ACUTE BACTERIAL MENINGITIS <ul><li>Alexander Rakowsky, M.D. </li></ul><ul><li>DAIDP/ODE4 </li></ul>
Presentations <ul><li>General Overview of Guidelines </li></ul><ul><li>Comments/Discussion by Dr. Joan Chesney </li></ul><...
PATHOGENS EXPECTED <ul><li>Streptococcus pneumoniae </li></ul><ul><li>Neisseria meningitidis </li></ul><ul><li>Haemophilus...
NOT ADDRESSED <ul><li>Indwelling catheters involving the CNS </li></ul><ul><li>Status/post recent neurosurgical procedures...
RECENT DEVELOPMENTS <ul><li>Haemophilus influenzae  type B vaccine </li></ul><ul><ul><li>Overall, decreased rate of mening...
FOREIGN STUDIES <ul><li>Anticipate more data from foreign countries </li></ul><ul><li>However, FDA approvals are for U.S. ...
ENROLLMENT <ul><li>Efforts should be made to enroll patients with strongly suspected bacterial infection </li></ul><ul><li...
INCLUSION CRITERIA <ul><li>Non-specific and specific signs/symptoms </li></ul><ul><li>Variable by age </li></ul><ul><li>Mo...
EXCLUSION CRITERIA <ul><li>As defined before </li></ul><ul><li>Potential role of Gram’s stain as an entry criteria </li></ul>
STUDY DRUG <ul><li>Adequate penetration into CSF and activity against common pathogens </li></ul><ul><li>Control Drug </li...
VISITS <ul><li>Entry </li></ul><ul><li>On-therapy  </li></ul><ul><li>End-of-therapy (EOT) </li></ul><ul><li>Test-of-cure (...
ENTRY VISIT <ul><li>Emphasis on complete neurologic exam, Coma scale, etc. </li></ul><ul><li>CSF analysis </li></ul><ul><l...
ON-THERAPY VISIT <ul><li>Repeat CSF analysis 24 to 36 hours (minimum of 24 hours) after initiation of therapy </li></ul><u...
Question #1 <ul><li>Is “delayed eradication” of  Haemophilus influenzae  a valid bacteriologic outcome for the 24-36 hour ...
EOT VISIT <ul><li>Continuation of therapy for longer period </li></ul><ul><li>Repeat lumbar puncture not needed in most si...
EARLY POST-THERAPY VISIT <ul><li>5-7 weeks after completion of all therapy </li></ul><ul><li>Lumbar puncture repeated only...
LATE POST-THERAPY VISIT <ul><li>5-7 months after completion of therapy </li></ul><ul><li>Emphasis on hearing/ development/...
PATIENT POPULATION <ul><li>Primary efficacy analysis: Clinical response of enrolled patients who have both clinical pictur...
Question #2 <ul><li>What role, if any, should the results of antigen testing have in clinical trials? </li></ul>
CLINICAL OUTCOMES <ul><li>Cure :  Resolution of signs/symptoms at early TOC visit. At both TOC visits, normal screening </...
CLINICAL OUTCOMES <ul><li>Clinical Failure </li></ul><ul><ul><li>Persistence of signs/symptoms at TOC visits </li></ul></u...
CLINICAL OUTCOMES <ul><li>Clinical Failure , Continued </li></ul><ul><ul><li>Prolongation of antimicrobial therapy for per...
Question #3 <ul><li>How should patients who die within the first 72 hours of therapy be classified? </li></ul>
MICROBIOLOGIC OUTCOMES <ul><li>Mostly “presumed” responses, since only repeat tap while still on therapy  </li></ul><ul><l...
MICROBIOLOGIC OUTCOMES <ul><li>Presumed Persistence : Either: </li></ul><ul><ul><li>A change in therapy during study perio...
Questions <ul><li>Is “delayed eradication” of  Haemophilus influenzae  a valid bacteriologic outcome for the 24-36 hour ta...
