Bacterial Pneumonia

06/25/98

BACTERIAL BACTERIAL PNEUMONIAPNEUMONIA

Developing AntimicrobialDeveloping Antimicrobial

Drugs For TreatmentDrugs For Treatment

Alma C. Davidson, M.D.Alma C. Davidson, M.D.

Division of Anti-Infective Drug ProductsDivision of Anti-Infective Drug Products

ODE IVODE IV

July 30, 1998July 30, 1998

2July 1998

Separation of CAP from NPSeparation of CAP from NP More stringent criteria for NPMore stringent criteria for NP Need for NP patients to have both Need for NP patients to have both

fever and leukocytosis plus at least fever and leukocytosis plus at least one of the other signs and symptoms one of the other signs and symptoms

ISSUES in ACM - March ISSUES in ACM - March 19971997

3July 1998

ISSUES in ACM - cont’dISSUES in ACM - cont’d

Diagnostic criteria for ventilator-Diagnostic criteria for ventilator-associated pneumonia (VAP)associated pneumonia (VAP)

Subsetting patients with VAPSubsetting patients with VAP How to handle patients who have How to handle patients who have

evidenceevidence

of multiple pathogens in sputumof multiple pathogens in sputum Gram stain should correlate with Gram stain should correlate with

culture results.culture results.

4July 1998

Questions and Comments Questions and Comments fromfromIndustry - cont’dIndustry - cont’d

Are blood cultures necessary for Are blood cultures necessary for outpatients with pneumonia?outpatients with pneumonia?

NoNo

5July 1998

Questions and Comments Questions and Comments fromfromIndustry - cont’d Industry - cont’d

Eliminate blood cultures as inclusion criteria since these Eliminate blood cultures as inclusion criteria since these are pending for two days after enrollment.are pending for two days after enrollment.

Recommend eliminating fever as inclusion criteria Recommend eliminating fever as inclusion criteria since fever is absent from one-third of pneumonia since fever is absent from one-third of pneumonia cases, especially in the elderlycases, especially in the elderly

Recommend eliminating WBC count since labs often Recommend eliminating WBC count since labs often pending for several hours at time of prestudy visit or pending for several hours at time of prestudy visit or are being sent to central labare being sent to central lab

6July 1998

Questions and Comments Questions and Comments fromfromIndustry - cont’d Industry - cont’d

For atypical pathogens, are sputum screen and For atypical pathogens, are sputum screen and culture required for inclusion ? culture required for inclusion ?

We prefer culture where applicable;We prefer culture where applicable;

sputum screen not needed.sputum screen not needed.

7July 1998

Changes in New Changes in New DocumentDocument

Separation of CAP and NPSeparation of CAP and NP Disease definition and additional text inDisease definition and additional text in

inclusion and exclusion criteria of CAPinclusion and exclusion criteria of CAP Clarification of evaluation visits Clarification of evaluation visits Dichotomous clinical outcome responsesDichotomous clinical outcome responses Nosocomial pneumonia - inclusion andNosocomial pneumonia - inclusion and

exclusion criteriaexclusion criteria

8July 1998

NOSOCOMIALNOSOCOMIAL

PNEUMONIAPNEUMONIA

9July 1998

Disease DefinitionDisease Definition

new coughnew cough auscultatory findingsauscultatory findings new infiltrate or progressive infiltrate(s) onnew infiltrate or progressive infiltrate(s) on

chest radiograph, accompanied by:chest radiograph, accompanied by: fever or hypothermia, leukocytosis, sputumfever or hypothermia, leukocytosis, sputum

productionproduction Etiology: polymicrobialEtiology: polymicrobial

10July 1998

Disease Definition - cont’dDisease Definition - cont’d

Acquired by a patient in the following Acquired by a patient in the following settings:settings: in a hospital or long-term-care facility after in a hospital or long-term-care facility after

being admitted for >48 hours or being admitted for >48 hours or <7 days after a patient is discharged from <7 days after a patient is discharged from

hospital ( patient’s initial hospitalization should hospital ( patient’s initial hospitalization should be be 3 days duration )3 days duration )

11July 1998

Risk FactorsRisk Factors

Host factors ( e.g. extremes of age, severe Host factors ( e.g. extremes of age, severe underlying disease ) underlying disease )

Colonization by gram-negative microorganismsColonization by gram-negative microorganisms Aspiration or refluxAspiration or reflux Prolonged mechanical ventilation Prolonged mechanical ventilation Factors that impede adequate pulmonary toiletFactors that impede adequate pulmonary toilet

12July 1998

Problems in Diagnosis of Problems in Diagnosis of NPNP

Clinical criteria lack specificityClinical criteria lack specificity No “gold standards” for diagnostic procedures (e.g. invasive No “gold standards” for diagnostic procedures (e.g. invasive

procedures)procedures) High potential for more than one ongoing infectious process High potential for more than one ongoing infectious process Use of antimicrobials in ICU empirically or use for infections Use of antimicrobials in ICU empirically or use for infections

of other sites or organs.of other sites or organs.

