Rodrigo Hasbun

The Diagnostic Accuracy of Kernig's Sign, Brudzinski's Sign, and Nuchal Rigidity in Adults with Suspected Meningitis

To determine the diagnostic accuracy of Kernigs sign, Brudzinskis sign, and nuchal rigidity for meningitis, 297 adults with suspected meningitis were prospectively evaluated for the presence of these meningeal signs before lumbar puncture was done. Kernigs sign (sensitivity, 5%; likelihood ratio for a positive test result [LR(+)], 0.97), Brudzinskis sign (sensitivity, 5%; LR(+), 0.97), and nuchal rigidity (sensitivity, 30%; LR(+), 0.94) did not accurately discriminate between patients with meningitis (>/=6 white blood cells [WBCs]/mL of cerebrospinal fluid [CSF]) and patients without meningitis. The diagnostic accuracy of these signs was not significantly better in the subsets of patients with moderate meningeal inflammation (>/=100 WBCs/mL of CSF) or microbiological evidence of CSF infection. Only for 4 patients with severe meningeal inflammation (>/=1000 WBCs/mL of CSF) did nuchal rigidity show diagnostic value (sensitivity, 100%; negative predictive value, 100%). In the broad spectrum of adults with suspected meningitis, 3 classic meningeal signs did not have diagnostic value; better bedside diagnostic signs are needed.

Recombinant Interferon-γlb as Adjunctive Therapy for AIDS-Related Acute Cryptococcal Meningitis

We conducted a phase 2, double-blind, placebo-controlled study to evaluate the safety and antifungal activity of adjuvant recombinant interferon (rIFN)- gamma 1b in patients with acquired immunodeficiency syndrome and acute cryptococcal meningitis. Patients received 100 or 200 microg of rIFN- gamma 1b or placebo, thrice weekly for 10 weeks, plus standard therapy with intravenous amphotericin B, with or without flucytosine, followed by therapy with fluconazole. End points included conversion of cerebrospinal fluid fungal cultures from positive to negative at 2 weeks, resolution of symptoms, and survival. Among 75 patients, 2-week culture conversion occurred in 13% of placebo recipients, 36% of rIFN- gamma 1b (100 microg) recipients, and 32% of rIFN- gamma 1b (200 microg) recipients. There was a trend toward improved combined mycologic and clinical success in rIFN- gamma 1b recipients (26% vs. 8%; P=.078). Therapy with rIFN- gamma 1b was well tolerated, and there was no apparent influence on serial CD4 cell counts and human immunodeficiency virus load measurements. Adjunctive therapy with rIFN- gamma 1b holds promise for patients with acute cryptococcal meningitis and warrants further study.

Induction of IL-17 and nonclassical T-cell activation by HIV-Tat protein

Chronic immune activation is a major complication of antiretroviral therapy (ART) for HIV infection and can cause a devastating immune reconstitution inflammatory syndrome (IRIS) in the brain. The mechanism of T-cell activation in this population is not well understood. We found HIV-Tat protein and IL-17–expressing mononuclear cells in the brain of an individual with IRIS. Tat was also present in the CSF of individuals virologically controlled on ART. Hence we examined if Tat protein could directly activate T cells. Tat transcriptionally dysregulated 94 genes and induced secretion of 11 cytokines particularly activation of IL-17 signaling pathways supporting the development of a proinflammatory state. Tat increased IL-17 transcription and secretion in T cells. Tat entered the T cells rapidly by clathrin-mediated endocytosis and localized to both the cytoplasm and the nucleus. Tat activated T cells through a nonclassical pathway dependent upon vascular endothelial growth factor receptor-2 and downstream secondary signaling pathways but independent of the T-cell receptor. However, Tat stimulation of T cells did not induce T-cell proliferation but increased viral infectivity. This study demonstrates Tat’s role as a virulence factor, by driving T-cell activation and contributing to IRIS pathophysiology. This supports the necessity of an anti-Tat therapy in conjunction with ART and identifies multiple targetable pathways to prevent Tat-mediated T-cell activation.

