@@Antimicrobial Rez Ghid | Antimicrobial Resistance | Pneumonia

Improving Patient Care: Reducing Antimicrobial Resistance in Respiratory Infections

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Improving Patient Care: Reducing Antimicrobial Resistance in Respiratory Infections
Presentations from a symposium held in Chicago, Illinois on Friday, April 29 during the 2005 Annual Meeting of the Society of Hospital Medicine Medicine

Good evening everyone and welcome to this evening’s program.

Improving Patient Care: Reducing Antimicrobial Resistance in Respiratory Infections

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Continuing Medical Education
Danielle R. Hanson
Office of Continuing Medical Education University of Wisconsin Medical School Madison, Wisconsin

My name is Danielle Hanson, and I’m from the University of Wisconsin Medical School Office of Continuing Medical Education.

We value your feedback on this symposium and would appreciate you completing the form and returning it to a staff member at the conclusion of the symposia. is a consultant for Abbott. Dr. and Sanofi-Aventis. and Pfizer. . you will find faculty disclosure information on your handout materials and also on the screen above. GlaxoSmithKline. honoraria for speaking from Abbott and GlaxoSmithKline. and Sanofi-Aventis. The University of Wisconsin Medical School and DesignWrite have received a grant from Ortho-McNeil Pharmaceutical to organize this program. GlaxoSmithKline. Dr. GlaxoSmithKline.Improving Patient Care: Reducing Antimicrobial Resistance in Respiratory Infections 3 Disclosures ‹ ‹ Dr. and has received honoraria for speaking from Abbott. Boehringer Ingelheim. Sanjay Sethi has received grants/research support from Bayer. To receive credit for this program. Ortho-McNeil. and an honorarium for reviewing this program’s scientific materials. Boehringer Ingelheim. AstraZeneca. Andrew W. you must complete the evaluation form. Urban has received grants/research support from Agouron/Pfizer and Amgen. Alpesh Amin has received honoraria for speaking from Ortho-McNeil Pharmaceutical. Pfizer. Bayer. Bayer. Pfizer. ‹ ‹ ‹ I would like to take this opportunity on behalf of the University of Wisconsin Medical School and DesignWrite to thank Ortho-McNeil for the educational grant that has allowed us to do this program. In compliance with the ACCME. Richard Quintiliani has received honoraria for speaking from Ortho-McNeil Pharmaceutical. Dr.

. The objectives for this program can be found in your handout materials and also on the screen above. Each physician should claim only those credits that he or she actually spent in this educational activity. the participant should be able to: ‹ Demonstrate strategies to manage patients with recurrent acute exacerbation of chronic bronchitis ‹ Analyze community-acquired pneumonia patterns of resistance and treatment ‹ Describe the effect of drug resistance on outcomes related to nosocomial pneumonia This program is accredited for 2 category 1 credits toward the AMA Physician’s Recognition Award.Improving Patient Care: Reducing Antimicrobial Resistance in Respiratory Infections 4 Learning Objectives By the end of the program.

Improving Patient Care: Reducing Antimicrobial Resistance in Respiratory Infections 5 Welcome and Introductions Alpesh Amin. Hospitalist Program Vice Chair for Clinical Affairs. I’m going to start off with a brief talk and then go into a small Q and A for a couple of minutes and then Dr. good. So I hope it’s going well for you all. The way our program is going to be tonight is. Dr. Please help me in welcoming Dr. MD. He is also Executive Director at the Hospitalist Program at the UCI Medical Center at Orange. California I would now like to take this time to introduce our Chairman. MBA. Amin. FACP Associate Professor of Medicine Executive Director. Thank you. Dr. Everybody? Good. Okay. California. Department of Medicine University of California. I’d like to say just a couple of words though. Well thank you everybody for coming on a Friday night in Chicago with the weather as good as it is after a long day at the annual meeting. Amin is the Associate Clinical Professor at the Department of Medicine at the University of California at Irvine. I know it’s been – I’ve heard very good feedback about it. Quintiliani will do the same thing. Apesh Amin. Irvine School of Medicine Irvine. I hope you’ve enjoyed the meeting so far. I’d like to also welcome you this evening. Can you hear me okay. How’s that? Yes? Okay. Sethi will come up and he’ll do his talk and have a Q and A and then Dr. . We’ve got two other wonderful faculty that are going to be joining me.

He serves as an attending physician in the Division of Pulmonary and Critical Care and has submitted numerous articles. Dr. MD State University of New York at Buffalo Buffalo. Richard Quintiliani is Professor of Medicine and Pharmacology at the University of Connecticut School of Medicine in Connecticut. MD. New York Richard Quintiliani. He is a Senior Consultant in Antibiotic Research Usage of Pharmacoeconomics at Hartford Hospital where again he has submitted over 450 articles and is very well published. California Dr. . Irvine School of Medicine Irvine. MD. Sanjay Sethi is an Associate Professor of Medicine in the Division of Pulmonary and Critical Care and in Sleep Medicine at the State University of New York at the Buffalo School of Medicine. FACP University of Connecticut School of Medicine Farmington. You can take a look at the information in the packet. Connecticut Alpesh Amin. MBA. which you can see in your faculty biographies there. FACP University of California.Improving Patient Care: Reducing Antimicrobial Resistance in Respiratory Infections 6 Program Faculty Sanjay Sethi.

all of which are obviously important for the hospitalist’s world. MBA. FACP Alpesh Amin. MD Faculty Richard Quintiliani. FACP Faculty So this is going to be our program for today and without further ado. . we’re going to start with pneumonia and we’re going to talk a little bit about bronchitis and then about nosocomial pneumonia. MD.Improving Patient Care: Reducing Antimicrobial Resistance in Respiratory Infections 7 Program Agenda Welcome and Introductions Managing Community-Acquired Pneumonia While Avoiding Resistance Risks Questions & Answers Acute Exacerbation of Chronic Bronchitis: Strategies for Reducing Drug Resistance Questions & Answers Antimicrobial Resistance: Implication for Nosocomial Pneumonia Patients Questions & Answers Alpesh Amin. MBA. FACP Faculty Sanjay Sethi. I’m going to go ahead and get started in talking a little bit about community-acquired pneumonia while avoiding resistance risk. MD. As you can see. MD.

Improving Patient Care: Reducing Antimicrobial Resistance in Respiratory Infections 8 Managing CommunityAcquired Pneumonia While Avoiding Resistance Risks Alpesh Amin. Department of Medicine University of California. Irvine School of Medicine Irvine. California . FACP Associate Professor of Medicine Executive Director. Hospitalist Program Vice Chair for Clinical Affairs. MD. MBA.

. and once they get to the ICU the rate of mortality jumps up tremendously. of which 1 million tend to get into the hospital. 2001.Improving Patient Care: Reducing Antimicrobial Resistance in Respiratory Infections 9 Community-Acquired Pneumonia (CAP) ‹ Approximately 5. but once they’re in the hospital it goes up to about 12%. just to remind you as background.163:1730-54. to 30% or 40%.6 million cases annually ‹ 1. First of all. Let me – community-acquired pneumonia is important for us for a number of reasons. Am J Respir Crit Care Med. there’s about 6 million cases of pneumonia a year. And the mortality range is less than 1% to 5% on the outpatient side.1 million require hospitalization ‹ Mortality in the outpatient setting ranges from <1% to 5% ‹ Mortality ~12% in CAP patients requiring hospitalization ‹ Mortality approaches 40% in patients requiring the ICU American Thoracic Society.

. but when you look at the cost of the illness. And we all know that patients above the age of 65 are a growing population that come into the hospital setting.1 million require hospitalization ● Over 75% treated as outpatients ‹ Costs of treating CAP exceed $8 billion ● $8. Vital Statistics Mortality Data.163:1730-54. so it’s a significant cause of mortality amongst our inpatient population. It’s the sixth leading cause of death in the United States and the number one cause of death from an infectious etiology in the United States.6 million cases annually ● 1. Clin Ther.0 billion inpatients ● $4. the cost is on the order of 8 billion dollars. Am J Respir Crit Care Med.Improving Patient Care: Reducing Antimicrobial Resistance in Respiratory Infections 10 CAP Is a Serious Illness ‹ Pneumonia: 6th leading killer in US ● No. Centers for Disease Control and Prevention. of which about 5 billion of that comes from patients above age 65. 1 cause of death from infection ● 5. National Center for Health Statistics. 1998.8 billion patients ≥65 yr ● $3. 75% of these patients are actually treated as an outpatient. Niederman MS.20:820-37. et al.6 billion patients <65 yr American Thoracic Society. 2001.

and 5. he was able to categorize patients into risk classification. 4. Fine published in the New England Journal of Medicine a prediction model based on the PSI score. I’m going to give you some thoughts to think about in terms of risk stratifying your patient. they were given a certain number of points. heart failure. or Fine’s criteria. et al. if they were younger than 50 but they had no comorbid conditions. based on their age. they were dropped into a class. they had no physical examination finding abnormalities.Improving Patient Care: Reducing Antimicrobial Resistance in Respiratory Infections 11 Algorithm For Prediction Model PATIENT WITH CAP OVER 50 YEARS OF AGE? NO YES HISTORY OF ANY OF THESE COMORBID CONDITIONS? • Renal disease • Neoplastic disease • Congestive heart failure • Liver disease • Cerebrovascular disease NO YES ASSIGN PATIENT TO RISK CLASS IIII-V BASED ON PREDICTION MODEL SCORING SYSTEM ANY OF THESE ABNORMALITIES ON EXAMINATION? • Altered mental status • Systolic BP <90 mmHg • Pulse ≥125/min • Temperature <35° <35°C • Respiratory rate ≥30/min or ≥40° 40°C NO YES ASSIGN PATIENT TO RISK CLASS 1 Fine MJ. Patients that were above the age of 50 that ended up having one of these comorbid conditions that you see up here – neoplastic disease. we should be thinking about risk stratification processes. Based on their points. If they had any one of these findings. they were given a certain number of points. . What he came up with is. 3. liver. The first is. or had signs of abnormal examination findings – these patients were given a point score. they were given a certain number of points. What he basically suggested was that for patients over the age of 50 years. If they were female. So a patient that had a certain age. N Engl J Med. also called the PORT score. 2. Now as hospitalists. they were given a certain number of points as you can see. when he added up the points. We had a group of hospitalists that got together about a year and a half or two years ago and one of the things we found was that patients sometimes were being inappropriately admitted to the floor when they should have possibly been in the ICU and vice versa. I think it’s really important that we take a step back and think about risk stratification of patients. We’re going to be asked more and more and as we work with our emergency medicine colleagues and our primary care doctors. And there was a point system that he modeled. So I’m going to just give a – even though the literature is kind of loose in this regard. renal. So you could see here that patients that were in risk class 1. cardiovascular.336:243-50. Dr. 1997. he assigned them a risk stratification class of 1.

their mortality rate was less than 1% so he made the conclusion – again. you know.Improving Patient Care: Reducing Antimicrobial Resistance in Respiratory Infections 12 Pneumonia PORT Risk Class: Mortality and Management Risk Class I II III IV V Points NA ≤70 71-90 91-130 >130 Predicted Mortality 0. Now his goal was not necessarily to help – to use this to identify which patients should be admitted and should not be admitted to the hospital but what he was able to show us is that patients that had a risk classification of 2. You have a mortality in the order of 8% or 29%.8% 8.1% 0. And risk class 3. you could see how the mortality rate starts to go up tremendously. say – their mortality was 0. et al. If they had risk class 4 or 5.6%. clinical judgment needs to supersede and you may consider either inpatient or outpatient therapy.2% Decision to Hospitalize No No Yes/No Yes Yes PORT = Pneumonia Patient Outcomes Research Team cohort study. N Engl J Med. Fine MJ. he basically said that. not a studied conclusion – but made the conclusion that patients could be managed as an outpatient if they had risk class 1 or 2.2% 29. .6% 2. 1997.336:243-50. So if they had a risk classification of 1 or 2.

with primary endpoints that looked at overall success outcomes at the end of treatment and secondary endpoints that looked at quality of life and satisfaction for the patients – and this article was published earlier this year in the Annals of Internal Medicine. Carratalá J. randomized and controlled – it looked at about 224 patients that were put into class 2 and 3 based on Dr. and they were randomized and given either oral levofloxacin or they were given IV and then followed up by oral.Improving Patient Care: Reducing Antimicrobial Resistance in Respiratory Infections 13 Outpatient Care vs Hospitalization in Low-Risk Patients with CAP ‹ Objective: determine whether outpatient care of PSI- defined low-risk patients with CAP is as safe and effective as hospitalization ‹ Study design: unblinded. We’re running with capacity issues. could I decide whether patients using these criteria should be outpatient or inpatient management based on – and how should I treat them?” And one of the things – and so this study looked at determining using the PSI score that Dr. 2005. et al. . randomized. Fine’s criteria. there was an article that was published in 2005 whose goal was to say “okay. We have a 95% fill rate right now in our hospital. controlled trial ● 224 CAP patients in risk class II or III (PSI score ≤90) ● Outpatient care with oral levofloxacin. Well what this study did was – it was an unblinded study. or could I just treat them with oral antibiotic and get the same outcome? Now you and I both know that today many hospitals are running with capacity issues. The question was. do I need to put them in the hospital on IV antibiotics and then switch them over to orals. PSI = Pneumonia Severity Index. Fine came up with and looking at low-risk patients. Well.142:165-73. hospitalization with sequential IV and oral levofloxacin ‹ Primary endpoint: % of patients with an overall successful outcome at end of treatment* ● Secondary endpoints included patient quality of life and satisfaction *According to 7 predefined criteria. so risk stratifying and identifying patients that can be safely treated and appropriately treated is going to be more and more important for us as hospitalists. what does this mean to us? Well very recently in the Annals of Internal Medicine. Ann Intern Med.

5 percentage points) ‹ Quality of life. There was 83% that were successfully managed as outpatients and 81% that were successfully managed in the hospitalized setting and that more patients were satisfied with being managed at home. Ann Intern Med. 1. 2. medical complications.2% vs 79. 12.8 to 22.6% of outpatients ● 80.142:165-73.7% of hospitalized patients ● Absolute difference.9 percentage points) ‹ More outpatients (91. and that their quality of life in terms of adverse drug reactions. and overall mortality were similar to the hospitalized group versus the outpatient group. .Improving Patient Care: Reducing Antimicrobial Resistance in Respiratory Infections 14 Outpatient Care vs Hospitalization in Low-Risk Patients with CAP ‹ Overall successful outcome achieved in: ● 83. and could be safely managed at home.1 to 12.1 percentage points (95% CI.1%) were satisfied with their overall care ● Absolute difference. 2005. -7.9 percentage points (95% CI. subsequent hospital admissions. subsequent hospital admissions. et al. and overall mortality were similar in the outpatient and hospitalization groups Carratalá J. % of patients with adverse drug reactions. medical complications. And what they found was that the overall success outcome was achieved in both groups.

et al. There are other things that have been published in the literature that have looked at potential ways of risk stratifying your patients to determine whether these patients should be admitted to the hospital or whether they are even severely sick or not. The mortality rates of these patients started going up. Mehr DR.286:2427-36.Improving Patient Care: Reducing Antimicrobial Resistance in Respiratory Infections 15 Dependence in Activities of Daily Living (ADL) Is a Risk Factor for Mortality in NHAP 25 N = 1044 % Mortality 20 15 10 5 0 0-3 4-7 8-11 12-15 16 No. . of ADL Dependencies NHAP = nursing home–acquired pneumonia. like activities of daily living. JAMA. 2001. There was an article published in JAMA that looked at the number of activities of daily living that where impaired in a large group of patients.

45]) ‹ Rapid respiratory rate predicts mortality ● Respiratory rate ≥30/min was related to 21.91 [95% CI 1.286:2427-36. et al. There is also data that looked at just getting a quick assessment of the respiratory rate.1% 30-day mortality (RR 1.482. . but when you’re a busy hospitalist looking at a patient that the emergency medicine doctor has called you on.2% 30-day mortality (RR 1. they had a 23% 30-day mortality rate.72 [1. If your patient has – there was a study that looked at patients with a pulse rate of greater than 100.Improving Patient Care: Reducing Antimicrobial Resistance in Respiratory Infections 16 CAP: Effect of Pulse and Respiratory Rate on Mortality in NHAP ‹ Rapid pulse rate predicts mortality ● Pulse ≥100/min was related to 23. they had a 21% 30-day mortality rate. whereas when they had a respiratory rate of greater than 30. There haven’t been any great studies that try to risk stratify your patients.332. hopefully you’ll think about these things as you are thinking about where these patients should be placed and how they should be managed. JAMA. 2001.21]) Mehr DR. So I’m not saying that these are all really good studies.

et al.6 mg/dL ‹ Revision of the BTS rule ● Add a fourth criterion ─ Confusion ● Define increased mortality risk ─ If 2 of 4 criteria Neill AM. . And then if you had a fourth criteria of confusion. and what they found was that respiratory rates above 30.Improving Patient Care: Reducing Antimicrobial Resistance in Respiratory Infections 17 “Mild to Moderate” vs “Severe” CAP: British Thoracic Society (BTS) Rule ‹ Original BTS rule to predict mortality ● Increased risk of mortality if 2 of 3 ─ Respiratory rate ≥30/min ─ Diastolic BP ≤60 mmHg ─ BUN >19. and BUNs of above 19 showed an increased risk of mortality. diastolic blood pressures below 60. if you had two out of the three findings. 1996. Thorax.51:1010-16. The British Thoracic Society way back when – almost 8 or 9 years ago – tried to also look at mild to moderate versus severe CAP patients and come up with some risks for mortality. it increased your risk of mortality by two to four times.

like Mycoplasma and Chlamydia. . Let’s jump into the most common causes of community-acquired pneumonia. pneumoniae H. Pneumocystis species. pneumoniae M. Once they get into the hospital setting. But let’s jump into – so that’s a little bit about risk stratification. We know from Dr. Strep pneumonia still continues to be our number one cause of community-acquired pneumonia. and as they get into the ICU setting you want to start thinking more about gram-negative and Pseudomonas and make sure that you’re covering for those appropriately. influenzae C. pneumoniae Legionella species H. Strep pneumonia – again Mycoplasma – you start thinking about things like Legionella and H. influenzae Legionella species Aspiration 1Based 2Excluding Severe (ICU)2 S. influenzae Gram-negative S. influenza. Am J Med Continuing Education Series.Improving Patient Care: Reducing Antimicrobial Resistance in Respiratory Infections 18 Etiology of CAP: Most Common Causes1 Ambulatory Patients S. Certainly in COPD patients you have to think of H. influenza. aureus on collective data from recent studies. pneumoniae C. making up about 60% of the patients. File et al. File and many other people who have looked at the common causes. pneumoniae H. pneumoniae bacilli Viruses Hospitalized (Non-ICU)2 S. 1997. pneumoniae M. And as you can see in ambulatory setting atypicals are common.

the whole concept of covering for atypicals. but if they had Strep pneumonia. [For those] that had Chlamydia pneumonia. et al. I know that we don’t have length of stay this high usually anymore in the hospital setting. But the combination of the two really increased the morbidity in patients and the risk for mortality in patients as they stayed in the hospital longer. pneumoniae S. . they were on the order of 10 days. 1996. This is a little bit of older data that was published in Thorax – you know.9 20 15 10. but you can see the patients that were treated.51:185-9.5 10 5 0 C. pneumoniae Both 8. length of stays in this study were in the order of 8 days. I think from a hospitalist’s standpoint.4 Kauppinen MT.Improving Patient Care: Reducing Antimicrobial Resistance in Respiratory Infections 19 Chlamydia Co-infection Prolongs Length of Stay (LOS) in CAP 25 Hospital LOS (days) N = 125 21. Thorax.

