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  2. 2. Our brain, the spinal cord and its surrounding structures could become infected by alarge spectrum of microorganisms . Central nervous system (CNS) infections arecaused by various pathogens, including bacteria, viruses, fungi, and parasites.Depending on the location of the infection, different names are given to the diseases.• MENINGITIS• Encephalitis• Myelitis• AbscessINTRODUCTION
  3. 3. • Meningitis is a serious and potentially life-threatening disease, involves aninflammation of the membranes that cover the brain and spinal cord, called the meninges.• If not treated, meningitis can lead to brain swelling and cause permanent disability,coma , and even death.• Most cases of meningitis are caused by bacteria and virus.• Acute bacterial meningitis develops within hours or days and can be rapidly fatal orlead to serious, permanent complications if not recognized and treated immediately. Pyogenic meningitis: With evidence of pathogenic bacteria in CSF. Aseptic meningitis: Without the usual evidence of pathogenic bacteria in CSF.
  4. 4. TYPES Acute pyogenic (bacterial) meningitis Acute aseptic (viral) meningitis Fungal meningitis Chronic bacterial infection (tuberculosis).EPIDEMIOLOGY Approximately 1.2 million cases of acute bacterial meningitis, excluding epidemics,occur every year around the world, resulting in 135,000 deaths. Overall mortality rates for patients with meningitis range from 2% to 30% dependingon the causative microorganism, approaching 20% in most cases of bacterial meningitis. Generally, 30% to 50% of patients who survive meningitis may develop neurologicdisabilities.
  5. 5. ETIOLOGYBacterialmeningitisStreptococcus pneumoniae (pneumococcus)Most common cause It more commonly causes pneumonia or ear or sinusinfections.Neisseria meningitidis (meningococcus)Commonly occurs when bacteria from an upper respiratory infection enterbloodstream.This infection is highly contagious.Haemophilus influenzae (haemophilus).Before the 1990s, Haemophilus influenzae type b (Hib) bacterium was the leadingcause of bacterial meningitis in children. HiB vaccination greatly reduced the numberof casesThere are various types of bacterial meningitis, but the two types
  6. 6. VIRAL MENINGITISCan also follow and develop afterchicken pox or mumps.some cases of viral meningitis arecaused from mosquito-born viruses.CAUSATIVE AGENT:• Enterovirus• polioviruses types 1,2,&3• coxsackievirus type A and B• HIV• measles• variola virus• rubella viruses• rhinovirus• varicella zooster virus
  7. 7. • Fungal meningitis is rare and usually the result of spread of a fungusthrough blood to the spinal cord• people with weak immune system like those with AIDS or cancer,are at riskFUNGAL MENINGITIS CryptococcusHistoplasmaBlastomycesCaused by the bacterium Mycobacterium tuberculosis. Infection withthis bacterium begins usually the lungs, but in about 2% of cases thebacteria travel via the bloodstream to the meninges and cause TBmeningitis.TUBERCULAR MENINGITISCan also result fromPolluted water Poor hygiene
  8. 8. ANATOMY
  9. 9. Subarachnoid spaceBACTERIAL LYSISby a hematogenousroute reach the meningesBacterial cell wallcomponent releaseEndothelial cells CNS macrophage cellsan intense host inflammatoryresponse triggeredCytokinerelease(IL-1, PGE2,TNF,PAF, etc.)Inflammatory response Neurologic damagePATHOPHYSIOLOGY
  10. 10. Inflammatory response Neurologic damageCont’d…CoagulationcascadeThrombosisVasogenicedemaIncreased ICP Decreased CBFswelling andproliferation of theendothelial cellsof arteriolesveins, causingmural thrombi andobstruction of flowan increase in intracellularsodium and intracellular waterAffectingcortical vesselsCytotoxicandinterstitialedemaoxygendepletionIncreasedCSF protein Decreased CSFglucoseIncreasedCSF lactatedevelopment of brain edemafurther compromises cerebralcirculationICP secretion ofADHThese factors contribute to the developmentof focal or generalized seizures(SIADH) withmeningitis causesfurther retention offree water
  11. 11. CLINICAL PRESENTATIONPHYSICALLY DEMONSTRABLE SIGNSBRUDZINSKI’S NECK SIGNSevere neck stiffness causes a patientships and knees to flex when the neck isflexed.KERNIG’S SIGNSevere stiffness of the hamstrings causesan inability to straighten the leg when thehip is flexed to 90 degrees.SEPTICAEMIC RASH/ PURPURIC RASHWatch out for tiny red or brown pin prickmarks which can change into purpleblotches or blood blisters.