Questions <ul><li>What role, if any, should the results of antigen testing have in clinical trials? </li></ul>
Questions <ul><li>How should patients who die within the first 72 hours of therapy be classified? </li></ul>
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ACUTE BACTERIAL MENINGITIS ACUTE BACTERIAL MENINGITIS

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ACUTE BACTERIAL MENINGITIS ACUTE BACTERIAL MENINGITIS

  1. 1. ACUTE BACTERIAL MENINGITIS <ul><li>Alexander Rakowsky, M.D. </li></ul><ul><li>DAIDP/ODE4 </li></ul>
  2. 2. Presentations <ul><li>General Overview of Guidelines </li></ul><ul><li>Comments/Discussion by Dr. Joan Chesney </li></ul><ul><li>Discussion of Questions </li></ul>
  3. 3. PATHOGENS EXPECTED <ul><li>Streptococcus pneumoniae </li></ul><ul><li>Neisseria meningitidis </li></ul><ul><li>Haemophilus influenzae </li></ul><ul><li>Group B Streptococcus </li></ul><ul><li>Escherichia coli </li></ul><ul><li>Listeria monocytogenes </li></ul>
  4. 4. NOT ADDRESSED <ul><li>Indwelling catheters involving the CNS </li></ul><ul><li>Status/post recent neurosurgical procedures or craniofacial fractures/trauma </li></ul><ul><li>Anatomic defects predisposing to CNS infections </li></ul><ul><li>Immunocompromised </li></ul><ul><li>Mycobacterial, fungal, parasitic or viral infections </li></ul><ul><li>Study of these encouraged, however </li></ul>
  5. 5. RECENT DEVELOPMENTS <ul><li>Haemophilus influenzae type B vaccine </li></ul><ul><ul><li>Overall, decreased rate of meningitis </li></ul></ul><ul><ul><li>However, due to pathogen shift, for those patients affected, there will be potentially higher mortality/morbidity rates </li></ul></ul><ul><li>Dexamethasone Use </li></ul><ul><li>Streptococcus pneumoniae resistance </li></ul><ul><ul><li>Vancomycin use ( Pediatrics , February 1997) </li></ul></ul><ul><ul><li>Combination therapy </li></ul></ul>
  6. 6. FOREIGN STUDIES <ul><li>Anticipate more data from foreign countries </li></ul><ul><li>However, FDA approvals are for U.S. population </li></ul><ul><li>Pathogens, their susceptibility profiles, and the standard of patient care should be comparable to U.S. </li></ul>
  7. 7. ENROLLMENT <ul><li>Efforts should be made to enroll patients with strongly suspected bacterial infection </li></ul><ul><li>Counter this with issue of delay in therapy </li></ul><ul><li>Potential use of Gram’s stain results </li></ul>
  8. 8. INCLUSION CRITERIA <ul><li>Non-specific and specific signs/symptoms </li></ul><ul><li>Variable by age </li></ul><ul><li>More non-specific in neonates/infants </li></ul><ul><li>Classic triad (fever, headache, nuchal rigidity) less common than expected </li></ul>
  9. 9. EXCLUSION CRITERIA <ul><li>As defined before </li></ul><ul><li>Potential role of Gram’s stain as an entry criteria </li></ul>
  10. 10. STUDY DRUG <ul><li>Adequate penetration into CSF and activity against common pathogens </li></ul><ul><li>Control Drug </li></ul><ul><li>Concomitant Therapy: Dexamethasone and possibly vancomycin </li></ul><ul><li>Issue of Oral “relay therapy” </li></ul>
  11. 11. VISITS <ul><li>Entry </li></ul><ul><li>On-therapy </li></ul><ul><li>End-of-therapy (EOT) </li></ul><ul><li>Test-of-cure (TOC) </li></ul><ul><ul><li>Early post-therapy </li></ul></ul><ul><ul><li>Late post-therapy </li></ul></ul>
  12. 12. ENTRY VISIT <ul><li>Emphasis on complete neurologic exam, Coma scale, etc. </li></ul><ul><li>CSF analysis </li></ul><ul><li>Baseline of: </li></ul><ul><ul><li>Hearing </li></ul></ul><ul><ul><li>Developmental status </li></ul></ul><ul><ul><li>Neurological status </li></ul></ul>
  13. 13. ON-THERAPY VISIT <ul><li>Repeat CSF analysis 24 to 36 hours (minimum of 24 hours) after initiation of therapy </li></ul><ul><li>Changes in therapy/concomitant therapy as needed </li></ul><ul><li>Evaluation of drug concentrations in CSF </li></ul>
