@@antimicrobial Rez Ghid

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 evenings program.
Continuing Medical Education

Danielle R. Hanson
Office of Continuing Medical Education University of Wisconsin Medical School Madison, Wisconsin
My name is Danielle Hanson, and Im from the University of Wisconsin Medical School Office of Continuing Medical Education.
Disclosures
Dr. Alpesh Amin has received honoraria for speaking from Ortho-McNeil Pharmaceutical. Dr. Sanjay Sethi has received grants/research support from Bayer, GlaxoSmithKline, and Pfizer; is a consultant for Abbott, Bayer, Boehringer Ingelheim, GlaxoSmithKline, Pfizer, and Sanofi-Aventis; and has received honoraria for speaking from Abbott, AstraZeneca, Bayer, Boehringer Ingelheim, GlaxoSmithKline, Ortho-McNeil, Pfizer, and Sanofi-Aventis. Dr. Richard Quintiliani has received honoraria for speaking from Ortho-McNeil Pharmaceutical. Dr. Andrew W. Urban has received grants/research support from Agouron/Pfizer and Amgen, honoraria for speaking from Abbott and GlaxoSmithKline, and an honorarium for reviewing this programs scientific materials. The University of Wisconsin Medical School and DesignWrite have received a grant from Ortho-McNeil Pharmaceutical to organize this program.
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, you will find faculty disclosure information on your handout materials and also on the screen above. To receive credit for this program, you must complete the evaluation form. 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.
Learning Objectives
By the end of the program, 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 Physicians Recognition Award. Each physician should claim only those credits that he or she actually spent in this educational activity. The objectives for this program can be found in your handout materials and also on the screen above.
Welcome and
Introductions
Alpesh Amin, MD, MBA, FACP

Associate Professor of Medicine Executive Director, Hospitalist Program Vice Chair for Clinical Affairs, Department of Medicine University of California, Irvine School of Medicine Irvine, California
I would now like to take this time to introduce our Chairman, Dr. Apesh Amin. Dr. Amin is the Associate Clinical Professor at the Department of Medicine at the University of California at Irvine. He is also Executive Director at the Hospitalist Program at the UCI Medical Center at Orange, California. Please help me in welcoming Dr. Amin. Thank you. Can you hear me okay. Everybody? Good. Okay. Hows that? Yes? Okay, good. 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. I hope youve enjoyed the meeting so far. I know its been Ive heard very good feedback about it. So I hope its going well for you all. Id like to also welcome you this evening. Weve got two other wonderful faculty that are going to be joining me. Id like to say just a couple of words though. The way our program is going to be tonight is, Im 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. Sethi will come up and hell do his talk and have a Q and A and then Dr. Quintiliani will do the same thing.
Program Faculty
Sanjay Sethi, MD State University of New York at Buffalo

Buffalo, New York
Richard Quintiliani, MD, FACP University of Connecticut School of Medicine
Farmington, Connecticut
Alpesh Amin, MD, MBA, FACP University of California, Irvine School of Medicine Irvine, California
Dr. 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. He serves as an attending physician in the Division of Pulmonary and Critical Care and has submitted numerous articles, which you can see in your faculty biographies there. Dr. Richard Quintiliani is Professor of Medicine and Pharmacology at the University of Connecticut School of Medicine in Connecticut. 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. You can take a look at the information in the packet.
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, MD, MBA, FACP Alpesh Amin, MD, MBA, FACP Faculty Sanjay Sethi, MD
Faculty Richard Quintiliani, MD, FACP Faculty
So this is going to be our program for today and without further ado, Im going to go ahead and get started in talking a little bit about community-acquired pneumonia while avoiding resistance risk. As you can see, were going to start with pneumonia and were going to talk a little bit about bronchitis and then about nosocomial pneumonia, all of which are obviously important for the hospitalists world.
Managing CommunityAcquired Pneumonia While Avoiding Resistance Risks

Alpesh Amin, MD, MBA, FACP
Associate Professor of Medicine Executive Director, Hospitalist Program Vice Chair for Clinical Affairs, Department of Medicine University of California, Irvine School of Medicine Irvine, California
Community-Acquired Pneumonia (CAP)

Approximately 5.6 million cases annually 1.1 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. Am J Respir Crit Care Med. 2001;163:1730-54.
Let me community-acquired pneumonia is important for us for a number of reasons. First of all, just to remind you as background, theres about 6 million cases of pneumonia a year, of which 1 million tend to get into the hospital. And the mortality range is less than 1% to 5% on the outpatient side, but once theyre in the hospital it goes up to about 12%, and once they get to the ICU the rate of mortality jumps up tremendously, to 30% or 40%.
10
CAP Is a Serious Illness

Pneumonia: 6th leading killer in US
No. 1 cause of death from infection 5.6 million cases annually 1.1 million require hospitalization Over 75% treated as outpatients
Costs of treating CAP exceed $8 billion

