Evaluating antimicrobial treatment for community-acquired pneumonia: clinical and microbiological responses

1
Evaluating antimicrobial treatment for
community-acquired pneumonia clinical and
microbiological responses

• Daniel M. Musher, MD
• Head of Infectious Diseases,
• VA Medical Center, Houston
• Professor of Medicine
• Professor of Molecular Virology and
  Microbiology
• Baylor College of Medicine
• Disclosures Research funding from Merck for
  followup of Pneumovax study Romark for
  nitazoxanide in C. difficile

2
Evaluating Rx for pneumonia philosophical
problems

• 1. The natural history of infectious diseases
  varying proportion resolve spontaneously
• 2. Generally a very high success rate of
  existing therapies for common pathogens (this
  could change with emergence of a new pathogenic
  organisms causing disease OR newly resistant
  organisms)
• 3. Empiricism in many cases, we dont know
  what infection we are treating. We unfortunately
  live with empiricism, but we must continue to
  recognize that this increasingly pervasive
  approach is antithetical to scientific study of
  medicine

3
Evaluating Rx for pneumonia

• Without correct diagnoses we have no idea
  whether, if a patient gets better on treatment,
  our drug is responsible
• True cases of the disease are diluted by those
  that might not respond to, or get better without
  regard to, treatment
• Even if we know what we are treating and develop
  criteria to recognize therapeutic success/failure
  can we design studies that are large enough to
  provide meaningful results but still practicable

4
US Army pneumonia vaccine trials, 1942-4
MacLeod, Hodges, Heidelberger, Bernhard, J Exp
Med 82445, 1945

• Pneumonia cases Controls
  Vaccinated
• Type Included n8546 n8449
• 1 yes 2 2
• 2 yes 14 1
• 4 no 6 8
• 5 yes 4 1
• 7 yes 6 0
• 12 no 24 21
• other - 28 27
• all pneumonia 84 60
• plt.05 pgt.05

5
Kayser Permanente study of 7-valent conjugate
vaccine (38,000 infants) invasive pneumococcal
disease in recipients

• Vax Nonvax
• Infected with vax strain 4 49
• Infected, nonvax strain 3 6
• Ped Infect Dis J 19187-195, 2000
• Only one of these had received the full set of
  three doses of vaccine

6
Kayser Permanente study of 7-valent conjugate
vaccine otitis media

• Reduction by vaccine
• All visits for otitis media 8.9
• OM 4 times per yr 9.3
• OM 5 times per yr 11.9
• OM 6 times per yr 22.8
• Tube placement 20.1
• Vaccine type pneumo in MEF 64.7
• Ped Infect Dis J 19187-195, 2000

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Evaluating Rx for pneumonia

• Thus, the goal for studying any new drug should
  be to eradicate disease for which the etiology is
  established
• Some clinicians object this is not a real
  life scenario
• If we were prescribing antibiotics only for
  patients who really needed them, the proposed
  approach would be much closer to a real life
  scenario

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Clinical criteria to evaluate therapeutic success

• 1. Time to defervescence or mean rate of fall in
  temperature using Kaplan-Meier analysis of
  highest recorded daily temp
• 2. Time to clinical stability Halm et al JAMA
  2791452, 1998
• 3. Symptom questionnaire Lamping Chest 122920,
  2002

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Median time to defervescence Welte et al CID
411697
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Median time to defervescence

• Even when measuring time to defervescence
• (a) in patients who are on their way to a cure,
  does a day or two of lower body temperature
  really matter? Yes.
• a. More rapid more rapid
• b. Fewer days in hospital
• c. Probably fewer complications
• (b) is the defervescence due to some other
  property of the antimicrobial agent?
• Obviously, failure to defervesce is
  consistent with clinical failure, although other
  causes possible

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Time to clinical stability Halm et al JAMA
2791452, 1998

• abnl at
• Criterion baseline Median days
• Temperature lt100 63 3
• lt99 80 3
• Pulse lt100 56 2
• Systolic BP gt90 7 2
• Respiratory rate lt24 49 3
• lt22 71 3
• lt20 78 4
• O2 saturation gt90 23 3
• gt92 31 3
• gt94 39 4
• Able to eat 11 2
• Mental status 8 3

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Symptom questionnaire Lamping Chest 122920, 2002