So appropriate coverage for atypical and typical organisms in the management of community-acquired pneumonia is extremely important. You also want to kind of think about if they have underlying cardiopulmonary disease or disease modifiers. American Thoracic Society has published its guidelines. IDSA has published its guidelines. no modifier C/P = cardiopulmonary Yes No American Thoracic Society. If you have community-acquired pneumonia. +/or modifier No C/P disease. the latest one in 2003. Am J Respir Crit Care Med.modifiers Risk for Pseudomonas + C/P disease. 2001. for example. are you dealing with mild to moderate disease or are you dealing with severe CAP? And if you’re dealing with severe CAP. you want to think about the risk for Pseudomonas because they may impact the type of therapy and whether you need double coverage or not. ATS basically says take a look at whether you’re thinking about outpatient therapy versus inpatient when you’re thinking about your risk stratification model.Improving Patient Care: Reducing Antimicrobial Resistance in Respiratory Infections 20 Guidelines for CAP Management: The ATS Algorithm of 2001 CAP is present Outpatient therapy No C/P disease History of C/P disease Inpatient therapy Mild to moderate illness Severe CAP No modifiers +/+/. the latest one in 2001.163:1730-54. And there are differences in the guidelines but the concepts are somewhat – are there. . do they have any cardiopulmonary disease or not? And do they have any disease modifiers or do they have a risk for drugresistant Strep pneumonia or drug-resistant Pseudomonas? You need to think about those things. So guidelines that are out there – there are various guidelines that are available. and then if they have outpatient therapy. On the inpatient side.

. if a patient has been on steroids or is an alcoholic. We have risk factors for patients that we need to think about. ceftriaxone Beta-lactam ICU. non-PSA: cefotaxime. or it was an IV fluoroquinolone that was recommended.163:1730-54. or has been on immunosuppressants. AP = anti-Pseudomonal. the recommendation was to suggest and look for the risk of Pseudomonas and then appropriately double-cover patients for Pseudomonas. + PSA: cefepime. When you got to the patient side – again similar types of things. cefuroxime. the treatment option was double coverage with something for atypicals like aminoglycosides plus a beta-lactam. ampicillin/sulbactam. the recommendation was to consider clarithromycin or azithromycin or consider – and then doxycycline was offered as a distant alternative. 3GC = thirdgeneration cephalosporin. or has a family member a child in a day care center. 2001. imipenem-cilastatin/ meropenem. For example. in any case. but there was also the recommendation of looking at drug-resistant organisms. When you’ve got patients who have had underlying cardiopulmonary disease and/or disease modifiers. FQ = fluoroquinolone So this is what ATS – and I know most of you probably already know this but just as a quick reminder. amoxicillin/clavulanate. Again. amoxicillin 1 gm TID. you want to think about the risks for drug-resistant Strep pneumonia. AMG = aminoglycoside. at drug-resistant Strep pneumonia or gram-negative risks. or has been treated with an antibiotic in the past 30 days. + Pseudomonas: IV AP + IV cipro or IV AP + IV AMG + IV azithromycin or IV FQ (not cipro) cipro) C/P = cardiopulmonary. ceftriaxone. If they were in the ICU setting. pneumoniae/gram negative bacilli. Am J Respir Crit Care Med. DRSP/GN = drug-resistant S. PSA = + Pseudomonas. hi-dose ampicillin Beta-lactam ICU. no modifiers Clarithromycin or azithromycin (doxycycline as alternate only) Inpatient WARD (mild(mild-moderate hospitalized) No C/P or DRSP/GN risk: IV azithromycin or IV beta­ betalactam + doxycycline (macrolide(macrolide-allergic) or IV fluoroquinolone alone + C/P or DRSP/GN risk: IV betabeta-lactam + IV/PO macrolide/doxycycline or fluoroquinolone alone History of C/P disease and/or modifiers BetaBeta-lactam + macrolide/doxycycline or fluoroquinolone alone ICU No risk of Pseudomonas: IV 3GC + IV azithromycin or IV fluoroquinolone Beta-lactam OP: cefpodoxime. ceftriaxone Beta-lactam IP: cefotaxime.Improving Patient Care: Reducing Antimicrobial Resistance in Respiratory Infections 21 ATS 2001 Recommendations for CAP CAP is present Outpatient No C/P disease. piperacillin/tazobactam American Thoracic Society. combination therapy with a beta-lactam and a macrolide or a fluoroquinolone alone was recommended. ATS basically has recommended if they have no – if they’re outpatient and they have no cardiopulmonary disease or modifiers.

But if they’ve had antibiotics in the past 3 months. . but use the opposite [combination] is what the recommendation is. et al. For example. with this guideline in 2003. no previous antibiotic – you could see a macrolide or doxycycline. and they’ve focused on some other things. the real recommendation in the past 3 months is considered – what they haven’t been on because of the risk of resistance – so you can either do a respiratory fluoroquinolone or combination therapy. healthy. diabetes. again use either respiratory fluoroquinolones or the combination therapy. Think about at-risk for aspiration because you’ll have to cover for atypical organisms. you could see what the recommendations are there in terms of macrolides and respiratory fluoroquinolones. 2003. IDSA.Improving Patient Care: Reducing Antimicrobial Resistance in Respiratory Infections 22 IDSA CAP Guidelines: 2003 Outpatient ‹ Healthy & no previous antibiotic therapy (3 months) ● Macrolide or doxycycline ‹ Healthy but has had previous antibiotic therapy ● Respiratory fluoroquinolone ● Advanced macrolide plus high-dose amoxicillin ● Advanced macrolide plus high-dose amoxicillin/clavulanate ‹ Comorbidities present (COPD.37:1405-33. If they have comorbidities but they haven’t been on antibiotics. If they’re healthy but they’ve had previous antibiotics. again. etc) ● No previous antibiotics ─ Advanced macrolide or respiratory fluoroquinolone ● Previous antibiotics within past 3 months ─ Respiratory fluoroquinolone or ─ Advanced macrolide plus a beta-lactam ‹ Suspected aspiration ● Clindamycin or amoxicillin/clavulanate Mandell LA. Clin Infect Dis. CHF. Now certainly also the other thing I think that’s important that you need to remember is that the IDSA guidelines have come out.

37:1405-33. 2003. again the question about whether they’ve been on antibiotics for the past 3 months needs to be asked because you’ll use the other combination.Improving Patient Care: Reducing Antimicrobial Resistance in Respiratory Infections 23 IDSA CAP Guidelines: 2003 Inpatient ‹ Medical Ward – no recent antibiotics (3 months) ● Respiratory fluoroquinolone or ● Advanced macrolide plus beta-lactam ‹ Medical Ward – recent antibiotic therapy (3 months) ● Respiratory fluoroquinolone or ● Advanced macrolide plus beta-lactam ● Regimen selected depends on nature of recent antibiotic therapy Mandell LA. et al. . IDSA. Clin Infect Dis. And then again when they get into the hospital setting. When they get into the medical ward.

et al. In the ICU. . aeruginosa infection ● No beta-lactam allergy ─ Beta-lactam plus either an advanced macrolide or a respiratory fluoroquinolone ● Beta-lactam allergy ─ Respiratory fluoroquinolone with or w/out clindamycin ‹ ICU – P.Improving Patient Care: Reducing Antimicrobial Resistance in Respiratory Infections 24 IDSA CAP Guidelines: 2003 Inpatient ‹ ICU – low risk of P. 2003. aeruginosa is an issue ● No beta-lactam allergy ─ Anti-Pseudomonal agent plus ciprofloxacin ─ Anti-Pseudomonal agent plus an aminoglycoside plus a respiratory fluoroquinolone or a macrolide ● Beta-lactam allergy ─ Aztreonam plus a respiratory fluoroquinolone with or w/out an aminoglycoside Mandell LA. Clin Infect Dis. and then whether they have beta-lactam allergies or not in your choice of antibiotics appropriately.37:1405-33. IDSA. the risk for Pseudomonas is raised again.

their guidelines. and they are going to tie payment structures to it based on quality measures and so forth.org OR If documented beta-lactam allergy: Aztreonam + aminoglycoside + antipneumococcal quinolone The interesting thing is that it is not only ATS and IDSA that’s coming up with guidelines. and asking us. . in the past 10 years before 2004. All of them were professional organizations that were publishing guidelines. Now look at what you’re seeing: Joint Commission and CMS – as was mentioned earlier this morning in terms of pay-for-performance coming into play and measurements of quality – so this is on the Joint Commission website. If you look at it. if the patient had • Secondary ICD-9 code of bronchiectasis or • Positive response to bronchiectasis question or • Malnutrition (as reflected by serum albumin >3) OR Quinolone monotherapy (IV or oral) OR Beta-lactam (IV) + quinolone (IV) These antibiotics would also be considered acceptable: IV anti-Pseudomonal beta-lactam + IV anti-Pseudomonal quinolone OR Beta-lactam (IV or IM) + doxycycline (IV or oral) OR If documented beta­ lactam allergy: quinolone IV + clindamycin (IV) OR IV anti-Pseudomonal beta-lactam + IV aminoglycoside + IV antipneumococcal quinolone or IV macrolide OR Quinolone (IV) + vancomycin (IV) http://www. British Thoracic Society. and they’re going to make choices and based on what professional societies and literature comes up with. ATS. The payers and the regulatory agencies and the accrediting bodies are starting to come up with guidelines. Nobody is going to be really focusing on this and I think we need to be aware of it. So I think as hospitalists this is going to be in our area. the Canadian Thoracic Society.jcaho. the guidelines that were published were published by professional societies – IDSA.Improving Patient Care: Reducing Antimicrobial Resistance in Respiratory Infections 25 JCAHO & CMS: 2004 Pneumonia Antibiotic Consensus Recommendation Non-ICU Patient Beta-lactam (IV or IM) + macrolide (IV or oral) ICU Patient Beta-lactam (IV) + macrolide (IV) Pseudomonal Risk* In addition to antibiotics listed under ICU.

Improving Patient Care: Reducing Antimicrobial Resistance in Respiratory Infections 26 Impact of Early and Effective Empiric Therapy in CAP ‹ 299 consecutive patients ‹ Overall mortality = 28. In setting up our systems.5% ‹ Mechanical ventilation ● 50% of patients 60 50 % Mortality 40 30 20 ‹ Effectiveness of Rx ● Assessed at 72 hrs Leroy O. Here was a study by Dr.22:1307-14. 1996. Leroy that looked at about 300 patients that were on ventilators and how effective therapy could reduce your risk for mortality. 10 0 Effective Ineffective The other thing as hospitalists. . Intensive Care Med. et al. to accomplish early and effective therapy is going to be more and more important. There have been studies that have shown that outcomes are better if you can initiate antibiotics early and initiate it effectively by choosing the right kind of antibiotic. is the important aspect of early and effective therapy.

113:142-6. I wanted to briefly just mention the concept of IV step-down therapy because IV step-down therapy offers us the ability to do early switch of antibiotics from oral to IV. Rhew DC. Chest. as a group of physicians. no disadvantage to oral observed ● Early discharge safe Ramirez JA. et al. . shortens LOS ‹ Switch when ● Defervesce ● Clinically improving ● GI tract functions ‹ VA study: 90% efficacy w/ 2 IV days (+8 PO) ● Same as with 8 days IV (+2 PO) ‹ After switch. colleagues. and H. prior to discharge. their GI tract is functioning. they are able to tolerate orals. The quality measures that we are going to need to be aware of and focus our attention on are giving pneumococcal vaccine. You can do safe and early discharge. and they’re oxygenating well. influenza. but you don’t have to wait for the fever to resolve if they’re clinically improving. There have been studies that have shown that by doing this you can save patients a number of days on IV therapy. et al. I think the other – and part of the quality guidelines that we all know that exist – is the concept of initiating your antibiotic therapy within 4 hours. 1998.159:2449-54. et al. and that you have 4 more hours after that – it’s going to be that these patients are going to need their antibiotics within 4 hours. Now the real recommendation is not the patients that come into the ER.110:965-71. Blood cultures prior to initiation of antibiotics. setting up our system so that we can do that. So I think you’ve seen in that last study that we’re going to need to be. And I think the latest guidelines are going to focus on switch therapy more and more. with our other hospitalists. 1999. Switch therapy allows for defervescence and should occur when patients are potentially defervescing. Arch Intern Med. specialists. There’ve been studies in the literature that have shown that [it] reduces cost and shortens length of stay.Improving Patient Care: Reducing Antimicrobial Resistance in Respiratory Infections 27 Intravenous Step-Down Therapy ‹ Early switch of antibiotics to oral from IV ● Reduces costs. take 2 hours to get evaluated because of wait time. Siegel RE. 1996. smoking cessation – those are all core quality measures that I think we can work with. and emergency medicine folks to accomplish. Chest.

90 to -1. -4. Arch Intern Med.Improving Patient Care: Reducing Antimicrobial Resistance in Respiratory Infections 28 Switch Therapy for CAP ‹ Average LOS is influenced by early switch programs (-3. et. al. 2001.161:722-7. 95% CI.19) ‹ Criteria for switch vary among studies ‹ Early switch and early discharge strategies may significantly and safely reduce mean LOS when recommended LOS is shorter than actual LOS ‹ IV to PO switch therapy works: patients get out of hospital faster Rhew DC. This was a study that the average length of stay could be influenced by doing appropriate switch therapy and you could even reduce your length of stay by 3 or 4 days based on doing appropriate switch therapy.04 days. .

70 years since the late 1930s and look at what we’re already dealing with. Bactrim. sulfa drugs have a resistance on the order of about 30% right now. The question that I think we have to raise to ourselves is what is the right way of using antibiotics? Because look – antibiotics have only been around for 50 years. We’re talking about in some areas there’s MRSA resistance. we’ve come this far in terms of our resistance. and you’ll see at the end of the talk some slides on resistance issues that we’re dealing with because there is a fair amount of resistance in the United States that’s occurring. . So in just 70 years. Up to as high as 50% in some institutions.Improving Patient Care: Reducing Antimicrobial Resistance in Respiratory Infections 29 Clinical Efficacy Studies Before I get into the clinical efficacy studies. Well. and one of the problems. My job here today is to raise some questions more than anything else. what’s the next 70 years look like or the 70 years after that look like? What kind of treatment are we going to have and how resistant are antibiotics going to be? So I’m wondering whether there are other ways and modalities of treating patients that would help deal with the concept of resistance. Macrolides around the country are showing resistances between 20% and 30%. I’m going to throw out [something]. 60 years.

We have antibiotics that have 80%. but we do have better antibiotics today. still. 14 days of treatment. hopefully getting rapid bactericidal killing. So the question of whether the concept of short-course might be an appropriate thing for us to think about as a group of physicians and where that will help. So the question is – if it can be done in the sicker patient. And the question is. 21 days – there’s no head-to-head good studies that show that patients should be treated that long necessarily. Clin Infect Dis. Resistance occurs if patients take antibiotics and get off of them before the organism is eradicated. Because certainly what was written 20 years ago or 30 years ago or 40 years ago in terms of antibiotic therapy – if you’re using an antibiotic that had 40% or 50% bioavailability versus an antibiotic that has 80 or 90% bioavailability in the appropriate patient. 90%. 2003. 12. 100% bioavailability. We know that there have been studies in the ICU that have shown that patients that have – that are given – effective early treatment of antibiotics. Marin Kollef has published a fair number of literatures on that. Resistance occurs with wrong utilization of antibiotics. if you were going to try to design an antibiotic that could fit these principals. can it be done in the less sicker patients or what kind of patients can we consider doing it? Well. you’d be looking to maximize concentrationdependent killing. We know that people had recommended treating for 10. Resistance occurs if you have biofilm formation. increasing your area under the curve. I’m not sure I have the answer today because. that they can potentially be weaned off their ventilator earlier or transferred out of the ICU earlier. good head-to-head studies need to be done in this regard. when the first sulfa drugs or the first penicillins that came out had bioavailabilities of 30% to 50%. Resistance occurs if you have overusage of antibiotics.Improving Patient Care: Reducing Antimicrobial Resistance in Respiratory Infections 30 Short-Course Therapy for CAP: Role of Fluoroquinolones ‹ High cure rates possible with short-course therapy with a potent. We also know that there’s some common principals that exist in terms of why resistance occurs. can you do this? .37:752-60. maybe you don’t need patients to be on them quite as long. rapidly acting antibacterial agent ‹ Pharmacodynamic principles and efficacy ● Maximize concentration-dependent killing ● Increased AUC and Cmax values ● Rapid bacterial killing ● Decreased adaptive resistance ‹ Safety considerations of high-dose quinolone therapy Dunbar LM. And you’re going to see me show some studies here to try to at least raise that question. et al. the concept of short-course.

37:752-60. Dunbar had published. you will see it’s 5000 mg versus 3750 so there’s less total amount of antibiotics that’s used if you follow this rationale. double-blind. Clin Infect Dis.Improving Patient Care: Reducing Antimicrobial Resistance in Respiratory Infections 31 Levofloxacin Short-Course Therapy for CAP ‹ Multicenter. here was a study that Dr. It was a multi-center randomized study that looked at giving 500 mg of Levaquin for 10 days versus 750 for 5 days. noninferiority study ‹ Comparison of 500 mg levofloxacin QD x 10 days vs 750 mg levofloxacin QD x 5 days ‹ Patients stratified according to Pneumonia Severity Index (PSI) ● PSI ≤70: Patients treated as inpatients or outpatients ● PSI >70 but ≤130: Patients treated as inpatients for at least 24 hours Dunbar LM. randomized. . Well. 2003. Now there is a problem with this study – they made two changes at the same time during the study – but it still gives us a hint into the concept. If you add up the total amount of antibiotics. et al.