$8.0 billion inpatients $4.8 billion patients 65 yr $3.6 billion patients <65 yr
American Thoracic Society. Am J Respir Crit Care Med. 2001;163:1730-54; Vital Statistics Mortality Data, National Center for Health Statistics, Centers for Disease Control and Prevention; Niederman MS, et al. Clin Ther. 1998;20:820-37.
Its 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, so its a significant cause of mortality amongst our inpatient population. 75% of these patients are actually treated as an outpatient, but when you look at the cost of the illness, the cost is on the order of 8 billion dollars, of which about 5 billion of that comes from patients above age 65. And we all know that patients above the age of 65 are a growing population that come into the hospital setting.
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 <35C Respiratory rate 30/min or 40 40C
NO
YES
ASSIGN PATIENT TO RISK CLASS 1

Fine MJ, et al. N Engl J Med. 1997;336:243-50.
Now as hospitalists, I think its really important that we take a step back and think about risk stratification of patients. Were going to be asked more and more and as we work with our emergency medicine colleagues and our primary care doctors, we should be thinking about risk stratification processes. 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. So Im going to just give a even though the literature is kind of loose in this regard, Im going to give you some thoughts to think about in terms of risk stratifying your patient. The first is, Dr. Fine published in the New England Journal of Medicine a prediction model based on the PSI score, or Fines criteria, also called the PORT score. What he basically suggested was that for patients over the age of 50 years, if they were younger than 50 but they had no comorbid conditions, they had no physical examination finding abnormalities, he assigned them a risk stratification class of 1. Patients that were above the age of 50 that ended up having one of these comorbid conditions that you see up here neoplastic disease, renal, liver, heart failure, cardiovascular, or had signs of abnormal examination findings these patients were given a point score. And there was a point system that he modeled. So a patient that had a certain age, they were given a certain number of points. If they were female, they were given a certain number of points, based on their age. If they had any one of these findings, they were given a certain number of points. What he came up with is, when he added up the points, he was able to categorize patients into risk classification. So you could see here that patients that were in risk class 1, 2, 3, 4, and 5, they were given a certain number of points as you can see. Based on their points, they were dropped into a class.
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 0.1% 0.6% 2.8% 8.2% 29.2% Decision to Hospitalize No No Yes/No Yes Yes
PORT = Pneumonia Patient Outcomes Research Team cohort study.

Fine MJ, et al. N Engl J Med. 1997;336:243-50.
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, say their mortality was 0.6%. So if they had a risk classification of 1 or 2, their mortality rate was less than 1% so he made the conclusion again, not a studied conclusion but made the conclusion that patients could be managed as an outpatient if they had risk class 1 or 2. If they had risk class 4 or 5, you could see how the mortality rate starts to go up tremendously. You have a mortality in the order of 8% or 29%. And risk class 3, he basically said that, you know, clinical judgment needs to supersede and you may consider either inpatient or outpatient therapy.
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, randomized, controlled trial 224 CAP patients in risk class II or III (PSI score 90) Outpatient care with oral levofloxacin; 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. PSI = Pneumonia Severity Index.
Carratal J, et al. Ann Intern Med. 2005;142:165-73.
Well, what does this mean to us? Well very recently in the Annals of Internal Medicine, there was an article that was published in 2005 whose goal was to say okay, 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. Fine came up with and looking at low-risk patients. The question was, do I need to put them in the hospital on IV antibiotics and then switch them over to orals, 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. Were running with capacity issues. We have a 95% fill rate right now in our hospital, 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. Well what this study did was it was an unblinded study, randomized and controlled it looked at about 224 patients that were put into class 2 and 3 based on Dr. Fines criteria, and they were randomized and given either oral levofloxacin or they were given IV and then followed up by oral, 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.
14
Outpatient Care vs Hospitalization in Low-Risk Patients with CAP

Overall successful outcome achieved in:
83.6% of outpatients 80.7% of hospitalized patients Absolute difference, 2.9 percentage points (95% CI, -7.1 to 12.9 percentage points)
More outpatients (91.2% vs 79.1%) were satisfied with their overall care
Absolute difference, 12.1 percentage points (95% CI, 1.8 to 22.5 percentage points)
Quality of life, % of patients with adverse drug reactions, medical complications, subsequent hospital admissions, and overall mortality were similar in the outpatient and hospitalization groups
Carratal J, et al. Ann Intern Med. 2005;142:165-73.
And what they found was that the overall success outcome was achieved in both groups. 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, and could be safely managed at home, and that their quality of life in terms of adverse drug reactions, medical complications, subsequent hospital admissions, and overall mortality were similar to the hospitalized group versus the outpatient group.
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 homeacquired pneumonia.
Mehr DR, et al. JAMA. 2001;286:2427-36.
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, like activities of daily living. 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. The mortality rates of these patients started going up.
16
CAP: Effect of Pulse and Respiratory Rate on Mortality in NHAP

Rapid pulse rate predicts mortality
Pulse 100/min was related to 23.1% 30-day mortality (RR 1.91 [95% CI 1.482.45])
Rapid respiratory rate predicts mortality