• Included chills/sweats cough sputum
  production chest pain shortness of breath
  vomiting/diarrhea fatigue trouble thinking
  trouble sleeping
• In a comparative study of three antibiotic
  regimens questionnaire was easily administered
  and well-accepted
• Shown to be reproducible, reliable and to give
  valid results

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Open label study, moxifloxacin vs ceftriaxone
erythromycin patient diaries
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Open label study, moxifloxacin vs ceftriax
erythromycin patient diaries
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Important to note

• Duration of hospitalization was shorter in moxy
  group (plt.001), but there is no oral form of
  ceftriaxone, so the comparison is misleading
  editors of respectable journals shouldnt accept
  such stuff
• Overall cure rate was identical in the two
  treatment groups (85.7 and 86.5)

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The problem of open-label studies

• Essentially not valid for comparative purposes,
  even if only include objective observations
• FDA simply should not endorse comparative studies
  that are not blinded the results (if favorable)
  will be used for marketing purposes
• Examples
• Moxifloxacin vs ceftriaxone erythromycin, data
  obtained from patients diaries
• If doctors know which drug, so do patients, and
  all subjective data are invalid

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What constitutes a clinical failure of treatment
for pneumonia?

• 1. Death 3-day, 7-10 day, 30-day?
• 2. Persistent or recurrent bacteremia by
  causative organism on Rx
• 3. Complication necrotic lung, empyema,
  remote infection (joint, bone, heart valve)
• 4. Rate of resolution/progression of
  pneumonia
• 5. Delayed defervescence
• 6. Duration of hospitalization

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What constitutes a clinical failure of treatment
for pneumonia?

• 1. Death 72 hours, 7-10 day, 30-day?
• Death within 72 hours due to overwhelming sepsis
  (cytokine storm) probably unaffected by Rx
  (Austrian and Gold, Ann Intern Med 60759, 1964
  Finland, Am Rev Resp Dis 120481, 1979)
• Death between 72 hr and 10 days influenced by
  above, but probably pretty good indicator
• Death by 30 days probably determined by other
  comorbid conditions questionable whether
  antibiotics will affect this, but should be
  covered by randomization

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Survival in bacteremic pneumococcal pneumonia no
Rx, Rx serum, Rx penicillin Austrian and Gold
(1964)
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Caveats in studying death as an endpoint in
pneumonia

• 1. Patients must be sick enough to for Rx to
  have an observable effect
• 2. The more broadly we cast our net in order to
  increase our numbers, the greater dilutional
  effect of death due to other causes.
• 3. Thus, a study designed to detect all deaths
  within 3 months may show no difference between
  treatments A and B, although one might be
  superior in treating the infection

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What constitutes a clinical failure of treatment
for pneumonia?

• 2. New, or persistent or recurrent bacteremia by
  causative organism, while patient is on Rx
• In CABP, a rare occurrence e.g., Gram neg rods
  severely immunocompromised patients, repeated
  bouts of COPD/pneumonia on many courses of
  antibiotics and steroids
• Obviously if bacteremia recurs, it is a failure,
  but the percentage in which it will be seen is
  way too small to be useful

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What constitutes a clinical failure of treatment
for pneumonia?

• 3. Complication necrotic lung, empyema, remote
  infection (joint, bone, heart valve)
• These are usually seen at the time of admission
  or they appear so soon afterwards that it is
  difficult to imagine they reflect poor Rx
• If they do appear on treatment, especially after
  3-4 days, very reasonable to consider them as
  treatment failure
• Appearance on Rx is so uncommon that, if drug is
  reasonably effective, it would be difficult to
  measure without huge sample Finland, The J. Burns
  Amberson Lecture, Am Rev Resp Dis 20481, 1979

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What constitutes a clinical failure of treatment
for pneumonia?

• 4. Rate of resolution/progression of pneumonia
• Infiltrates may progress in first few days
  because inflammatory process continues despite
  effective antimicrobial agent
• Study variables in the PORT score (pulse,
  respiratory rate, temperature, BP, BUN, Na,
  oxygenation etc.) and apply Kaplan-Meier analysis
• VERY complicated dependent upon intensity of Rx
  and skill of MDs, but in a blinded study, these
  should average out

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What constitutes a clinical failure of treatment
for pneumonia?

• Other possible considerations
• Days in ICU (for those requiring ICU care)
• Days of intubation (ICU with intubation)
• Days of IV therapy (for protocols where switch
  to oral therapy is an option)
• CAN ONLY USE THESE IN BLINDED STUDIES
• Total days in hospital (too dependent on
  comorbidities)

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What constitutes a bacteriological cure?