. 2003.2 n=103 92.4 n=198 91. Dunbar LM.Improving Patient Care: Reducing Antimicrobial Resistance in Respiratory Infections 32 Levofloxacin Short-Course Therapy for CAP: Clinical and Microbiologic Results 100 750 mg 500 mg 80 92. et al.4 n=92 % of Patients 60 40 20 0 Clinical Success* (Clinically evaluable population) *Clinical success includes cured and improved.37:752-60. and what she found was that the clinical success rates and the microbiological outcomes for the patient were basically the same in patients with 750 versus 500 mg. Dr. Microbiologic Eradication (Microbiologically evaluable population) And in this one.1 n=192 93. Dunbar looked at the PSI score in terms of stratifying her patients. Clin Infect Dis.

†Any treatment-emergent adverse event assessed by investigator as probably or very likely related to study drug.0) 5 (1.8.8) 18 (7. Dunbar LM. . or was deemed medically important.8) 18 (7.0) 25 (9. et al.3) 9 (3. Clin Infect Dis.9) 500 mg (N=265) 158 (59. required or prolonged inpatient hospitalization. the adverse events were less in the 750 group compared to the 500 group and the number of deaths were also less in those groups.37:752-60. immediately life-threatening.Improving Patient Care: Reducing Antimicrobial Resistance in Respiratory Infections 33 Levofloxacin Short-Course Therapy for CAP: Safety No. (%) of Patients 750 mg (N=256) ≥1 treatment-emergent* AE ≥1 treatment-related† AE ≥1 serious‡ AE Discontinuation due to AE Deaths§ 148 (57. was a congenital anomaly.5) *Any adverse event that was new in onset or increased in intensity or frequency during the study period. ‡Any treatment-emergent adverse event that was fatal. §Any death that occurred from study entry to the post. caused permanent or significant disability.study visit is included.6) 15 (5.7) 37 (14.4) 95% CI (-6. 10.0) 22 (8. And when she looked at adverse events. 2003.

03 Schrag SJ. JAMA.286:49-56.Improving Patient Care: Reducing Antimicrobial Resistance in Respiratory Infections 34 Amoxicillin Short-Course Therapy for CAP: Resistant Pneumococcal Carriage Analysis ‹ 795 patients in an outpatient clinic in the Dominican Republic ‹ Randomized to receive 90 mg/kg per day for 5 days vs 40 mg/kg per day for 10 days ‹ PRSP carriage (nasopharyngeal) assessed ‹ PRSP at 28 days: short-course (24%). standard-course (32%). Again. . and this also showed in penicillin-resistant Strep pneumonia that potentially short-course therapy as compared to standard course might actually show some beneficial outcomes. higher doses but shorter courses. P = . et al. 2001. pneumoniae There’ve been studies looking at short courses of amoxicillin also for community-acquired pneumonia patients to deal with resistant pneumococcal carriage analysis. PRSP = penicillin-resistant S.

815) O’Doherty B. et al. compared with 91% (32/35) isolated from clarithromycin group ‹ Incidences of treatment-related adverse events were similar for the two groups (P=0. . 1998.17:828-33. There have been studies that compare azithromycin for 3 days versus clarithromycin given for 10 days.518 ‹ 97% (31/32) pathogens isolated azithromycin group were eradicated. Again. and the outcomes are also comparable in both groups. the concept of short-course raised again.Improving Patient Care: Reducing Antimicrobial Resistance in Respiratory Infections 35 Azithromycin vs Clarithromycin Short-Course Therapy for CAP ‹ 203 patients with mild to moderate CAP were randomized to receive: ● ● ‹ azithromycin 500 mg once daily for 3 days (n = 101) or clarithromycin 250 mg twice daily for 10 days (n = 102) A satisfactory clinical response was recorded at end of therapy in: ● 94% (83/88) azithromycin group ● 95% (84/88) clarithromycin group ● P=0. Eur J Clin Microbiol Infect Dis.

activecontrolled study ‹ Regimens: ● 5 days of oral telithromycin 800 mg once daily (n = 193) ● 7 days of oral telithromycin 800 mg once daily (n = 195) ● 10 days of oral clarithromcyin 500 mg twice daily (n = 187) Tellier G. . Telithromycin. 2004. et al. double-blind. J Antimicrob Chemother. randomized. the newest upper respiratory antibiotic that is marketed as having two binding sites to deal with resistance issues and is the first ketolide on the market – here they tried to compare 5 days of telithromycin versus 7 days versus 10 days of clarithromycin.54:515-23.Improving Patient Care: Reducing Antimicrobial Resistance in Respiratory Infections 36 Telithromycin vs Clarithromycin Short-Course Therapy for CAP ‹ Multicentre.

pneumoniae 10-day clarithromycin % of Patients n=159 n=161 n=146 89. 2004.8 91.Improving Patient Care: Reducing Antimicrobial Resistance in Respiratory Infections 37 Telithromycin vs Clarithromycin Short-Course Therapy for CAP 100 80 60 40 20 0 Clinical Cure Rates 5-day telithromycin Bacteriological eradication rates for S. J Antimicrob Chemother.7 29/30 88.8 23/24 96. And the results were fairly comparable in the 5-day group and the 7-day group versus the 10-day group.8 95.54:515-23.3 88.5 23/26 7-day telithromycin Tellier G. and so it’s gotten the recommendation for sinusitis and bronchitis for 5-day therapy for telithromycin compared to 7-10 day therapy for pneumonia. . et al.

J Chemother. Washington J. USA 1992–1998 50 % of Isolates 40 30 20 10 0 1992 (n=125) PenI PenR EryR 1993 (n=185) 1994 (n=147) 1995 (n=81) 1996 (n=79) 1997 (n=124) 1998 (n=149) *Resistance defined as erythromycin MIC >1 µg/mL. It’s been on the rise for the last decade or so. 2000. pneumoniae Resistance* to Penicillin and Macrolides. 1999.11(suppl 1):5-21. J Antimicrob Chemother.Improving Patient Care: Reducing Antimicrobial Resistance in Respiratory Infections 38 S. . Felmingham D. I raised this question today only because look at what’s happening to the resistance of Strep pneumonia to penicillin and macrolide. You can see it continuously.45:191-203. Felmingham D. Gruneberg RN.

pneumoniae Resistance Rates for Selected Agents.8 16.2 *n = 1.3 1.45:1721-9.9 8.4 30.Improving Patient Care: Reducing Antimicrobial Resistance in Respiratory Infections 39 S. Antimicrob Agents Chemother. . 2001.531 isolates.4 8. Doern GV. And as I’ve mentioned before. 33 US medical centers. et al. 1999–2000* Antimicrobial Macrolides Clindamycin Tetracycline Chloramphenicol Trimethoprim/sulfamethoxazole Fluoroquinolones % Resistance 25. winter (1999-2000). macrolides have a resistance of almost 20%-30% and Bactrim to 30%.

the PROTECT study had shown that the resistance in the Far East may be as high as 60% or 70%.Improving Patient Care: Reducing Antimicrobial Resistance in Respiratory Infections 40 Antimicrobial Resistance Trend: S.0 *Penicillin-resistant = MIC >2µg/ml.0 1.5 24. you’re on the order of 24% and 26%. penicillins are shown to be in the order of 18% or so.5 26.9 227 4456 1. USA. of isolates Levofloxacin MIC90 (µg/ml) TRUST 6 (2002) 18.0 TRUST 7 (2003) 17. NCCLS broth microdilution – centralized lab.7 0. 2003. of institutions No. The resistance is quite high and we need to kind of deal with this across the board. in Japan or Korea. 2003(suppl 3):S4-S11. look at Bactrim. pneumoniae. Focus Technologies. In vitro activity does not necessarily correlate with clinical results. et al.0 1. Karlowsky JA. .36:963-70. Clin Infect Dis. Again. you can see again there. 2002-2003 Antimicrobial Agent.4 27. Still we’re lucky with some of the fluoroquinolones that have resistances of less than 1%. In fact. Other comparative industry-sponsored studies are showing the same results. Sahm DF. to macrolides and penicillin-resistant Strep pneumonia.9 239 7671 1.5 0. % Resistant Penicillin* Azithromycin Trimeth/sulfa Ceftriaxone (nonmeningitis) Levofloxacin No. The Trust data – that was industry-sponsored data – has been looking at resistance patterns every year.3 27. Clin Cornerstone.

3% R 12%-19. pneumoniae Antimicrobial Resistance TRUST 7 (2002–2003) S. Those are the areas that I’d be very concerned about.Improving Patient Care: Reducing Antimicrobial Resistance in Respiratory Infections 41 S. MIC ≥2 µg/mL) Azithromycin Resistance (Resistant. They’ve already shown a greater than 20% resistance. Look at how much of the United States we’re dealing with for penicillin and azithromycin across the board.5% R Erythromycin = 27.9% R <12% R National Rates: Azithromycin = 27. . pneumoniae S. pneumoniae Penicillin Resistance (Resistant. 2003(suppl 3):S4-S11. Clin Cornerstone. You can see here in Trust 7 data – look at all the red-colored areas.9% R Sahm DF. MIC ≥2 µg/mL) DC DC ≥20% R National Rate: Penicillin = 17.

In terms of the fluoroquinolones. antimicrobial susceptibility to Pseudomonas where we don’t have that many great agents that are up in the 90% or 100% efficacy. % Resistant Ceftazidime Cefepime Gentamicin Pip/Tazo Imipenem Ciprofloxacin Levofloxacin Isolates (labs) In vitro activity does not necessarily correlate with clinical results.8 81. nothing there above 90%.5 72. really the only thing we have are cipro and Levaquin. Poster presentation at IDSA 2003.Improving Patient Care: Reducing Antimicrobial Resistance in Respiratory Infections 42 Antimicrobial % Susceptibility: P. and more and more we’re starting to worry about resistance issues. et al.9 67. We have gentamicin and piperacillin but again.7 998 (36) TRUST 7 (2003) 80. .8 68. Poster presentation at IDSA 2002.0 78. That’s part of the reason we have to consider double coverage. Blosser-Middleton RS.7 85.4 67.6 79.7 NT 76.3 882 (36) Also. aeruginosa. TRUST 6 (2002) 79. 2002-2003 Antimicrobial Agent.3 87. et al.8 65. USA. Thornsberry C. Chicago (Poster 71). San Diego (Poster 222).

influenza.Improving Patient Care: Reducing Antimicrobial Resistance in Respiratory Infections 43 Pay-for-Performance Initiative ‹ Hospital Quality Initiative requires hospitals to report on 17 quality measures ‹ Failure to report performance date will result in 0. This is the whole concept of pay-for-performance that I brought up earlier. oxygenation assessment ‹ Top 20% of hospitals will be given a financial bonus http://www. There is the concept right now that’s being thrown around that failure to report performance may result in a 0.gov/quality/hospital/overview. as I mentioned earlier in this talk. blood cultures. blood culture before first antibiotic.pdf So tying all of this together is – I think as hospitalists. Hospital quality initiatives require hospitals to report 17 quality measures. antibiotics within 4 hours.hhs. include smoking cessation. for the most common illness or the sixth or seventh leading cause of death and the most common infectious cause of death in the hospital setting and the numbers that we have – we’re certainly going to be tied to quality and efficiency and performance issues by our employers and by the public. The top 20% of hospitals may actually get a financial bonus for doing the appropriate job and I think that’s going to fall on our shoulders as hospitalists to deal with. .4% reduction in payments from CMS. Measures related to pneumonia.4% reduction in annual payment from CMS ‹ Measures related to pneumonia include: smoking cessation. vaccination – Pneumovax and H.cms. initial antibiotic within 4 hrs of hospital arrival. oxygenation assessment.

Recent data suggests that outpatient care could be effective in the appropriate low-risk patients and hospitalization may not be required. and that may be one of the new ways of looking at the management of this common disease state. but the good thing is that both organizations are actually coming together and they’ve already produced a combined guideline for hospital acquired-pneumonia. and the community-acquired guideline is suspected to come out soon. higher-dose therapy may offer some advantages in terms of dealing with the concept of resistance.Improving Patient Care: Reducing Antimicrobial Resistance in Respiratory Infections 44 Conclusions ‹ CAP is a relatively common and serious respiratory tract infection ‹ There is no universal consensus for the treatment of CAP. and also increases patient satisfaction ‹ Short-course. . azithromycin. higher-dose therapy for CAP offers a number of potential advantages: rapid eradication of pathogen. guidelines include those from the ATS and IDSA ‹ Recent data suggest that outpatient care is as effective as hospitalization in low-risk patients with CAP. There is no universal consensus for the treatment of community-acquired pneumonia. increased patient compliance. They vary a little bit. or telithromycin has shown promise So I’m going to wrap up today by saying that community-acquired pneumonia is relatively common and a serious respiratory tract infection that is really being managed by hospitalists on a day-to-day basis with our infectious disease and pulmonary colleagues. The concept of short-course. and reduced resistance rates ● Short-course therapy with levofloxacin. but there are guidelines by ATS and IDSA.

in that range. ATS was kind of equivocal on it. Same thing with blood cultures. one other comment that I wanted to make in regards to getting the sputum is that there are differences in the two guidelines. I think that people are understanding that getting the sputum is not the easiest thing in the world. get it down to the lab immediately. you can de-escalate therapy and appropriately treat. And if the patient is dehydrated to get the sputum it is more difficult. Now even though we are doing it for academic reasons. If it sits around. If you see gram-positive cocci on your sputum.Improving Patient Care: Reducing Antimicrobial Resistance in Respiratory Infections 45 Questions & Answers How many of the pneumonias actually are viral? What personally do you feel are the utility of sputum and blood cultures. Going back to the sputum. IDSA strongly in the past – I will see what the combined guidelines show – but in the past. You know. And the best thing to do is get the sputum. As far as sputum utility – it’s interesting because I’ll even tell you just a personal experience of my institution. it was highly recommended to get the sputum sample. The problem is that getting sputums is not always easy because you’ve got to collect it and you’ve got to get it down to the lab. In a patient that potentially could have bacteremia – and in fact it is a quality indicator – you need to get blood cultures prior to antibiotics and you need to document that you have done that. Now does that mean that we shouldn’t do it? The answer is no. you run into problems of getting inappropriate results. because it still has a utility. That doesn’t mean we shouldn’t do it. There was a strong demand by our infectious disease specialist and chief of infection control during the first time I put out the guidelines on community-acquired pneumonia that they absolutely need to get sputums done. . One of the concepts of dealing with resistance might be appropriately de-escalating therapy and treating appropriately. in terms of what we actually end up doing? Studies that I’ve seen in terms of viral pneumonias have ranged anywhere from 10% to 30%-40%.

. That’s being raised as a question. I think that’s what really the regulatory agencies that are recommending this are trying to get us to try to do. I’m called when I can’t do anything about the 4 hours – Any suggestions? Yes. I think we all would agree that the very first thing is that we should be giving antibiotics appropriately. but I think it’s starting to be raised nationally about whether 1) it’s possible. It’s still there and I need to say that we need to be pushing that agenda today still. as that’s being discussed on a national scale. This to me is an opportunity for us as hospitalists to look and to first define the problem in our institution. you know. and work with everybody to see what we can do to streamline some of that process and basically take a performance improvement process. Given that as a hospitalist.Improving Patient Care: Reducing Antimicrobial Resistance in Respiratory Infections 46 Questions & Answers And our hospital didn’t rank as well for the antibiotics. does it really change outcomes. In any case. work with our lab. We should try to go about doing that. Work with our colleagues in emergency medicine and infectious disease. the 4-hour issue is actually starting to come into question today. Why can’t it be done? Work with and take a leadership role. what can you do I think is the next question. and 2) whether it’s really truly effective.

This variability in recommendations needs to be worked through a little bit. you need to do sputum cultures and – It becomes a pay-for-performance. to work with the regulatory agencies to deal with that. Right. . JACHO has their antibiotics but since ATS and IDSA can vary. And that’s the reason I brought this up today at this talk is because I think we all need to be aware that there may be competing interests that exist and we will need to work as a society to deal with that as a group of physicians. And hopefully what’s going to happen is that IDSA and ATS combine and release their guidelines. what happens if JACHO picks – oh.Improving Patient Care: Reducing Antimicrobial Resistance in Respiratory Infections 47 Questions & Answers What about. JACHO and so forth will use the similar guidelines.

What we’re trying to do is not necessarily give every detail of what should be done but the process of how to go about doing it and the tools that can be used to develop your process. you know. I would agree with that. so you’ve got to take all of those factors into account. The resource rooms that I was telling everybody to look at the Cybernet Café is that whole process. And certainly. . I agree with you.Improving Patient Care: Reducing Antimicrobial Resistance in Respiratory Infections 48 Questions & Answers … we need to develop therapeutic approaches with those two background sort of notions and then observe the effectiveness over time. I think you take the national recommendations and you need to develop your own process in your own institution to apply the principles of those but you may have to tweak them and make them apply to your local institution. And that should be your take-home message. because if we are trying to apply a national approach in a local scene I think it’s fraught with a lot of problems then. and I think that’s what you’re seeing us starting to do is really try to give ideas of how to implement things. even if you compare my MRSA rate to a hospital 30 minutes away from me is a huge difference.

you can stop by and see me in the back. I don’t know whether – I think this is maybe something – I could be something that you could try to think about at your own local institution and see how to implement it. Sethi up here to give his talk. It’s a tough thing. I want to say thank you. I’ll be in the back for whoever asked it. I think you’re also going to need to think about this in terms of infection control issues within your setting. And the other question here was – Is there a role for gene therapy? – I can’t quite read this question. . With that. and I’d like to invite Dr.Improving Patient Care: Reducing Antimicrobial Resistance in Respiratory Infections 49 Questions & Answers Is it possible to legislate that people should wear masks if they are coughing? I assume it’s possible.

I think I will try to point out those areas which do relate to inpatient settings and I’d also like to point out some of the information that we have in that situation. A lot of what I will present is actually based on outpatient studies. Unfortunately. My job is to discuss acute exacerbations of chronic bronchitis. MD Associate Professor Pulmonary.Improving Patient Care: Reducing Antimicrobial Resistance in Respiratory Infections 50 Acute Exacerbation of Chronic Bronchitis: Strategies for Reducing Drug Resistance Sanjay Sethi. SUNY Good evening here and thanks for being here. . and it’s a nice opportunity to talk to a different audience. which has been my area of research for the last 10 years or so. Critical Care and Sleep Medicine University at Buffalo. there is not a lot of data about antibiotic use and exacerbations in the inpatient setting.