13July 1998

Nosocomial Bacterial Nosocomial Bacterial Pneumonia - EtiologyPneumonia - Etiology

Gram-negative enteric bacilli (predominant)Gram-negative enteric bacilli (predominant) Gram-positive cocci, including: Gram-positive cocci, including:

Staphylococcus aureus Staphylococcus aureus ( e.g.,( e.g., MRSA MRSA ), ), Streptococcus pneumoniaeStreptococcus pneumoniae

AnaerobesAnaerobes OthersOthers

14July 1998

Inclusion Criteria Inclusion Criteria (Clinical)(Clinical)

The following clinical findings should beThe following clinical findings should be

present:present: Fever or hypothermia Fever or hypothermia Leukocytosis or leukopenia Leukocytosis or leukopenia

15July 1998

Inclusion Criteria Inclusion Criteria (Clinical)(Clinical)

AndAnd at least two of the following : at least two of the following : new coughnew cough new onset of purulent sputum or significant changes new onset of purulent sputum or significant changes

in character of sputumin character of sputum auscultatory findings auscultatory findings dyspneadyspnea tachypneatachypnea

16July 1998

Inclusion CriteriaInclusion Criteria (Clinical )(Clinical )

Hypoxemia by pulse oximetry or by Hypoxemia by pulse oximetry or by arterial blood gas arterial blood gas

Respiratory failure requiring mechanical Respiratory failure requiring mechanical ventilation ventilation

Intubated patients requiring increased Intubated patients requiring increased oxygenationoxygenation

17July 1998

Inclusion CriteriaInclusion Criteria (Radiographic)(Radiographic)

New or evolving infiltrate (s) on New or evolving infiltrate (s) on chest radiograph which is not chest radiograph which is not related to another disease process. related to another disease process. Caveat: State of hydrationCaveat: State of hydration

18July 1998

Inclusion CriteriaInclusion Criteria (Microbiologic)(Microbiologic)

Gram stain and culture of respiratory Gram stain and culture of respiratory tract specimentract specimen

Antimicrobial susceptibility testing shouldAntimicrobial susceptibility testing should

be performed on pathogenic isolatesbe performed on pathogenic isolates Alternate diagnostic tests ( Alternate diagnostic tests ( Legionella Legionella ))

19July 1998

Inclusion CriteriaInclusion Criteria (Microbiologic)(Microbiologic)

Blood cultures, two sets ( aerobic Blood cultures, two sets ( aerobic and anaerobic from two different and anaerobic from two different sites ) - up to 48 hours prior to sites ) - up to 48 hours prior to initiation of therapyinitiation of therapy

20July 1998

Inclusion Criteria Inclusion Criteria (Microbiologic)(Microbiologic)

Blood culture isolates should be Blood culture isolates should be utilized toutilized to

corroborate with the sputum corroborate with the sputum culture results in cases where culture results in cases where multiple pathogens are isolated.multiple pathogens are isolated.

21July 1998

Caveat:Caveat:

No consensus on criteria for No consensus on criteria for interpretation of culture results of interpretation of culture results of specimens obtained from specimens obtained from mechanically ventilated patientsmechanically ventilated patients

22July 1998

PEDIATRIC PATIENTSPEDIATRIC PATIENTS

Same clinical and radiographic criteriaSame clinical and radiographic criteria

( definitions of fever and WBC ( definitions of fever and WBC different from adults )different from adults )

Blood cultures could be substituted Blood cultures could be substituted when sputum is lackingwhen sputum is lacking

23July 1998

Exclusion CriteriaExclusion Criteria

Patients excluded in CAP and in generalPatients excluded in CAP and in general

considerations ( COPD not excluded )considerations ( COPD not excluded ) Patients with sustained shockPatients with sustained shock APACHE II score <8 or >25APACHE II score <8 or >25 Known or suspected concomitant bacterialKnown or suspected concomitant bacterial

infection requiring additional systemic infection requiring additional systemic

treatmenttreatment

24July 1998

Exclusion Criteria- Exclusion Criteria- cont’dcont’d

Chronic immunosuppressive therapyChronic immunosuppressive therapy Neutropenia Neutropenia Epilepsy or seizureEpilepsy or seizure Recent alcohol or drug abuse orRecent alcohol or drug abuse or

dependencedependence

25July 1998

Drug and Drug Dosing Drug and Drug Dosing RegimensRegimens

The proposed duration of study The proposed duration of study drug and comparator may vary drug and comparator may vary depending ondepending on

specific antimicrobial agent andspecific antimicrobial agent and

respiratory pathogen isolated.respiratory pathogen isolated.

