Pediatric Bacterial Pediatric Bacterial Meningitis in the PhilippinesMeningitis in the Philippines

Cecilia C. Maramba-Cecilia C. Maramba-Untalan, MDUntalan, MD

Bacterial Meningitis in the Philippines

One of the top leading causes of mortality in children 0-4 yrs oldPathogens and susceptibility patterns are different from those identified in other countriesManagement recommendations must be appropriate for the Philippine settingTask Force on Meningitis convened in order to address this problem

Signs and Symptoms of Signs and Symptoms of MeningitisMeningitis

are variable and depend on the age of the patient, and the duration of illness before treatmentneonates and young infants may have minimal signs and symptomssigns of symptoms of neonatal sepsis are indistinguishable from neonatal meningitisall neonates being evaluated for sepsis should be evaluated for meningitis

Signs and Symptoms of Bacterial Signs and Symptoms of Bacterial MeningitisMeningitis

Signs and Signs and symptomssymptoms

NeonatesNeonates Older infants and childrenOlder infants and children

NonspecificNonspecific Fever or hypothermia, abnormally sleepy or lethargic, disinterest in feeding, poor feeding, cyanosis, grunting, apneic episodes, vomiting

Fever, anorexia, confusion, irritability, photophobia, nausea, vomiting, headache, seizure

Meningeal Meningeal inflammationinflammation

Neck rigidity, Neck rigidity, Kernig and Brudzinski sign

Increased Increased intracranial intracranial pressurepressure

Bulging fontanel, diastasis of sutures, convulsions, opisthotonus

Headache, bulging fontanel, diastasis of sutures in infants, papilledema, mental confusion, altered state of consciousness

Focal Focal neurologic neurologic signssigns

Hemiparesis, ptosis, facial nerve palsy

Hemi paresis, ptosis, deafness, facial nerve palsy, optic neuritis

Lumbar puncture is essentialCornerstone in the diagnosisshould be performed in all cases whenever the diagnosis of meningitis is known or suspected on the basis of clinical signs

Contraindications to doing a lumbar tap1. presence of significant cardio-pulmonary compromise and

shock2. signs of increased ICP3. suspected case of space occupying lesion4. infection in the area that the spinal needle will traverse to obtain

CSF5. hematologic problems

Laboratory Diagnosis of Bacterial MeningitisLaboratory Diagnosis of Bacterial Meningitis

CSF Findings in Bacterial Meningitis

a. CSF pressure - usually elevatedb. CSF cells count and chemistry leukocytosis- >1000/cu mm % PMN - 90% Glucose- <40 mg/dl CSF blood to glucose ratio <0.40 Protein 50-500 mg/dlc. stained smears of CSF gram stain - (+) for bacteria AFB smear - (-) India ink - (-) d. CSF culture *a negative culture does rule out meningitis

Other CSF Tests Useful in Diagnosis Bacterial Meningitis

Antigen detection tests - Coagglutination - - Latex agglutination - antigens of H. influenzae B, S.

pneumoniae, Group B. streptococcus, E. coli and Neisseria meningitidisAntigen detection tests should never be substituted for culture and gram stainif only a small amount of CSF is obtained, do gram stain and culture

Other Useful Laboratory Tests

Culture of other normally sterile fluids aside from CSF

Blood culture- should be obtained in every patient suspected of having bacterial meningitis

Middle ear fluid- in patients with otitis media• do not do cultures from throat, nasopharynx

and urine

Neuroimaging and Bacterial Meningitis

Cranial Ultrasound - when lumbar puncture is contraindicated and when the

anterior fontanel is open - most useful in diagnosing complications of meningitis - normal ultrasound does not rule out the presence of meningitisStudy by Lee, et al*

224 cases of bacterial meningitis202 had abnormal cranial ultrasound findingshighly echogenic sulci- 75%

thick, highly echogenic convexity leptomeninges - 47% hydrocephalus - 44% effusion or empyema - 33% malacic changes - 9%

Neuroimaging and Bacterial Neuroimaging and Bacterial MeningitisMeningitis

Computed tomography and Magnetic resonance Imaging - in early stages of meningitis may be normal or

nonspecific Study by Cabral, et al* - out of 41 children with bacterial

meningitis, only 14 had abnormal CT scan For MRI -meningeal enhancement demonstrated is nonspecific and

is also seen in tumors, intracranial hemorrhage, trauma and after radiation therapy indicated only for cases of suspected intracranial indicated only for cases of suspected intracranial complications of bacterial meningitis and are complications of bacterial meningitis and are not not routinely requiredroutinely required

Empiric Therapy for Bacterial Empiric Therapy for Bacterial MeningitisMeningitis

Bacterial meningitis is a medical emergency, delay in treatment may lead to increased sequelae or deathDrug of choice must be bactericidal for pathogen involvedMust achieve adequate levels in the CSFInitial regimen should cover most likely pathogens for specific age groups, and reach bactericidal levels in the CSFKnowledge of local susceptibility patterns is essential

Philippine Data

Meningitis is the 8th leading cause of death in 0-4 yrs old(Arciaga)

most common cause is H. influenzae and S. pneumoniae

<1 yr old - Gram negative bacilli Group B streptococcus is an infrequent cause of

meningitis and Listeria monocytogenes has not been isolated in CSF cultures For a developing country with limited resources, the most cost-effective drug must be used.