I will show you some more data about how drug-resistant bacteria are growing. Then there is more and more data. I think that’s one of the best things we can do when we treat exacerbations. As we mentioned – I will show you some data – we already saw some data for the pneumococcus. . So obviously one way to confront the challenge of resistance is to use less antibiotics and to use them appropriately. and the fact that the major reason they develop resistance is because of antibiotic use. There is actually the best data for community-acquired pneumonia and ventilator-associated pneumonia. We need some timely action. as we have learned over the years. And so basically we need to do something. and there are some facts that we can state. First of all. bacteria have been here before us humans and most probably will outlast us and so – and they have a remarkable ability to develop antibiotic resistance. but there is also some data now on exacerbations that more resistance is associated with more and more increased costs and poor outcomes in these patients. I think in my area what I will be discussing is how to use antibiotics appropriately. I mean there is no reason why if a bacterial species that had previously been sensitive would expend its energies to develop resistance unless there is antibiotic pressure.Improving Patient Care: Reducing Antimicrobial Resistance in Respiratory Infections 51 Confronting the Challenge of Microbial Resistance ‹ Bacteria have a remarkable ability to develop antibiotic resistance ‹ Antibiotic use exerts selective pressure that favors proliferation of resistant bacteria ‹ Drug-resistant pathogens are a growing menace ‹ Resistance is associated with poor outcomes and increased healthcare costs ‹ Timely action needed to preserve efficacy of existing antibiotics So basically we are discussing about microbial resistance and I just wanted to point out – which was pointed out by Dr. Amin also – that microbial resistance has become a problem and has become a challenge.

but you’ll be surprised that every time I meet with a group of COPD specialists we are still discussing what exactly is an exacerbation. We will talk a little bit about resistance and I’ll mention a couple of studies and then discuss this stratification approach. You saw that for community-acquired pneumonia and that’s becoming advocated for acute exacerbations. for AECB. also. In spite of – I think we all know an exacerbation when we see it. I will make some comments about etiology.Improving Patient Care: Reducing Antimicrobial Resistance in Respiratory Infections 52 Acute Exacerbations of Chronic Bronchitis (AECB) ‹ Definition ‹ Etiology ‹ Antimicrobial resistance ‹ Antibiotic studies ‹ Stratification approach I will start out with some basics about definition. . I think that’s important and that has been my area of interest.

Improving Patient Care: Reducing Antimicrobial Resistance in Respiratory Infections 53 Definition of COPD COPD Airflow limitation/ obstruction present Bronchiectasis Emphysema Chronic Bronchitis AECB Increased dyspnea Increased sputum volume Increased sputum purulence Barnes PJ. 1999. and an increase in sputum purulence. Now these are the three classical cardinal symptoms which define a patient with underlying COPD or chronic bronchitis.343:269-80. 6:327-32. It’s a symptomatic diagnosis and it’s based on change in the baseline symptoms of these patients. N Engl J Med. Clin Pulm Med. an increase in sputum volume or sputum production. . which seems to be now a natural part of the history of the disease. 2000. and then they have increased symptoms. So that’s the bottom line of the diagnosis. I’ll point out these three symptoms up there – dyspnea – an increase in dyspnea. Sethi S. which make us suspect that the patient has an exacerbation. Let’s start with definition and essentially we know that COPD comprises patients with chronic bronchitis and/or emphysema. A fair number of those patients may even have a touch of bronchiectasis.

So they have this day-to-day variability in symptoms. he’s got a pneumonia so we need to treat the pneumonia. I’m bad. they are prone to pneumonia. But that’s not all to the definition.Improving Patient Care: Reducing Antimicrobial Resistance in Respiratory Infections 54 Definition of COPD Exacerbation (AECB) ‹ Duration of 24 hours to 2 weeks ‹ Increased symptoms greater than day-to-day variation ‹ Exclusion of other causes ● Pneumonia ● Congestive heart failure ● Pulmonary embolism ● Others Sethi S.23:217-25. The other thing is that again patients with COPD tend to have daily variations in symptoms. doesn’t have the congestive heart failure – has a real pure exacerbation. I think that’s the kind of patients that we should be focusing on and we’ll be discussing in the subsequent few slides. The exclusion of those causes – you know. They always have some extent of dyspnea. So that’s a specific cause of the increased symptoms. they may get pulmonary emboli. Tomorrow. So it’s an acute or subacute illness in terms of onset by the time you see the patient. it’s a bad day. Today. So if you have somebody whose got underlying COPD or chronic bronchitis and comes in with increased dyspnea and sputum and has an infiltrate. I was fine. There are other aspects that we need to pay attention to as physicians and those are that. which is often ignored. how are you doing today? Well. and sputum. first of all. we’d like to define a time period of at least 24 hours and maybe up to about 2 weeks of increased symptoms. cough. is that patients with COPD also have other reasons to get more dyspnea. I don’t know how many of you do outpatient management of these patients but if you do. So the increase in symptoms to diagnose an exacerbation has to be more than the day-to-day variation. how long have there been increased symptoms? I mean. how long have they been having those increased symptoms? Generally. And I think the third important aspect. patients with COPD and chronic bronchitis are always symptomatic. The question comes up. Many of them have coexistent cardiac disease. J Resp Dis. 2002. you’ll see it all the time: Well. I’ll be fine again. . the patient who doesn’t have the pneumonia. Yesterday.

I’m sure many of us were taught or remember from medical school. proportional worsening. when they get worse over time. exacerbations now – we have data from the Lung Health Study – that they actually do contribute to the progression of lung disease. Which makes absolute sense. . So let’s move on to – before I really get into etiology. not all of it is related to exacerbations. There is a lot of data. the patient comes in. because when is the last time you hospitalized somebody with stable COPD? You don’t hospitalize stable COPD. feels slightly worse. you give him medications to get better. Well that perception has changed dramatically in the last 10 years. There is also good data that exacerbations are actually a major determinate of their loss of quality of life over time in these patients. And again. I just wanted to point out that I’m sure that most of us. contrary to what we were taught. And hospitalization is a big part of the cost of taking care of any disease. and really it’s more for like a chest cold or a nuisance problem. or much worse. that was more of the definition issue. and even now in medical schools. and I’ll show you some of it. So their FEV1s. that many times there is the perception that is taught to us that exacerbations are a nuisance problem. So we need to be more serious about exacerbations. that as much of one-third or up to 45% of the costs of taking care of patients with COPD is related to exacerbations.Improving Patient Care: Reducing Antimicrobial Resistance in Respiratory Infections 55 AECB Perception vs Reality Perception ‹ A nuisance problem with no serious consequences Reality ‹ Contributes to ● Cost of health care ● Poor quality of life ● Mortality ● Progression of lung disease But let’s talk about – before I kind of – so. It’s the most common cause of respiratory mortality in these patients. you hospitalize patients with exacerbations. You know.

patients hospitalized for exacerbations in the ICU.Improving Patient Care: Reducing Antimicrobial Resistance in Respiratory Infections 56 Outcome After Exacerbations 60 50 47 41 59 Mortality (%) 40 30 30 20 10 0 24 Hospital Hospital stay. So at one year. et al JAMA. And then the patients who were more than 65 years of age. . it’s almost at 50%. and what they found was that for the hospital stay there was about a 24% mortality in these patients. they could get the data down the road because they were all Medicare patients. all pts stay. if you look at outcomes – so this is a study which was done in ICU – these are all patients with exacerbations without pneumonia. As you can see. 1995. In fact. there’s progressive mortality in these patients. and they were able to look at their mortality over time. without congestive heart failure.274:1852-7. It’s a multi-center study by Seneff. so exacerbations have serious consequences. So that’s worse than a lot of malignancies and other problems. pts >65 (n = 362) yrs (n = 167) 90 days 180 days 1 year Time After Hospitalization (pts >65 years) Seneff MG.

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Outcome of AECB
In ICU Patients ‹ Hospital mortality: 24% In Hospitalized Patients ‹ Hospital mortality: 6%-12% In ER Patients ‹ Relapse (repeat ER visit): 22%-32% In Outpatients ‹ Treatment failure rate: 13%-33%
Seneff MG, et al JAMA. 1995;274:1852-7; Murata GH, et al. Ann Emerg Med .1991;20:125-9; Adams SG, et al. Chest. 2000;117:1345-52.

In fact, if you look overall, as I mentioned, the hospital mortality in different studies ranges from 24%-28% in the ICU. If you have patients on the floor with an exacerbation, the mortality is 6%-12%, so that’s quite considerable. If you look at outpatients – and again there you don’t really measure mortality, you’re more concerned with relapses, you’re more concerned with poor outcomes in terms of patients coming back or failing treatment. The rates are anywhere generally in most studies about 25%-33%, which means that one 1 of every 4 or 1 out of every 3 patients that we treat with exacerbations as an outpatient actually do do well.

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Cartoon - Pneumonias

Pneumonia

AECB

S. Harris.

So these are real problematic issues which we need to deal with in better ways, which brings me to this slide, which is very appropriate being sandwiched between two pneumonia talks. “What burns me up is that I work as hard as I can and they call me a low-grade infection” – and that’s exacerbation talking to pneumonia. I think we have – we see the infiltrate and we get so excited, but in a patient with underlying significant lung disease exacerbations have serious consequences.

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Treatment of AECB
‹ Medical therapy
● Bronchodilators ● Oxygen ● Antibiotics ● Systemic corticosteroids

‹ Ventilatory support
● Non-invasive ventilation (NIV) ● Invasive ventilation

So let’s get into treatment issues. The approach to treatment, and this applies definitely to inpatients and in most outpatients, too, that the treatment of an acute exacerbation of chronic bronchitis or COPD is the multi-modality approach. It’s not, we throw a bunch of things at these patients which includes bronchodilators, which we use in all patients, oxygen – and bronchodilators we’ve always used because there wouldn’t be any randomized controlled trials. There are no placebo-controlled trials but I guess we’ll never do that. Oxygen and hypoxic patients – again, that’s something we always do and presume it’s of benefit. Antibiotics in the majority of your patients and we’ll discuss that subsequently. Corticosteroids in most hospitalized patients, we should be using them; there are a couple of good studies now, showing that corticosteroids compared to placebo are of benefit. Not a huge benefit but at least a 10% or 15% improvement over placebo in terms of outcome. I really don’t want to be discussing corticosteroids but I just wanted to mention a point, that there are now a couple of studies showing that we don’t need the big asthma doses of steroids in these patients. Many times, 40-60mg of prednisone or equivalent for 7 to 10 days is adequate. Oral or IV, whichever way you want to use it. I don’t have slides for that because of time limitations but I can discuss that later. What’s new also in terms of the real severe patients – we end up using ventilatory support. What’s new with that is non-invasive ventilation. COPD exacerbations are very amenable to noninvasive ventilation and a lot of good studies showing that it actually reduces mortality and length of stay.

of course.Improving Patient Care: Reducing Antimicrobial Resistance in Respiratory Infections 60 Etiology of AECB Noninfectious H.18:1-11. catarrhalis Virus Obaji A. the first question that comes up is: if there is a need for antibiotics and exacerbations. parainfluenza may play a role within the more severely compromised patients. As you get into more severe patients – many times [these are] the type of patients that you see in the hospital – then you start getting into issues of gram-negatives and Pseudomonas in those patients. influenzae M. And you know that the sudden proportion of exacerbations are noninfectious. 2001. and H. it doesn’t take much to tip those patients over and it may be environmental factors and things like those. the pneumococcus and Hemophilus and Moraxella are three major predominant pathogens in these patients. Viruses. Among the bacteria. So let’s get a focus on the antibiotic issue. Once you get into a real severe COPD. The atypical Chlamydia has been shown to have a role in about 5%-10% of exacerbations. you know. . Drugs Aging. And when we focus on the antibiotic issue. pneumoniae H. para Gram-neg Pseudomonas Chlamydia S. what’s causing it? Are bacteria really causing exacerbations? Like pneumonia – but even to a larger extent – exacerbations can be caused by a bunch of different causes. Sethi S. about one-third of exacerbations are related to viral infections.

we isolate the same bacteria from these patients when they are stable. is it viral.Improving Patient Care: Reducing Antimicrobial Resistance in Respiratory Infections 61 Evidence for Bacterial Etiology of AECB ‹ Bacteria can be cultured from the distal airways in significant concentrations in >50% of patients ‹ Acquisition of strains of bacteria new to the patient is associated with a greater than 2-fold increase in the risk of exacerbation Monso E. um – we have large cohort studies that we’ve been doing. we are overtreating. Chest.152:1316-20. 2002. we can actually culture bacteria from the distal airways in significant concentrations in about half the patients. bacterial. And about 50% of exacerbations are bacterial and we use antibiotics in all the patients. 2004. I will give you some hints and then some studies which help us to some extent. The problem we have as clinicians is that you know – I’ve dealt with this issue for the last.465-71.118:1557-65. 2000. or environmental? It’s very difficult to tell. Am J Respir Crit Care Med. Sethi S. but in most patients we don’t know. it’s the acquisition of a new strain of a pathogen which gives them exacerbations. what’s the etiology of the exacerbation in that particular patient. and I still don’t know in individual patients. There are some interesting things being developed but none of them have reached clinical utility. Sethi S. 347. NEJM. So do we have the spectrum of etiology? We still don’t have good reliable diagnostic tests that can tell in an individual patient that you are dealing with – you know. and I must have treated more than 1000 exacerbations in the last 10 years. 1995.168:448-53. But on the other hand the consequences of undertreatment are many times worse than overtreatment. et al. . et al. If you do studies with bronchoscopy. Am J Respir Crit Care Med. Again. what does it mean having bacteria when you isolate that from the sputum in patients with exacerbations? Again. et al. And we have done some work to show that it’s not the same strain that these patients are colonized with which gives them exacerbations. et al. I could spend my whole day talking about that but essentially now there is a bunch of evidence from different sources or different ways that show that bacteria are responsible for about one half of the exacerbations. Sethi S. now this is something that you may not be much aware of but there was a lot of – again about 10 years ago – a lot of debate about. do bacteria really cause exacerbations? You know.

Am J Respir Crit Care Med. et al. 1995. and we have also shown that these patients have much more neutrophilic airway inflammation when they have bacterial versus nonbacterial exacerbations. We and others have shown development of specific immune responses to the pathogens following exacerbations. 2004. et al. .Improving Patient Care: Reducing Antimicrobial Resistance in Respiratory Infections 62 Evidence for Bacterial Etiology of AECB (cont) ‹ Specific immune responses develop to infecting bacterial strains following exacerbation ‹ Neutrophilic airway inflammation is associated with recovery of bacterial pathogens during an exacerbation Monso E. Sethi S. NEJM. et al.118:1557-65. Sethi S. 347. Sethi S. 2002.168:448-53. Am J Respir Crit Care Med. et al. So I think the whole question of “do bacteria cause exacerbations?” is pretty much settled also within the academic community.465-71. Chest.152:1316-20. 2000.

some of it has already been mentioned so I’ll kind of breeze through it. So let’s get onto resistance issues. but resistance is a problem.Improving Patient Care: Reducing Antimicrobial Resistance in Respiratory Infections 63 Antibiotic Resistance S. So hopefully. we won’t live to see that day when mutations will reach a point that we’ll be putting bacteria in cages. . And again. I’ll just focus on the three community-acquired pathogens. Harris.

I was enjoying the conversation about sputum in the earlier talk. basically we have kind of given up on microbiology. Influenzae in Sputum from Patient with AECB I’m sure you are all very familiar with Pseudomonas-resistant pathogens and gram-negative resistant pathogens. . and the little red dot is there. But Hemophilus influenza – these are all sputum smears from a study with patients with exacerbations.Improving Patient Care: Reducing Antimicrobial Resistance in Respiratory Infections 64 H. which is kind of unfortunate in my opinion – we should be using more microbiology – but anyway that’s Hemophilus influenza. so they are always difficult to see.

which again is one of the industrial studies – industry-responsive studies.Improving Patient Care: Reducing Antimicrobial Resistance in Respiratory Infections 65 H.5 100 80 60 40 20 0 BLNAR North Central 68.9 28.6 30.2 β L+ β L- β L+ β L- BLNAR Southwest 100 80 60 40 20 0 24.org BLNAR β L+ β L- BLNAR This is actually the PROTECT study.3 100 80 60 40 20 0 Northeast 70.5 0. About 30%-35% of strains (depending on which part of the country you are) – that’s the blue bars over here – are beta lactamase producing.2 20 0 Southeast 74.4 β L+ β L- BLNAR β L+ β L- BLNAR South Central 100 80 60 40 20 0 28.7 0.3 80 60 40 25.protektus.9 74.706) 100 80 60 40 20 0 34. .2 1. and that means that amoxicillin will not work for these patients.7 1 100 70. Essentially the biggest problem with Hemophilus influenza is beta lactamase production. influenzae β-Lactamase Production: US Isolates (n=2.9 0.3 β L+ β L- www.5 0 Northwest 65.

and again you heard a fair bit about the pneumococcal resistance. about 20%-25%.Improving Patient Care: Reducing Antimicrobial Resistance in Respiratory Infections 66 S. again from a sputum smear in a patient with exacerbation. pneumoniae in Sputum from Patient with AECB This is the pneumococcus. Again. up to 35% – depending upon where you are – have what we call high-grade penicillin resistance: the one that really matters in respiratory infections. .

This is showing trends in macrolide resistance development.5 Southeast 36.1 100 80 29.7 38.3 23.5 40.7 26. pneumoniae Resistance: US Isolates (n=10.6 Northeast 21.5 27.2 Northwest 100 80 60 40 20 0 North Central 31.1 32.6 100 80 60 40 20 0 Penl 27.8 25. And again. in the 30%-35% range for the pneumococcus in the United States at this point in time. .org PenR MacR We also have issues of macrolide resistance.5 Penl PenR MacR South Central 100 80 60 40 20 0 Penl PenR MacR 18.4 26.protektus.4 Penl PenR MacR Southwest 100 80 60 40 20 0 Penl PenR MacR 26.9 17.Improving Patient Care: Reducing Antimicrobial Resistance in Respiratory Infections 67 S.103) 100 80 60 40 20 0 Penl PenR MacR 33.2 www.3 60 40 20 0 24.

