acute bacterial meningitis acute bacterial meningitis

7/24/98 7/29/98 AC Mtg 1

ACUTE BACTERIAL MENINGITIS

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

7/24/98 7/29/98 AC Mtg 2

Presentations

• General Overview of Guidelines

• Comments/Discussion by Dr. Joan Chesney

• Discussion of Questions

7/24/98 7/29/98 AC Mtg 3

PATHOGENS EXPECTED

• Streptococcus pneumoniae

• Neisseria meningitidis

• Haemophilus influenzae• Group B Streptococcus

• Escherichia coli

• Listeria monocytogenes

7/24/98 7/29/98 AC Mtg 4

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

7/24/98 7/29/98 AC Mtg 5

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

7/24/98 7/29/98 AC Mtg 6

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.

7/24/98 7/29/98 AC Mtg 7

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

7/24/98 7/29/98 AC Mtg 8

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

7/24/98 7/29/98 AC Mtg 9

EXCLUSION CRITERIA

• As defined before

• Potential role of Gram’s stain as an entry criteria

7/24/98 7/29/98 AC Mtg 10

STUDY DRUG

• Adequate penetration into CSF and activity against common pathogens

• Control Drug

• Concomitant Therapy: Dexamethasone and possibly vancomycin

• Issue of Oral “relay therapy”

7/24/98 7/29/98 AC Mtg 11

VISITS

• Entry

• On-therapy

• End-of-therapy (EOT)

• Test-of-cure (TOC)– Early post-therapy– Late post-therapy

7/24/98 7/29/98 AC Mtg 12

ENTRY VISIT

• Emphasis on complete neurologic exam, Coma scale, etc.

• CSF analysis

• Baseline of:– Hearing– Developmental status– Neurological status

7/24/98 7/29/98 AC Mtg 13

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

7/24/98 7/29/98 AC Mtg 14

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?

7/24/98 7/29/98 AC Mtg 15

EOT VISIT

• Continuation of therapy for longer period

• Repeat lumbar puncture not needed in most situations studied

7/24/98 7/29/98 AC Mtg 16

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

7/24/98 7/29/98 AC Mtg 17

LATE POST-THERAPY VISIT

• 5-7 months after completion of therapy

• Emphasis on hearing/ development/ neurological findings

• Behavioral difficulties should be documented as well

7/24/98 7/29/98 AC Mtg 18

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.

7/24/98 7/29/98 AC Mtg 19

Question #2

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

7/24/98 7/29/98 AC Mtg 20

CLINICAL OUTCOMES

• CureCure: Resolution of signs/symptoms at early TOC visit. At both TOC visits, normal screening

• Cure with Mild SequelaeCure 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”

7/24/98 7/29/98 AC Mtg 21

CLINICAL OUTCOMES

• Clinical FailureClinical 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

7/24/98 7/29/98 AC Mtg 22

CLINICAL OUTCOMES

• Clinical FailureClinical 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)

7/24/98 7/29/98 AC Mtg 23

Question #3

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

7/24/98 7/29/98 AC Mtg 24

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 EradicationDocumented Eradication: Repeat CSF culture done off therapy shows no persistence of initial pathogen

7/24/98 7/29/98 AC Mtg 25

MICROBIOLOGIC OUTCOMES

• Presumed PersistencePresumed 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 PersistenceDocumented Persistence: Repeat CSF culture (including the 24-36 hour post-study drug initiation culture) shows persistence of initial pathogen

7/24/98 7/29/98 AC Mtg 26

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?

7/24/98 7/29/98 AC Mtg 27

Questions

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

7/24/98 7/29/98 AC Mtg 28

Questions

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