# Presentation: 081664

## ACUTE BACTERIAL MENINGITIS

- Alexander Rakowsky, M.D.
- DAIDP/ODE4

- 7/29/98 AC Mtg

- 7/24/98

## Presentations

- General Overview of Guidelines
- Comments/Discussion by Dr. Joan Chesney
- Discussion of Questions

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- 7/24/98

## PATHOGENS EXPECTED

*Streptococcus pneumoniae*
*Neisseria meningitidis*
* **Haemophilus influenzae*
- Group B Streptococcus
*Escherichia coli*
*Listeria monocytogenes*

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- 7/24/98

## NOT ADDRESSED

- Indwelling catheters involving the CNS
- Status/post recent neurosurgical procedures or craniofacial fractures/trauma
- Anatomic defects predisposing to CNS infections
- Immunocompromised
- Mycobacterial, fungal, parasitic or viral infections
- Study of these encouraged, however

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- 7/24/98

## RECENT DEVELOPMENTS

*Haemophilus influenzae* type B vaccine
- Overall, decreased rate of meningitis
- However, due to pathogen shift, for those patients affected, there will be potentially higher mortality/morbidity rates
- Dexamethasone Use
*Streptococcus pneumoniae* resistance
- Vancomycin use (_Pediatrics_, February 1997)
- Combination therapy

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## FOREIGN STUDIES

- Anticipate more data from foreign countries
- However, FDA approvals are for U.S. population
- Pathogens, their susceptibility profiles, and the standard of patient care should be comparable to U.S.

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## ENROLLMENT

- Efforts should be made to enroll patients with strongly suspected bacterial infection
- Counter this with issue of delay in therapy
- Potential use of Gram’s stain results

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## INCLUSION CRITERIA

- Non-specific and specific signs/symptoms
- Variable by age
- More non-specific in neonates/infants
- Classic triad (fever, headache, nuchal rigidity) less common than expected

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## EXCLUSION CRITERIA

- As defined before
- Potential role of Gram’s stain as an entry criteria

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## STUDY DRUG

- Adequate penetration into CSF and activity against common pathogens
- Control Drug
- Concomitant Therapy: Dexamethasone and possibly vancomycin
- Issue of Oral “relay therapy”

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## VISITS

- Entry
- On-therapy
- End-of-therapy (EOT)
- Test-of-cure (TOC)
- Early post-therapy
- Late post-therapy

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## ENTRY VISIT

- Emphasis on complete neurologic exam, Coma scale, etc.
- CSF analysis
- Baseline of:
- Hearing
- Developmental status
- Neurological status

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- 7/24/98

## ON-THERAPY VISIT

- Repeat CSF analysis 24 to 36 hours (minimum of 24 hours) after initiation of therapy
- Changes in therapy/concomitant therapy as needed
- Evaluation of drug concentrations in CSF

- 7/29/98 AC Mtg

- 7/24/98

## Question #1

- Is “delayed eradication” of  *Haemophilus influenzae *a valid bacteriologic outcome for the 24-36 hour tap or should this be seen as a failure of therapy?

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## EOT VISIT

- Continuation of therapy for longer period
- Repeat lumbar puncture not needed in most situations studied

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## EARLY POST-THERAPY VISIT

- 5-7 weeks after completion of all therapy
- Lumbar puncture repeated only if clinically indicated
- Audiologic examination: BAER in infants. Appropriate range of tones should be tested.
- Developmental: A complete developmental package. Chosen prior to study initiation.
- Neurologic testing: Full exam. Documented findings

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## LATE POST-THERAPY VISIT

- 5-7 months after completion of therapy
- Emphasis on hearing/ development/ neurological findings
- Behavioral difficulties should be documented as well

- 7/29/98 AC Mtg

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## PATIENT POPULATION

- Primary efficacy analysis: Clinical response of enrolled patients who have both clinical picture c/w acute bacterial meningitis and bacteriologic confirmation.
- Either CSF culture positive OR
- CSF culture negative, but blood culture positive and CSF analysis c/w bacterial infection.

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## Question #2

- What role, if any, should the results of antigen testing have in clinical trials?

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- 7/24/98

## CLINICAL OUTCOMES

**Cure**: Resolution of signs/symptoms at early TOC visit. At both TOC visits, normal screening
**Cure with Mild Sequelae**: Resolution of signs/symptoms at early TOC visit. Mild deficits noted at late post-therapy (or at early post-therapy in cases where no late f/up available).
- Need predefined parameters for “mild deficit”

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## CLINICAL OUTCOMES

**Clinical Failure**
- Persistence of signs/symptoms at TOC visits
- Moderate to severe sequelae or seizure disorder
- Persistence of pathogen at 24-36 hr. tap leading to additional therapy or change in therapy. If pathogen resistant, pt. Unevaluable

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## CLINICAL OUTCOMES

**Clinical Failure**, Continued
- Prolongation of antimicrobial therapy for period of time out of the ordinary
- Initiation of new or further therapy for the treatment of meningitis between the EOT and TOC visits
- Deaths (if have completed at least 72 hours of therapy)

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## Question #3

- How should patients who die within the first 72 hours of therapy be classified?

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## MICROBIOLOGIC OUTCOMES

- Mostly “presumed” responses, since only repeat tap while still on therapy
**Presumed Eradication**: No repeat CSF cultures obtained after completion of therapy, but clinical cure at TOC visits.
**Documented Eradication**: Repeat CSF culture done off therapy shows no persistence of initial pathogen

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## MICROBIOLOGIC OUTCOMES

**Presumed Persistence**: Either:
- A change in therapy during study period, but no repeat CSF culture obtained
- Prolongation or initiation of further therapy due to a lack of clinical improvement, with no repeat CSF culture obtained
**Documented Persistence**: Repeat CSF culture (including the 24-36 hour post-study drug initiation culture) shows persistence of initial pathogen

- 7/29/98 AC Mtg

- 7/24/98

## Questions

- Is “delayed eradication” of  *Haemophilus influenzae *a valid bacteriologic outcome for the 24-36 hour tap or should this be seen as a failure of therapy?

- 7/29/98 AC Mtg

- 7/24/98

## Questions

- What role, if any, should the results of antigen testing have in clinical trials?

- 7/29/98 AC Mtg

- 7/24/98

## Questions

- How should patients who die within the first 72 hours of therapy be classified?

- 7/29/98 AC Mtg

- 7/24/98