44:749-59.11:555-6. et al. Hoban D. Jones RN.106:19S-25S. Jones ME. influenzae (1977-2001) 40 Penicillin-resistant S. .Improving Patient Care: Reducing Antimicrobial Resistance in Respiratory Infections 68 Changing Resistance Patterns for S. Hogan PA. pneumoniae 35 30 Macrolide-resistant S. Diagn Microbiol Infect Dis.27:75-83. 1999. 1997. Clin Ther. 1999. 1989. Doern GV. The problem is that many times the resistances go together. Farrar GE. Antimicrob Agents Chemother. Clin Infect Dis. et al. Forward KR. Thornsberry C. Diagn Microbiol Infect Dis. et al. Emerg Infect Dis. influenzae Isolates (%) 25 20 15 10 5 0 0 1 9 8 7 -‘9 8-‘9 -200 0-’0 77 979 981 984 985 989 990 993 995 6-‘9 7 9 9 0 9 1 99 1 1 1 1 1 1 1 1 9 19 199 1 20 19 Year Jacobs MR. 1999. Thornsberry C. 1999.42:3313-14. et al. Am J Med.4:243-54. 1999.19:119-123.5:757-65. 2003. Semin Respir Infect. J Antimicrob Chemother. The pneumococcus has learned how to put all these resistance genes into what they call a transposon so that many times. IJAA. pneumoniae and H. pneumoniae β-Lactamase + H.34:S4-16. 1998.4:385-389. et al. 2002. This is an example. Antimicrob Agents Chemother. Doern GV.45:251-9. 1999. et al. strains that are resistant to one antibiotic are resistant to the others – and [you have] so-called multi-drug resistance strains.

et al. and you can see that.Improving Patient Care: Reducing Antimicrobial Resistance in Respiratory Infections 69 Penicillin-Resistant S. many times because of the lack of microbiology we don’t even know what we’re dealing with. So that’s a problem. they are many of the times resistant to a lot of the other antibiotics at the same time. pneumoniae Is Often Resistant to Other Antimicrobials 100 % 80 60 40 20 0 Azithromycin Clarithromycin Cefuroxime TMP/SMX Amox/clav Gatifloxacin Levofloxacin N = 329 PRSP strains Doern GV.45:1721-9. if they are resistant to penicillin. . Antimicrob Agents Chemother. again – you know. Here you have penicillin-resistant pneumococci. 2001.

and there still is in Canada. I think we have to be cautious and circumspect about how we use quinolones in these patients. It’s about the same number in the US and it seems to be plateauing out. 1999. This is data from Canada. which shows that over the 1990s there was a lot of quinolones use. That’s from 1998. . and still remain good drugs. Fluoroquinolones are great drugs. which is good. it’s about a 3%-4% range of pneumococcal resistance to the fluoroquinolones. Then with the last period. but again.341:233-9. et al. The good news is that it seems to have plateaued out in Canada and in the US also. there was the emergence of quinolone resistance. but we also have to be careful about how we use them because otherwise resistance will develop to the quinolones also. N Engl J Med.Improving Patient Care: Reducing Antimicrobial Resistance in Respiratory Infections 70 % Ciprofloxacin-Resistant Pneumococci Fluoroquinolone Use and Pneumococcal Resistance in Canada 5 15-64 years 6 ≥ 65 years Quinolone use Prescriptions per 100 Persons 4 3 5 4 3 2 2 1 0 1988 1989 1990 1991 1992 1993 1994 1995 1996 1997 1998 Year 1 0 Chen DK.

. catarrhalis in Sputum from Patient with AECB Moraxella catarrhalis – again.Improving Patient Care: Reducing Antimicrobial Resistance in Respiratory Infections 71 M. the red dots are there.

catarrhalis Pfaller MA. . and there is some emerging resistance to trimethoprim sulfa.Improving Patient Care: Reducing Antimicrobial Resistance in Respiratory Infections 72 Prevalence of Antimicrobial Resistance in the Community Among Adults 100 80 60 40 20 0 %Resistant Penicillin Amox/Clav Macrolide Tetracycline TMP/SMX Gatifloxacin M. Am J Med. And with that. 2001.111:4S-12S. et al. the major problem again is the beta lactamase production and resistance – and because of that to penicillin and amoxicillin.

the most common cause for the individual patient to have a resistant strain is having been exposed to antibiotics in the previous 3 months. and I’m sure a portion of those are because of resistance. So as we’ll discuss later. The question that was again raised by Dr. that’s why they don’t pick up resistant strains. there is much more in vitro data for resistance than there is in vivo data. but the problems with the studies – there are several problems with the studies which could explain that. We all have clinical failures when you treat these patients. the don’t do good diagnostics to document microbiologic failures. but we never do microbiology so we never know.Improving Patient Care: Reducing Antimicrobial Resistance in Respiratory Infections 73 Clinical Relevance of Antimicrobial Resistance ‹ Difficulties in demonstrating clinical relevance ● Exclusion criteria in antibiotic comparison trials ● Observational studies ─ Low-level resistance ─ Use of newer antimicrobial agents ● Immune response can cause resolution of infection over time in spite of ineffective antibiotics ● Inadequate diagnostic methods to document microbiologic failures So that’s about resistance. . Many of the studies actually exclude the kind of patients who have resistant strains. what is the clinical relevance of this resistance? You know. So many of the times. Amin is. If you examine this question on the surface. So I think that’s the kind of problems we have in trying to show clinical relevance. Part of the problem is the kind of studies that are done. Many times. you’ll say that all these studies seem to show equivalent efficacy with all the antibiotics. Most of the studies exclude those patients.

Chest. There are a couple of studies in exacerbations which have shown clinical relevance.117:1345-52. . and this was actually the most interesting of all. This was done in a VA in the emergency department and they looked at patients who got treated for exacerbations and how many of them relapsed in the next 2 weeks and they found that about 22% of them relapsed over the next 2 weeks. et al.Improving Patient Care: Reducing Antimicrobial Resistance in Respiratory Infections 74 Antibiotics and Relapse of AECB ‹ Retrospective chart analysis ‹ VA Emergency Department charts over 18 mos ‹ Relapse defined as patient returning within 14 days ‹ 362 patient visits ● 283 (78%) nonrelapses ● 79 (22%) relapses Adams SG. 2000.

yes. you will actually have high rates of relapse. So these kind of studies which hint at that resistance is relevant in these patients. this is just looking at what antibiotics they got. et al. but what was interesting was that.117:1345-52. What it shows is that when you give an ineffective antibiotic when the patient. Again.05 Relapse Rate. % 40 30 20 10 0 None (92) Antibiotics (270) Amoxicillin (37) Amox/Clav (59) Macrolides (63) TMP/SMX (82) Cipro (9) Cephalosoprin (20) Adams SG. it was about 30%. you think.Improving Patient Care: Reducing Antimicrobial Resistance in Respiratory Infections 75 Antibiotics and Relapse of AECB 60 50 P < 0. Then when they broke down this group into what antibiotic was used. Chest. the antibiotics decreased the rate of relapse in these patients. Without antibiotics. so it’s kind of interesting I think. They didn’t have microbiology in these patients. 2000. . needs an antibiotic. so that’s the antibiotics with the relapse rate of about 19%. the highest relapse rate was the amoxicillin.

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Approaching Antibiotic Therapy of Respiratory Tract Infections (RTI)
‹ Stratification approach ‹ Choose antibiotics based on
● Severity of acute illness ● Expected outcome ● Expected resistance

‹ Guidelines

So then how do you put this all together? So then, I’d talk a little bit about the stratification approach. Where – instead of what’s happened with all of this resistance emergence is that obviously we can’t treat everyone with the same drug now, because if you do that, we will end up undertreating or overtreating patients. So now there is this push that we should chose antibiotics based on the severity of the acute illness and expected outcome, so that the patients that are prone to more outcomes, we use more aggressive antibiotic therapy up front, and also in those patients in whom we think could be a resistant strain, we again use antibiotics to counter that. And you kind of saw the stratification approach that we have for community-acquired pneumonia.

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Antibiotics in AECB

‹ Cardinal symptoms of exacerbation
were increased dyspnea, sputum
volume, and sputum purulence
‹ Exacerbations were classified as Type 1, 2 or 3
● Type 1: All 3 cardinal symptoms present ● Type 2: 2 of the 3 present ● Type 3: 1 of the 3 symptoms plus URTI, fever, cough, wheeze or a 20% increase HR or RR
Anthonisen NR, et al. Ann Intern Med. 1987:106:196-204.

So let’s look at severity of disease. And as I’ve said there is – again, there is one study which helps us kind of define the severity of an exacerbation. Again, we don’t have a Fine classification but we have an Anthonisen typing of exacerbations. So let me show you that. This is a study done by Nick Anthonisen way back in the 1980s. It was a placebo-controlled trial of antibiotics, and they basically defined the exacerbation by the three symptoms and they classified the exacerbations as type 1, 2, or 3 based on the number of symptoms present. So a very simple system. So the patient came in and said, “my breathing is worse, I’m coughing more sputum, and it’s more yellow” – and it’s a type 1 exacerbation. On the other hand, if the patient came in and said “you know, there’s only al little bit of change in my sputum color and everything else is fine and I have a bit of a cold” – that’s a type 3 exacerbation.

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Antibiotics in AECB: Results
80 70

P < 0.01

% Success

60 50 40 30 20 10 0 All Type 1 Type 2 Type 3

Placebo Antibiotic

Type of Exacerbation
Anthonisen NR, et al. Ann Intern Med. 1987:106:196-204.

So they went ahead and classified. They prospectively classified their exacerbations and, again, this was comparing placebo versus antibiotics – and what they found was that antibiotics helped, with about 15% difference between the two arms. And then what they found was that most of the benefit was in the more symptomatic or severe exacerbations. So if you have single-symptom exacerbations, something that you may not commonly deal with in your setting – in that setting, antibiotics don’t seem to make a difference, and also there is a very high rate of spontaneous resolution in those patients.

there was about an 18% failure rate on placebo versus about half of that with antibiotics.05 % Deterioration 25 20 15 10 5 0 All Type 1 Type 2 Type 3 Placebo Antibiotic Type of Exacerbation Anthonisen NR. . Ann Intern Med. et al. As you see over here. but there is a much more substantial benefit with antibiotics in type 2 and 3 exacerbations. what this tells us is that the real mild exacerbations – mild symptoms. In fact. single symptoms – maybe they don’t need antibiotics. So essentially. it’s more dramatic when you look at failures. 1987:106:196-204.Improving Patient Care: Reducing Antimicrobial Resistance in Respiratory Infections 79 Antibiotics in AECB: Results 35 30 P < 0. and again the predominant benefit was in type 1 exacerbations and some in type 2.

are the ones who tend to relapse. Again. How are the patients themselves? How was their underlying disease? Can we predict or can we tell which patients are not going to do well? There are studies to show that. again in the outpatient setting. .8 1.8 0. especially cardiac problems and frequent visits with frequent exacerbations.0 Dyspnea IHD Visits/yr ‹ 2414 patients ‹ Relapse in 507 patients in 1 month (21%) ● 262 (11%) return visit ● 161 (7%) ER visit ● 84 (3.Improving Patient Care: Reducing Antimicrobial Resistance in Respiratory Infections 80 Relapse After Outpatient AECB: A Multivariate Regression Model ‹ Prospective study ‹ 268 general practices Odds Ratios 1. and it showed that patients with more underlying severe lung disease with comorbid conditions. and again it was about 21% relapse rate in those patients.4 0. looking at a bunch of patients and looking at their relapse rates.2 1. relapses result in ER visits and hospitalizations.2 0.4 1.17:928-33. but then they looked at what predicted relapse which caused the patient to relapse in a multivariate model.0 0.5%) hospitalization Miravitlles M. 2001.6 1. and this is a study done from Spain. et al. Eur Respir J.6 0.

The presence of one or more of these risk factors and those patients are then called complicated chronic bronchitis or complicated COPD. . FEV1 = Forced expiratory volume in 1 second. 1994. CMAJ. and have relatively preserved lung function (defined as an FEV1 of more than 50%) – those patients are classified as simple chronic bronchitis. So in fact this was kind of integrated into a system where we define patients with chronic bronchitis or COPD into two groups – patients who do not have comorbid conditions.151(10 suppl):1-23.Improving Patient Care: Reducing Antimicrobial Resistance in Respiratory Infections 81 Important New Questions Expected Outcome ‹ Risk factors for poor outcome ● Comorbid conditions (cardiac disease) ● Frequent exacerbations (>4 / past year) ● Severe obstructive disease (FEV1 <50%) No risk factors Risk factors + Chronic Bronchitis Simple Chronic Bronchitis Complicated Chronic Bronchitis Balter MS. do not have frequent exacerbations. et al.

and of the guidelines that are out there I like these ones the best so I’ll present those. with a need for chronic steroids. FEV1 = Forced expiratory volume in 1 second. in patients without comorbid illness and without frequent exacerbations and relatively preserved lung function – in those patients you can use a macrolide. There are still guidelines from the American College of Physicians that would say that the last good placebo-controlled study was the Anthonisen study from the 1980s. but they are based on the best knowledge or the best science that we have right now. These are mostly – 99% of these patients are outpatients. Now there are again several guidelines for treatment of exacerbations with antibiotics. In an inpatient setting. selective cephalosporins with good pneumococcal activity. complicated and complicated ones at risk for Pseudomonas. And in those patients. or an FEV1 of less than 50%. Complicated exacerbations are the kind of patient that you’re going to see and these are patients who have any one or more of these risk factors. that’s like saying “because we don’t have the data and placebo-controlled trials” that nobody wants to do. into simple or uncomplicated exacerbations. and again in those patients. Can Respir J. Again.10(suppl A):11A-33A. et al. I think the first three are the important ones – frequent exacerbations. TMP/SMX = Trimethoprim/sulfamethoxazole So this is all being put together in a set of guidelines. it’s by mistake. 2003. aeruginosa ƒ Patients with chronic bronchial sepsis Serious comorbid illness ƒ Need for chronic FEV1 <50% corticosteroid therapy Home oxygen and frequent (>4/yr) courses of antibiotics Chronic oral steroids ƒ FEV1 <35% Advanced macrolide Selected cephalosporins Doxycycline TMP/SMX New fluoroquinolones Amoxicillin/clavulanate Fluoroquinolone with anti-Pseudomonal activity O’Donnell DE. The Canadian guidelines have kind of incorporated those issues. we should be ignoring a large body on resistance and outcome. I mean I’m reluctant to throw three antibiotics at these patients. be using either one of the new fluoroquinolones or amoxicillin. up front. Then there’s a third group. or even doxy or trimethoprim sulfa. But again. What they did in these guidelines was to classify the patients. we don’t know. these are the not patients that most probably you are going to see in the hospital setting. as I mentioned. I mean. the recommendation is to stick with a fluoroquinolone with some anti-Pseudomonal activity in an outpatient setting. I think the best thing to do in these patients is to get sputum cultures because then you know if you’re dealing with Pseudomonas or not and then you can guide your therapy. so I still tend to use a single agent with anti-Pseudomonal activity in these patients in the inpatient setting. You’re going to start seeing the similarity to the pneumonia set-up. the recommendation is that we should.Improving Patient Care: Reducing Antimicrobial Resistance in Respiratory Infections 82 Proposed Therapies for AECB According to Patient Subsets Simple. which is complicated and at risk for Pseudomonas. Again. as I showed you. if they get admitted. With simple uncomplicated. serious comorbid illness. these guidelines haven’t been tested in evidence-based situations. Home oxygen and steroids kind of correlate with having bad lung disease. uncomplicated AECB ƒ ≤4 exacerbations/yr ƒ No comorbid illness ƒ FEV1 >50% Complicated AECB ƒ >4 exacerbations/yr ƒ ƒ ƒ ƒ Complicated AECB at risk for P. and again most of those guidelines differ or disagree with each other. These are patients defined by very severe underlying COPD. The idea being that in those patients we need more aggressive therapy up front to minimize the risk of failure in those patients. . so let’s forget about all this resistance emergence and outcome issues and still treat everyone with amoxicillin to start with or Bactrim.

Murphy TF. patients you won’t see in the hospital setting.18:861-82. then again simple and complicated – we kind of discussed that already and its pretty much based on the same kind of break-up. I will try to simplify it even more and incorporate the idea of Anthonisen and when can we not use antibiotics. Once they have a moderate to severe exacerbation based on having two of the three cardinal symptoms at least. consider ciprofloxacin and obtain sputum culture Worsening clinical status or inadequate response in 72 hrs Reevaluate Consider sputum culture Sethi S. But I think Pseudomonas patients fall into this group and those kinds of patients should receive sputum cultures to guide their therapy. clarithromycin) • Ketolide (telithromycin) • Cephalosporin (cefuroxime. cefpodoxime. again. gatifloxacin. levofloxacin) • Amoxicillin-clavulanate • If at risk for Pseudomonas. cefdinir) • Doxycycline Complicated COPD • Fluoroquinolone (moxifloxacin. gemi­ floxacin. maybe antibiotics are not indicated. . This is something that I wrote last year in the Infectious Disease Clinics.Improving Patient Care: Reducing Antimicrobial Resistance in Respiratory Infections 83 Risk Stratification and Acute Exacerbations of COPD Exacerbations MILD Only 1 of the 3 cardinal symptoms: • Increased dyspnea • Increased sputum volume • Increased sputum purulence MODERATE OR SEVERE At least 2 of the 3 cardinal symptoms: • Increased dyspnea • Increased sputum volume • Increased sputum purulence No antibiotics Simple COPD • Advanced macrolide (azithromycin. 2004. Infect Dis Clin N Am. It’s kind of based on the same one. So in patients who are mild.

Improving Patient Care: Reducing Antimicrobial Resistance in Respiratory Infections 84 Antibiotic Steak S. So that’s in terms of guidelines of treatment And of course if nothing else works. . you can tell them to eat a steak that has so many antibiotics in it that you’ll get cured. Harris.

Improving Patient Care: Reducing Antimicrobial Resistance in Respiratory Infections 85 Approaching Antibiotic Therapy of RTI ‹Severity of acute illness ‹Expected outcome ‹Expected resistance ‹Adverse effects ‹Overall cost Just kind of to summarize. You need to start taking into account the severity of the acute illness. and also adverse effects and costs. The way I like to say it is – it won’t apply so much to you folks. I think approaching antibiotic therapy of exacerbations. expected resistance. We have to worry about LDL and HDL and all those things – the same thing with antibiotic use. . but it’s like cholesterol therapy has become much more complicated. and outcomes issues. and even other respiratory tract infections. has become somewhat complicated by the whole resistance emergence issues and we have to become a bit more careful.

the chances are is that the hospitalization is going to be prolonged and they are going to develop complications. And this is well exemplified – this is data again from the study I’ve shown you. 2002. we should look at the overall cost of treatment rather than just the cost of the antibiotic acquisition. et al Chest. They looked at the costs of the failures and showed that 21% of failures were responsible for almost two-thirds of the costs. So I think saving a few dollars on the initial antibiotic therapy and being conservative.Improving Patient Care: Reducing Antimicrobial Resistance in Respiratory Infections 86 Cost of Therapy ‹ The most expensive therapy is one which does not work Cost ($) Cost of AECB Treatment 600 500 400 300 200 100 0 Average Success Failure ‹ Failures (21%) were responsible for 63% of the costs ‹ Reduction in failures by 50% will translate to a 33% reduction in costs Miravitlles M.121:1449-55. It goes over the patients who got hospitalized and required additional diagnostic testing. . I think this really applies again to the setting in which you work in – that if a patient comes in initially and doesn’t get appropriate treatment. can be harmful many times. the Spanish study. And I think – it’s a famous quote – that the most expensive therapy is one which does not work. But I think when it comes to costs. in this situation.