• First consider bacteriological diagnosis
• Extensive literature on the unreliability of
  sputum gram stain and culture in diagnosing
  bacterial pneumonia
• Problem is with the patients included in the
  study- the denominator

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Results of sputum gram stain clear bars or
culture solid bars showing pneumococci in
proven pneumococcal pneumonia Musher CID 2005

• All patients Any sputum
  Valid sample (70) (55)

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Results of sputum gram stain clear bars or
culture solid bars in proven pneumococcal
pneumonia relation to antibiotics Musher CID 2005
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Bacteriological cure

• If it is difficult to establish the diagnosis in
  pneumonia, even more difficult to evaluate
  efficacy of antibiotic therapy in eradicating
• Most who could provide a sample before Rx can not
  do so afterwards
• Most who can ? poor/useless sample
• FDA requirement encourages bad data
• Culture detects colonizing organisms
• a. original organism may persist as
  airway colonizer Calder Lancet 11156, 1971
• b. new organism may colonize (Tillotson and
  Finland, J Infect Dis 119597, 1969) and may not
  be able to exclude without molecular
  fingerprinting

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Bacteriological failure is easier

• Failure to eradicate in absence of clinical
  failure ? significance, but common sense
  dictates
• a. Persistence of large numbers of the
  original infecting organism in purulent sputum
  (i.e. gram stain proof) suggests poor
  antimicrobial effect. This would most likely be
  associated with poor clinical response, but
  requires good micro
• b. Emergence of resistance in the original
  infecting organism (only if you know the original
  infecting organism)

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Microbiological cure

• Note that these comments address bacterial
  pneumonia only for nonbacterial causes, no one
  has even proposed studying this in pneumonia due
  to viruses, mycoplasma, chlamydia, or even
  Legionella

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What about placebo studies?

• Ethical considerations
• My opinion is simple. Unacceptable. Anyone who
  signs consent hasnt been fully informed or
  isnt competent to sign
• Scientific Can design study of people who dont
  have serious disease spontaneous cures will
  dilute response.
• Some may progress to serious disease Must
  exclude pneumococcal pneumonia

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Mortality in bacteremic pneumococcal pneumonia
(Musher, Mandell ID Text, 2006)
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Summary and Conclusions evaluating clinical and
microbiological responses during Rx of CAP

• Symptom questionnaire
• Time to defervescence
• Time to clinical stability
• Mortality between 72 hr and 10 day
• Stay in ICU, days of intubation
• Development of a complication on Rx
• Emergence of resistant bacterium
• (must prove that it is same organism)
• Persistent bacteremia
• only in double-blind studies

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BACKUP SLIDES
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Causes of pneumonia syndrome

• Common Less common
• Streptococcus pneumoniae Moraxella catarrhalis
• Haemophilus influenzae Staphylococcus aureus
• Lung cancer Klebsiella pneumoniae
• Pneumocystis carinii Influenza virus
• Mycobacterium tuberculosis Legionella
• CHF, ARDS Pseudomonas aeruginosa
• Respiratory syncytial virus
• Microaerophilic/anaerobic
• Histoplasma, Coccidioides
• NonTB mycobacteria
• Chlamydia pneumoniae
• Nocardia
• Pulmonary infarction
• Hammann-Rich, UIP, DIP BOOP, etc.

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Is microbiologic evaluation of sputum (Gram stain
and culture) useful?

• A good quality specimen is obtained in only
  slightly gt50 cases of pneumonia
• When obtained before antibiotics are given or
  within 6 hours of the first dose,
• and analyzed in an ordinary lab but with
  motivated laboratory technicians
• Has an 85 yield by gram stain and/or culture
• Thats not bad as diagnostic tests go

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Causes of pneumonia, 1930s (Heffron)
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Bacteriological cure

• b. appearance of new potential pathogen
• May be S. pneumo (must plan to serotype to
  detect new type) (Finland)
• May be S. aureus, GNR, etc. (Tillotson Finland,
  J Infect Dis 119597, 1969), either colonizing
  or causing disease clinical response remains
  determining factor
• Nosocomial acquisition, likely to be resistant
  to antibiotics
• 3. A strong incentive to have sample ? bad
  data on bacterial eradication

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Appearance of new organisms in sputum during Rx

• Very common, especially in more debilitated and
  older patients. In the absence of clinical
• If patient has clinical failure AND now has
  pathogenic organisms in sputum,
• Is this failure of original Rx?
• (did organism develop resistance?)
• Is this superinfection?