Respiratory rate 30/min was related to 21.2% 30-day mortality (RR 1.72 [1.332.21])
Mehr DR, et al. JAMA. 2001;286:2427-36.
There is also data that looked at just getting a quick assessment of the respiratory rate. If your patient has there was a study that looked at patients with a pulse rate of greater than 100, they had a 23% 30-day mortality rate, whereas when they had a respiratory rate of greater than 30, they had a 21% 30-day mortality rate. So Im not saying that these are all really good studies. There havent been any great studies that try to risk stratify your patients, but when youre a busy hospitalist looking at a patient that the emergency medicine doctor has called you on, hopefully youll think about these things as you are thinking about where these patients should be placed and how they should be managed.
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 >19.6 mg/dL
Revision of the BTS rule Add a fourth criterion

Confusion
Define increased mortality risk

If 2 of 4 criteria
Neill AM, et al. Thorax. 1996;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, and what they found was that respiratory rates above 30, diastolic blood pressures below 60, and BUNs of above 19 showed an increased risk of mortality, if you had two out of the three findings. And then if you had a fourth criteria of confusion, it increased your risk of mortality by two to four times.
18
Etiology of CAP:
Most Common Causes1
Ambulatory Patients S. pneumoniae M. pneumoniae H. influenzae C. pneumoniae bacilli Viruses Hospitalized (Non-ICU)2 S. pneumoniae M. pneumoniae C. pneumoniae H. influenzae Legionella species Aspiration
1Based 2Excluding
Severe (ICU)2 S. pneumoniae Legionella species H. influenzae Gram-negative S. aureus
on collective data from recent studies.

Pneumocystis species.
File et al, Am J Med Continuing Education Series, 1997.
But lets jump into so thats a little bit about risk stratification. Lets jump into the most common causes of community-acquired pneumonia. We know from Dr. File and many other people who have looked at the common causes. Strep pneumonia still continues to be our number one cause of community-acquired pneumonia, making up about 60% of the patients. And as you can see in ambulatory setting atypicals are common, like Mycoplasma and Chlamydia. Certainly in COPD patients you have to think of H. influenza. Once they get into the hospital setting, Strep pneumonia again Mycoplasma you start thinking about things like Legionella and H. influenza, and as they get into the ICU setting you want to start thinking more about gram-negative and Pseudomonas and make sure that youre covering for those appropriately.
19
Chlamydia Co-infection Prolongs Length of Stay (LOS) in CAP

25
Hospital LOS (days)
N = 125
21.9
20 15 10.5 10 5 0
C. pneumoniae S. pneumoniae Both
8.4
Kauppinen MT, et al. Thorax. 1996;51:185-9.
This is a little bit of older data that was published in Thorax you know, the whole concept of covering for atypicals. I think from a hospitalists standpoint, I know that we dont have length of stay this high usually anymore in the hospital setting, but you can see the patients that were treated. [For those] that had Chlamydia pneumonia, length of stays in this study were in the order of 8 days, but if they had Strep pneumonia, they were on the order of 10 days. 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.
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
+/+/- modifiers
Risk for Pseudomonas + C/P disease, +/or modifier No C/P disease, no modifier
C/P = cardiopulmonary
Yes
No
So appropriate coverage for atypical and typical organisms in the management of community-acquired pneumonia is extremely important. So guidelines that are out there there are various guidelines that are available. American Thoracic Society has published its guidelines, the latest one in 2001. IDSA has published its guidelines, the latest one in 2003. And there are differences in the guidelines but the concepts are somewhat are there. If you have community-acquired pneumonia, for example, ATS basically says take a look at whether youre thinking about outpatient therapy versus inpatient when youre thinking about your risk stratification model, and then if they have outpatient therapy, 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. On the inpatient side, are you dealing with mild to moderate disease or are you dealing with severe CAP? And if youre 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. You also want to kind of think about if they have underlying cardiopulmonary disease or disease modifiers.
21
ATS 2001 Recommendations for CAP

