Treatment: General Principle

• Avoidance of delay

• Emperical antibiotic

• Drug entry into CSF —Most drugs reach peak concentrations in the CSF that are only 10 to 20 percent of peak concentrations in the serum. This is because the blood-brain barrier blocks macromolecule entry into the CSF, with small, lipophilic molecules penetrating most easily.

• The peak concentration of drugs in CSF increases with inflammation of the blood-brain barrier. The mean CSF/serum ratio two hours after administration of the same intravenous dose of penicillin was 42 percent on the first day of therapy but fell to less than 10 percent on the tenth day, when the inflammatory changes had subsided

Immediate management

• Assurance of adequate ventilation and cardiac perfusion. • Initiation of hemodynamic monitoring• Establishment of venous access. • Administration of fluids as necessary to treat septic shock,

if present. • Administration of dexamethasone if warranted. before

or immediately after the first dose of antimicrobial therapy.• Administration of the first dose of empiric antibiotics • Administration of glucose (0.25 g/kg) for documented

hypoglycemia (serum glucose concentration less than 40 mg/dL

• Treatment of acidosis and coagulopathy

Supportive care• Fluid and electrolyte management —

– Isotonic fluid to maintain blood pressure and cerebral perfusion.

– Children who are hypovolemic, but not in shock, should be rehydrated with careful and frequent attention to fluid status.

– For children who are neither in shock nor hypovolemic, moderate fluid restriction (1200 mL/m2 per day) initially, especially if the serum sodium is less than 130 meq/L. Fluid administration can be liberalized gradually as the serum sodium reaches 135 meq/L. Most children can receive maintenance fluid intake within 24 hours of hospitalization.

• Monitoring —– increased intracranial pressure, seizure activity, development

of infected subdural effusions, particularly during the first two to three days of treatment,

– Heart rate, blood pressure, and respiratory rate should be monitored regularly with a frequency appropriate to the care setting.

– A complete neurologic examination should be performed daily; rapid assessment of neurologic function should be performed several times per day for the first several days of treatment.

– Head circumference should be measured daily in children younger than 18 months

• In US (nelson)– 25-50% S.pneumoniae resistant to penicillin– 25 % S Pneumoniae resistant to cefotax or

ceftraixone– 30-40 % Hib resistant to ampicillin

• In INDIA ?

JIPMER Study

Organisms were isolated from the cerebrospinal fluid (CSF) in 35% of cases. Among infants and children, the two major pathogens were H. influenzae (17%) and S. pneumoniae (12%). RESULTS: The illness at presentation was mild in 13% and severe in 36% of cases. The

Emperic Therapy

• empiric regimen should include coverage for Hib, penicillin resistant S. pneumoniae and N. meningitidis. E.coli in young infants

• High dose of 3rd generation cephalosporin + Vancomycin

Antibiotic Therapy• Certainly Bacterium

– Once the pathogen has been identified and the antibiotic sensitivities determined, the most appropriate drugs should selected.

• N meningitidis : penicillin, tert- cephalosporin

• S pneumoniae: penicillin, tert- cephalosporin, vancomycin

• H influenzae: ampicillin, tert- cephalosporin

• S aureus: penicillin, nefcillin, vancomycin

• E coli: ampicillin, chloramphenicol, tert- cephalosporin

Dexamethasone• Animal studies:hearing loss is associated with the

severe inflammatory changes• RCT and meta-analyses indicate that dexamethasone

therapy provides no survival advantage in children, but reduces the incidence of deafness and severe neurologic complications in selected children, predominantly those with meningitis caused by Hib. The data are insufficient to demonstrate a clear benefit in children with pneumococcal meningitis

• before or within one hour of the first dose of antibiotic therapy

• concern that the CSF concentration of vancomycin may be diminished when administered with dexamethasone

• > 6 weeks of age• 0.15 mg/kg per dose) every 6 hours for 2 to 4 days

Duration of treament

• S. pneumoniae: 10-14 days• N. meningitidis: 5-7 days• Hib: 7-10 days• Gram –ve: 3 weeks• CSF analysis near the end of therapy,

particularly in young infants, needs longer therapy if– Percentage of neutrophils >30 percent, – or CSF glucose concentration <20 mg/dL

Bacterial Meningitis - Treatment

Neonatal (<3 mo) • Ampicillin (covers Listeria)