  14. 14. Question #1 <ul><li>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? </li></ul>
  15. 15. EOT VISIT <ul><li>Continuation of therapy for longer period </li></ul><ul><li>Repeat lumbar puncture not needed in most situations studied </li></ul>
  16. 16. EARLY POST-THERAPY VISIT <ul><li>5-7 weeks after completion of all therapy </li></ul><ul><li>Lumbar puncture repeated only if clinically indicated </li></ul><ul><li>Audiologic examination: BAER in infants. Appropriate range of tones should be tested. </li></ul><ul><li>Developmental: A complete developmental package. Chosen prior to study initiation. </li></ul><ul><li>Neurologic testing: Full exam. Documented findings </li></ul>
  17. 17. LATE POST-THERAPY VISIT <ul><li>5-7 months after completion of therapy </li></ul><ul><li>Emphasis on hearing/ development/ neurological findings </li></ul><ul><li>Behavioral difficulties should be documented as well </li></ul>
  18. 18. PATIENT POPULATION <ul><li>Primary efficacy analysis: Clinical response of enrolled patients who have both clinical picture c/w acute bacterial meningitis and bacteriologic confirmation. </li></ul><ul><li>Either CSF culture positive OR </li></ul><ul><li>CSF culture negative, but blood culture positive and CSF analysis c/w bacterial infection. </li></ul>
  19. 19. Question #2 <ul><li>What role, if any, should the results of antigen testing have in clinical trials? </li></ul>
  20. 20. CLINICAL OUTCOMES <ul><li>Cure : Resolution of signs/symptoms at early TOC visit. At both TOC visits, normal screening </li></ul><ul><li>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). </li></ul><ul><li>Need predefined parameters for “mild deficit” </li></ul>
  21. 21. CLINICAL OUTCOMES <ul><li>Clinical Failure </li></ul><ul><ul><li>Persistence of signs/symptoms at TOC visits </li></ul></ul><ul><ul><li>Moderate to severe sequelae or seizure disorder </li></ul></ul><ul><ul><li>Persistence of pathogen at 24-36 hr. tap leading to additional therapy or change in therapy. If pathogen resistant, pt. Unevaluable </li></ul></ul>
  22. 22. CLINICAL OUTCOMES <ul><li>Clinical Failure , Continued </li></ul><ul><ul><li>Prolongation of antimicrobial therapy for period of time out of the ordinary </li></ul></ul><ul><ul><li>Initiation of new or further therapy for the treatment of meningitis between the EOT and TOC visits </li></ul></ul><ul><ul><li>Deaths (if have completed at least 72 hours of therapy) </li></ul></ul>
  23. 23. Question #3 <ul><li>How should patients who die within the first 72 hours of therapy be classified? </li></ul>
  24. 24. MICROBIOLOGIC OUTCOMES <ul><li>Mostly “presumed” responses, since only repeat tap while still on therapy </li></ul><ul><li>Presumed Eradication : No repeat CSF cultures obtained after completion of therapy, but clinical cure at TOC visits. </li></ul><ul><li>Documented Eradication : Repeat CSF culture done off therapy shows no persistence of initial pathogen </li></ul>
  25. 25. MICROBIOLOGIC OUTCOMES <ul><li>Presumed Persistence : Either: </li></ul><ul><ul><li>A change in therapy during study period, but no repeat CSF culture obtained </li></ul></ul><ul><ul><li>Prolongation or initiation of further therapy due to a lack of clinical improvement, with no repeat CSF culture obtained </li></ul></ul><ul><li>Documented Persistence : Repeat CSF culture (including the 24-36 hour post-study drug initiation culture) shows persistence of initial pathogen </li></ul>
  26. 26. Questions <ul><li>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? </li></ul>
  27. 27. Questions <ul><li>What role, if any, should the results of antigen testing have in clinical trials? </li></ul>
  28. 28. Questions <ul><li>How should patients who die within the first 72 hours of therapy be classified? </li></ul>

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