R.MADHURIROLL N0:5 PHARM-D III YEAR

MENINGITIS

Our brain, the spinal cord and its surrounding structures could become infected by a large spectrum of microorganisms . Central nervous system (CNS) infections are caused 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

• Abscess

INTRODUCTION

• Meningitis is a serious and potentially life-threatening disease, involves an inflammation 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 or lead 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.

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% depending on the causative microorganism, approaching 20% in most cases of bacterial meningitis.

Generally, 30% to 50% of patients who survive meningitis may develop neurologic disabilities.

ETIOLOGYBacterial meningitis Streptococcus pneumoniae (pneumococcus) Most common cause It more commonly causes pneumonia or ear or sinus infections.

Neisseria meningitidis (meningococcus) Commonly occurs when bacteria from an upper respiratory infection enter bloodstream. This infection is highly contagious.

Haemophilus influenzae (haemophilus). Before the 1990s, Haemophilus influenzae type b (Hib) bacterium was the leading cause of bacterial meningitis in children. HiB vaccination greatly reduced the number of cases

There are various types of bacterial meningitis, but the two types that signify the majority of the bacterial meningitis are called Meningococcal and Pneumococcal.

They can be spread among people from: sneezing , coughing , physical contact

VIRAL MENINGITIS

Can also follow and develop after chicken pox or mumps.

some cases of viral meningitis are caused 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

• Fungal meningitis is rare and usually the result of spread of a fungus through blood to the spinal cord• people with weak immune system like those with AIDS or cancer, are at risk

FUNGAL MENINGITIS

Cryptococcus

Histoplasma

Blastomyces

Caused by the bacterium Mycobacterium tuberculosis. Infection with this bacterium begins usually the lungs, but in about 2% of cases the bacteria travel via the bloodstream to the meninges and cause TB meningitis.

TUBERCULAR MENINGITIS

Can also result from

Polluted water

Poor hygiene

ANATOMY

Subarachnoid space

BACTERIAL LYSIS

by a hematogenous route

reach the meninges

Bacterial cell wallcomponent release

Endothelial cells CNS macrophage cells

an intense host inflammatory response triggered

Cytokine release(IL-1, PGE2, TNF,PAF, etc.)

Inflammatory response

Neurologic damage

PATHOPHYSIOLOGY

Inflammatory response

Neurologic damage

Cont’d…

Coagulation cascade

Thrombosis

Vasogenic edema

Increased ICP Decreased CBF

swelling and proliferation of the endothelial cells of arterioles

veins, causing mural thrombi and obstruction of flow

an increase in intracellular sodium and intracellular water

Affecting cortical vessels

Cytotoxic andinterstitial edema

oxygen depletion

IncreasedCSF protein

Decreased CSF glucose

IncreasedCSF lactate

development of brain edema further compromises cerebral circulation

ICP secretion of ADH

These factors contribute to the development of focal or generalized seizures

(SIADH) with meningitis causes further retention of free water

CLINICAL PRESENTATIONPHYSICALLY DEMONSTRABLE

SIGNS BRUDZINSKI’S NECK SIGNSevere neck stiffness causes a patient's hips and knees to flex when the neck is flexed.

KERNIG’S SIGNSevere stiffness of the hamstrings causes an inability to straighten the leg when the hip is flexed to 90 degrees.

SEPTICAEMIC RASH/ PURPURIC RASHWatch out for tiny red or brown pin prick marks which can change into purple blotches or blood blisters.

Nuchal rigidity Lethargy Irritability Apnea Apathy Jaundice Pallor Shock Hypoglycemia Convulsions Anorexia Coma Fever Tachycardia Diaphoresis Weakness Photophobia Seizures Headache Aching

muscles

OTHER SYMPTOMS

DIAGNOSISBlood and other specimens culture: A minimum of 20 mL of blood in each of two to three separate cultures per each 24- hour period is necessary for the detection of most bacteremias.

Gram stain and culture of the CSF Most important laboratory tests performed for bacterial meningitis. When performed before antibiotic therapy is initiated, Gram stain is both rapid and sensitive and can confirm the diagnosis of bacterial meningitis 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 and specific. PCR testing of the CSF is the preferred method of diagnosing most viral meningitis infections.

Latex fixation, latex coaglutination, and enzyme immunoassay For the rapid identification of several bacterial causes of meningitis, including S. pneumoniae, N. meningitidis, and Hib. The rapid antigen tests should be used in situations in which the Gram stain is negative.

•Diagnostic tests for fungal meningitis include culture, direct microscopic examination of stained and unstained specimens of CSF•Diagnosis of tuberculosis meningitis employs acid-fast staining, culture, and PCR of the CSF.

A lumbar puncture

Or spinal tap, is a procedure to collect cerebrospinal fluid to check for the presence of disease or injury.

