Bacterial Meningitis Linnea Giovanelli

What Is Meningitis? The three layers of the meninges Bacteria can reach the meninges through the bloodstream or direct contact Inflammation of the meninges through bacterial spread in cerebrospinal fluid, CSF --Inflammatory host response to infection – the strong the inflammatory response, the more damage caused. --Little control of infection can occur in CSF because of low immune system response Direct contact of meninges occurs through severe head injuries or ear/nose infections and sometimes just randomly. Bloodstream infection – bacteria from another injury on body enter and travel through bloodstream http://training.seer.cancer.gov/brain/tumors/anatomy/meninges.html

Bacterial Infection – Why Meningitis Is Difficult Many species of bacteria can cause bacterial meningitis Neisseria meningitidis Haemophilus influenzae Streptococcus pnemoniae Listeria monocytogenes FIVE TYPES - Bacterial, viral, parasitic, fungal, non-infectious (CDC) Strep – most common cause in adults; NM – most common in children (since advent of HiB vaccine) and 2nd most common in adults FOCUS on N. meningitidis because it is the only one that causes epidemic meningitis http://lib.jiangnan.edu.cn/ASM/032-Examination%20of%20Gram%20Stains%20of%20Spinal%20Fluid-Bacterial%20Meningitis-Introduce.htm

Different Ages Have Different Risks Newborns Group B Streptococcus (GBS), E. coli, L. monocytogenes Infants and Children S. pneumoniae, N. meningitidis, H. influenzae type b Adolescents and Young Adults N. meningitidis, S. pneumoniae Older Adults S. pneumoniae, N. meningitidis, L. monocytogenes Newborns – highest risk. Vertical infection of GBS from mother

Transmission and Incubation Bacteria is largely carried in the nose and throat of humans Most people carry these colonies Bacteria are about as contagious as the flu or common cold L. monocytogenes is spread through contaminated food Incubation usually lasts about four days but can be as long as ten Meningococcal disease =/= meningitis – any disease caused by N. menin. is meningococcal disease, but not all these diseases are meningitis N. meningitidis is spread through respiratory/throat secretions

Nesseria meningitidis Gram negative anaerobe Iron reduction is a necessary part of metabolism 12 total serogroups Types A, B, C, Y and W135 Specific capsular proteins A and B are most pathogenic --Group B is the leading cause of endemic meningitis in industrialized countries – 30-40% of cases in US and up to 80% in Europe --Group A causes large scale epidemics in developing countries, especially the sub-Saharan Africa “meningitis belt” --does not exist outside humans because iron intake is dependent on human iron compounds CSF culture of N. meningitidis

N. meningitidis Antiphagocytic polysaccharide capsule Lives and replicates inside cytoplasm of neutrophils Major toxin is lipooligosaccharide, LOS LOS has been shown to suppress leukotriene B4 synthesis CAPSULE – most important virulence factor --Capsular proteins provide an important targeting factor for the immune system --LOS = highly lethal when purified in lab; very potent endotoxin and major component of bacterial cell wall --Endotoxin – toxic factor that is only released when cell wall is destroyed --B4 – a chemokinetic and chemotactic factor important in leukocytes http://lipidlibrary.aocs.org/lipids/lipidA/Figure1.png

SYMPTOMS Untreated or late-stage: Always exhibit: Seizures Coma Fever Headache Neck stiffness And may exhibit one or more of the following: Altered mental state Nausea, vomiting Photophobia Untreated or late-stage: Seizures Coma Death --Can be chronic (one month or more), acute (rapid onset – 80% of cases) or mild/aseptic --Brain does swell and bleed in advanced cases --N MEN – characteristic purple/red skin rash

Diagnosis and Treatment

Mortality Rate Dropped Sharply With Use of Antibiotics Sulphonamide resistance – 1960s, N. meningitidis Penicillin resistance – 1990s, pnemoccocal Ampicillin resistance – 1970s, H. influenzae Death rates dropped dramatically in the 1940s due to the introduction of sulfonamides - Further drug development led to successful treatment with penicillin, ampicillin, vancomycin and cephalosporins Resistance? - In the US, resistance to the three early drugs – sulphonamide, penicillin and ampicillin arose as early as the 1960s

In the Developed World… Current US case rates between 2003-2007 Streptoccocus pneumoniae remains the leading cause of death Risk has decreased for children, but the rates of infection in infants under 2 months has remained the same WHO estimates that bacterial meningitis causes around 170,000 deaths/year worldwide An estimated 4,100 cases, with roughly 500 deaths occurred each year in US – of the deaths observed in 2003-2007, 70% were from S. pneumoniae Death occurs in 10/11% of cases

800,000 cases in last 15 years – 96-2010 10% resulted in deaths, 10-20% survived with neurological defects --Large outbreaks have occurred in Asia, and smaller ones in Europe + US in the past 30 years but most large-scale outbreaks occur in Africa. --Epidemics cycle in Africa and large outbreaks generally occur in the dry season (WHO)

Diagnostic Methods Clinical Analysis Laboratory Analysis Patient presents with typical symptoms – bacterial meningitis is suspected when other causatives are ruled out Laboratory Analysis Lumbar puncture to produce cerebrospinal fluid, CSF Gram stain of CSF Culture of CSF Identification of bacterial antigen -OTHER CAUSATIVES: TB, viral infections --Controversy over start of antibiotics courses – at clinical diagnosis or at laboratory?

