

Outcomes of ceftriaxone use compared to standard of therapy in methicillin susceptible staphylococcal aureus (MSSA) bloodstream infections.

BACKGROUND: Standard of care therapy (SOCT) for the treatment of methicillin susceptible staphylococcal aureus (MSSA) infections requires multiple daily infusions. Despite questionable efficacy due to high protein binding, ceftriaxone (CTX) is frequently used for treatment of MSSA at Hines VA Hospital. OBJECTIVE: The objective of this study was to determine clinical and microbiological outcomes in patients with MSSA bacteremia treated with CTX compared to SOCT. SETTING: This retrospective study was conducted at the Edward Hines, Jr. VA Hospital which is a comprehensive health care center serving the veteran population of the greater metropolitan Chicago and northwest Indiana regions and is institutionally affiliated with the Loyola University Medical Center. The Hines VA provides medical care to over 56,000 veterans and operates approximately 500 hospital beds, including acute care and nursing home beds. METHOD: We conducted a retrospective cohort study of patients with MSSA bacteremia treated at Hines VA Hospital between January 2000 and September 2009. Patients who received either SOCT or CTX for >50% of the treatment course and for the appropriate duration were included. Patients who were on multiple antibiotics concurrently or who received <14 days of therapy were excluded. MAIN OUTCOME MEASURE: The primary outcome of this study is to compare clinical outcomes of patients with MSSA bacteremia who were treated with CTX compared to those who received standard of care agents. RESULTS: Ninety-three patients with MSSA bacteremia were included in the analysis. Fifty-one were treated with SOCT and 42 with CTX. There were no differences in microbiological cure between SOCT (94.1%) and CTX (95.2%) (p = 0.812). Clinical cure was similar between groups (74.5% for SOCT, 83.3% for CTX) (p = 0.303). CTX was used more often to treat Staphylococcus aureus bacteremia associated with osteomyelitis whereas endocarditis and central line associated infections were treated more frequently with SOCT (p = 0.01). More patients treated with CTX were managed in the ambulatory setting (64 vs. 24%; p = <0.001). There was a trend toward a longer hospital stay with SOCT. CONCLUSION: Clinical outcomes for MSSA bacteremia did not differ significantly between patients treated with CTX and SOCT. Findings suggest that CTX may be an alternative for outpatient management of MSSA bacteremia.

Infections Associated with Prosthetic Knee and Prosthetic Hip.

Arthroplasty of the knee and hip is a common procedure. There is a risk of infection with primary arthroplasty, with an incidence of 1% to 2%. Significant cost and morbidity are associated with infection of the prosthetic joint. Most infections (60% to 70%) are caused by staphylococci, but approximately 10% are caused by streptococci and/or enterococci, whereas the remainder are caused by gram-negative enteric aerobes or anaerobic flora. Surgical revision is often required for cure because the biofilm that adheres to the infected prosthesis precludes antibiotic therapy from being effective. Biofilm formation occurs consistently as a consequence of host protein deposition on the prostheses, which serve as ligands for bacterial receptors. Once established, biofilm infections require removal of the prosthesis in order to effect a cure. Clinical and radiologic features are not specific for the diagnosis. Culture is specific but not sensitive enough to establish a pathogen in all cases. Surgical approaches are varied and range from debridement with retention of the prostheses to amputation of the limb. The most favored approach is the two-stage delayed reimplantation, in which patients receive specific antibiotic therapy for 6 weeks or more. Several additional antibiotics other than vancomycin are available for methicillin-resistant staphylococcal infection, but these are still unproven in the treatment of osteomyelitis or prosthetic joint infection.

Nosocomial Pneumonia: More Than Just Ventilator-Associated.

We reviewed literature published from 1995 through 2000 on developments in ventilator-associated pneumonia. There is no gold standard with which to compare the accuracy of various invasive procedures performed for diagnosis. Moreover, leaders in the field are calling for an outcomes-based analysis to assess the utility of invasive procedures. Two things are clear: 1) adequate empiric therapy is beneficial, and 2) changes in therapy based on recovery of pathogens by invasive means do not affect outcome. Clinicians are urged to review local antimicrobial resistance patterns and to initiate empiric therapy on the basis of those data.