CAP is present Outpatient
No C/P disease, 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, cefuroxime, amoxicillin 1 gm TID, amoxicillin/clavulanate, ceftriaxone Beta-lactam IP: cefotaxime, ceftriaxone, ampicillin/sulbactam, hi-dose ampicillin Beta-lactam ICU, non-PSA: cefotaxime, ceftriaxone Beta-lactam ICU, + PSA: cefepime, imipenem-cilastatin/ meropenem, piperacillin/tazobactam
+ Pseudomonas:
IV AP + IV cipro or IV AP + IV AMG + IV azithromycin or IV FQ (not cipro) cipro)
C/P = cardiopulmonary; PSA = + Pseudomonas; 3GC = thirdgeneration cephalosporin; DRSP/GN = drug-resistant S. pneumoniae/gram negative bacilli; AP = anti-Pseudomonal, AMG = aminoglycoside; FQ = fluoroquinolone
So this is what ATS and I know most of you probably already know this but just as a quick reminder. ATS basically has recommended if they have no if theyre outpatient and they have no cardiopulmonary disease or modifiers, the recommendation was to consider clarithromycin or azithromycin or consider and then doxycycline was offered as a distant alternative. When youve got patients who have had underlying cardiopulmonary disease and/or disease modifiers, combination therapy with a beta-lactam and a macrolide or a fluoroquinolone alone was recommended. When you got to the patient side again similar types of things, but there was also the recommendation of looking at drug-resistant organisms, at drug-resistant Strep pneumonia or gram-negative risks. We have risk factors for patients that we need to think about. For example, if a patient has been on steroids or is an alcoholic, or has been on immunosuppressants, or has been treated with an antibiotic in the past 30 days, or has a family member a child in a day care center, you want to think about the risks for drug-resistant Strep pneumonia. Again, in any case, the treatment option was double coverage with something for atypicals like aminoglycosides plus a beta-lactam, or it was an IV fluoroquinolone that was recommended. If they were in the ICU setting, the recommendation was to suggest and look for the risk of Pseudomonas and then appropriately double-cover patients for Pseudomonas.
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, CHF, diabetes, 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, et al; IDSA. Clin Infect Dis. 2003;37:1405-33.
Now certainly also the other thing I think thats important that you need to remember is that the IDSA guidelines have come out, with this guideline in 2003, and theyve focused on some other things. For example, again, healthy, no previous antibiotic you could see a macrolide or doxycycline. If theyre healthy but theyve had previous antibiotics, the real recommendation in the past 3 months is considered what they havent been on because of the risk of resistance so you can either do a respiratory fluoroquinolone or combination therapy. If they have comorbidities but they havent been on antibiotics, you could see what the recommendations are there in terms of macrolides and respiratory fluoroquinolones. But if theyve had antibiotics in the past 3 months, again use either respiratory fluoroquinolones or the combination therapy, but use the opposite [combination] is what the recommendation is. Think about at-risk for aspiration because youll have to cover for atypical organisms.
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
When they get into the medical ward, again the question about whether theyve been on antibiotics for the past 3 months needs to be asked because youll use the other combination. And then again when they get into the hospital setting.
24
IDSA CAP Guidelines: 2003 Inpatient
ICU low risk of P. 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. 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
In the ICU, the risk for Pseudomonas is raised again, and then whether they have beta-lactam allergies or not in your choice of antibiotics appropriately.
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, 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.jcaho.org
OR
If documented beta-lactam allergy: Aztreonam + aminoglycoside + antipneumococcal quinolone
The interesting thing is that it is not only ATS and IDSA thats coming up with guidelines. If you look at it, in the past 10 years before 2004, the guidelines that were published were published by professional societies IDSA, ATS, British Thoracic Society, the Canadian Thoracic Society. All of them were professional organizations that were publishing guidelines. Now look at what youre 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, their guidelines, and theyre going to make choices and based on what professional societies and literature comes up with. The payers and the regulatory agencies and the accrediting bodies are starting to come up with guidelines, and asking us, and they are going to tie payment structures to it based on quality measures and so forth. So I think as hospitalists this is going to be in our area. Nobody is going to be really focusing on this and I think we need to be aware of it.
26
Impact of Early and Effective Empiric Therapy in CAP

299 consecutive patients Overall mortality = 28.5% Mechanical ventilation
50% of patients
60 50
% Mortality
40
30
20
Effectiveness of Rx
Assessed at 72 hrs
Leroy O, et al. Intensive Care Med. 1996;22:1307-14.
10
Effective
Ineffective
The other thing as hospitalists, is the important aspect of early and effective therapy. In setting up our systems, 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. Here was a study by Dr. Leroy that looked at about 300 patients that were on ventilators and how effective therapy could reduce your risk for mortality.
27
Intravenous Step-Down Therapy
Early switch of antibiotics to oral from IV

Reduces costs, 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, no disadvantage to oral observed

