Evaluating antimicrobial treatment for community-acquired ...

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 1 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 2 treating. We unfortunately live with 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 to3 US Army pneumonia vaccine trials, 1942-4 MacLeod, Hodges, Heidelberger, Bernhard, J Exp Med 82:445, 1945 Pneumonia cases Controls n=8546 Vaccinated Type Included n=8449 1 yes 2 yes 4 no 5 yes 7 yes 12 no 2 14 6 4 6 24 2 1* 8 1 0* 21 4 Kayser Permanente study of 7-valent conjugate vaccine (38,000 infants): invasive pneumococcal disease in recipients * Vax Nonvax Infected with vax strain 49 Infected, nonvax strain 6 4 ** 3 5 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 OM 5 times per yr OM 6 times per yr Tube placement 9.3% 11.9% 22.8% 6 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 7 Clinical criteria to evaluate therapeutic success 1. Time to defervescence or mean rate of fall in temperature using KaplanMeier 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 8 Median time to defervescence Welte et al CID 41:1697 9 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? 10 Time to clinical stability Criterion Temperature Pulse <100 Systolic BP >90 Respiratory rate Halm et al JAMA 279:1452, 1998 <100 <99 O2 saturation <24 <22 <20 >90 >92 >94 # abnl at baseline 63 80 56 7 49 71 78 23 31 39 Median days 3 3 2 2 3 3 4 3 3 4 11 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 wellaccepted Shown to be reproducible, reliable 12 Open label study, moxifloxacin vs ceftriaxone + erythromycin: patient diaries 13 Open label study, moxifloxacin vs ceftriax + erythromycin: patient diaries 14 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%) 15 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 16 patients diaries 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 17 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 18 other comorbid conditions; questionable Survival in bacteremic pneumococcal pneumonia: no Rx, Rx serum, Rx penicillin Austrian and Gold (1964) 19 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 20 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 will21 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, 22 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 KaplanMeier analysis 23 VERY complicated; dependent upon 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 24 Total days in hospital (too dependent on 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 25 Results of sputum gram stain [clear bars] or culture [solid bars] showing pneumococci in proven pneumococcal pneumonia Musher CID 2005 All patients Any sputum (70%) Valid sample (55%) 26 Results of sputum gram stain [clear bars] or culture [solid bars] in proven pneumococcal pneumonia: relation to antibiotics Musher CID 2005 27 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 28 b. new organism may colonize 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 29 original infecting organism (only if you 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 30 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 31 Mortality in bacteremic pneumococcal pneumonia (Musher, Mandell ID Text, 2006) 32 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 33 34 BACKUP SLIDES 35 Causes of “pneumonia” syndrome Common Streptococcus pneumoniae Haemophilus influenzae Lung cancer Pneumocystis carinii Mycobacterium tuberculosis CHF, ARDS • Less common Moraxella catarrhalis Staphylococcus aureus Klebsiella pneumoniae Influenza virus Legionella Pseudomonas aeruginosa Respiratory syncytial virus Microaerophilic/anaerobic Histoplasma, Coccidioides NonTB mycobacteria Chlamydia pneumoniae Nocardia Pulmonary infarction Hammann-Rich, UIP, DIP 36 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 37 Causes of pneumonia, 1930‟s (Heffron) 38 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 39 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‟? 40 Open label study, linezolid vs. vanco: length of hospital stay Itani, Int J Antimicrob Ther, 2005 41 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 42 develop after initiation of antibiotics What about placebo studies? Even seemingly simple ones: Retapamulin vs placebo for Rx impetigo, defined as a “superficial, usually selflimited 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 43 these cases, which would justify a placebo Considerations in the Design of CAP Studies Steve Gitterman DSPTP, FDA 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 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 PORT Criteria IV studies II [or III] or greater Study design Analysis/ Microbiology Non-inferiority • Clinical criteria • Nonbacterial etiology excluded • (+/-) mycoplamsa Clinical failure (including death) 10% Clinical endpoints Non-inferiority margin 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 (?) Study design Analysis/ Microbiology Clinical endpoints Non-inferiority margin I or greater Noninferiority/Superiority • Confirmed (?) • By pathogen (?) • PRO • Clinical Failure Discussion II (III) or greater Non-inferiority • Clinical criteria • Nonbacterial etiology excluded Clinical failure 10% CAP Considerations Thank-you.