+• Cefotaxime

– High CSF levels– Less toxicity than aminoglycosides– No drug levels to follow– Not excreted in bile not inhibit bowel

flora

Pneumococcal meningitis

Antibiotic susceptibility

• Susceptible

• Non-susceptible

• Resistant

Pneumococcal resistance• Strep pneumococcus - most common cause

of invasive bacterial infections in children >2 months old

• Incidence of PCN-, cefotaxime- & ceftriaxone-nonsusceptible isolates has ’d to ~40%

• Strains resistant to PCN, cephalosporins, and other -lactam antibiotics often resistant to trimethoprim-sulfamethoxazole (Bactrim™, Septra™), erythromycin, chloramphenicol, tetracycline

Mechanism of resistance• PCN-binding proteins synthesize

peptidoglycan for new cell wall formation• PCN, cephalosporins, and other -lactam

antibiotics kill S pneumoniae by binding irreversibly to PCN-binding proteins located in the bacterial cell wall

• Chromosomal changes can cause the binding affinity for the -lactam antibiotics to decrease

Pneumococcal meningitis – Mgmt

• Vancomycin + cefotaxime or ceftriaxone, if > 1 month old

• If hypersensitive (allergic) to -lactam antibiotics, use vancomycin + rifampin

• D/C vancomycin once testing shows PCN-susceptibility

• Consider adding rifampin if susceptible & condition not improving, or cefotaxime or ceftriaxone MIC high

• Not vancomycin alone

• PCN-susceptible organism:– PenG 250,000 - 400,000 U/kg/day Q 4

- 6 h– Ceftriaxone 100 mg/kg/day Q 12 - 24 h– Cefotaxime 225 - 300 mg/kg/day Q 8 h– Chloramphenicol 50 - 100 mg/kg/day

Q 6 h

• Adequate cephalosporin levels in CSF ~2.8 hours after dose administration

ROLE OF VANCOMYCIN• Combination therapy since late 90’s• At initiation-

– Baseline urinalysis– BUN and creatinine

• Enters the CSF in the presence of inflamed meninges within 3 hours

• Should not be used as solo agent, but with cephalosporin for synergy

Vancomycin use inpneumococcal meningitis

• Vancomycin 60 mg/kg/day Q 6 h• Trough levels immediately before 3rd

dose• (10-15 mcg/mL or less)• Peak serum level 30-60 minutes

after completion of a 30-minute infusion(35-40 mcg/mL)

RESISTANT CASES

• Rifampin– 20 mg/kg/day Q

12

– Not a solo agent– Slowly

bactericidal

• Meropenem– Carbapenem– 120 mg/kg/day Q

8 h seizure incidence, not generally used in meningitis

– Resistance reported

Dexamethasone Role

• Consider if H flu & S pneumo meningitis & > 6 wks old 0.6 mg/kg/day Q 6h x 2d

local synthesis of TNF-, IL-1, PAF & prostaglandins resulting in BBB permeability, meningeal irritation

• Debate if it incidence of hearing loss• If used, needs to be given shortly before or

at the time of antibiotic administration• May adversely affect the penetration of

antibiotics into CSF

Pneumococcal meningitis - Treatment

• LP after 24-48 hours to evaluate therapy if:– Received dexamethasone

– PCN-non-susceptible

– MIC’s not available

– Child’s condition not improving

Infection control precautions

• CDC recommends Standard Precautions

• Airborne, Droplet, Contact are NOT recommended

• Nasopharyngeal cultures of family members and contacts is NOT recommended

• No isolation of contacts

• No chemoprophylaxis for contacts

Meningococcemia - Isolation

• Capable of transmitting organism up to 24 hours after initiation of appropriate therapy

• Droplet precautions x 24 hours, then no isolation

• Incubation period 1 - 10 days, usually <4 days

Meningococcemia - Treatment

• Antibitotic resistance rare

• Antibitotics:– PCN

– Cefotaxime or Ceftriaxone

• Patient should get rifampin prior to discharge

Meningococci – Care Takers

• Day care where child attends >25 h/wk, kids are >2 years old, & 2 cases have occurred

• Day care where kids not all vaccinated• Persons who have had “intimate contact”

w/ oral secretions prior & during 1st 24 h of antibiotics

• “Intimate contact” – 300-800x risk(kissing, eating/ drinking utensils, mouth-to-mouth,

suctioning, intubating)