Early discharge safe
Ramirez JA, et al. Arch Intern Med. 1999;159:2449-54; Rhew DC, et al. Chest. 1998;113:142-6; Siegel RE, et al. Chest. 1996;110:965-71.
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. So I think youve seen in that last study that were going to need to be, as a group of physicians, setting up our system so that we can do that. Now the real recommendation is not the patients that come into the ER, take 2 hours to get evaluated because of wait time, and that you have 4 more hours after that its going to be that these patients are going to need their antibiotics within 4 hours. The quality measures that we are going to need to be aware of and focus our attention on are giving pneumococcal vaccine, and H. influenza, prior to discharge. Blood cultures prior to initiation of antibiotics, smoking cessation those are all core quality measures that I think we can work with, with our other hospitalists, colleagues, specialists, and emergency medicine folks to accomplish. 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. Thereve been studies in the literature that have shown that [it] reduces cost and shortens length of stay. Switch therapy allows for defervescence and should occur when patients are potentially defervescing, but you dont have to wait for the fever to resolve if theyre clinically improving, their GI tract is functioning, they are able to tolerate orals, and theyre oxygenating well. There have been studies that have shown that by doing this you can save patients a number of days on IV therapy. You can do safe and early discharge. And I think the latest guidelines are going to focus on switch therapy more and more.
28
Switch Therapy for CAP
Average LOS is influenced by early switch programs (-3.04 days; 95% CI, -4.90 to -1.19) 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, et. al. Arch Intern Med. 2001;161:722-7.
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.
29
Clinical Efficacy Studies
Before I get into the clinical efficacy studies, Im going to throw out [something]. My job here today is to raise some questions more than anything else, and one of the problems, and youll see at the end of the talk some slides on resistance issues that were dealing with because there is a fair amount of resistance in the United States thats occurring. Bactrim, sulfa drugs have a resistance on the order of about 30% right now. Macrolides around the country are showing resistances between 20% and 30%. 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, 60 years, 70 years since the late 1930s and look at what were already dealing with. Were talking about in some areas theres MRSA resistance. Up to as high as 50% in some institutions. So in just 70 years, weve come this far in terms of our resistance. Well, whats 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 Im wondering whether there are other ways and modalities of treating patients that would help deal with the concept of resistance.
30
Short-Course Therapy for CAP: Role of Fluoroquinolones

High cure rates possible with short-course therapy with a potent, 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, et al. Clin Infect Dis. 2003;37:752-60.
And youre going to see me show some studies here to try to at least raise that question. Im not sure I have the answer today because, still, good head-to-head studies need to be done in this regard, but we do have better antibiotics today. We have antibiotics that have 80%, 90%, 100% bioavailability, when the first sulfa drugs or the first penicillins that came out had bioavailabilities of 30% to 50%. We know that people had recommended treating for 10, 12, 14 days of treatment, 21 days theres no head-to-head good studies that show that patients should be treated that long necessarily. We also know that theres some common principals that exist in terms of why resistance occurs. Resistance occurs if you have biofilm formation. Resistance occurs with wrong utilization of antibiotics. Resistance occurs if you have overusage of antibiotics. Resistance occurs if patients take antibiotics and get off of them before the organism is eradicated. 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. Because certainly what was written 20 years ago or 30 years ago or 40 years ago in terms of antibiotic therapy if youre using an antibiotic that had 40% or 50% bioavailability versus an antibiotic that has 80 or 90% bioavailability in the appropriate patient, maybe you dont need patients to be on them quite as long. 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, that they can potentially be weaned off their ventilator earlier or transferred out of the ICU earlier. Marin Kollef has published a fair number of literatures on that. So the question is if it can be done in the sicker patient, can it be done in the less sicker patients or what kind of patients can we consider doing it? Well, the concept of short-course, if you were going to try to design an antibiotic that could fit these principals, youd be looking to maximize concentrationdependent killing, increasing your area under the curve, hopefully getting rapid bactericidal killing. And the question is, can you do this?
31
Levofloxacin Short-Course Therapy for CAP

Multicenter, randomized, double-blind, 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
Well, here was a study that Dr. Dunbar had published. 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. It was a multi-center randomized study that looked at giving 500 mg of Levaquin for 10 days versus 750 for 5 days. If you add up the total amount of antibiotics, you will see its 5000 mg versus 3750 so theres less total amount of antibiotics thats used if you follow this rationale.
32
Levofloxacin Short-Course Therapy for CAP: Clinical and Microbiologic Results

100 750 mg 500 mg 80
92.4
n=198
91.1
n=192
93.2
n=103
92.4
n=92
% of Patients
60
40
20
0 Clinical Success* (Clinically evaluable population) *Clinical success includes cured and improved.
Microbiologic Eradication (Microbiologically evaluable population)
And in this one, Dr. Dunbar looked at the PSI score in terms of stratifying her patients, 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.
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 (57.8) 18 (7.0) 25 (9.8) 18 (7.0) 5 (1.9) 500 mg (N=265) 158 (59.6) 15 (5.7) 37 (14.0) 22 (8.3) 9 (3.4) 95% CI (-6.8, 10.5)
*Any adverse event that was new in onset or increased in intensity or frequency during the study period. Any treatment-emergent adverse event assessed by investigator as probably or very likely related to study drug. Any treatment-emergent adverse event that was fatal, immediately life-threatening, required or prolonged inpatient hospitalization, caused permanent or significant disability, was a congenital anomaly, or was deemed medically important. Any death that occurred from study entry to the post- study visit is included.
And when she looked at adverse events, 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.
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%); P = .03
Schrag SJ, et al. JAMA. 2001;286:49-56.
PRSP = penicillin-resistant S. pneumoniae
Thereve been studies looking at short courses of amoxicillin also for community-acquired pneumonia patients to deal with resistant pneumococcal carriage analysis, 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. Again, higher doses but shorter courses.
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=0.518
97% (31/32) pathogens isolated azithromycin group were

eradicated, compared with 91% (32/35) isolated from
clarithromycin group
Incidences of treatment-related adverse events were similar for the two groups (P=0.815)
ODoherty B, et al. Eur J Clin Microbiol Infect Dis. 1998;17:828-33.
There have been studies that compare azithromycin for 3 days versus clarithromycin given for 10 days, and the outcomes are also comparable in both groups. Again, the concept of short-course raised again.
36
Telithromycin vs Clarithromycin Short-Course Therapy for CAP

