Current Antifungal Agents for Treatment of Central Nervous System Infections

Invasive fungal infections have been increasing in incidence worldwide, primarily due to the growing population of immunosuppressed patients. Fungal central nervous system infections carry a high rate of morbidity and mortality due to difficulty in diagnosis and treatment. This paper provides a review of antifungal agents currently available in the United States, highlighting the pros and cons of each medication in the treatment of CNS infections. Investigational treatment approaches with combination therapy and iron chelation for CNS infections are also discussed. Despite our many advances in modern medicine, we still lack highly effective therapeutic options for treatment of cerebral infections with the angioinvasive fungi Aspergillus and the zygomycetes.     

Chemotherapy for Bacterial Infections of the Central Nervous System

Over the past six years, many new agents have become available for the treatment of bacterial central nervous system (CNS) infections. Certain principles guide the use of these agents for CNS infections: first, an antimicrobial agent must be able to penetrate the CNS to be effective; second, the CNS is a “relatively immunoincompetent site” so that an antimicrobial must achieve levels within the CNS capable of killing the offending bacterium. The lack of efficacy of chloramphenicol for meningitis due to gram-negative aerobes is probably due to its failure to achieve such killing levels, whereas the success of the newer cephalosporins, such as cefotaxime and ceftriaxone, is due to their very high killing activity against these organisms. Penicillin remains the first choice for pneumococcal and meningococcal meningitis. Ampicillin plus chloramphenicol is still recommended as initial therapy for meningitis due to Hemophilus influenzae. The newer cephalosporins are now the first choice for the treatment of meningitis due to many gram-negative bacilli. Trimethoprim-sulfamethoxazole may also be useful in some of these infections and those due to Listeria monocytogenes. In the treatment of severe CNS infections, a team approach is advised to ensure optimal therapy.     

Patients with Infections of The Central Nervous System Have Lowered Gut Microbiota Alpha Diversity

There are multiple lines of evidence for the existence of communication between the central nervous system (CNS), gut, and intestinal microbiome. Despite extensive analysis conducted on various neurological disorders, the gut microbiome was not yet analyzed in neuroinfections. In the current study, we analyzed the gut microbiome in 47 consecutive patients hospitalized with neuroinfection (26 patients had viral encephalitis/meningitis; 8 patients had bacterial meningitis) and in 20 matched for age and gender health controls. Using the QIIME pipeline, 16S rRNA sequencing and classification into operational taxonomic units (OTUs) were performed on the earliest stool sample available. Bacterial taxa such as Clostridium, Anaerostipes, Lachnobacterium, Lachnospira, and Roseburia were decreased in patients with neuroinfection when compared to controls. Alpha diversity metrics showed lower within-sample diversity in patients with neuroinfections, though there were no differences in beta diversity. Furthermore, there was no significant change by short-term (1–3 days) antibiotic treatment on the gut microbiota, although alpha diversity metrics, such as Chao1 and Shannon’s index, were close to being statistically significant. The cause of differences between patients with neuroinfections and controls is unclear and could be due to inflammation accompanying the disease; however, the effect of diet modification and/or hospitalization cannot be excluded.     

Prevalence and Correlation of Infectious Agents in Hospitalized Children with Acute Respiratory Tract Infections in Central China

Acute respiratory tract infections (ARTIs) are associated with significant morbidity and mortality worldwide, especially in children under the age of 5 years. Almost 2 million children die from ARTIs each year, and most of them are from developing countries. The prevalence and correlation of pathogens in ARTIs are poorly understood, but are critical for improving case prevention, treatment, and management. In this study, we investigated the prevalence and correlation of infectious agents in children with ARTIs. A total of 39,756 children with one or more symptoms, including fever, cough, sore throat, tonsillitis, pharyngitis, herpangina, pneumonia, and bronchiolitis, were enrolled in the study. All patients were hospitalized in Wuhan Children’s Hospital between October 1, 2010 and September 30, 2012, and were evaluated for infectious agents. Pathogens, including Mycoplasma pneumoniae, influenza A virus, influenza B virus, adenoviruses, respiratory syncytial virus, parainfluenza virus, Legionella pneumophila, Chlamydophila pneumoniae, and Coxiella burnetii, were screened simultaneously in patient blood samples using anti-pathogen IgM tests. Regression analysis was used to reveal correlations among the pathogens. Our results showed that one or more pathogens were identified in 10,206 patients, and that Mycoplasma pneumoniae, adenoviruses, and influenza B virus were the leading infectious agents. Mixed-infections of pathogens were detected in 2,391 cases, with Mycoplasma pneumoniae as the most frequent pathogen. The most common agents in the co-infections were Mycoplasma pneumoniae and influenza B virus. Regression analysis revealed a linear correlation between the proportion of mixed infections and the incidence of multi-pathogen infections. The prevalence of infectious agents in children with ARTIs was determined. Equations were established to estimate multiple infections by single-pathogen detection. This revealed a linear correlation for pathogens in children with ARTIs. This study provides useful information for improving case prevention and management.     