Carlos C, et al. (Philippine) Antimicrobial Resistance Surveillance Program,January-December, 2000

34

11

0

2

4

6

8

10

12%

resi

stan

ce

AMP CHL SXT

Percent resistance of Hemophilus influenzae, 2000

No significant resistance of H. influenzae to cotrimoxazole, ampicillin and chloramphenicol

The three drugs are still recommended for use for H. influenzae

Higher resistance to penicillin than 1999Only 13(18%) of 72 resistance isolates were sent for confirmation of which only 4(6%) were truly penicillin resistant by MICTrue extent of penicillin resistant S. pneumoniae still unknown

7

18.4

11.8

0

2

4

6

8

10

12

14

16

18

20

% r

esis

tan

ce

CHL PEN SXT

Percent resistance of Streptococcus pneumoniae 2000

3.7

76.3

33.6

5.8

19.1

56.2

1.90

10

20

30

40

50

60

70

80

% r

esis

tanc

e

AMIK AMP AMS CRO GEN SXT FEP

Percent resistance of Escherichia coli , 2000

8.9

40

13.6

23.9

0.72.6

0

5

10

15

20

25

30

35

40

% r

esis

tan

ce

AMK AMS CRO GEN IMP FEP

Percent resistance of Klebsiella spp, 2000

13.9

33.9

17.6

32.5

14.0

7.4

0

5

10

15

20

25

30

35

% r

esis

tanc

e

AMK CIP CAZ GEN IMP FEP

Percent resistance of Pseudomonas aeruginosa , 2000

Pseudomonas aeruginosa- resistance was generally higher than 1999.

Many Enterobacteriacae show high resistance rates.

Aminoglycosides have high resistance rates.

Physicians should base their treatment recommendations for gram negative bacilli on their region’s prevailing resistance patterns.

Empiric Therapy for Bacterial MeningitisEmpiric Therapy for Bacterial Meningitis

Patient group

Likely etiology Antimicrobial choice

Primary Alternative

0-2 mos E. coliGram (-) bacilliS. pneumoniae

Ampicillin or Penicillin + Aminoglycoside

Ampicillin + Cefotaxime or Ceftriaxone

2mos – 5 yrs H. influenzaeS. pneumoniaeN. meningitidis

Ampicillin or Chloramphenicol

Cefotaxime or Ceftriaxone

>5 yrs S. pneumoniaeN. meningitidis

Penicillin G Chloramphenicol

Empiric Therapy for Bacterial MeningitisEmpiric Therapy for Bacterial Meningitis

Patient group Likely etiology Antimicrobial choice

Primary Alternative

Immunodeficient G(-) organismsS. aureusS. pneumoniae

Ampicillin + Ceftazidime +Aminoglycoside

TMP/SMX + Ceftazidime +Aminoglycoside

Neurosurgical problems & open head trauma

S. pneumoniaeS. aureusColiformsP. aeruginosa

Oxacillin + Ceftazidime or TMP/SMX

Ceftazidime + Vancomycin

Closed head trauma

S. pneumoniae Penicillin G Chloramphenicol or Ceftriaxone or Cefotaxime

Shunt meningitis and meningocoeles

S. epidermidisS. aureusColiforms

Oxacillin + Cefotaxime or Ceftriaxone

Vancomycin + Ceftriaxone or Cefotaxime

Bacteria Standard therapy Alternative therapiesH. Influenzae ß lactamase negative ß lactamase positive

AmpicillinChloramphenicol

Chloramphenicol, 3rd gen Ceph1

Neissersia meningitidis Penicillin MIC <0.1 µg/ml

Penicillin MIC >0.1 µg/mlPenicillinChloramphenicol

Ampicillin3rd gen Ceph

Streptococcus pneumoniae Penicillin MIC <0.1 µg/ml Penicillin MIC 0.1- 1.0 µg/ml Penicillin MIC >2.0 µg/ml

Penicillin3rd gen cephVancomycin + 3rd gen ceph

Ampicillin, ChloramphenicolMeropenem, VancomycinMeropenem

Enterobacteriaceae 3rd gen ceph Cefepime, Meropenem, Cotrimoxazole

Pseudomonas aeruginosa Ceftazidime + aminoglycoside

Cefepime, Meropenem + aminoglycoside

Staphylococcus aureus Methicillin sensitive Methicillin resistant

Oxacillin or nafcillinVancomycin

Vancomycin

Specific Antimicrobial Therapy for Bacterial Meningitis*

Tunkel AR, Scheld WM, Amer Family Physician 1997, 56(5):1355-62

Duration of Therapy of Bacterial Meningitis*

Pathogen Suggested duration of therapy (days)