Multicentre, randomized, double-blind, 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, et al. J Antimicrob Chemother. 2004;54:515-23.
Telithromycin, 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.
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. pneumoniae 10-day clarithromycin
% of Patients
n=159 n=161 n=146
89.3
88.8
91.8
95.8
23/24
96.7
29/30
88.5
23/26
7-day telithromycin
Tellier G, et al. J Antimicrob Chemother. 2004;54:515-23.
And the results were fairly comparable in the 5-day group and the 7-day group versus the 10-day group, and so its gotten the recommendation for sinusitis and bronchitis for 5-day therapy for telithromycin compared to 7-10 day therapy for pneumonia.
38
S. pneumoniae Resistance* to Penicillin and Macrolides, USA 19921998

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 g/mL.

Felmingham D, Washington J. J Chemother. 1999;11(suppl 1):5-21; Felmingham D, Gruneberg RN. J Antimicrob Chemother. 2000;45:191-203.
I raised this question today only because look at whats happening to the resistance of Strep pneumonia to penicillin and macrolide. You can see it continuously. Its been on the rise for the last decade or so.
39
S. pneumoniae Resistance Rates

for Selected Agents, 19992000*
Antimicrobial Macrolides Clindamycin Tetracycline Chloramphenicol Trimethoprim/sulfamethoxazole Fluoroquinolones % Resistance 25.9 8.8 16.4 8.4 30.3 1.2
*n = 1,531 isolates; 33 US medical centers, winter (1999-2000).
Doern GV, et al. Antimicrob Agents Chemother. 2001;45:1721-9.
And as Ive mentioned before, macrolides have a resistance of almost 20%-30% and Bactrim to 30%.
40
Antimicrobial Resistance Trend:

S. pneumoniae, USA, 2002-2003
Antimicrobial Agent, % Resistant Penicillin* Azithromycin Trimeth/sulfa Ceftriaxone (nonmeningitis) Levofloxacin No. of institutions No. of isolates Levofloxacin MIC90 (g/ml) TRUST 6 (2002) 18.4 27.5 26.0 1.7 0.9 239 7671 1.0 TRUST 7 (2003) 17.3 27.5 24.0 1.5 0.9 227 4456 1.0
*Penicillin-resistant = MIC >2g/ml; NCCLS broth microdilution centralized lab, Focus Technologies. In vitro activity does not necessarily correlate with clinical results. Karlowsky JA, et al. Clin Infect Dis. 2003;36:963-70; Sahm DF. Clin Cornerstone. 2003(suppl 3):S4-S11.
The resistance is quite high and we need to kind of deal with this across the board. The Trust data that was industry-sponsored data has been looking at resistance patterns every year, you can see again there, penicillins are shown to be in the order of 18% or so. Still were lucky with some of the fluoroquinolones that have resistances of less than 1%. Again, look at Bactrim, youre on the order of 24% and 26%. Other comparative industry-sponsored studies are showing the same results. In fact, the PROTECT study had shown that the resistance in the Far East may be as high as 60% or 70%, in Japan or Korea, to macrolides and penicillin-resistant Strep pneumonia.
41
S. pneumoniae Antimicrobial
Resistance TRUST 7 (20022003)
S. pneumoniae S. pneumoniae
Penicillin Resistance
(Resistant, MIC 2 g/mL)
Azithromycin Resistance
(Resistant, MIC 2 g/mL)
DC
DC
20% R
National Rate:
Penicillin = 17.3% R
12%-19.9% R <12% R
National Rates: Azithromycin = 27.5% R Erythromycin = 27.9% R
Sahm DF. Clin Cornerstone. 2003(suppl 3):S4-S11.
You can see here in Trust 7 data look at all the red-colored areas. Those are the areas that Id be very concerned about. Theyve already shown a greater than 20% resistance. Look at how much of the United States were dealing with for penicillin and azithromycin across the board.
42
Antimicrobial % Susceptibility:
P. aeruginosa, USA, 2002-2003
Antimicrobial Agent, % Resistant Ceftazidime Cefepime Gentamicin Pip/Tazo Imipenem Ciprofloxacin Levofloxacin Isolates (labs)
In vitro activity does not necessarily correlate with clinical results. Blosser-Middleton RS, et al. Poster presentation at IDSA 2002, Chicago (Poster 71); Thornsberry C, et al. Poster
presentation at IDSA 2003, San Diego (Poster 222).
TRUST 6 (2002) 79.7 NT 76.7 85.8 81.9 67.4 67.7 998 (36)
TRUST 7 (2003) 80.6 79.5 72.3 87.0 78.8 68.8 65.3 882 (36)
Also, antimicrobial susceptibility to Pseudomonas where we dont have that many great agents that are up in the 90% or 100% efficacy. Thats part of the reason we have to consider double coverage, and more and more were starting to worry about resistance issues. In terms of the fluoroquinolones, really the only thing we have are cipro and Levaquin. We have gentamicin and piperacillin but again, nothing there above 90%.
43
Pay-for-Performance Initiative
Hospital Quality Initiative requires hospitals to report on 17 quality measures Failure to report performance date will result in 0.4% reduction in annual payment from CMS Measures related to pneumonia include: smoking cessation, initial antibiotic within 4 hrs of hospital arrival, blood culture before first antibiotic, oxygenation assessment Top 20% of hospitals will be given a
financial bonus
http://www.cms.hhs.gov/quality/hospital/overview.pdf
So tying all of this together is I think as hospitalists, 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 were certainly going to be tied to quality and efficiency and performance issues by our employers and by the public. This is the whole concept of pay-for-performance that I brought up earlier. Hospital quality initiatives require hospitals to report 17 quality measures. There is the concept right now thats being thrown around that failure to report performance may result in a 0.4% reduction in payments from CMS. Measures related to pneumonia, as I mentioned earlier in this talk, include smoking cessation, antibiotics within 4 hours, blood cultures, oxygenation assessment, vaccination Pneumovax and H. influenza. The top 20% of hospitals may actually get a financial bonus for doing the appropriate job and I think thats going to fall on our shoulders as hospitalists to deal with.
44
Conclusions
CAP is a relatively common and serious respiratory tract infection There is no universal consensus for the treatment of CAP; 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, and also increases patient satisfaction Short-course, higher-dose therapy for CAP offers a number of potential advantages: rapid eradication of pathogen, increased patient compliance, and reduced resistance rates Short-course therapy with levofloxacin, azithromycin, or telithromycin has shown promise
So Im 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. There is no universal consensus for the treatment of community-acquired pneumonia, but there are guidelines by ATS and IDSA. They vary a little bit, but the good thing is that both organizations are actually coming together and theyve already produced a combined guideline for hospital acquired-pneumonia, and the community-acquired guideline is suspected to come out soon. Recent data suggests that outpatient care could be effective in the appropriate low-risk patients and hospitalization may not be required. The concept of short-course, higher-dose therapy may offer some advantages in terms of dealing with the concept of resistance, and that may be one of the new ways of looking at the management of this common disease state.
45
Questions & Answers
How many of the pneumonias actually

