BACTERIAL

PNEUMONIA
Developing Antimicrobial
Drugs For Treatment
Alma C. Davidson, M.D.
Division of Anti-Infective Drug Products
ODE IV
July 30, 1998
06/25/98

ISSUES in ACM - March

1997
Separation of CAP from NP
More stringent criteria for NP
Need for NP patients to have both
fever and leukocytosis plus at least
one of the other signs and symptoms

July 1998

ISSUES in ACM - contd

Diagnostic criteria for ventilatorassociated pneumonia (VAP)
Subsetting patients with VAP
How to handle patients who have
evidence
of multiple pathogens in sputum
Gram stain should correlate with
culture results.
July 1998
3

Questions and Comments

from
Industry - contd

Are blood cultures necessary for

outpatients with pneumonia?
No

July 1998

Questions and Comments

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

are pending for two days after enrollment.

Recommend eliminating fever as inclusion criteria since
fever is absent from one-third of pneumonia cases,
especially in the elderly
Recommend eliminating WBC count since labs often
pending for several hours at time of prestudy visit or are
being sent to central lab

July 1998

Questions and Comments

from
Industry - contd

For atypical pathogens, are sputum screen and culture

required for inclusion ?
We prefer culture where applicable;
sputum screen not needed.

July 1998

Changes in New
Document

Separation of CAP and NP

Disease definition and additional text in
inclusion and exclusion criteria of CAP
Clarification of evaluation visits
Dichotomous clinical outcome responses
Nosocomial pneumonia - inclusion and
exclusion criteria

July 1998

NOSOCOMIAL
PNEUMONIA

July 1998

Disease Definition
new cough
auscultatory findings
new infiltrate or progressive infiltrate(s) on
chest radiograph, accompanied by:
fever or hypothermia, leukocytosis, sputum
production
Etiology: polymicrobial

July 1998

Disease Definition - contd

Acquired by a patient in the following

settings:

in a hospital or long-term-care facility after

being admitted for >48 hours or
<7 days after a patient is discharged from
hospital ( patients initial hospitalization should
be 3 days duration )

July 1998

10

Host factors ( e.g. extremes of age, severe

underlying disease )
Colonization by gram-negative microorganisms
Aspiration or reflux
Prolonged mechanical ventilation
Factors that impede adequate pulmonary toilet

Risk Factors

July 1998

11

Problems in Diagnosis of
NP
Clinical criteria lack specificity
No gold standards for diagnostic procedures (e.g. invasive
procedures)
High potential for more than one ongoing infectious process
Use of antimicrobials in ICU empirically or use for infections of
other sites or organs.

July 1998

12

Nosocomial Bacterial
Pneumonia - Etiology
Gram-negative enteric bacilli (predominant)
Gram-positive cocci, including:
Staphylococcus aureus ( e.g., MRSA ),
Streptococcus pneumoniae
Anaerobes
Others

July 1998

13

Inclusion Criteria
(Clinical)
The following clinical findings should be
present:
Fever or hypothermia
Leukocytosis or leukopenia

July 1998

14

Inclusion Criteria
(Clinical)
And at least two of the following :
new cough
new onset of purulent sputum or significant changes in
character of sputum
auscultatory findings
dyspnea
tachypnea

July 1998

15

Inclusion Criteria
(Clinical )
Hypoxemia by pulse oximetry or by arterial
blood gas
Respiratory failure requiring mechanical
ventilation
Intubated patients requiring increased
oxygenation

July 1998

16

Inclusion Criteria
(Radiographic)
New or evolving infiltrate (s) on

chest radiograph which is not

related to another disease process.

July 1998

Caveat: State of hydration

17

Inclusion
Gram stain andCriteria
culture of respiratory
tract specimen
(Microbiologic)
Antimicrobial susceptibility testing should

be performed on pathogenic isolates

Alternate diagnostic tests ( Legionella )

July 1998

18

Inclusion Criteria

Blood cultures, two sets ( aerobic

(Microbiologic)
and anaerobic from two different
sites ) - up to 48 hours prior to
initiation of therapy

July 1998

19

Inclusion Criteria
(Microbiologic)

Blood culture isolates should be

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

July 1998

20

Caveat:
No

consensus on criteria for

interpretation of culture results of
specimens obtained from
mechanically ventilated patients

July 1998

21

PEDIATRIC PATIENTS
Same clinical and radiographic criteria
( definitions of fever and WBC
different from adults )
Blood cultures could be substituted
when sputum is lacking

July 1998

22

Exclusion Criteria
Patients excluded in CAP and in general
considerations ( COPD not excluded )
Patients with sustained shock
APACHE II score <8 or >25
Known or suspected concomitant
bacterial
infection requiring additional systemic
treatment

July 1998

23

Exclusion Criteriacontd
Chronic immunosuppressive therapy
Neutropenia
Epilepsy or seizure
Recent alcohol or drug abuse or
dependence

July 1998

24

Drug and Drug Dosing

Regimens

The proposed duration of study

drug and comparator may vary
depending on
specific antimicrobial agent and
respiratory pathogen isolated.

July 1998

25

EVALUATION VISITS

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

July 1998

26

Pre-Therapy Visit

Documentation of history ( including risk

factors ), P.E. , chest x-ray, lab tests ( Gram
stain, culture and susceptibility testing, blood
cultures ), and baseline O saturation by pulse
oximetry or arterial blood gas;
Apache II Score ( if available ) in ICU patients

July 1998

27

Daily clinical assessments should be

recorded in the case report form
Laboratory assessments to be made
during the course of the study should
be tailored to the antimicrobial agent.

On-Therapy Visit

July 1998

28

On-Therapy Visit - contd

General

principles during this visit:

Culture

of respiratory tract secretions

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

July 1998

29

On Therapy Visit - contd

Blood

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

July 1998

30

7 - 14 days after completion of

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

Test-of-Cure Visit

July 1998

31

OUTCOME
Clinical

Outcome - primary efficacy variable

Clinical responses
1. Clinical cure
2. Clinical failure

July 1998

32

Microbiologic Outcome
Eradication ( Documented eradication )
Presumed eradication
Persistence ( Documented persistence )
Presumed persistence

July 1998

33

July 1998

34

QUESTIONS to ACM :
1. How should we set the diagnostic
criteria for ventilator-associated
pneumonia ?
2. Should we screen BALs in a similar
manner as sputum (in terms of
cytological screening) to determine
adequacy of specimen ?

July 1998

35

ACKNOWLEDGMENT
Thanks to the following colleagues :
Renata Albrecht, M.D.
Mercedes Albuerne, M.D.
John Alexander, M.D.
Sousan Altaie, Ph.D.
Lillian Gavrilovich, M.D.
Holli Hamilton, M.D., MPH
Mamodikoe Makhene, M.D., MPH
Alexander Rakowsky, M.D.
July 1998

36