Treatment procedures depend on causative bacteria Correct diagnosis of causative bacteria is essential. Though any of the above procedures will most likely eliminate all of the bacteria, there is the potential for resistance emerging when the optimal combination is not used. Tunkel, A.R; Practice Guidelines for the Management of Bacterial Meningitis

Cephalosporins – 3rd Generation β-lactam antibiotics Derived from fungus Acremonium Similar in structure and action to penicillin Each generation has increasing activity against Gram negative bacteria and decreasing activity against Gram positive Acremonium (previously called Cephalosporium) Acremonium (cultured) http://www.sciencephoto.com/image/297092/530wm/M8740591-Cultured_Acremonium_fungus-SPL.jpg

β-Lactam Core of several antibiotics like penicillin and cephalosporins Attack peptioglycans in bacterial cell walls Inhibition of cell wall synthesis Resistance forms when bacteria develop β-lactamase Microbiology: A Human Perspective, Nester 7th edition --The chemical structure of cephalosporins make them resistant to inactivation by some beta-lactamases --inhibit cell wall synthesis leading to cell lysis --extended spectrum lactamase = higher resistance --R group variation

Resistance Pneumococcal meningitis has shown increasing rates of penicillin resistance Mildly resistant strains to other popular drugs are emerging Cephalosporin resistance is not common R groups can be changed – many variations

Vaccinations - Meningococcal Active against types A, C, Y and W-135 Two vaccines available in the US, a polysaccharide and a conjugate Conjugate vaccine Strongly recommended for 11-21 years old Boosters needed after five years 85-100% effective No vaccine for type B Important to note that they are NOT active against subgroup B – cause of roughly 1/3 all cases in the US. Vaccine is fractional and contains only a part of the microbe – aka it will not infect you. --No B because components of the polysaccharide coat have similarity to components in human neurological tissues --

Vaccinations Pnemoccocal vaccines also have two types – conjugate, PCV13 and polysaccharide, PPVSV HiB Vaccine Recommended for all children under 5 Pnemoccocal also has few side effects Pics: http://www.thehealthmagazine.com/wp-content/uploads/2012/01/prevnar-13.jpg http://www.aafp.org/online/etc/medialib/aafp_org/images/news_folder/aafp_news_now/2009-8/hib-vaccine.Par.0001.Image.250.gif

Vaccinations in the Developing World Vaccination clinic International Coordinating Group (ICG)on Vaccine Provision for Epidemic Meningitis Control Established in 1997 Coordinate meningitis vaccine distribution --Get vaccines where needed most, avoid wastage --Composed of Doctors w/o Borders, Red Cross, UNICEF and WHO --Created largely for prevention/amelioration of outbreaks in Africa, it is available to any country facing potential epidemic WHO – developed and currently working on spreading and approving access to their vaccine specifically for Type A in the highest risk countries http://www.who.int/csr/disease/meningococcal/icg/en/index.html

References http://www.nlm.nih.gov/medlineplus/ency/article/000680.htm http://www.cdc.gov/meningitis/bacterial.html http://www.who.int/nuvi/meningitis/en/index.html http://www.merckmanuals.com/home/brain_spinal_cord_and_nerve_disorders/meningitis/acute_bacterial_meningitis.html https://www.qiagen.com/geneglobe/pathwayview.aspx?pathwayID=50 http://textbookofbacteriology.net/neisseria_6.html Nester, E.; Anderson, D.; Roberts, C.E.; Microbiology: A Human Perspective. McGraw Hill Higher Education, 7th ed., 2012. Hameed, N.; Tunkel, A. R.; Curr. Infect. Dis. Rep. 2010, 12, 274. (Treatment of Drug-resistant Pneumococcal Meningitis) Gold, R.; Infect. Dis. Clin. North Am. 1999, 13, 515. (Epidemiology of bacterial meningitis) Swartz, M. N.; N. Eng. J. Med. 2004, 351, 1826. (Bacterial Meningitis – A View of the Past 90 Years) Ginsberg, L. J. Neurol. Neurosurg. Psychiatry 2004, 75. (Difficult and Recurrent Meningitis) Tunkel, A. R.; Hartman, B. J.; Sheldon, L. K.; et al. Clin. Infect. Dis. 2004, 39, 1267. (Practice Guidelines for the Management of Bacterial Meningitis) Thiqpen, M. C.; Whitney, C. G.; Messonnier, N. E.; Zell, E. R.; et al. N. Engl. J. Med. 2011, 26, 2016. (Bacterial Meningitis in the United States, 1998-2007)