are viral?
What personally do you feel are the utility of sputum and blood cultures, in terms of what we actually end up doing?
Studies that Ive seen in terms of viral pneumonias have ranged anywhere from 10% to 30%-40%, in that range. As far as sputum utility its interesting because Ill even tell you just a personal experience of my institution. 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. The problem is that getting sputums is not always easy because youve got to collect it and youve got to get it down to the lab. And if the patient is dehydrated to get the sputum it is more difficult. And the best thing to do is get the sputum, get it down to the lab immediately. If it sits around, you run into problems of getting inappropriate results. Now even though we are doing it for academic reasons, I think that people are understanding that getting the sputum is not the easiest thing in the world. Now does that mean that we shouldnt do it? The answer is no. That doesnt mean we shouldnt do it, because it still has a utility. If you see gram-positive cocci on your sputum, you can de-escalate therapy and appropriately treat. One of the concepts of dealing with resistance might be appropriately de-escalating therapy and treating appropriately. Same thing with blood cultures. 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. Going back to the sputum, one other comment that I wanted to make in regards to getting the sputum is that there are differences in the two guidelines. You know, IDSA strongly in the past I will see what the combined guidelines show but in the past, it was highly recommended to get the sputum sample. ATS was kind of equivocal on it.
46
Questions & Answers
And our hospital didnt rank as well for the antibiotics. Given that as a hospitalist, Im called when I cant do anything about the 4 hours Any suggestions?
Yes, you know, the 4-hour issue is actually starting to come into question today. Its still there and I need to say that we need to be pushing that agenda today still, but I think its starting to be raised nationally about whether 1) its possible, and 2) whether its really truly effective, does it really change outcomes. Thats being raised as a question. In any case, as thats being discussed on a national scale, what can you do I think is the next question. I think we all would agree that the very first thing is that we should be giving antibiotics appropriately. This to me is an opportunity for us as hospitalists to look and to first define the problem in our institution. Why cant it be done? Work with and take a leadership role. Work with our colleagues in emergency medicine and infectious disease, work with our lab, and work with everybody to see what we can do to streamline some of that process and basically take a performance improvement process. I think thats what really the regulatory agencies that are recommending this are trying to get us to try to do. We should try to go about doing that.
47
Questions & Answers
What about, JACHO has their antibiotics but since ATS and IDSA can vary, what happens if JACHO picks oh, you need to do sputum cultures and It becomes a pay-for-performance.
Right. And thats 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, to work with the regulatory agencies to deal with that. And hopefully whats going to happen is that IDSA and ATS combine and release their guidelines. JACHO and so forth will use the similar guidelines. This variability in recommendations needs to be worked through a little bit.
48
Questions & Answers
we need to develop therapeutic approaches with those two background sort of notions and then observe the effectiveness over time, because if we are trying to apply a national approach in a local scene I think its fraught with a lot of problems then.
I would agree with that. 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 certainly, you know, even if you compare my MRSA rate to a hospital 30 minutes away from me is a huge difference, so youve got to take all of those factors into account, I agree with you. And that should be your take-home message, and I think thats what youre seeing us starting to do is really try to give ideas of how to implement things. The resource rooms that I was telling everybody to look at the Cybernet Caf is that whole process. What were 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.
49
Questions & Answers