Epidemiology of bacterial meningitis in the USA from 1997 to 2010: a population-based observational study

BACKGROUND Bacterial meningitis continues to be a substantial cause of morbidity and mortality, but the epidemiological trends after adjunctive dexamethasone recommendations are unknown in the USA. We aimed to describe the changing patterns among the most common bacterial causes in the USA after conjugate vaccination and to assess the association between adjunctive dexamethasone and mortality. METHODS For this population-based observational study, we searched information available from hospital discharges about incidence and inpatient mortality for the most important causes of community and nosocomial bacterial meningitis based on International Classification of Diseases coding across all hospitals in the USA between 1997 and 2010 with the HealthCare Cost Utilization Project (HCUP) network database. We calculated incidences according to US Census Bureau data and used a negative binomial regression model to evaluate the significance of changes over time. We assessed mortality from pneumococcus for three periods 1997-2001 (baseline), 2002-04 (transition years), and 2005-08 (after corticosteroid recommendations were available). FINDINGS Streptococcus pneumoniae incidence fell from 0·8 per 100 000 people in 1997, to 0·3 per 100 000 people by the end of 2010 (RR 0·3737, 95% CI 0·1825-0·7656). Mortality from pneumococcal meningitis decreased between 2005 (0·049 per 100 000 people) and 2008 (0·024 per 100 000 people) compared with between 2002 (0·073 per 100 000 people) and 2004 (0·063 per 100 000 people; RR 0·5720, 95% CI 0·4303-0·7582). The incidence of Neisseria meningitidis infection decreased from 0·721 per 100 000 people in 1997, to 0·123 per 100 000 people in 2010 (RR 0·1386, 95% CI 0·048-0·4284), which has placed this pathogen close to common bacterial causes of nosocomial meningitis such as staphylococcus and Gram-negative bacteria and to Haemophilus influenzae. INTERPRETATION S pneumoniae continues to be the leading identifiable cause of bacterial meningitis in the USA, but with a significant decrease in incidence and mortality associated with the introduction of conjugated vaccines and a mortality decrease that is associated with the introduction of recommendations for use of adjunctive dexamethasone for pneumococcal meningitis. FUNDING National Center for Research Resources.

Clostridium difficile infection: update on emerging antibiotic treatment options and antibiotic resistance

Clostridium difficile infection (CDI) is the most common cause of identifiable diarrhea in hospitalized patients. The incidence and severity of CDIs are increasing. The increased incidence and severity of the disease has sparked interest in the optimal treatment of CDI as well as the use of new therapies and drug discovery. Current treatment strategies are inadequate with decreased response rates to metronidazole, and high recurrence rates with the use of metronidazole and oral vancomycin. Although incidence rates continue to be low, in vitro resistance to antibiotics used for the treatment of CDI has been noted. Recently, important data has emerged on new anti-C. difficile antibiotics such as rifaximin, rifalazil, fidaxomicin, nitazoxanide, tigecycline and ramoplanin. The purpose of this review is to provide an update on the in vitro susceptibility and new antibiotic treatment options for CDI. This review will focus primarily on scientific studies published in the last 36 months in order to provide an up-to-date review on the topic.

2017 Infectious Diseases Society of America's Clinical Practice Guidelines for Healthcare-Associated Ventriculitis and Meningitis.

The Infectious Diseases Society of America (IDSA) Standards and Practice Guidelines Committee collaborated with partner organizations to convene a panel of 10 experts on healthcare-associated ventriculitis and meningitis. The panel represented pediatric and adult specialists in the field of infectious diseases and represented other organizations whose members care for patients with healthcare-associated ventriculitis and meningitis (American Academy of Neurology, American Association of Neurological Surgeons, and Neurocritical Care Society). The panel reviewed articles based on literature reviews, review articles and book chapters, evaluated the evidence and drafted recommendations. Questions were reviewed and approved by panel members. Subcategories were included for some questions based on specific populations of patients who may develop healthcare-associated ventriculitis and meningitis after the following procedures or situations: cerebrospinal fluid shunts, cerebrospinal fluid drains, implantation of intrathecal infusion pumps, implantation of deep brain stimulation hardware, and general neurosurgery and head trauma. Recommendations were followed by the strength of the recommendation and the quality of the evidence supporting the recommendation. Many recommendations, however, were based on expert opinion because rigorous clinical data are not available. These guidelines represent a practical and useful approach to assist practicing clinicians in the management of these challenging infections.

Vancomycin-resistant enterococcal bacteraemia: is daptomycin as effective as linezolid?

BACKGROUND The treatment of vancomycin-resistant enterococcal (VRE) bacteraemia remains challenging. Daptomycin is a new antibiotic with bactericidal activity against VRE, but available clinical data are limited. METHODS A retrospective study was performed on 98 adult patients with VRE bacteraemia admitted to two hospitals between September 2003 and December 2007 to compare the efficacy of daptomycin with that of linezolid. Multivariable analyses were performed to compare the microbiological and clinical outcomes of both groups. RESULTS Out of 98 patients with VRE bacteraemia, 68 were treated with linezolid and 30 with daptomycin. Univariate analyses showed no significant differences between the groups regarding baseline demographic and clinical characteristics, severity of illness and co-morbidity. Daptomycin was associated with a trend towards a higher mortality rate (26.7% versus 20.6%), longer median duration of bacteraemia (3 days versus 2 days) and higher relapse rate (6.7% versus 2.9%), but these differences did not reach statistical significance (P > 0.2). Microbiological cure rates were 90% for the daptomycin group and 88.2% for the linezolid group (P = 0.92). CONCLUSIONS Despite a trend towards worse outcomes, daptomycin was as effective as linezolid in treating VRE bacteraemia. A randomized clinical trial is needed to confirm these results.