Studies of Pseudomonas aeruginosa Infections Among Hospitalized Patients

A rapid identification method of glucose nonfermentative gram-negative rods was established and 320 strains isolated were divided into five groups according to their characteristics in pigmentation, acid from glucose, cytochrome oxidase activity and motility. Further characterization of the strains in each group resulted in the identification that the strains in group I were Pseudomonas aeruginosa, strains in group II, P. aeruginosa and Pseudomonas putida. Achromogenic strains of P. aeruginosa were classified into group III, Pseudomonas maltophilia, Pseudomonas alcaligenes and Alcaligenes faecalis into group IV and Acinetobacter calcoaceticus (Acinetobacter anitratus and Achromobacter lwoffii) in group V. When fluorescent pigment production was taken as a standard, 259 out of 263 chromogenic strains were identified as P. aeruginosa and the remaining four were P. putida. Whereas forty-five achromogenic strains included twenty-four A. calcoaceticus, eight P. aeruginosa, six A. faecalis, five P. maltophilia and two P. alcaligenes. From May 1970 to June 1971, 368 strains of glucose nonfermentative rods were isolated from clinical specimens sent to the Central Laboratories of Tohoku University Hospital and three fourth (286/368) of the isolates were P. aeruginosa     

Vimentin in the Central Nervous System

Intermediate filament proteins were identified by two-dimensional gel electrophoresis in urea extracts of rat optic nerves undergoing Wallerian degeneration and in cytoskeletal preparations of rat brain and spinal cord during postnatal development. The glial fibrillary acidic (GFA) protein and vimentin were the major optic nerve proteins following Wallerian degeneration. Vimentin was a major cytoskeletal component of newborn central nervous system (CNS) and then progressively decreased until it became barely identifiable in mature brain and spinal cord. The decrease of vimentin occurred concomitantly with an increase in GFA protein. A protein with the apparent molecular weight of 61,000 and isoelectric point of 5.6 was identified in both cytoskeletal preparations of brain and spinal cord, and in urea extracts of normal optic nerves. The protein disappeared together with the polypeptides forming the neurofilament triplet in degenerated optic nerves.     

Riboflavin Homeostasis in the Central Nervous System

Abstract: The mechanisms by which riboflavin, which is not synthesized in mammals, enters and leaves brain, CSF, and choroid plexus were investigated by injecting [¹⁴C]riboflavin intravenously or intraventricularly. Tracer amounts of [¹⁴C]riboflavin with or without FMN were infused intravenously at a constant rate into normal, starved, or probenecid-pretreated rabbits. At 3 h, [¹⁴C]riboflavin readily entered choroid plexus and brain, and, to a much lesser extent, CSF. Over 85% of the [¹⁴C]riboflavin in brain and choroid plexus was present as [¹⁴C]FMN and [¹⁴C]FAD. The addition of 0.2 mmol/kg FMN to the infusate markedly depressed the relative entry of [¹⁴C]riboflavin into brain, choroid plexus, and, less so, CSF, whereas starvation increased the relative entry of [¹⁴C]riboflavin into brain and choroid plexus. After intraventricular injection (2 h), most of the [¹⁴C]riboflavin was extremely rapidly cleared from CSF into blood. Some of the [¹⁴C]riboflavin entered brain, where over 85% of the ¹⁴C was present as [¹⁴C]FMN plus [¹⁴C]FAD. The addition of 1.2³μmol FAD (which was rapidly hydrolyzed to riboflavin) to the injectate decreased the clearance of [¹⁴C]riboflavin from CSF and the phosphorylation of [¹⁴C]riboflavin in brain. Probenecid in the injectate also decreased the clearance of [¹⁴C]riboflavin from CSF. These results show that the control of entry and exit of riboflavin is the mechanism, at least in part, by which total riboflavin levels in brain cells and CSF are regulated. Penetration of riboflavin through the blood-brain barrier, saturable efflux of riboflavin from CSF, and saturable entry of riboflavin into brain cells are three distinct parts of the homeostatic system for total riboflavin in the central nervous system.     

Cytokine Actions in the Central Nervous System

Cytokines and chemokines have been implicated in contributing to the initiation, propagation and regulation of immune and inflammatory responses. Also, these soluble mediators have important roles in contributing to a wide array of neurological diseases such as multiple sclerosis, AIDS Dementia Complex, stroke and Alzheimers disease. Cytokines and chemokines are synthesized within the central nervous system by glial cells and neurons, and have modulatory functions on these same cells via interactions with specific cell-surface receptors. In this article, I will discuss the ability of glial cells and neurons to both respond to, and synthesize, a variety of cytokines. The emphasize will be on three select cytokines; interferon-gamma (IFN-γ), a cytokine with predominantly proinflammatory effects; interleukin-6 (IL-6), a cytokine with both pro- and anti-inflammatory properties; and transforming growth factor-beta (TGF-β), a cytokine with predominantly immunosuppressive actions. The significance of these cytokines to neurological diseases with an immunological component will be discussed.     