  12. 12.  Nuchal rigidity Lethargy Irritability Apnea Apathy Jaundice Pallor Shock Hypoglycemia Convulsions Anorexia Coma Fever Tachycardia Diaphoresis Weakness Photophobia Seizures Headache AchingmusclesOTHER SYMPTOMS
  13. 13. Blood and other specimens culture:A minimum of 20 mL of blood in each of two to three separatecultures per each 24- hour period is necessary for the detection of mostbacteremias.Gram stain and culture of the CSFMost important laboratory tests performed for bacterialmeningitis. When performed before antibiotic therapy is initiated, Gram stainis both rapid and sensitive and can confirm the diagnosis of bacterialmeningitis in 75% to 90% of cases.Polymerase chain reaction (PCR)Used to diagnose meningitis caused by N. meningitidis, S. pneumoniae,and H. influenzae type b (Hib). PCR is considered to be highly sensitive andspecific. PCR testing of the CSF is the preferred method of diagnosing mostviral meningitis infections.Latex fixation, latex coaglutination, and enzyme immunoassayFor the rapid identification of several bacterial causes ofmeningitis, includingS. pneumoniae, N. meningitidis, and Hib. The rapid antigen tests should beused in situations in which the Gram stain is negative.
  14. 14. A lumbar punctureOr spinal tap, is a procedure to collectcerebrospinal fluid to check for the presenceof disease or injury.A spinal needle is inserted, usually betweenthe 3rd and 4th lumbar vertebrae in thelower spine. Once the needle is properlypositioned in the subarachnoid space (thespace between the spinal cord and itscovering, the meninges), pressures can be
  15. 15. Glucose(mg/dL):40–85 < 40<40<40Normal(> 40)Protein(mg/dL)15 - 45 > 250 25 - 500 50 - 500 <100WBCs(cells/µL)0–5/µL (usually >1000).Early: Maybe < 100Variable(10 -1000)< 500Variable(10 -1000)< 500< 100Celldifferential:60–70% L30% Mmacrophageother cells2% or less.Neutrophils LymphocytesLymphocytesEarly:NeutrophilsLate:LymphocytesCulture: sterile +ve +ve +ve -veOpeningPressure50–180 Elevated VariableVariable UsuallynormalNORMAL BACTERIAL FUNGAL TUBERCULARVIRALCSFANALYSIS
  16. 16.  The choice of antibiotic depends on the organism isolated. In most casesthe initial treatment has to be empirical. Animal studies have shown that a bactericidal effect is necessary forsterilisation of the CSF and survivalThere are three factors affecting antibiotic activity:• Ability to penetrate the CSF•Concentration•Intrinsic activity in infected fluid.In a child with suspected meningitis• urgent transfer to hospital• Followed by concurrent microbiological investigation and antibiotictreatment are the cornerstones of management. Lack of adequate blood and CSF culture may result in difficulty decidingon the duration of treatment and uncertainty over the antimicrobialsusceptibility of organism.
  17. 17. Duration of treatment and choice of antibiotic The duration of antibiotic therapy depends on the organism isolated.• For S.pneumoniae and H.influenzae, 10–14 days recommended• N.meningitidis a seven day course is sufficient.• In Listeria monocytogenes and group B streptococcal meningitis, antibiotics should begiven for 14–21 days.• For Gram negative bacilli a minimum of three weeks is needed. A broad spectrum cephalosporin (cefotaxime or ceftriaxone) is the mostappropriate empirical choice in children over 3 months old. Ampicillin should be added in young infants (less than 3 months old) tocover Listeria monocytogenes. Ceftriaxone may be effective when given as a single daily dose (80–100mg/kg) to treat serious bacterial infections including meningitis in children
  18. 18. Drug Dose Frequency Maximum total dailydosePenicillin G 50 mg/kg 4–6 14.4 gCefotaxime 50 mg/kg 4 3 gCeftriaxone 80–100 mg/kg 1 4 gAmpicillin 100 mg/kg 4 3 gCeftazidime 50 mg/kg 3 6 gVancomycin 15 mg/kg then10 mg/kg4 2 gDosages and frequency of the common antibiotics used in bacterialmeningitis
  19. 19.  Antibiotic therapy may need to be modified once a pathogen is cultured andantibiotic susceptibility testing becomes available. If pneumococcal meningitis is high on the differential diagnosis and there isa clear history of anaphylaxis to beta lactamsvancomycin + chloramphenicol For more complicated cases such as immunosuppressed patients or thosewith recent history of head trauma or neurosurgery and those withcerebrospinal fluid shunts.vancomycin + ceftazidime Studies comparing the use of rifampicin with ceftriaxone in experimentalS.pneumoniae meningitis support the use of rifampicin because of•A reduction in the release of proinflammatory mediators•Decreased secondary brain injury•A lower early mortality ratefollowed by addition of a beta lactam may result in reduction oftissue damage and a better outcome. Other less frequently used carbapenem antibiotics, such as imipenem andmeropenem, are very active in vitro against most isolates of S.pneumoniae,although some penicillin resistant strains have shown reduced susceptibility