H. influenzae 7-10S. pneumoniae 10-14N. meningitidis 7Grp. B. streptococci 14-21

G(-) bacilli 21

*Quagliarello, et al, NEJM 1997, 336(10):708-716

• Rational for Use of Rational for Use of DexamethasoneDexamethasone

The bacteria that have invaded the CSF The bacteria that have invaded the CSF proliferate, undergo degradation, and release proliferate, undergo degradation, and release toxins and techoic acids. The inflammatory toxins and techoic acids. The inflammatory response is activated and principal mediators are response is activated and principal mediators are IL-1ß, TNF, PAF, PMN’s and macrophages.IL-1ß, TNF, PAF, PMN’s and macrophages. promote leukocyte-cerebral capillary endothelial promote leukocyte-cerebral capillary endothelial cell interaction, platelet-mediated thrombosis, cell interaction, platelet-mediated thrombosis, and cytotoxic, interstitial and vasogenic edemaand cytotoxic, interstitial and vasogenic edema dexamethasone inhibits the synthesis of dexamethasone inhibits the synthesis of interleukin 1 and TNFinterleukin 1 and TNF

Meta-analysis* of 11 trials

(mostly in developed countries)

dexamethasone given prior to antibiotics reduces the incidence of hearing loss for Hib meningitis, but did not decrease mortality

*McIntyre et al. JAMA. 1997; 278:925-931

Dexamethasone studies from developing Dexamethasone studies from developing countriescountries

Islamabad (placebo controlled double-blind, 2mos-12 yrs on Ampicillin and Chloramphenicol)- dexamethasone group had increased risk of sequelae and worsened mortality Pakistan*- (double-blind placebo controlled trial in 89 children)

DexamethasoneDexamethasone PlaceboPlacebo

Mortality 25% 12%

Neurologic sequelae 26.5% 24%

Hearing impairment 24% 30%

may be due to late presentation of patients; use of antibiotics prior to hospital presentation; CSF results wherein no bacteria was isolated1997 WHO Workshop on the Treatment of Bacterial Meningitis in 1997 WHO Workshop on the Treatment of Bacterial Meningitis in Developing Countries: Dexamethasone as routine adjuvant therapy Developing Countries: Dexamethasone as routine adjuvant therapy was NOT recommendedwas NOT recommended

THE ROUTINE USE OF THE ROUTINE USE OF DEXAMETHASONE IN DEXAMETHASONE IN CHILDREN WITH BACTERIAL CHILDREN WITH BACTERIAL MENINGITIS IN THE MENINGITIS IN THE PHILIPPINE SETTING IS NOT PHILIPPINE SETTING IS NOT RECOMMENDED*RECOMMENDED*

*Task force Meningitis, PSMID*Task force Meningitis, PSMID

Use of Dexamethasone may be Use of Dexamethasone may be used:used:

a. in cases where the causative organism can be reliably diagnosed, particularly those with H. influenzae meningitis

b. in patients with markedly increased intracranial pressure

- dose of 0.15 mg/kg/dose IV q 6 hrs for 2 days- 1st dose of dexamethasone should be given

prior to or with the 1st dose of antibiotics- give with an H2 antagonist

Supportive management

IV Fluids and hydration

maintain normal blood pressure, watch out for SIADH

Control of increased intracranial pressure

Nutritional support

Prevention- chemoprophylaxis, immunizations, infection control

Conclusions

Must come up with own guidelines because conditions in other countries are different and specific recommendations may be inappropriate for other settings

Local data is essential to provide a rational approach to the management of bacterial meningitis in children

TASK FORCE ON MENINGITIS*TASK FORCE ON MENINGITIS*

SUBGROUP ON DIAGNOSIS

Lulu C. Bravo, MD

Aida Salonga, MD

Rose Capeding, MD

Ma. Liza Gonzales, MD

Rosalinda Soriano, MD

Enrique Carandang, MD

Michelle Medalla, MD

Mabel San Juan

SUBGROUP ON THERAPY

Salvacion R. Gatchalian, MD (Chairman of Task Force)

Malen Ortiz, MD

Rosemarie Arciaga, MD

Estrella Paje-Villar, MD

Celia Carlos, MD

Elaine Galicia, MD

Cecilia Maramba-Untalan, MD

Grace Martinez, MD

Ms. Jenny Panisales

•SUBGROUP ON PREVENTION Josefina Carlos, MD Prof. Grace Agustin Prof. Victoria Vidal Cleotilde How, MD Mary Anne Banez, MD Ms. Racquel Ardiente Lorna Abad, MD

*convened by Philippine Society ofMicrobiology and Infectious Diseases