26July 1998

EVALUATION VISITSEVALUATION VISITS Pre-therapy Pre-therapy On- therapy On- therapy End-of-therapy ( Optional )End-of-therapy ( Optional ) Early Post-therapy ( Optional )Early Post-therapy ( Optional ) Test-of- Cure Test-of- Cure

27July 1998

Pre-Therapy VisitPre-Therapy Visit

Documentation of history ( including riskDocumentation of history ( including risk

factors ), P.E. , chest x-ray, lab tests ( Gram factors ), P.E. , chest x-ray, lab tests ( Gram stain, culture and susceptibility testing, blood stain, culture and susceptibility testing, blood cultures ), and baseline Ocultures ), and baseline O saturation by pulse saturation by pulse oximetry or arterial blood gas;oximetry or arterial blood gas;

Apache II Score ( if available ) in ICU patientsApache II Score ( if available ) in ICU patients

28July 1998

On-Therapy VisitOn-Therapy Visit

Daily clinical assessments should be Daily clinical assessments should be recorded in the case report form recorded in the case report form

Laboratory assessments to be made Laboratory assessments to be made during the course of the study should during the course of the study should be tailored to the antimicrobial agent.be tailored to the antimicrobial agent.

29July 1998

On-TherapyOn-Therapy VisitVisit - - cont’dcont’d

General principles during this visit:General principles during this visit: Culture of respiratory tract secretions Culture of respiratory tract secretions

obtained by semi-invasive obtained by semi-invasive technique(s) and susceptibility technique(s) and susceptibility testing, should be obtained at 72 testing, should be obtained at 72 hours after initiation of therapy in hours after initiation of therapy in patients who are clinically failing.patients who are clinically failing.

30July 1998

On Therapy Visit - cont’dOn Therapy Visit - cont’d

Blood cultures and Blood cultures and susceptibility testing susceptibility testing should be repeated at 72 should be repeated at 72 hours if (+) at entry or if hours if (+) at entry or if patient is clinically failing.patient is clinically failing.

31July 1998

Test-of-Cure VisitTest-of-Cure Visit

7 - 14 days after completion of 7 - 14 days after completion of therapy therapy

Repeat culture and susceptibility Repeat culture and susceptibility testing should be done in patients testing should be done in patients with continuing significant with continuing significant respiratory secretions.respiratory secretions.

32July 1998

OUTCOMEOUTCOME

Clinical OutcomeClinical Outcome - primary efficacy - primary efficacy variablevariable

Clinical responses Clinical responses

1. Clinical cure1. Clinical cure

2. Clinical failure2. Clinical failure

33July 1998

Microbiologic OutcomeMicrobiologic Outcome

Eradication ( Documented eradication )Eradication ( Documented eradication ) Presumed eradication Presumed eradication Persistence ( Documented persistence )Persistence ( Documented persistence ) Presumed persistencePresumed persistence

34July 1998

35July 1998

QUESTIONS to ACM :QUESTIONS to ACM :

1. How should we set the diagnostic1. How should we set the diagnostic

criteria for ventilator-associatedcriteria for ventilator-associated

pneumonia ? pneumonia ?

2. Should we screen BALs in a similar 2. Should we screen BALs in a similar

manner as sputum (in terms of manner as sputum (in terms of

cytological screening) to determine cytological screening) to determine

adequacy of specimen ?adequacy of specimen ?

36July 1998

ACKNOWLEDGMENTACKNOWLEDGMENT

Thanks to the following colleagues :Thanks to the following colleagues : Renata Albrecht, M.D.Renata Albrecht, M.D. Mercedes Albuerne, M.D.Mercedes Albuerne, M.D. John Alexander, M.D.John Alexander, M.D. Sousan Altaie, Ph.D.Sousan Altaie, Ph.D. Lillian Gavrilovich, M.D.Lillian Gavrilovich, M.D. Holli Hamilton, M.D., MPHHolli Hamilton, M.D., MPH Mamodikoe Makhene, M.D., MPHMamodikoe Makhene, M.D., MPH Alexander Rakowsky, M.D.Alexander Rakowsky, M.D.