  20. 20. Fluroquinolones,such as trovafloxacin, gatifloxacin, and moxifloxacin are potentially effectivein the treatment of multiple resistant pneumococcal isolates because of theiractivity and CSF penetration, even when dexamethasone is also given.The resistance of S.pneumoniae to penicillin and other beta lactam antibioticsis caused by either alteration in• penicillin binding proteins• production of beta lactamaseAmerican Academy of Pediatrics recommended combination therapy, initiallywith vancomycin and either cefotaxime or ceftriaxone for all children 1 monthof age or older with definite or probable bacterial meningitis.In the case of N meningitidis isolates, the great majority are susceptible topenicillin and ampicillin
  21. 21. This reduces the likelihood of the syndrome ofinappropriate secretion of antidiuretic hormone(SIADH). The incidence of SIADH reported in studiesvaries considerably, from4% to 88%SIADH leads to hyponatraemia and fluid retention, whichmay worsen cerebral oedema.Hyponatraemia has been correlated with an increasedrisk of seizures and neurological abnormalities. Althoughhyponatraemia can occur as a result of excessive fluidadministration or SIADH, it can also occur in childrenwith dehydration.However, a significant proportion of meningitis casespresent with dehydration or hypovolaemia and are inclinical need of fluid resuscitation.It is therefore important that the degree of hydrationis carefully assessed in order to correctly manage the
  22. 22. o Empiric antimicrobial therapy should be instituted as soon as possible toeradicate the causative organism.o Antimicrobial therapy should last at least 48 to 72 hours or until the diagnosisof bacterial meningitis can be ruled out.Continued therapy should be based on the assessment of• clinical improvement• Cultures• susceptibility testing results.o Once a pathogen is identified, antibiotic therapy should be tailored to thespecific pathogen.With increased meningeal inflammation, there will be greater antibioticpenetrationProblems of CSF penetration may be overcome by direct instillation ofantibiotics by• intrathecal• intracisternal• Intraventricular
  23. 23. Dexamethasone as an Adjunctive Treatmentfor Meningitiscommonly used therapy for the treatment of pediatric meningitis.MOA : causes a significant improvement in CSF concentrations ofproinflammatory cytokines, glucose, protein, and lactate as well as a significantlylower incidence of neurologic sequelae commonly associated with bacterialmeningitis.The American Academy of Pediatrics suggests that the use of dexamethasone beconsidered for infants and children aged 2 months or older with pneumococcalmeningitis and that it be given to those with H. influenzae meningitis.IV dexamethasone dose• 0.15 mg/kg every 6 hours for 4 days. Alternatively,• 0.15 mg/kg every 6 hours for 2 days or 0.4 mg/kg every 12 hours for 2 daysis equally effective and a potentially less toxic regimen.
  24. 24. Neisseria meningitidis (Meningococcus)Aggressive, early intervention with high-dose IV crystalline penicillin G 50,000units/kg every 4 hoursSeveral third generation cephalosporins (e.g., cefotaxime, ceftizoxime,ceftriaxone,& cefuroxime)Meropenem and fluoroquinolones are suitable alternatives for treatment ofpenicillinnon-susceptible meningococci.Prophylaxis of contacts should be started only after consultation with the localhealth department.• Adult patients -600 mg of rifampin orally every 12 hours for four doses.• 1 month to 12 years of age -10 mg/kg of rifampin orally 12 hours for fourdoses• younger than 1 month - 5 mg/kg orally every 12 hours for four doses.
  25. 25. The treatment of choice until susceptibility of the organism is thecombination of vancomycin + ceftriaxone.Penicillin may be used for drug-susceptible isolates.A high percent of S. pneumoniae is either intermediately or highly resistantto penicillin.A heptavalent conjugate vaccine is available for use in infants between 2months and 9 years of age.For all healthy infants younger than 2 years of age to be immunized with theheptavalent vaccine at 2, 4, 6, and 12 to 15 months.Streptococcus pneumoniae(Pneumococcusor Diplococcus)
  26. 26. 30% to 40% of H. influenzae are ampicillin resistant. For this reason, manyclinicians use a third-generation cephalosporin (cefotaxime or ceftriaxone) forinitial antimicrobial therapy.Cefepime and fluoroquinolones are suitable alternatives regardless of β-lactamase activity.Prophylaxis of close contacts• children 20 mg/kg (maximum 600 mg)• adults 600 mg daily in one dose for 4 days.Fully vaccinated individuals should not receive prophylaxis.Vaccination with Hib conjugate vaccines is usually begun in children at 2months.The vaccine should be considered in patients older than 5 years with sickle celldisease, asplenia, or immunocompromising diseases.Haemophilus influenzae
  27. 27. Listeria monocytogenesThe combination of penicillin G or ampicillin with an aminoglycoside results ina bactericidal effect.Patients should be treated for 2 to 3 weeks after defervescence to preventthe possibility of relapse.Trimethoprim-sulfamethoxazole may be an effective alternative becauseadequate CSF penetration is achieved with these agents.
