# Presentation: 402875

## 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*

## 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 don’t 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**

## 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**

## US Army pneumonia vaccine trials, 1942-4  MacLeod, Hodges, Heidelberger, Bernhard, J Exp Med 82:445, 1945

**	****	****	****       ****P****neumonia cases****	****	****	****            Controls****	****  Vaccinated**
**Type   Included****	****    n=8546****	****     n=8449**
**   ****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****
**	****	****	****	****      ***p_<_.05	**p_>_.05

## 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 19;187-195, 2000**
******** ****Only one of these had received the full set of three doses of vaccine ****	****	**

## 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 19;187-195, 2000

## 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**

## 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 279:1452, 1998
**3.  Symptom questionnaire **Lamping Chest 122:920, 2002

## Median time to defervescence Welte et al CID 41:1697

**Notes:**
These data were obtained in an open label trial.  I can not see how bias could alter the results, but, as a general matter, i do not trust such studies.

## 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**

## Time to clinical stability Halm et al JAMA 279:1452, 1998

**	****	****	****	****     ****# abnl at****	****    **
**Criterion ****	****	****	****      baseline****	****   Median days**
**Temperature         **_**<**_**100****	****	****63****	****	****3**
**	****	****	**_**<**_**99****	****	****80****	****	****3**
**Pulse **_**<**_**100****	****	****	****	****56****	****	****2**
**Systolic BP **_**>**_**90****	****	****	****  7****	****	****2**
**Respiratory rate ****	**_**<**_**24****	****	****49****	****	****3**
**	****	****	**_**<**_**22****	****	****71****	****	****3**
**	****	****	**_**<**_**20****	****	****78****	****	****4**
**O2 saturation****	**_**>**_**90****	****	****23****	****	****3**
**	****	****	**_**>**_**92****	****	****31****	****	****3**
**	****	****	**_**>**_**94****	****	****39****	****	****4**
**Able to eat****	****	****	****	****11****	****	****2**
**Mental status****	****	****	****  8****	****	****3**

**Notes:**
Note: slower response than in early literature, indicating a much sicker population (used to Rx all pneumonia as inpatients)
Note: slower response than in early literature, indicating a much sicker population (used to Rx all pneumonia as inpatients)
Note: slower response than in early literature, indicating a much sicker population (used to Rx all pneumonia as inpatients)

## Symptom questionnaire Lamping Chest 122:920, 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**

## Open label study, moxifloxacin vs ceftriaxone + erythromycin: patient diaries

## Open label study, moxifloxacin vs ceftriax + erythromycin: patient diaries

## Important to note:

**Duration of hospitalization was shorter in moxy group (p<.001), but there is no oral form of ceftriaxone, so the comparison is misleading [editors of respectable journals shouldn’t accept such stuff]**
**Overall cure rate was identical in the two treatment groups (85.7% and 86.5%)**

## 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**

## 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**** **

## 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 60:759, 1964; Finland, Am Rev Resp Dis 120:481, 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**

## Survival in bacteremic pneumococcal pneumonia: no Rx, Rx serum, Rx penicillin Austrian and Gold (1964)

## 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   **

## 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 **

## 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 20:481, 1979

## 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**

## 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)**
**	**

## 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**

## 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%)

**Notes:**
Using as a denominator:  1 = all patients;  2 = those who could cough up sputum;  3 = those who coughed up good sample 

## Results of sputum gram stain [clear bars] or culture [solid bars] in proven pneumococcal pneumonia: relation to antibiotics Musher CID 2005

## 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 1:1156, 1971
**	****    ****b. new  organism may colonize **(Tillotson and Finland, J Infect Dis 119:597, 1969) **and may not be able to exclude without molecular fingerprinting**

## 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)**

## 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***

## What about placebo studies?

**Ethical considerations:**
**My opinion is simple. Unacceptable.   Anyone who signs consent hasn’t been   fully informed or isn’t competent to sign**
**Scientific: Can design study of people who don’t have serious disease; spontaneous cures will dilute response.  **
**	****Some may progress to serious disease       ****	****Must exclude pneumococcal pneumonia**

## Mortality in bacteremic pneumococcal pneumonia  (Musher, Mandell ID Text, 2006)

## 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**

## BACKUP SLIDES

## 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.

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

**A good quality specimen is obtained in only slightly >50% 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**
**That’s not bad as diagnostic tests go**

## Causes of pneumonia, 1930’s (Heffron)

## 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 119:597, 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**

## 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’?**

## Open label study, linezolid vs. vanco: length of hospital stay Itani, Int J Antimicrob Ther, 2005

**Notes:**
Itani, Int J Antimicrob Ther, 2005 ; linezolid significantly shortened hospital stay (p<.01) OPEN LABEL STUDY

## Bacteriological cure Finland, The J. Burns Amberson Lecture, Am Rev Resp Dis 20:481, 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**

## 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 (2:1 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? **

## Considerations in the Design of CAP Studies

- Steve Gitterman
- 	DSPTP, FDA

## 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 

**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**

**Intertwined Considerations**

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

|  | Oral Studies | IV studies |
| --- | --- | --- |
|  |  |  |
| Inclusion (PORT ?)
Criteria |  |  |
| Analysis/
Microbiology |  |  |
| Clinical endpoints |  |  |
| Non-inferiority margin |  |  |

## 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**

## 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)**

## Inpatient (Parenteral) Studies

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

## 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% |

## 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**

## Outpatient (Oral) Studies

**Clinical Endpoint**
**PRO – FDA recommendation of clinically meaningful endpoint**
**Separate symptoms**
**Failure **
**‘****Diagnostics’**
**State of the Art**
**Biomarker qualification process**** **

## 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**

## 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% |

## CAP Considerations

- Thank-you.