TWEAK and the Central Nervous System

Tumor necrosis factor-like weak inducer of apoptosis (TWEAK) is a member of the tumor necrosis factor superfamily that acts on responsive cells via binding to a cell surface receptor named fibroblast growth factor-inducible 14 (Fn14). TWEAK can regulate numerous cellular responses in vitro and in vivo. Recent studies have indicated that TWEAK and Fn14 are expressed in the central nervous system (CNS), and that in response to a variety of stimuli, including cerebral ischemia, there is an increase in TWEAK and Fn14 expression in perivascular astrocytes, microglia, endothelial cells, and neurons with subsequent increase in the permeability of the blood–brain barrier (BBB) and cell death. Furthermore, there is a growing body of evidence indicating that TWEAK induces the activation of the NF-κB in the CNS with release of proinflammatory cytokines and matrix metalloproteinases. In addition, inhibition of TWEAK activity by either treatment with a Fn14-Fc fusion protein or neutralizing anti-TWEAK antibodies has shown therapeutic efficacy in animal models of ischemic stroke, cerebral edema, and multiple sclerosis.     

The Relationship between Poverty and Healthcare Seeking among Patients Hospitalized with Acute Febrile Illnesses in Chittagong,Bangladesh

Delays in seeking appropriate healthcare can increase the case fatality of acute febrile illnesses, and circuitous routes of care-seeking can have a catastrophic financial impact upon patients in low-income settings. To investigate the relationship between poverty and pre-hospital delays for patients with acute febrile illnesses, we recruited a cross-sectional, convenience sample of 527 acutely ill adults and children aged over 6 months, with a documented fever ≥38.0°C and symptoms of up to 14 days’ duration, presenting to a tertiary referral hospital in Chittagong, Bangladesh, over the course of one year from September 2011 to September 2012. Participants were classified according to the socioeconomic status of their households, defined by the Oxford Poverty and Human Development Initiative’s multidimensional poverty index (MPI). 51% of participants were classified as multidimensionally poor (MPI>0.33). Median time from onset of any symptoms to arrival at hospital was 22 hours longer for MPI poor adults compared to non-poor adults (123 vs. 101 hours) rising to a difference of 26 hours with adjustment in a multivariate regression model (95% confidence interval 7 to 46 hours; P = 0.009). There was no difference in delays for children from poor and non-poor households (97 vs. 119 hours; P = 0.394). Case fatality was 5.9% vs. 0.8% in poor and non-poor individuals respectively (P = 0.001)—5.1% vs. 0.0% for poor and non-poor adults (P = 0.010) and 6.4% vs. 1.8% for poor and non-poor children (P = 0.083). Deaths were attributed to central nervous system infection (11), malaria (3), urinary tract infection (2), gastrointestinal infection (1) and undifferentiated sepsis (1). Both poor and non-poor households relied predominantly upon the (often informal) private sector for medical advice before reaching the referral hospital, but MPI poor participants were less likely to have consulted a qualified doctor. Poor participants were more likely to attribute delays in decision-making and travel to a lack of money (P<0.001), and more likely to face catastrophic expenditure of more than 25% of monthly household income (P<0.001). We conclude that multidimensional poverty is associated with greater pre-hospital delays and expenditure in this setting. Closer links between health and development agendas could address these consequences of poverty and streamline access to adequate healthcare.     

Identification by PCR of Non-typhoidal Salmonella enterica Serovars Associated with Invasive Infections among Febrile Patients in Mali

Background

In sub-Saharan Africa, non-typhoidal Salmonella (NTS) are emerging as a prominent cause of invasive disease (bacteremia and focal infections such as meningitis) in infants and young children. Importantly, including data from Mali, three serovars, Salmonella enterica serovar Typhimurium, Salmonella Enteritidis and Salmonella Dublin, account for the majority of non-typhoidal Salmonella isolated from these patients.

Methods

We have extended a previously developed series of polymerase chain reactions (PCRs) based on O serogrouping and H typing to identify Salmonella Typhimurium and variants (mostly I 4,[5],12:i:-), Salmonella Enteritidis and Salmonella Dublin. We also designed primers to detect Salmonella Stanleyville, a serovar found in West Africa. Another PCR was used to differentiate diphasic Salmonella Typhimurium and monophasic Salmonella Typhimurium from other O serogroup B, H:i serovars. We used these PCRs to blind-test 327 Salmonella serogroup B and D isolates that were obtained from the blood cultures of febrile patients in Bamako, Mali.

Principal Findings

We have shown that when used in conjunction with our previously described O-serogrouping PCR, our PCRs are 100% sensitive and specific in identifying Salmonella Typhimurium and variants, Salmonella Enteritidis, Salmonella Dublin and Salmonella Stanleyville. When we attempted to differentiate 171 Salmonella Typhimurium (I 4,[ 5],12:i:1,2) strains from 52 monophasic Salmonella Typhimurium (I 4,[5],12:i:-) strains, we were able to correctly identify 170 of the Salmonella Typhimurium and 51 of the Salmonella I 4,[5],12:i:- strains.

Conclusion

We have described a simple yet effective PCR method to support surveillance of the incidence of invasive disease caused by NTS in developing countries.