  28. 28. Gram-Negative Bacillary MeningitisMeningitis caused by Pseudomonas aeruginosa is initially treated with• ceftazidime or cefepime,• piperacillin + tazobactam, (or )• meropenem + aminoglycoside, usually tobramycin.If resistance developed…An intraventricular aminoglycoside should be considered along with IV AG(0.03mg of tobramycin or gentamicin per mL of CSF and 0.1 mg of amikacin permL of CSF every 24 hours)Gram-negative organisms, other than P. aeruginosa• 3rd generation or 4th generation cephalosporin•In adults, dailydoses of 8 to 12 g/day of these third-generation cephalosporins or 2 g ofceftriaxone twice daily should produce CSF concentrations of 5 to 20 mg/L.
  29. 29. Mycobacterium tuberculosisA regimen of four drugs Isoniazid, rifampin, pyrazinamide, and ethambutol,15 to 20 mg/kg/day (maximum 1.6 g/day) for the first 2 months generallyfollowed by isoniazid plus rifampin for the duration of therapy.In children, the usual dose of isoniazid is 10 to 15 mg/kg/day (max 300 mg/day).Adults usually receive 5 mg/kg/day or a daily dose of 300 mg.Concurrent administration of rifampin is recommended at doses of• 10 to 20 mg/kg/day (maximum 600 mg/day) for children• 600 mg/day for adults.The addition of pyrazinamide to the regimen of isoniazid and rifampin isrecommended.(children and adults, 15 to 30 mg/kg/ day; maximum in both, 2 g/day)
  30. 30. Patients with M. tuberculosis meningitis should be treated for a duration of 9months or longer with multiple-drug therapy, and patients with rifampin-resistant strains should receive 18 to 24 months of therapy.The use of glucocorticoids for tuberculous meningitis remains controversial.The administration of steroids such asoral prednisone, 60 to 80 mg/ day (1 to 2 mg/kg/day in children),(or) 0.2 mg/kg/day of IV dexamethasone, tapered over 4 to 8 weeks,• Improves neurologic sequelae and survival in adults & decrease mortality,• Prevents Long-term neurologic complications, and permanent sequelae inchildren.
  31. 31. Cryptococcus neoformansAmphotericin B is the drug of choice for treatment of acute C. neoformansmeningitis. Amphotericin B, 0.5 to 1 mg/kg/day, combined with flucytosine,100 mg/kg/day,is more effective than amphotericin alone.In the (AIDS) population,flucytosine is often poorly tolerated, causing bone marrow suppression and GIdistress.Due to the high relapse rate following acute therapy…AIDS patients require lifelong maintenance or suppressive therapy. Thestandard of care for AIDS-associated cryptococcal meningitis is primary therapyof generally using amphotericin B with or without flucytosine followed bymaintenance therapy with fluconazole for the life of the patient.
  32. 32. •Nonpolio enteroviruses such as coxsackievirus A and B, echoviruses, andenterovirus 70 and 71 cause approximately 85% of all viral encephalitis cases.•The remaining 10% to 15% of viral encephalitis cases are caused by a variety ofpathogens, such as arboviruses, adenoviruses, influenzae virus A and B, rotavirus,corona virus, cytomegalovirus, varicella-zoster, herpes simplex virus•Acyclovir is the drug of choice for herpes simplex encephalitis. In patients withnormal renal function, acyclovir usually is administered 10 mg/kg intravenouslyevery 8 hours for 2 to 3 weeks.•Herpes virus resistance to acyclovir has been reported with increasing incidence,particularly from immunocompromised patients with prior or chronic exposures toacyclovir.•The alternative treatment of acyclovir-resistant herpes simplex virus isfoscarnet. The major toxicity of foscarnet is renal impairment, and doses must beindividualized for renal function.•For patients with normal renal function is 40 mg/kg infused over 1 hour every 8to 12 hours for 2 to 3 weeks. Ensuring adequate hydration is imperative. Monitorfor seizures related to alterations in plasma electrolyte levels.VIRAL MENINGITIS
  33. 33. Acute complications•Seizures•Syndrome of inappropriate antidiuretic hormone (SIADH)secretion•Hemodynamic instability•Increased intracranial pressure•Subdural effusions•Focal neurologic deficitsChronic complications•Deafness•Seizure disorders•Motor deficits•Language deficits•Behavior disorders•Mental retardation
  34. 34. REFERENCE•Text Book of Pharmacotherapy, By Joseph T.Dipiro.•••••••
  35. 35. THANK YOU