This would be the ideal approach to treating any respiratory tract infection we have – a very accurate diagnosis of what the syndrome is. and the therapy has to be right on the dot. what’s causing it.Improving Patient Care: Reducing Antimicrobial Resistance in Respiratory Infections 87 Antibiotic Treatment of RTI: Ideal Approach ‹ Accurate diagnosis ● Syndrome ● Etiology ● Susceptibility ‹ Therapy ● Focused ● Narrow-spectrum What we would like to have is this. .

Improving Patient Care: Reducing Antimicrobial Resistance in Respiratory Infections 88 Antibiotic Treatment of RTI: Pragmatic Approach ‹ Educated guess ● Syndrome ● Etiology ● Susceptibility ‹ Therapy ● Empiric ● Risk stratification The problem is is that we don’t have the tools to do that. Right now. what’s causing for example the exacerbation. the best we can do is an educated guess as to what’s going on with this patient. . and then base the therapy in an emphatic way on a risk stratification approach that we discussed.

Besides the issue of adverse affects. we had this other approach – or the other extreme people have – that most patients get better anyway. We would always talk to the patient and always give the most simple antibiotic first so that you decrease antibiotic resistance – never based on any data but that was the concept. and that may not be based on fact. mortality and health care costs for several diseases Again. I think we have to be more circumspect about antibiotics. also the issues of resistance emergence because of antibiotic use. use high doses for short duration. morbidity and health care costs of exacerbations in a lot of other diseases. Now you know. And antibiotics are known to reduce mortality. . But now the approach is that we should use the risk stratification approach and choose initial therapy based on that. The concept that antibiotics are pretty harmless is also not true. most patients get better anyway ‹ Antibiotics reduce morbidity. On the other hand. That’s becoming the approach that may be the best way to decrease antibiotic exposure. Not everyone has to fail the first-line therapy to get second-line antibiotics.Improving Patient Care: Reducing Antimicrobial Resistance in Respiratory Infections 89 Antibiotic Treatment of RTI: Changing Paradigms ‹ Initial therapy is always first-line ‹ Choose initial therapy based on risk stratification ‹ Use low doses for long duration ‹ Use high doses for short duration ‹ Antibiotics do no harm ‹ We have to be more circumspect about antibiotics ‹ Antibiotics do little good. there’s some philosophical viewpoints about antibiotic treatment of respiratory tract infections that a lot of the paradigms that we were brought up with are changing. Using low doses for long duration – that was alluded to.

. . .Improving Patient Care: Reducing Antimicrobial Resistance in Respiratory Infections 90 Elegant Solutions S. So again. “Whatever happened to elegant solutions?” It does get more complicated with time. Harris. it gets more complicated. . As it says over there.

.Improving Patient Care: Reducing Antimicrobial Resistance in Respiratory Infections 91 Research at the VA But if you fix those patients up there. . . . they can go back to doing what they should be doing – that’s playing golf. That’s the VA and that’s the research building I work in.

Improving Patient Care: Reducing Antimicrobial Resistance in Respiratory Infections 92 A Must See in Buffalo I always like to put us this to show that there’s more things in Buffalo besides snow. .

Improving Patient Care: Reducing Antimicrobial Resistance in Respiratory Infections 93 Questions & Answers Why are there not any studies – Why are there not many studies for acute exacerbation of chronic bronchitis? Is it because it would be unethical or is it because – or what? Well in terms of antibiotic comparison studies. which is a painful change for many companies. and that is to get FDA approval for the new drug that’s coming on. There are literally hundreds of studies. There is a move now by the FDA that they want to look at superiority again. which is not true when you look at the few placebo-controlled trials. The problem is that all the antibiotic comparison studies are industry-sponsored and were done for only one purpose. All right? Sure. which is existing in the market. . and the studies take on generally simpler patients so that all the results – about 80% to 90% of the patients get better. which is good in a way – was show us that you’re as good as what’s available in the market and approved for that particular indication. They’re bringing about some change. And what the FDA wanted – and that’s changing. and that’s exactly what it did. there are hundreds of studies. but may be actually worthwhile down the road. Because all the studies are designed very carefully that they fall within 10% or 15%. So every study was designed to show non-inferiority to a competitor.

But I think it’s more of a quality measure than anything else. You know. there are no core measures for exacerbations as of yet. if you were giving the vaccine right then that means you were doing other things right. it’s terrible data. hey. so it’s analogous to the 4 hours. Fortunately. it’s actually – you’re right – it’s very soft data. In terms of the data for adults. the data was soft for that. It’s a retrospective analysis of a large database in which they do a multivariate analysis and say we adjusted for the weight of both and they come up with a P-value which is significant and an odds ratio which is slightly above 1. So that’s why I think they are going back to the 8 hours because really the difference in the 8 hours and 4 hours is minimal. And you know. . the discussion with the 4 hours and the 8 hours was very interesting. I would love to comment on that that. 8 hours. They are defending it – the hospital administrators defend it by saying that. If you look at the data that it’s based on. The data for pneumococcal vaccine is soft but it’s a core measure that they’re measuring. but it’s just a matter of time. But can I go back to your question? Yes. So that’s why it’s still a core measure.Improving Patient Care: Reducing Antimicrobial Resistance in Respiratory Infections 94 Questions & Answers Do you see a role for a better pneumococcal vaccine in adults? We are.

Improving Patient Care: Reducing Antimicrobial Resistance in Respiratory Infections 95 Questions & Answers Are they working on a better vaccine? Yes. you know. To impose it as a quality measure I think is a bit unfair. but from what I’ve heard through the grapevine the adult studies have not been as good as they expected with the new pneumococcal conjugate vaccine that they have for kids. there actually has been some adult studies and this is totally unofficial. I may not use it every 5 years and do all those things but I think. but who said that our federal authorities are fair? All right. When they tried that in adults. . they didn’t have any dramatic effects as they had in the kids. What I do is I use it in my patients. if you look at the overall safety/benefit ratio it may be okay to use it at least once. So there is development – there are attempts to develop better vaccines. Thank you very much. We obviously need a better pneumococcal vaccine.

. I promise I will try to end it as indicated. No later than 9:30. so I hope that everybody is alive enough to hang in here with my presentation. I probably will have to strike a deal and I’ll have to pretend I’m talking and you’d have to pretend you’re listening and so I don’t want to get into that issue. So I will use both of those backgrounds in this brief presentation. Connecticut As it is shown on the program. My background is shown on the pamphlet that’s been distributed as a blend of infectious diseases and pharmacology. MD. I’m the last speaker.Improving Patient Care: Reducing Antimicrobial Resistance in Respiratory Infections 96 Antimicrobial Resistance: Implication for Nosocomial Pneumonia Patients Richard Quintiliani. FACP Professor of Medicine and Pharmacology University of Connecticut School of Medicine Farmington. I suspect if I speak much longer than that..

the ATS and the IDSA published actually their 2005 guidelines as to how one should be dealing with this type of infection. Several months ago. and HealthcareAssociated Pneumonia I’ll be focusing mainly on nosocomial pneumonia. . VentilatorAssociated. as mentioned. which used to be viewed as pneumonia that develops in a hospital setting. hospital-acquired pneumonia into different subsets of patients. I will try to show to you in this talk that the term nosocomial is no longer going to become very popular because we are now trying to stratify.Improving Patient Care: Reducing Antimicrobial Resistance in Respiratory Infections 97 Antimicrobial Resistance: Implication for HospitalAcquired.

So this is the new breakdown of pneumonia in the high-risk category. . and Healthcare-Associated Pneumonia ‹ Hospital-acquired pneumonia (HAP) ● Pneumonia occurring ≥48 hours after admission that was not incubating at the time of admission (some patients with severe HAP may require intubation and should be managed similar to patients with VAP) ‹ Ventilator-associated pneumonia (VAP) ● Pneumonia that arises >48 hours after endotracheal intubation ‹ Healthcare-associated pneumonia (HCAP) ● Pneumonia in patients who have resided in a nursing home or long-term care facility ● Patients who were hospitalized for at least 2 days in an acute care hospital within 90 days prior to the onset of the pneumonia ATS/IDSA. a new subtle type now is patients who have been in an acute care hospital 90 days and were in that hospital for at least 2 days and 90 days prior to the onset of this new pneumonia. 2004. Usually the term nosocomial was an encompassing term for all of these three. and this is pneumonia in patients who have a history of being in a nursing home or are in a nursing home or long-term facility. the definition according to the new ATS guidelines is pneumonia that arises 48 hours or longer after endotracheal intubation.18:939-62. So this is now hospitalacquired pneumonia. And again. this is really the new way to break down pneumonia that’s acquired in a hospital but also acquired outside of a hospital. Am J Respir Crit Care Med.171:388-416. Now also viewing perhaps one of the most difficult types of hospital-associated pneumonia – and this is now referred to as VAP. For instance. et al. Ventilator-Associated. Also now.Improving Patient Care: Reducing Antimicrobial Resistance in Respiratory Infections 98 Hospital-Acquired. And lastly – kind of a brand new kind of definition here – is referred to healthcare-associated pneumonia or HCAP. 2005. often referred to in the past as nosocomial pneumonia. Now on the first slide. Moreover they should not have any evidence of incubating a pneumonia at the time of their admission. or ventilator-associated pneumonia. Infect Dis Clin North Am. Craven DE. we now talk about hospital-acquired pneumonia – so called HAP – and these are persons who develop pneumonia at 48 hours or longer after being admitted to a hospital.

Craven DE. Now we are going to see in a moment that the antibiotic approach really varies tremendously whether the patient has this early. et al.Improving Patient Care: Reducing Antimicrobial Resistance in Respiratory Infections 99 HAP and VAP ‹ Early-onset: pneumonia that occurs within the first 4 days after hospitalization or incubation ‹ Late-onset: pneumonia that occurs ≥5 days after hospitalization or incubation ATS/IDSA.171:388-416. Also to make it further. The late-onset are the ones that occur 5 days or later. 2004.18:939-62. Infect Dis Clin North Am. . Am J Respir Crit Care Med. of which one is referred to as early-onset whereas the other is referred to as late-onset. Early-onset is a pneumonia that occurs within the first 4 days after hospitalization or incubation. 2005. but it’s very important to do this because it really will determine the choice of antimicrobials – now when we talk about ventilator-associated pneumonia or hospital-acquired pneumonia its being broken down into two very distinctive types.or late-onset type of pneumonia. and perhaps maybe even more difficult.

sputum cultures actually have more value for their negative than their positive value. many organisms will often colonize. but if we can’t find them they are almost certainly not the source of that lung infection. we do not want a delay in therapy once a patient develops any of those three types of pneumonias that I mentioned. . healthcare­ associated pneumonia – and again. if we have some negative reports. Unfortunately.171:388-416. They are usually colonized not with a common oropharyngeal pathogens but the more complicated ones. In my mind. But it’s also going to be important that after we get those.Improving Patient Care: Reducing Antimicrobial Resistance in Respiratory Infections 100 ATS/IDSA 2005 Guidelines* ‹ HCAP is included in the spectrum of HAP and VAP ● HCAP patients need therapy for multidrugresistant pathogens (MDR) similar to late-onset HAP or VAP ‹ Lower respiratory tract culture needs to be collected from all patients before antibiotic therapy ● Do not delay the initiation of therapy waiting for the results of culture reports ‹ Negative cultures can be used to stop antibiotic therapy *ATS/IDSA. 2005. we are going to use this information very heavily to decide how to simplify or de-escalate therapy. Also. The reason is pretty obvious. It is important to get initial cultures. that hospital. these are the patients from the chronic care facilities. nursing homes – should really be treated similar to hospital-acquired or VAP of the late-onset. Now also from the guidelines. the following point should really be underscored. just like in community-acquired pneumonia. Am J Respir Crit Care Med. So they really are viewing these people who reside in chronic care facilities as being really a very high-risk group of patients. um.

Improving Patient Care: Reducing Antimicrobial Resistance in Respiratory Infections 101 ATS/IDSA 2005 Guidelines* ‹ Early. make sure it’s given in adequate doses. Also. . Am J Respir Crit Care Med.171:388-416. Also initial therapy should include agents from different antibiotic classes that the patient has recently received and again back into this concept of deescalation should be considered on the basis of the information that comes from the initial culture reports. broad-spectrum antibiotic therapy should be prescribed with adequate doses ‹ Empiric therapy should include agents from a different antibiotic class than the patient has recently received ‹ De-escalation of antibiotics should be considered based on results of cultures and patient’s clinical response *ATS/IDSA. we’re back to making sure – if you’re going to prescribe an antibiotic. 2005. appropriate. The clue to treating any infection is obviously to have the right choice. the right time to give that dose – early-onset as we heard earlier – the right dose and obviously the right way to dose that drug.

particularly in these hospital-associated pneumonias. and then once we get this information. VAP. then we would change the antibiotic regimen accordingly. initiate therapy with very narrow-spectrum antibiotics. . this concept of starting simple and getting a better basis delays the appropriate therapy. and HCAP ‹ Start simple (narrow-spectrum) ‹ Reserve the “big guns” Suspect infection Determine most likely pathogen Initiate narrow-spectrum Abx against suspected pathogens Isolate susceptible pathogen Patient deteriorates or pathogen identified as resistant to therapy Successful outcome! Abx = antibiotics Add other Abx Now it’s interesting that there’s quite a paradigm shift. If you initiate therapy inappropriately. We always used to think in this traditional way – to try to get our cultures. there’s a high mortality and of course this is now what’s being recognized.Improving Patient Care: Reducing Antimicrobial Resistance in Respiratory Infections 102 Traditional Empiric Antimicrobial Therapy in HAP. But unfortunately.

and often we see a lung infiltrate – and maybe it’s not a lung infection at all. so they are always upset if we start with some of these big guns. hey. the pharmacists are always nagging us to keep the costs down. which tend to be typically a lot more expensive than the more narrow-spectrum agents. Perhaps if we do not use the so-called “big-gun” antibiotics. And of course again. we probably don’t need an ID consult. which is what it is being referred to in these guidelines.Improving Patient Care: Reducing Antimicrobial Resistance in Respiratory Infections 103 Reasoning Behind Traditional (Conservative) Approach ‹ Avoid need for an ID consult ‹ Reduce the development of resistance to the “big guns” ‹ Reason that not everything that looks like an infection is actually an infection ‹ Reduce antimicrobial budget (cost) Now the reason behind this old approach. if we start simple. is that. we won’t see as much resistance developing to them. which could be expensive. .

and one of the main reasons for this actually is to avoid so-called collateral damage to the organisms in our intestinal tract. These organisms turn out to be one of our best protectors against exogenous infections. We want to cover all the suspected or target pathogens. .Improving Patient Care: Reducing Antimicrobial Resistance in Respiratory Infections 104 New Concepts About Empiric Antimicrobial Therapy in HAP. We’ve already heard in the past about 3-day therapy. with 3 days of azithromycin for mild to moderate pneumonia. with some of the respiratory fluoroquinolones. ventilator-associated and the healthcare-associated pneumonias – is that we want to start initially with big guns. particularly in Europe. VAP. and once we get the information from our culture reports – hopefully do get some information that will now allow us to de-escalate or simplify therapy. We are really learning quite nicely now that we also don’t have to go very long to cure many causes of lung infections. for instance. and HCAP Suspect infection Determine potential pathogens and resistance rates Initiate broad-spectrum Abx (often multiple drugs) Isolate pathogen Narrow (de-escalate) Abx coverage based on susceptibility results Patient deteriorates or pathogen identified as resistant to therapy Successful outcome! Change Abx The new concept. the new paradigm – and this applies definitely to the hospital-acquired. So there’s a big movement in the area of respiratory tract infections to abbreviate duration of therapy. We’ve been hearing about short-course therapy for community-acquired pneumonia – 5 days. So short-term therapy is less likely to be disruptive to gut flora. Many of the newer antibiotics that we have are very rapid eliminators of microorganisms.

powerful antibiotics. . Start with the combination therapy. indirectly that leads to excessive costs as well. and then try to simplify therapy hopefully when we get further information.Improving Patient Care: Reducing Antimicrobial Resistance in Respiratory Infections 105 Reasoning Behind New Approach ‹ Get it right up front (aggressive approach) ‹ Reduce mortality associated with inappropriate empiric antimicrobial therapy ‹ Streamline antibiotic therapy once susceptibility data are available ‹ Avoid prolonged and unnecessary use of “big guns. called an aggressive approach – is to try to get it right up front. because if you don’t get it right right up front there’s excessive mortality.” which avoids “collateral damage” to GI flora and development of resistant organisms ‹ Costs saved by avoiding treatment failure greater than costs spent by using more of the “big guns” So the new approach – this is the new paradigm. And of course. So it’s kind of a reverse of things.

1997. Now the early-onset again applies to the hospital-acquired or the ventilator pneumonia. Am J Respir Crit Care Med.113:412-20. 1997. 2000. Chest. There is a tremendous increase in mortality if you do not choose a proper antimicrobial for whatever happens to be the responsible pathogen in that patient.118:146-55. Now here again is the reason behind breaking down these pneumonias into early. et al.156:196-200. Chest. . Ibrahim EH. We don’t use those terms for the healthcare-associated because you really can’t do that. et al. Kollef MH. 1998. Chest. Luna CM. Here for example – back up here – this slide just shows what inappropriate therapy does in a serious infection. et al.Improving Patient Care: Reducing Antimicrobial Resistance in Respiratory Infections 106 Initial Inappropriate Therapy in Patients with Serious Infections: Mortality Rello et al Infection-related mortality Kollef & Ward Crude mortality Ibrahim et al Infection-related mortality Luna et al Crude mortality 0 20 40 60 80 100 Initial appropriate therapy Initial inappropriate therapy Mortality (%) Rello J.111:676-85. because they’re there for weeks or months or whatever.and late-onset. Ward S.

you might want to treat them just like you do for community acquired-pneumonia. But again. with combination therapy of a macrolide and a third-generation cephalosporin.Improving Patient Care: Reducing Antimicrobial Resistance in Respiratory Infections 107 Common Potential Pathogens for Early-Onset (≤4 days) HAP or VAP ‹ Usually caused by non-multidrug resistant pathogens that commonly colonize the oropharynx ● Streptococcus pneumoniae ● Haemophilus species ● Oropharyngeal anaerobes (not B. 1999. They’re viewed as patients who have late-onset.27:887-92. the usual responsible pathogen is a typical organism that colonizes in the oropharynx. for all HCAP use late-onset treatment Interestingly. in the patients who have developed hospital-acquired pneumonia in this short time period of around 4 days. that any patient coming from a chronic care facility. fragilis) ● Legionella species Richards MJ. et al. one can still use “traditional” or “conservative” approach. I want to underscore that. or monotherapy with one of the respiratory fluoroquinolones. monotherapy with “respiratory quinolone” or ceftriaxone + macrolide) ‹ For early-onset. or long-term care facility is not looked upon as somebody who warrants early-onset type of antibiotic therapy. according to these new guidelines. . So what these new guidelines are suggesting is that in early onset of hospital-acquired pneumonia. however. Crit Care Med. So very similar to what we see in community acquired-pneumonia. nursing home. ‹ Treatment similar to agents used for community-acquired pneumonia (eg.