Meningococcemia - Prophylaxis

• No randomized controlled trials of effectiveness

• Treat within 24 hours of exposure

• Vaccinate affected population, if outbreak

• Rifampin– Urine, tears, soft contact lenses orange;

OCP’s ineffective– <1 mo 5 mg/kg PO Q 12 x 2 days– >1 mo 10 mg/kg (max 600 mg) PO Q 12 x

2 days

• Ceftriaxone 12 y 125 mg IM x 1 dose– >12 y 250 mg IM x 1 dose

• Ciprofloxacin 18 y 500 mg PO x 1 dose

Meningococcal meningitis - Outcomes

• Substantial morbidity: 11% - 9% of survivors have sequelae– Neurologic disability– Limb loss– Hearing loss

• 10% case-fatality ratio for meningococcal sepsis

• 1% mortality if meningitis alone

Summary• Antibiotics ASAP, even if LP not yet done

• Vanco + cephalosporin until some identification known– CSF, Latex, exam

• Isolate if bacterial x 24 hours, Universal Precautions

• Monitor for status changes– Pupils, LOC, HR, BP, resp– Seizures– Hemodynamics– DIC, coagulopathy– Fluid, electrolyte issues

Meningitis - Treatment duration

• Neonates: 14 – 21 days

• Gram negative meningitis: 21 days

• Pneumococcal, H flu: 10 days

• Meningococcal: 7 days

Out patient therapy

• Completion of at least 6 days of inpatient therapy

• Afebrile for at least 24 to 48 hours before initiation of outpatient therapy.

• No significant neurologic dysfunction or focal findings.

• No seizure activity.

• Clinical stability.

Response to therapy• duration of fever is typically four to six

days after the initiation of adequate therapy

• Persistence of fever beyond 8 days and secondary fever have a number of causes, including:– Inadequate treatment– Development of nosocomial infection – Discontinuation of dexamethasone – Development of a suppurative complication

(pericarditis, pneumonia, arthritis, subdural empyema)– Drug fever (a diagnosis of exclusion)

Repeat CSF

• Poor clinical response after 24-36 hours of antibiotics

• Persistence or recurrence of fever

• Gram –ve meningitis

Neuroimaging

• Focal neurologic signs, increasing head circumference, or prolonged obtundation, irritability, or seizures (>72 hours after the start of treatment);

• Persistently positive CSF cultures despite appropriate antibiotic therapy

• Persistent elevation of CSF neutrophils at the completion of standard duration of therapy (more than 30 to 40 percent)

• Recurrent meningitis

Prognosis

• Mortality:meta-analysis: 4520 children 4.8 %in developed countries and 8.1 % in developing countries

• Hib:3.8 %, N. meningitidis: 7.5 %, S. pneumoniae: 15.3 %

• Neurological sequele:16% in developed and 26 % in developing countries– Deafness — 11 percent, including bilateral severe

or profound deafness in 5 percent– Mental retardation — 4 percent – Spasticity and/or paresis — 4 percent – Seizures — 4 percent

Poor prognostic factors

• Etiology: more with pneumocaccal

• Seizure after 72 hours

• CSF sugar < 20 mg per dl at admission

• Delayed sterlization of CSF : > 24 hours

Meningitis - Acute complications

• Hydrocephalus• Subdural effusion

or empyema ~30%

• Stroke• Abscess• Dural sinus

thrombophlebitis

Complications of meningitis in infants and children.

- Hearing loss is the most encountered sequelae; it occurs * in 30% cases of S. pneumoniae meningitis, * in 20% of H. influenzae meningitis, * in 10% of N. meningitidis meningitis.– Mental retardation, seizures, delay in language acquisition, visual impairment, behavioural problems and hydrocephalus.

• Thrombocytosis, eosinophilia, and anemia may develop during therapy for meningitis. Anemia may be due to hemolysis or bone marrow suppression.

• DIC is most often associated with the rapidly progressive pattern of presentation and is noted most commonly in patients with shock and purpura.

• The combination of endotoxemia and severe hypotension initiates the coagulation cascade; the coexistence of ongoing thrombosis may produce symmetric peripheral gangrene.

Bacterial meningitis - Outcomes

• Neonates: ~20% mortality

• Older infants and children:– <10% mortality

– 33% neurologic abnormalities at discharge

– 11% abnormalities 5 years later

• Sensorineural hearing loss 2 - 29%