41
Open label study, linezolid vs. vanco length of
hospital stay Itani, Int J Antimicrob Ther, 2005
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Bacteriological cure Finland, The J. Burns
Amberson Lecture, Am Rev Resp Dis 20481, 1979

• 1. Bacteremia rapidly cleared, usually before
  second dose of penicillin
• 2. Also rapid eradication of organisms from
  sputum with modern doses
• 3. Clinical relapses in pneumococcal pneumonia
  also related to low doses of penicillin
• 4. Pneumonia due to different type S. pneumo soon
  after Rx ? ? need to serotype
• 5. Extrapulmonary complications do not develop
  after initiation of antibiotics

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What about placebo studies?

• Even seemingly simple ones
• Retapamulin vs placebo for Rx impetigo, defined
  as a superficial, usually self-limited
  infection
• Treated 210 patients (21 drug vs placebo)
• Clinical success rate 85.6 vs 52.1
• Two other trials of same drug vs cephalexin each
  had about 90 cure rate might raise objection in
  MRSA era that there was a placebo effect for some
  of these cases, which would justify a placebo
  study
• But how self-limited is impetigo if 48 failure
  rate? And how honest was informed consent?

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Considerations in the Design of CAP Studies

• Steve Gitterman
• DSPTP, FDA

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Intertwined Considerations

• Study design
• Study population
• Analysis populations
• Clinical endpoints
• Microbiology outcome
• Non-inferiority margin
• Inclusion Criteria
• Exclusion criteria
• Failure
• Route of Administration
• Diagnostics
• Blinding
• Spectrum of approval for CAP

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Outpatient (Oral) vs. Inpatient (IV) Studies
Oral Studies IV studies

Inclusion (PORT ?) Criteria
Analysis/ Microbiology
Clinical endpoints
Non-inferiority margin
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CAP Considerations

• Although challenges exist for both inpatient and
  outpatient studies..
• The more difficult issue may be identifying an
  appropriate non-inferiority margin for drugs that
  have only oral formulations

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Inpatient (Parenteral) Studies

• Study design
• Non-inferiority
• Superiority
• Study Population
• PORT score as criterion (?)
• PORT II or III as minimum
• Analysis populations
• Bacteriologically confirmed (exclude mycoplasma?)
• Without bacteriological confirmation
• Non-bacterial infections (safety only)

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Inpatient (Parenteral) Studies

• Clinical endpoints
• Failure/success
• Mortality
• Non-inferiority margin
• IDSA recommendations presented

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Outpatient (Oral) vs. Inpatient (IV) Studies
Oral Studies IV studies
PORT Criteria II or III or greater
Study design Non-inferiority
Analysis/ Microbiology Clinical criteria Nonbacterial etiology excluded (/-) mycoplamsa
Clinical endpoints Clinical failure (including death)
Non-inferiority margin 10
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Outpatient (Oral) Studies

• Study design
• Non-inferiority or superiority
• Study Population
• PORT criterion (?)
• Minimum PORT criterion (I or II)
• Placebo more difficult as PORT increases
• Analysis populations (Microbiology criteria)
• Bacteriologically confirmed
• Pathogen requirements
• Powering separately for pneumococcal pneumonia
  (i.e., by pathogen) however, this has practical
  concerns, regardless of endpoint
• Is a minimum number of each pathogen appropriate
  approach
• Non-bacterial infections excluded

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Outpatient (Oral) Studies

• Clinical Endpoint
• PRO FDA recommendation of clinically meaningful
  endpoint
• Separate symptoms
• Failure
• Diagnostics
• State of the Art
• Biomarker qualification process

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Discussion Regarding Outpatient (Oral) Studies

• Non-inferiority margin
• Predicated on specific endpoint, e.g., PRO vs.
  failure
• Relationship of previous mycoplasma studies
• IDSA recommendations presented

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Outpatient (Oral) vs. Inpatient (IV) Studies
Oral Studies IV studies
PORT Criteria (?) I or greater II (III) or greater
Study design Non-inferiority/Superiority Non-inferiority
Analysis/ Microbiology Confirmed (?) By pathogen (?) Clinical criteria Nonbacterial etiology excluded
Clinical endpoints PRO Clinical Failure Clinical failure
Non-inferiority margin Discussion 10
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CAP Considerations

• Thank-you.