Interestingly. hospital-acquired or ventilator-associated pneumonia or HCAP. these are the major pathogens we want to make sure we cover in our initial empiric therapy. I’m going to come up with what I think is going to make the best sense in terms of treating patients with late-onset. Now how about the late-onset? There’s tremendous change in the target organisms if you develop your pneumonia 5 days or later. and often fourth-generation as well. Here are the major causes of late-onset hospital-acquired pneumonia. so no beta-lactam antibiotics – whether you’re talking about Primaxin or Zosyn – have any activity against MRSA. I’m going to display some of the drugs that are the best choices. clindamycin. and unfortunately one half of these now exhibit resistance to methicillin. But also remember. aureus (~50% methicillinresistant S. as does Enterobacter. and usually you have to resort to drugs like vancomycin or linezolid. . Also you do have to know a little bit about pharmacokinetics to understand how to dose antibiotics in the best way to maximize bacterial killing. we have to chose the right drug and we’ve got to give it at the right time. and that’s why we require these so-called very broad-spectrum drugs. VAP and HCAP ‹ Pseudomonas aeruginosa ‹ S. Again. However. 1999. the so-called ESBLs. Crit Care Med.27:887-92. And of course. et al. but now we are seeing what is called expanded-spectrum beta-lactamase. Also Enterobacter species and then lastly Acinetobacter. Klebsiella ranks high. and tetracyclines. Right at the end. including expanded-spectrum β-lactamase producing organisms (ESBLs) ‹ Acinetobacter species Richards MJ. these community-acquired ones tend to be more virulent than the ones that are acquired in a hospital which have a more difficult antibiogram but are not as invasive. These so-called MRSAs are resistant to all beta-lactam antibiotics. aureus [MRSA]) ‹ Enterobacter species ‹ Klebsiella species. there has been a tremendous increase now in Staph areus as a cause of hospital-associated pneumonia. this is somewhat of a misnomer. ventilator-associated or HCAP: Pseudomonas ranks among the worst. These are organisms that will hydrolyze the beta-lactam ring of third-generation cephalosporins. however. These are our major targets and these are the reasons for all this new stratification.Improving Patient Care: Reducing Antimicrobial Resistance in Respiratory Infections 108 Common Etiologies for Late-Onset (≥5 days) HAP. paradoxically. the community-acquired MRSAs are not infrequently susceptible to some of the older remedies like Bactrim. So as mentioned earlier. We’ve got to give it at the right dose but we also have to give it by the right mode of administration.

so these antibiotics are now referred to as concentration-independent or time-dependent killing. Lastly. the area under the serum concentration curve after a dose of antibiotics. and the goal is to try to keep the levels of that time-dependent antibiotic to be equal or greater than 50% of any one dosing interval. and where they do not kill any better if they are way up at the peak concentration. the pneumococcus is rapidly killed with an AUC of about 30 whereas organisms like Pseudomonas require very high and long exposure. The AUC is nothing more than a measurement of the exposure of the organism to that antibiotic through any one dosing interval. which is a measurement of how high and how long levels stay above the MIC – this is the area right there. I mean you can use them but you have to use them in combination with another anti-Pseudomonas drug. you get the best killing if the levels are roughly ten times above the MIC for the target organism. ≥125 for gram ─ Time > MIC (time-dependent) Goal: ≥50% dosing interval MIC 0 Quintiliani R. Infect Med. And the rule here is that with these kind of antibiotics. High AUCs of around 125 and actually there is no single fluoroquinolone that should be used alone to treat serious systemic Pseudomonas infection because you cannot attain this target of equal or greater than an AUC of 125. there is the so-called AUC. this just shows blood levels on antibiotics after a dose.Improving Patient Care: Reducing Antimicrobial Resistance in Respiratory Infections 109 Pharmacokinetic/Pharmacodynamic Parameters Affecting Antibiotic Potency Peak/MIC (concentration-dependent) Goal: peak/MIC ≥10 Concentration AUC/MIC Goal: ≥30 for gram +. It’s kind of fascinating that certain organisms require very little exposure to be rapidly inhibited. where the levels just exceed their MIC for that pathogen way down here just above the MIC. Obviously at some time. Time (Hours) Just quickly. For instance. certain classes of antibiotics kill bacteria the same. Now on the other hand. May 2004:219-32. . the drug has to drop below its MIC – the concentration that’s necessary to kill the target organism. For instance. certain antibiotics do kill better if the concentrations are quite high in relationship to the MIC towards the pathogen and so they are referred to as a concentration-dependent or dose-dependent antibiotics. this one slide – it sums up the three basic pharmacokinetic concepts that are now being used to dose antibiotics in the best way. Now interestingly.

So that’s going to be all the penicillins and cephalosporins kill in that fashion and so our goal is really just to get the levels just above the MIC and try to keep it there for at least 50% or more of the dosing interval. penems.Improving Patient Care: Reducing Antimicrobial Resistance in Respiratory Infections 110 Pharmacokinetic/Pharmacodynamic Parameters of Antimicrobial Classes Concentration-Independent (Time-Dependent) ‹ Beta-lactams (penicillins. We dose ceftazidime frequently by constant infusion. monobactams) ‹ Clindamycin ‹ Erythromycin ‹ Clarithromycin ‹ Linezolid ‹ Vancomycin Concentration-Dependent (Dose-Dependent) ‹ Fluoroquinolones ‹ Aminoglycosides ‹ Amphotericin B ‹ Metronidazole ‹ Daptomycin And so it’s on your handout here – these are antibiotics that use mainly time to kill organisms and these are the ones that use mainly concentration. At Hartford Hospital. that typically have to be given very often. cephalosporins. This has been tremendously useful in the dosing of beta-lactams that have relatively short half-lives. we dose Zosyn by constant infusion. constant infusion turns out to be once-daily dosing. thereby saving all kinds of monies from avoidance of labor and supplies. In fact the observation that for these time-dependent antibiotics – oops. For instance. and therefore result in laws of labor and supply costs. . we’re going to go back here for a second – we’ll go back just one here – these antibiotics that kill the same when the level is just above the MIC are way up at the peak – this is the explanation of the constant infusion of beta-lactam is coming back. for instance.

Unfortunately they have very poor activity against MRSA. what are we going to use? And it turns out that we’re probably going to have to end up using three antibiotics. we’re always concerned about do we have nephro. VAP. modest activity against ESBL-producing Klebsiella and Acinetobacter baumannii ● Concerns over nephrotoxicity and ototoxicity ● Use once-daily dosing method Now let’s first look at possible choices – I mean. or HCAP ‹ Aminoglycosides (gentamicin/tobramycin) ● Good aerobic gram-negative activity but must be given in combination with another anti-Pseudomonas drug ● Poor activity against MRSA.and tobramycin have remained very active against most aerobic enterics and includes Pseudomonas.and ototoxicity. And of course. aminoglycosides like genta.Improving Patient Care: Reducing Antimicrobial Resistance in Respiratory Infections 111 Empiric Antibiotic Combination Therapy Choices for Late-Onset HAP. . and so certainly we can’t use them alone and they have very modest activity against these expanded-spectrum betalactamase–producing Klebsiella and Acinetobacter. That’s like back to the future – when we used to do that in overwhelming intra-abdominal sepsis – well.

The once-a-day program that we developed at Hartford that is used now in around 90% of the hospital is that we give a large dose of 7 mg/kg and above those peak around 20.Improving Patient Care: Reducing Antimicrobial Resistance in Respiratory Infections 112 Aminoglycoside Dosing Methods 20 Concentration (µg/mL) 18 16 14 12 10 8 6 4 2 0 4 8 12 16 20 24 Once-daily (7 mg/kg) Conventional (1. And then the levels drop to zero at the end of 12 hours and then you go to a drug-free period. They thought we’d have undue oto. The thing that’s associated with toxicity with aminoglycosides is how much accumulates in the ears and kidneys and you actually accumulate more with intermittent dosing because you don’t have a large wash out period.and nephrotoxicity. A few challenges – a neutropenic animal with a potential lethal dose of Pseudomonas. So it’s back to the point that if you’re going to give this drug. The reason why is that in humans there exists a saturation capacity to move aminoglycoside from serum into the renal tubular cells or the inner ear cells and it occurs way down here around 1. you can’t drive any more drug into those sites. When you go above that. But if you’re going to use them. Infect Med. let’s dose it in the best possible way. May 2004:219-32. No one thought we could do this. It usually requires around 1. Now why did we use that dose? Because the Pseudomonas is the usual most difficult target organism.and nephrotoxicity but you don’t. you get less. . So that’s the way these drugs should be given. Many more animals survive that challenge if they get the dose this way as opposed to the intermittent dosing technique where the levels only peak around 4 or 5 and go down to 1 at the end of 8 hours.5 or 2.5 mg/kg q8h) Time (hours) Quintiliani R. you use the once-daily dosing method. There is no question that that dosing approach is associated with much more rapid killing and paradoxically much less oto.5 to 2 mcg loading at ten times above that and that’s the only way you do it.

the organisms way out here on the end can survive. . and often what can happen is. Moreover. May 2004:219-32. the emergence of resistance is less.Improving Patient Care: Reducing Antimicrobial Resistance in Respiratory Infections 113 Bacterial Killing as a Function of MIC BACTERIAL POPULATION Number of Organisms MIC 50% MIC 90% 10x MIC Minimum Inhibitory Concentration Quintiliani R. you have a bell-shaped curve where some organisms are less and some more susceptible. Infect Med. that if you suboptimally dose with typical intermittent dosing. In any population of bacteria.

the chance of that happening is over zero. they form a whole new population. 12 18 17 15 . May 2004:219-32. When that happens. Infect Med. So – aminoglycoside is one of the drugs we’re going to be using right at the end and so let’s at least dose it in the best way. If you actually start out with a dose ten times above the MIC. much higher MIC – 50 to 90 – that’s referred to as emergence of bacterial killing the resistance.Improving Patient Care: Reducing Antimicrobial Resistance in Respiratory Infections 114 Bacterial Killing as a Function of MIC BACTERIAL POPULATION Number of Organisms MIC 50% MIC 90% New MIC 90% 10x MIC Minimum Inhibitory Concentration Quintiliani R. they begin growing.

approaching 100% with levo and 93 or 94 with gati. ciprofloxacin 70% What about the quinolones? The quinolones are fine in the urine but again systemically you can’t use them alone for systemic Pseudomonas. they have no significant oto. . or moxifoxacin because it has very modest Pseudomonas activity and has not even been tested in the laboratory. And for Tequin – gatifloxacin – it’s only tested for urine isolates. though. between these two drugs in terms of the activity against that bacterium.or nephrotoxicity. You can’t use amox or lactam. and the amount needed to kill an organism. and cipro was a little less – down around 70%. There is no difference. You have to integrate blood levels and it’s a wash between these two drugs. only around 65% of Pseudomonas now will test susceptible to either levo or cipro. Not so. So we’re not going to be able to use fluoroquinolones alone for Pseudomonas. They have no core activity against MRSA. Nicely.Improving Patient Care: Reducing Antimicrobial Resistance in Respiratory Infections 115 Fluoroquinolones ‹ ~65% of Pseudomonas aeruginosa susceptible to levofloxacin and ciprofloxacin and therefore they must be used with other anti-Pseudomonas drugs ‹ Poor activity against MSRA and modest activity against Acinetobacter species and ESBL-producing Klebsiella ‹ No significant nephrotoxicity or ototoxicity ‹ Oral bioavailability: levofloxacin ~100%. The common mistake as a clinician – look only at the MIC. Moreover. modest against Acinetobacter and ESBLs. by the way. The oral formulations really have excellent bioavailability. and assume that the drug with a low MIC is the best choice. gatifloxacin 94%. moxifloxacin 93%.

Wolter DJ. you also get killing for about 8 to 12 hours but then it begins to break through so neither one can be used alone. However if you put them together. These are what we call time kill curves. We measure the rate of bacterial kill after exposing the organism to the drug. this is information we’ll need to justify the final conclusions. I know it’s been done with the levo and with the imipenem. Again. Clin Infect Dis. . ESBL as mentioned.Improving Patient Care: Reducing Antimicrobial Resistance in Respiratory Infections 116 Pharmacodynamics of LEV. We get often asked is there any synergy between these respiratory quinolones and any other anti-Pseudomonas drugs. But they’re good potential drugs for this de-escalation because if you get an aerobic gram-negative other than Pseudomonas. aeruginosa 236 10 9 8 7 LEV Levofloxacin (LEV) Alone ‹ ‹ ‹ Rapid 3-log kill by 6 hr followed by regrowth between 6 and 24 hrs Emergence of resistant subpopulation (MIC of 10 mutants was 16 µg/mL) One mutant (444LEV) exhibited dual resistance to imipenem and overexpressed the mexEF-oprN efflux pump Rapid 3-log kill by 6 hr with level remaining constant between 6 and 24 hr Emergence of resistant subpopulation (MIC of 10 mutants was 16 µg/mL) Rapidly bactericidal (4-log decrease by 2-hr time point) Bacterial eradication observed by 12 hr No emergence of resistant isolates Log 10 CFU/mL 6 5 4 3 2 1 0 0 4 8 12 16 20 24 36 ‹ ‹ LEV-IMP IMP ‹ ‹ Imipenem (IMP) Alone LEV-IMP Combination ‹ Time (h) Lister PD. you can use monotherapy with them as long as the gram-negative is not an Acinetobacter. IMP. then you get very good killing for 24 hours. If you expose that organism just to Primaxin. This is the killing with levo right here. You know. this has been done with levofloxacin and imipenem. 2005.40(suppl 2):S105-14. Whether this type of study has been done with cipro. I don’t know. It kills for about 6 hours and then it breaks through. imipenem. and LEV-IMP Combination against P.

cepacia – although you not uncommonly grow them out. Now one of the things that you have to recognize – although certain organisms we grow out. aeruginosa activity Now the carbapenems. but how often do you see Candida pneumonia? Almost zero. Unfortunately. Meropenem) ‹ Anti-Pseudomonas activity closely similar to that of an aminoglycoside. Stenotrophomonas is a very difficult bug to treat. . So they probably have the best overall antiPseudomonas activity. you often see it. but again for the best – you need new therapy – and for the best synergetic activity. So there’s a difference in different organisms in terms of their virulence. They are very closely similar to that of aminoglycosides. Also we see that when we isolate Candida from sputums. is no activity against MRSA and really modest against Stenotrophomonas maltophilia. there is another carbapenem out there called ertapenem (Invanz) – you can’t use that one. It is by far the most active class of drugs against ESBLproducing Klebsiella and Acinetobacter. anti-Pseudomonas fluoroquinolone) ‹ Most active class of drugs against ESBL-producing Klebsiella and Acinetobacter baumannii ‹ No significant activity against MRSA and Stenotrophomonas maltophilia ‹ Ertapenem. aminoglycoside. They. Be careful with that drug because it has very poor Pseudomonas and Acinetobacter activity. and one other organism. should not be used in the empiric treatment of HCAP since it has poor Acinetobacter and P. The problem here. another carbapenem. they are very seldom invasive. Some people worry that if you use too much of this drug in a hospital setting. you begin to encourage resistance of Pseudomonas to imipenem or meropenem. however. but for best synergistic activity should be given with non-beta lactam antibiotic (eg.Improving Patient Care: Reducing Antimicrobial Resistance in Respiratory Infections 117 The Carbapenems (Imipenem. it doesn’t mean they are the significant pathogen – there’s another organism. you want to give it usually with a non–beta-lactam antibiotic like an aminoglycoside or an anti-Pseudomonas fluoroquinolone. like imipenem and meropenem.

baumannii.375 g q4h Ciprofloxacin 400 mg q12h Ciprofloxacin 400 mg q8h 100 100 96 ─ 100 ─ 95 ─ 85 ─ Probability of Target Attainment (%) KP 100 100 90 ─ 99 ─ 89 ─ 80 ─ AB 88 92 59 69 50 67 56 65 41 46 PSA 91 89 84 89 82 93 70 85 53 59 MYSTIC = Meropenem Yearly Susceptibility Test Information Collection Programme. Yes. If you look above. They have very good activity against major pathogens of late-onset pneumonia. To compare these two carbapenems and again – they’re the same. PSA = P. Again. et al. coli. Antimicrob Agents Chemother. coli. Now – [comment from faculty member: What do you treat that with?] Bactrim is a very good drug. If you have a Pseudomonas aeruginosa that tests resistant to everything. ─ indicates not tested. It has a lot of nephrotoxicity but no ototoxicity. 2004. this shows you that – I think you’re going to have to have a carbapenem as one of your three choices. KP = K.Improving Patient Care: Reducing Antimicrobial Resistance in Respiratory Infections 118 OPTAMA (Optimizing Pharmacodynamic Target Attainment Using the MYSTIC Antibiogram) Regimen EC Meropenem 1 g q8h Imipenem 1g q8h Ceftazidime 1 g q8h Ceftazidime 2 g q8h Cefepime 1 g q12h Cefepime 2 g q12h Pip/Taz 3. aeruginosa Kuti JL. test polymyxin – they’re coming back very fast. In fact we don’t have time because of timelines here tonight. This is E. AB = A. sometimes the old remedies come back.375 g q6h Pip/Taz 3. pneumoniae. This is Acinetobacter and Pseudomonas. so there’s a lot of interest in that drug again. This is Klebsiella. but probably the best anti-Pseudomonas drug is polymyxin or Colistin. EC = E. . these two drugs are the same.48:2464-70.