A spinal needle is inserted, usually between the 3rd and 4th lumbar vertebrae in the lower spine. Once the needle is properly positioned in the subarachnoid space (the space between the spinal cord and its covering, the meninges), pressures can be measured and fluid can be collected for testing.

Glucose (mg/dL):

40–85 < 40<40 <40 Normal  

(> 40)

Protein (mg/dL)

15 - 45 > 250 25 - 500 50 - 500 <100

WBCs (cells/µL)

0–5/µL (usually > 1000).  Early: May be < 100

Variable (10 -1000)< 500

Variable (10 -1000)< 500

< 100

Cell differential:

60–70% L30% M macrophageother cells 2% or less.

Neutrophils

Lymphocytes

Lymphocytes

Early:Neutrophils Late:Lymphocytes

Culture: sterile +ve +ve +ve -ve

Opening Pressure(mmH2O)

50–180 Elevated VariableVariable Usually

normal

NORMAL BACTERIAL FUNGAL TUBERCULAR VIRAL

CS

F A

NA

LYS

IS

TREATMENT The choice of antibiotic depends on the organism isolated. In most cases the initial treatment has to be empirical. Animal studies have shown that a bactericidal effect is necessary for sterilisation of the CSF and survival

There 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 antibiotic treatment are the cornerstones of management.

Lack of adequate blood and CSF culture may result in difficulty deciding on the duration of treatment and uncertainty over the antimicrobial susceptibility of organism.

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 be given for 14–21 days. • For Gram negative bacilli a minimum of three weeks is needed.

A broad spectrum cephalosporin (cefotaxime or ceftriaxone) is the most appropriate empirical choice in children over 3 months old.

Ampicillin should be added in young infants (less than 3 months old) to cover Listeria monocytogenes.

Ceftriaxone may be effective when given as a single daily dose (80–100 mg/kg) to treat serious bacterial infections including meningitis in children

Drug Dose Frequency Maximum total daily dose

Penicillin G 50 mg/kg 4–6 14.4 g

Cefotaxime 50 mg/kg 4 3 g

Ceftriaxone 80–100 mg/kg

1 4 g

Ampicillin 100 mg/kg 4 3 g

Ceftazidime 50 mg/kg 3 6 g

Vancomycin 15 mg/kg then 10 mg/kg

4 2 g

Dosages and frequency of the common antibiotics used in bacterial meningitis

Antibiotic therapy may need to be modified once a pathogen is cultured and antibiotic susceptibility testing becomes available.

If pneumococcal meningitis is high on the differential diagnosis and there is a clear history of anaphylaxis to beta lactams vancomycin + chloramphenicol

For more complicated cases such as immunosuppressed patients or those with recent history of head trauma or neurosurgery and those with cerebrospinal fluid shunts. vancomycin + ceftazidime

Studies comparing the use of rifampicin with ceftriaxone in experimental S.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 rate followed by addition of a beta lactam may result in reduction of tissue damage and a better outcome.

Other less frequently used carbapenem antibiotics, such as imipenem and meropenem, are very active in vitro against most isolates of S.pneumoniae, although some penicillin resistant strains have shown reduced susceptibility

Fluroquinolones, such as trovafloxacin, gatifloxacin, and moxifloxacin are potentially effective in the treatment of multiple resistant pneumococcal isolates because of their activity and CSF penetration, even when dexamethasone is also given.

Antibiotic resistance

The resistance of S.pneumoniae to penicillin and other beta lactam antibiotics is caused by either alteration in • penicillin binding proteins• production of beta lactamase

American Academy of Pediatrics recommended combination therapy, initially with vancomycin and either cefotaxime or ceftriaxone for all children 1 month of age or older with definite or probable bacterial meningitis.

In the case of N meningitidis isolates, the great majority are susceptible to penicillin and ampicillin

Use of intravenous fluidsThis reduces the likelihood of the syndrome of inappropriate secretion of antidiuretic hormone (SIADH). The incidence of SIADH reported in studies varies considerably, from 4% to 88%

SIADH leads to hyponatraemia and fluid retention, which may worsen cerebral oedema.

Hyponatraemia has been correlated with an increased risk of seizures and neurological abnormalities. Although hyponatraemia can occur as a result of excessive fluid administration or SIADH, it can also occur in children with dehydration.

However, a significant proportion of meningitis cases present with dehydration or hypovolaemia and are in clinical need of fluid resuscitation.

It is therefore important that the degree of hydration is carefully assessed in order to correctly manage the fluid balance

o Empiric antimicrobial therapy should be instituted as soon as possible to eradicate the causative organism.

o Antimicrobial therapy should last at least 48 to 72 hours or until the diagnosis of 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 the specific pathogen.