Streptococcus pneumoniae bacteremia: Duration of previous antibiotic use and association with penicillin resistance

Previous antibiotic exposure is one of the most important predictors for acquisition of penicillin-nonsusceptible Streptococcus pneumoniae (PNSP) infection. To determine the impact of duration of exposure to different antibiotic classes, a study of 303 patients with S. pneumoniae bacteremia was undertaken. Ninety-eight cases of bacteremia (32%) were caused by a penicillin-nonsusceptible isolate. Bivariate analysis revealed that use of beta-lactams, sulfonamides, and macrolides within the last 1 and 6 months before presentation was associated with PNSP bacteremia (P<.05). Fluoroquinolone consumption was not related to bacteremia due to PNSP (P>.1). Both short- and long-term beta-lactam use significantly increased the risk for PNSP infection. Logistic regression analysis revealed that use of beta-lactams and macrolides in the 6 months before the first positive blood culture result were independent risk factors (P<.05). Risk for acquiring PNSP infection depends on both the class of antibiotic to which the patient was exposed and the duration of therapy.

Influence of Minimum Inhibitory Concentration in Clinical Outcomes of Enterococcus faecium Bacteremia Treated With Daptomycin: Is it Time to Change the Breakpoint?

BACKGROUND Daptomycin has become a front-line antibiotic for multidrug-resistant Enterococcus faecium bloodstream infections (BSIs). We previously showed that E. faecium strains with daptomycin minimum inhibitory concentrations (MICs) in the higher end of susceptibility frequently harbor mutations associated with daptomycin resistance. We postulate that patients with E. faecium BSIs exhibiting daptomycin MICs of 3-4 µg/mL treated with daptomycin are more likely to have worse clinical outcomes than those exhibiting daptomycin MICs ≤2 µg/mL. METHODS We conducted a multicenter retrospective cohort study that included adult patients with E. faecium BSI for whom initial isolates, follow-up blood culture data, and daptomycin administration data were available. A central laboratory performed standardized daptomycin MIC testing for all isolates. The primary outcome was microbiologic failure, defined as clearance of bacteremia ≥4 days after the index blood culture. The secondary outcome was all-cause in-hospital mortality. RESULTS A total of 62 patients were included. Thirty-one patients were infected with isolates that exhibited daptomycin MICs of 3-4 µg/mL. Overall, 34 patients had microbiologic failure and 25 died during hospitalization. In a multivariate logistic regression model, daptomycin MICs of 3-4 µg/mL (odds ratio [OR], 4.7 [1.37-16.12]; P = .014) and immunosuppression (OR, 5.32 [1.20-23.54]; P = .028) were significantly associated with microbiologic failure. Initial daptomycin dose of ≥8 mg/kg was not significantly associated with evaluated outcomes. CONCLUSIONS Daptomycin MICs of 3-4 µg/mL in the initial E. faecium blood isolate predicted microbiological failure of daptomycin therapy, suggesting that modification in the daptomycin breakpoint for enterococci should be considered.

Toscana meningoencephalitis: A comparison to other viral central nervous system infections

BACKGROUND Toscana virus (TOSV) is an emerging pathogen causing central nervous system (CNS) infection in Mediterranean countries, mostly during summer season. OBJECTIVES To compare the clinical and laboratory characteristics of Toscana CNS infections to the most common viral pathogens seen in the United States. STUDY DESIGN We performed a case series of patients with 41 TOSV infection and compared the clinical characteristics, laboratory findings, imaging results and clinical outcomes to the most commonly recognized viral causes of meningoencephalitis in the US [enterovirus (n=60), herpes simplex virus (n=48), and West Nile virus (n=30)] from our multi-center study of patients with aseptic meningoencephalitis syndromes in the Greater Houston area. RESULTS TOSV infection occurs in different age groups compared to enterovirus, HSV, and WNV. All infections most frequently occur during summer-fall except HSV which distributes throughout the year. All patients with TOSV had history of travel to endemic areas. There are differences in clinical presentation and CSF findings comparing TOSV and enterovirus, HSV, and WNV infection. There are no significant differences in outcomes of each infection except WNV meningoencephalitis which had a poorer outcome compared to TOSV infection. CONCLUSIONS TOSV is an emerging pathogen that should be considered in the differential diagnosis of patients with CNS infections and a recent travel history to endemic areas.