. this is the MICs. aeruginosa (193) 100 Cumulative % Inhibited 90 80 70 60 50 40 30 20 10 0 0.Improving Patient Care: Reducing Antimicrobial Resistance in Respiratory Infections 119 MYSTIC Americas Results P.25 0. 2000.46(topic T2):25-37. J Antimicrob Chemother.06 0.12 0.03 0. Jones RN. they’re very low for both. between the two – meropenem and imipenem. Again.016 Meropenem Piperacillin/Tazobactam Cefepime Imipenem 0. but they are more intensely active as compared with cefepime or piperacillin/tazobactam. this is meropenem.5 1 2 4 8 16 MIC (mg/L) Pfaller MA. So there are really no major difference.

Improving Patient Care: Reducing Antimicrobial Resistance in Respiratory Infections 120 Appropriate Therapy Antibiotic Third-generation cephalosporins Cefepime Quinolones Piperacillin/tazobactam Carbapenems ESBLs – – +/– +/– +++ AmpC – +++ + +/– +++ Let’s skip this because of the time. .

This was the study that was actually done by Richard Wunderink.5 43. Why? .182 60 40 20 0 ‹ 59.009 P = .124:1789-97.5 Linezolid Vancomycin S.3–8. they bring up an observation that the failure rate with vancomycin is rather high at 40%. P = . and I think linezolid could be that choice. aureus MRSA Linezolid therapy was 3.3 times as likely as vancomycin (95% CI: 1. who’s from Chicago. Chest. et al. 2003. Randomized Controlled Trials. And so we’ve got to reconsider that maybe we should be thinking about an alternative drug. The other question is – what are we going to do with these MRSA? And when you read the guidelines by the ATS.3.4 35.0 51.Improving Patient Care: Reducing Antimicrobial Resistance in Respiratory Infections 121 Linezolid vs Vancomycin in the Treatment of NP Due to MRSA Clinical Cure (% of Patients) Data from 2 Double-Blind.011) to result in a clinical cure Wunderink RG. where he compared outcomes and nosocomial pneumonia here – we see the term again – due to MRSA and the cure rate was higher with linezolid. n=116 80 P = .

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Linezolid Lung Penetration at Steady State
25 healthy volunteers received 600 mg linezolid orally q12h for 5 doses before bronchoalveolar lavage Mean Concentration (mg/L)
70 60 50 40 30 20 10 0 Plasma Alveolar Cell Epithelial Lining Fluid 15.5 8.9 10.2 1.8 2.2 1.5 1.4 0.2 7.6 64.3

4 Hours 8 Hours 12 Hours 24 Hours
31.4 24.3

Conte JE Jr, et al. Antimicrob Agents Chemother. 2002;46:1475-80.

Well, number one it had much higher penetration characteristics, levels in endothelial fluid, alveolar macrophage, around four times what you see in plasma. So there’s very high penetration quantities into the lung.

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Penetration of Vancomycin Into Human Lung Tissue
Vancomycin Concentration (µg/mL)
‹ 30 patients administered 1 g IV vancomycin ‹ Lung tissue:serum concentration ratio ranged from 0.24 to 0.41 at 1 and 12 h, respectively ‹ 1/6 patients observed at 6 h and 3/7 patients at 12 h did not have detectable levels of vancomycin in lung tissue ‹ 1 g dose of vancomycin does not achieve sustained lung concentrations > MIC for susceptible staphylococci over a dosing interval of 12 h
Cruciani M, et al. J Antimicrob Chemother. 1996;38:865-9.

45 40 35 30 25 20 15 10 5 0 1 2 3.5 6 12 Time (hours) Serum Lung MIC

As compared with vancomycin – rather modest. This is a study on the penetration of vancomycin again into lung, appearance of blood levels peaking around 40, but here’s the levels in lung tissue, rather modest peaking around 10 and coming down as shown. But for an organism to be considered susceptible, for MRSA to be considered susceptible, to vancomycin it should be killed at around 4 mcg. And you drop below that level at around 3 and a half hours. So if we dose vancomycin every 12 hours, which we often do, we don’t meet that criteria – equal or greater than 50% time above the MIC. Vancomycin is also a time-dependent antibiotic. For this reason, for vanco if you use it, you’ll probably have to dose it every 8 hours, and we’re going to worry more about oto- and nephrotoxicity. So we’ll be hearing more about linezolid. Unfortunately, it’s rather pricey, even by the oral formulation; however, linezolid is again another one of those antibiotics that’s almost 100% absorbed, so you obtain concentrations essentially the same as you would if you had the patient on IV formulation. So it’s another good drug like respiratory fluoroquinolones for de-escalation.

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Linezolid vs Vancomycin

Linezolid
Serum assays Need renal-adjust dose Oral bioavailability Adverse potential No No 100% Thrombocytopenia, Interaction with SSRIs Excellent

Vancomycin
Yes Yes 0% Ototoxicity and nephrotoxicity

MRSA activity

Excellent

So if you look at these two drugs in a little more depth, although very pricey, you don’t have to do serum assays with linezolid, you don’t have to renal adjust the dose because it has very minimal renal elimination, where as you have to do with vanco, and tremendous bioavailability, vanco you can’t give by mouth. There’s been some thrombocytopenia and some interactions with these SSRIs, you know, the serotonin uptake inhibitors like Prozac and Zoloft, Paxil, so you just have to probably stop those if the patient is going to be on those drugs. Again, we have the oto- and nephrotoxicity with vanco, and both of them have superb MRSA activity.

well. . Established criteria for duration of therapy: try to avoid more than 7 days So we’ll end here with what I would think would make some sense. My view is that you have two options here. There is one way you have to use an aminoglycoside – gentamicin. You can decide which one makes more sense. Modify therapy within 48 hours based on micro­ biological data 3. um. which is always managed identical to the late-onset hospital-acquired or the ventilator-associated pneumonia. So that would be an approach to the three types of pneumonia – the hospital. healthcare-associated.Improving Patient Care: Reducing Antimicrobial Resistance in Respiratory Infections 125 Aminoglycoside Combination Therapy for HCAP and Late-Onset HAP and VAP 1. they talk about all of these things and they kind of scramble it a bit and they say – well you probably should do this or that – but they don’t really finally say. here’s what we think is probably the most reasonable approach. Combination therapy based on unit-specific antibiogram Imipenem Imipenemor or Meropenem Meropenem + + Tobramycin Tobramycin + + Vancomycin Vancomycin or Linezolid orLinezolid 2. You also have to use a MRSA drug – there’s no way around that and so you have to choose between vancomycin or linezolid and then I think we need a carbapenem. and if you’ll read in depth the ATS guidelines. tobramycin.

If we want a nonnephrotoxic/ototoxic. . Combination therapy based on unit-specific antibiogram Imipenem Imipenemor or Meropenem Meropenem + + Levofloxacin Levofloxacinor or ciprofloxacin ciprofloxacin + + Linezolid Linezolid 2. it would have to be linezolid. You need an MRSA drug. and this is what I would call the nonoto-. For clinically stable patients who can eat. Modify therapy within 48 hours based on micro­ biological data 3. consider oral quinolone or oral linezolid Now there’s another possibility here. Again. Established criteria for duration of therapy: try to avoid more than 7 days. Nonototoxic) for HCAP and Late-Onset HAP and VAP 1.Improving Patient Care: Reducing Antimicrobial Resistance in Respiratory Infections 126 Non-aminoglycoside Combination Therapy Protocol (Nonnephrotoxic. we need a carbopenem – either Primaxin or meropenem. either levofloxacin or ciprofloxacin. nonnephrotoxic drug. and then you combine it with one of the respiratory fluoroquinolones.

monotherapy with one of the fluoroquinolones. maybe 60% to 70% are susceptible to cefepime – that’s the next good drug – or even Zosyn. . you can do that as well. I’ve heard literally just like “zilch” and it doesn’t do it. you can then move them down to their oral formulation and again with linezolid. Any questions on this? A lot of people are unfamiliar with these guidelines because they have been so recently published. But there is no question. So there’s a need as I mentioned for an approach on how to de-escalate as well as how to start with. you could move down to. coli. are any antibiotics in your opinion more inducers of ESBL or no? The question was – is any antibiotic more prone to induce these ESBLs? No. let’s say. Yes. the initial approach is going to be triple therapy. I guess that the whole view is that when you get the new data. And then in fact with the respiratory fluoroquinolones. we should be able to simplify. Yes? I’ve gone to a few talks and it seems like one antibiotic – the question is. If you isolated a non-ESBL producing Klebsiella or E. Also in terms – because of timelines here – let’s now approach de-escalation. okay? So if you had Klebsiella that produced ESBLs. So you could then move down to one of those and get away from a more expensive agent like Primaxin or meropenem. I don’t see anyway around that.Improving Patient Care: Reducing Antimicrobial Resistance in Respiratory Infections 127 Questions & Answers Are any antibiotics in your opinion more inducers of ESBL or no? So we have about three minutes.

although that drug is very active against MRSA. And there’s a concern because that drug alone. very low MICs. it should never ever be used in lung infection. and bone. soft tissue. It has no penetration into lung tissue. It’s daptomycin. it should never be used for lung and in fact the package insert says that but often it is not noticed. I’m often asked if certain antibiotics can induce or cause the emergence of MRSA – and basically. . It’s a drug by Aventis. They have a black box – its called Cubicin. So it’s all beta-lactams. good against MRSA and skin. but any antibiotic that has minimal to no activity against MRSA will encourage the emergence of that pathogen. any antibiotic that is not active against MRSA can do this.Improving Patient Care: Reducing Antimicrobial Resistance in Respiratory Infections 128 Questions & Answers I just wanted to know if there are certain antibiotics that induce ESBL more than others? No. all fluoroquinolones. There is a last one – there is a drug called daptomycin – one thing as a note of caution. The quinolones get blamed more than anyone else. it’s all except the two that I mentioned. You’ve probably have seen it.

it’s kind of a fascinating observation – it’s now felt that you don’t die from VRE. But it’s really not that bad. And that’s true. pneumococcal infection in an animal. It would seem a lot more vancomycin-resistant enterococci. The hospital epidemiologists go crazy. Patrice Courvalin from the Pasteur Institute. You die with VRE. okay? They can do that but it’s at the expense of a whole bunch of metabolic processes. and he spoke recently at our hospital. Dr. he’s the most famous guy on enterococci. and multidrug-resistant pathogens tend to be not that invasive. And actually. Remember the hospitalacquired MRSA are not as virulent as the ones that are community-associated. So that’s a generalization that has held up very well. our nephrologists have us convinced that Zosyn will induce resistant enterococcus and they’ve requested that we don’t use it because it becomes a problem with their access infections. They want to burn down the hospital when they see that. okay? I don’t see why that would be an issue. the MVR organisms. say. okay? Here again though. okay? Again. Very easy to do it if we challenge the animal with a penicillinsensitive Strep pneumoniae but not easy at all when it is penicillin-resistant. Piperacillin is very good against enterococci. I already mentioned Stenotrophomonas maltophilia as another example of that observation. penicillin-resistant pneumococci are not as virulent as penicillin-susceptible. you get really sick. and that’s why you rarely see proven serious infection from VRE. probably you’re not going to last much longer – it is not a very invasive organism. VRE. . And he said that the reason is that when you have these antibiotics that have multiple drug resistance. you know. The question is “why?” Well. that organism is often resistant to many classes but is susceptible to linezolid. We do a lot of animal research and so we often try to produce. and by messing with many metabolic processes.Improving Patient Care: Reducing Antimicrobial Resistance in Respiratory Infections 129 Questions & Answers On resistance. it ends up with less virulence. As a marker.

good aerobic and good penetration characteristics. But there’s a fascinating observation – in fact I wrote an article on this with data give to me by Parke-Davis. occasionally. We may in time. Also 100% absorbed. Yeah. don’t give it by mouth if at all possible.Improving Patient Care: Reducing Antimicrobial Resistance in Respiratory Infections 130 Questions & Answers How about chloramphenicol? Well chloramphenicol – well it depends upon a lot of your training in infectious diseases. okay? I think that was a great mistake. You know. within a year or two hopefully. Oral is also quite safe. It’s definitely not a commercial. it’s a rare complication of that drug. They’ll come maybe but not for a long time. As far as I can tell. I think it’s kind of a major loss to our armamentarium as they say. But we’ll see.000 will develop aplastic anemia. I don’t know if I’m allowed to do that. We may want to comment on what’s ahead. have a cephalosporin to treat MRSA. And so the answer to that drug was. it produces. But unfortunately. What about cephalosporins? There is one being studied for MRSA. we can’t get it now in the United States. there were only around 500 reports in the United States.but the strange observation that IV chloramphenicol is very safe. The one exception – some kind of psychotic patient who was using eye drops over and over – you know 30 cc a day and was probably swallowing it . thrombocytopenia or aplastic anemia. at that time. It’s no longer available in the United States except on a compassion and plea basis. (continued) . Good anaerobic. It’s a tremendous antibiotic. okay? The aminoglycosides. When we have seen aplastic anemia. Still used extensively in the world. you might want to know what’s ahead. you have to stay within this little path here. Every one of those patients had received chloramphenicol except one by the oral route of administration. we love those drugs that are totally absorbed like that. Cheap as can be as well. just about 10 years ago. nothing new there. but unfortunately one out of every maybe 40. But even then. No new sulfa drugs. if I’m allowed to talk about – with all these regulations. Somebody asked me during the coffee break. there’s no more quinolones.

paste the poor frog over the wound. no. Why? Because they excrete through their pores long-chain amino acids and therefore they’re called peptides. it’s always amazing some of the old. It is now known that all forms of life on this planet have those. wrap it up. they have analogs of minocycline called glycylcyclines. and as long as he could remember as a child. I was out there today.Improving Patient Care: Reducing Antimicrobial Resistance in Respiratory Infections 131 Questions & Answers How about chloramphenicol? Um. and they carry a positive electronic charge (a strong one) that is attractive to negative charges in the cell wall. they used to capture a frog. But the class of antibiotics that most people are talking about that are probably two or three years off are the peptides. Frogs and toads – they don’t get skin infections. you know. was born in a small village just outside of Lima. when people used to get wound infections. The reason is that psoriasis patients secrete normal amounts of these peptides. Eczema patients do not. . We’re getting more and more drugs against MRSA because that’s becoming a common pathogen. We have them. These have been recently discovered – although known about forever – and explained why amphibians are resistant to skin infections. there’s an analog of minocycline coming – in fact if you go to Lederle. he knew that. Again. To me. I was recently a visiting professor in New Orleans where they see a lot of tropical diseases. there is a bit of clinical observation that patients with severe eczema are very prone to secondary bacterial infections – people with psoriasis. Peru. There was an article in the New England Journal of Medicine about one year ago that compared eczema patients – people with bad eczema with people that have bad psoriasis. and they noted very impressive improvement. The word magainin is a Hebrew word which means “shield of protection. You talk about rapid cure – within 30 minutes they kill the organism. A lot of people train there and go through there from South America. and so he’s named these peptides that they’re developing as magainins. which are also good against MRSA. old observations that no one’s taken advantage of until the last 5 or 10 years.” So the senior researcher spoke Hebrew. and one of the senior ID physicians got up in the audience and said he. And there is already a pharmaceutical company interested in development of these new class – they are called magainins.

you can’t use linezolid. it is. It’s when you say you can’t use vanco.Improving Patient Care: Reducing Antimicrobial Resistance in Respiratory Infections 132 Questions & Answers What about Synercid. can’t use daptomycin. QTc prolongation. and so it’s a very unpopular drug. then you might want to use Synercid. About 25% get line sepsis. Synercid I find no longer an acceptable drug. all kinds of interference with other drugs that are handled by the CP450 system. That’s the combination of quinupristin and dalfopristin – the problem with the drug is not that it’s not a good active drug against MRSA. . but it has a huge side effect profile.

. you want activity against three target gram-negatives – E. Unfortunately. So you’ve got to watch that drug and that’s why a lot of ID people have troubles with it. if it gets to be overused in the hospital. the resistance mechanism is such that you can theoretically see ertapenem encouraging Pseudomonas-developed resistance to Primaxin and to meropenem. Proteus. gall bladder. and Klebsiella. and you give it once a day – it’s kind of nice. and it’s very good against bacteria. particularly in prophylaxis. When you have someone with diverticulitis undergo an elective surgery of appendix. coli. okay? It’s being use mostly – which I think is more appropriately – in intraabdominal problems. but you need aerobic activity.Improving Patient Care: Reducing Antimicrobial Resistance in Respiratory Infections 133 Questions & Answers What’s the role of ertapenem? Ertapenem is actually a – it could be used.

and bioavailability is now about 60%. a lot of GI side effects. Thirdly. which is typical of all macrolides. my own view is that it’s not going to be that popular. Unfortunately. but about 25% of the people get like a chemical phlebitis. By accumulation.” When they did that. What they did was that they took the 14-membered ring lactone structure. what about telithromycin? That wasn’t mentioned for a brief moment. hence “ketolide. Why? Because it’s very hard to create a well-tolerated IV macrolide. you’ve got to address that drug. they basically created a macrolide that was highly active against penicillin-resistant pneumococci. Well. which is a classic macrolide. It’s still a macrolide. It typically occurs about one hour after its administration. And fifthly. Erythromycin. Thirdly.Improving Patient Care: Reducing Antimicrobial Resistance in Respiratory Infections 134 Questions & Answers What about Telithromycin? Again. so we don’t have that. yes. . there’s no IV formulation. It lasts about an hour. And any discussion with respiratory tract infections should also address that drug. We have no IV clarithromycin in the United States. it has some disturbance in combination. Fourthly. That’s a problem. It’s called a ketolide. a lot of interaction with the CP450. somebody asked me. You have to go through a lot of discussion with a patient about this potential. so statins should be used. But when we were talking about community acquired pneumonia – to make it a balanced talk. and they detached a sugar side chain – it’s called cladinose – put in a ketone root. it has modest activity against H. we have it. which is recently being marketed in the United States fairly heavily. macrolide – all the macrolide-resistant pneumococci – so it’s a very impressive drug when it comes to the pneumococcus. it’s kind of a fascinating drug. So it’s complicated. flu and that’s a potential problem. I mean why not use a respiratory quinolones? That’s my view instead of that drug.

Illinois on April 29 29 during duringthe the2005 2005Annual Annual Meeting the Society of Hospital Hospital Medicine Medicine Meeting of of the Society of Okay.Improving Patient Care: Reducing Antimicrobial Resistance in Respiratory Infections 135 Improving Patient Care: Reducing Antimicrobial Resistance in Respiratory Infections Presentations aa symposium held in Presentationsfrom from symposium held in Chicago. . April Chicago. and I hope you have a good night. Thank you. Illinois on Friday. Thank you hanging in here. Friday.

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