With increased meningeal inflammation, there will be greater antibiotic penetrationProblems of CSF penetration may be overcome by direct instillation of antibiotics by • intrathecal• intracisternal• Intraventricular routes of administration

SPECIFIC TREATMENT

Dexamethasone as an Adjunctive Treatment for Meningitis

commonly used therapy for the treatment of pediatric meningitis.

MOA : causes a significant improvement in CSF concentrations of proinflammatory cytokines, glucose, protein, and lactate as well as a significantly lower incidence of neurologic sequelae commonly associated with bacterial meningitis.

The American Academy of Pediatrics suggests that the use of dexamethasone be considered for infants and children aged 2 months or older with pneumococcal meningitis 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 days is equally effective and a potentially less toxic regimen.

Neisseria meningitidis (Meningococcus)

Aggressive, early intervention with high-dose IV crystalline penicillin G 50,000 units/kg every 4 hours

Several third generation cephalosporins (e.g., cefotaxime, ceftizoxime, ceftriaxone,& cefuroxime)

Meropenem and fluoroquinolones are suitable alternatives for treatment of penicillin non-susceptible meningococci.

Prophylaxis of contacts should be started only after consultation with the local health 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 four doses• younger than 1 month - 5 mg/kg orally every 12 hours for four doses.

The treatment of choice until susceptibility of the organism is the combination of vancomycin + ceftriaxone.

Penicillin may be used for drug-susceptible isolates.

A high percent of S. pneumoniae is either intermediately or highly resistant to penicillin.

A heptavalent conjugate vaccine is available for use in infants between 2 months and 9 years of age.

For all healthy infants younger than 2 years of age to be immunized with the heptavalent vaccine at 2, 4, 6, and 12 to 15 months.

Streptococcus pneumoniae (Pneumococcus or Diplococcus)

30% to 40% of H. influenzae are ampicillin resistant. For this reason, many clinicians use a third-generation cephalosporin (cefotaxime or ceftriaxone) for initial 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 2 months.

The vaccine should be considered in patients older than 5 years with sickle cell disease, asplenia, or immunocompromising diseases.

Haemophilus influenzae

Listeria monocytogenes

The combination of penicillin G or ampicillin with an aminoglycoside results in a bactericidal effect.

Patients should be treated for 2 to 3 weeks after defervescence to prevent the possibility of relapse.

Trimethoprim-sulfamethoxazole may be an effective alternative because adequate CSF penetration is achieved with these agents.

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 per mL 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 of ceftriaxone twice daily should produce CSF concentrations of 5 to 20 mg/L.

Mycobacterium tuberculosis

A 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 generally followed 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 is recommended. (children and adults, 15 to 30 mg/kg/ day; maximum in both, 2 g/day)

Patients with M. tuberculosis meningitis should be treated for a duration of 9 months 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 as oral 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 in children.

Cryptococcus neoformansAmphotericin B is the drug of choice for treatment of acute C. neoformans meningitis. 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 GI distress.

Due to the high relapse rate following acute therapy… AIDS patients require lifelong maintenance or suppressive therapy. The standard of care for AIDS-associated cryptococcal meningitis is primary therapy of generally using amphotericin B with or without flucytosine followed by maintenance therapy with fluconazole for the life of the patient.

•Nonpolio enteroviruses such as coxsackievirus A and B, echoviruses, and enterovirus 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 of pathogens, 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 with normal renal function, acyclovir usually is administered 10 mg/kg intravenously every 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 to acyclovir.

•The alternative treatment of acyclovir-resistant herpes simplex virus is foscarnet. The major toxicity of foscarnet is renal impairment, and doses must be individualized for renal function.

•For patients with normal renal function is 40 mg/kg infused over 1 hour every 8 to 12 hours for 2 to 3 weeks. Ensuring adequate hydration is imperative. Monitor for seizures related to alterations in plasma electrolyte levels.

VIRAL MENINGITIS

COMPLICATIONS

Acute complications•Seizures•Syndrome of inappropriate antidiuretic hormone (SIADH) secretion•Hemodynamic instability•Increased intracranial pressure•Subdural effusions•Focal neurologic deficits

Chronic complications•Deafness•Seizure disorders•Motor deficits•Language deficits•Behavior disorders•Mental retardation

REFERENCE

•Text Book of Pharmacotherapy, By Joseph T.Dipiro.

•http://emedicine.medscape.com/article/1165557-differential•http://www.rightdiagnosis.com/v/viral_meningitis/intro.htm•http://bacmen.weebly.com/pathophysiology.html•http://www.jaapa.com/meningitis-distinguishing-the-benign-from-the-serious/article•http://bacmen.weebly.com/pathophysiology.html•http://www.nlm.nih.gov/medlineplus/meningitis.html•http://www.globalrph.com/cerebrospinal_fluid.htm

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