Is it possible to legislate that people should wear masks if they are coughing?
I assume its possible. I dont 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. Its a tough thing. I think youre 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 cant quite read this question. Ill be in the back for whoever asked it, you can stop by and see me in the back. With that, I want to say thank you, and Id like to invite Dr. Sethi up here to give his talk.
50
Acute Exacerbation of Chronic Bronchitis: Strategies for Reducing Drug Resistance

Sanjay Sethi, MD
Associate Professor Pulmonary, Critical Care and Sleep Medicine University at Buffalo, SUNY
Good evening here and thanks for being here. My job is to discuss acute exacerbations of chronic bronchitis, which has been my area of research for the last 10 years or so, and its a nice opportunity to talk to a different audience. A lot of what I will present is actually based on outpatient studies. Unfortunately, there is not a lot of data about antibiotic use and exacerbations in the inpatient setting. I think I will try to point out those areas which do relate to inpatient settings and Id also like to point out some of the information that we have in that situation.
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, 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, as we have learned over the years, and the fact that the major reason they develop resistance is because of antibiotic use. 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. So obviously one way to confront the challenge of resistance is to use less antibiotics and to use them appropriately. As we mentioned I will show you some data we already saw some data for the pneumococcus. I will show you some more data about how drug-resistant bacteria are growing. Then there is more and more data. There is actually the best data for community-acquired pneumonia and ventilator-associated pneumonia, 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. And so basically we need to do something. We need some timely action. I think in my area what I will be discussing is how to use antibiotics appropriately. I think thats one of the best things we can do when we treat exacerbations.
52
Acute Exacerbations of Chronic Bronchitis (AECB)

Definition Etiology Antimicrobial resistance Antibiotic studies Stratification approach
I will start out with some basics about definition. In spite of I think we all know an exacerbation when we see it, but youll be surprised that every time I meet with a group of COPD specialists we are still discussing what exactly is an exacerbation. I will make some comments about etiology. I think thats important and that has been my area of interest. We will talk a little bit about resistance and Ill mention a couple of studies and then discuss this stratification approach. You saw that for community-acquired pneumonia and thats becoming advocated for acute exacerbations, for AECB, also.
53
Definition of COPD
COPD
Airflow limitation/ obstruction present
Bronchiectasis
Emphysema
Chronic Bronchitis
AECB
Increased dyspnea Increased sputum volume Increased sputum purulence
Barnes PJ. N Engl J Med. 2000;343:269-80; Sethi S. Clin Pulm Med. 1999; 6:327-32.
Lets 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, which seems to be now a natural part of the history of the disease, and then they have increased symptoms. Ill point out these three symptoms up there dyspnea an increase in dyspnea, an increase in sputum volume or sputum production, and an increase in sputum purulence. Now these are the three classical cardinal symptoms which define a patient with underlying COPD or chronic bronchitis, which make us suspect that the patient has an exacerbation. So thats the bottom line of the diagnosis. Its a symptomatic diagnosis and its based on change in the baseline symptoms of these patients.
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. J Resp Dis. 2002;23:217-25.
But thats not all to the definition. There are other aspects that we need to pay attention to as physicians and those are that, first of all, how long have there been increased symptoms? I mean, patients with COPD and chronic bronchitis are always symptomatic. They always have some extent of dyspnea, cough, and sputum. The question comes up, how long have they been having those increased symptoms? Generally, wed like to define a time period of at least 24 hours and maybe up to about 2 weeks of increased symptoms. So its an acute or subacute illness in terms of onset by the time you see the patient. The other thing is that again patients with COPD tend to have daily variations in symptoms. I dont know how many of you do outpatient management of these patients but if you do, youll see it all the time: Well, how are you doing today? Well, its a bad day. Yesterday, I was fine. Today, Im bad. Tomorrow, Ill be fine again. So they have this day-to-day variability in symptoms. So the increase in symptoms to diagnose an exacerbation has to be more than the day-to-day variation. And I think the third important aspect, which is often ignored, is that patients with COPD also have other reasons to get more dyspnea. Many of them have coexistent cardiac disease, they are prone to pneumonia, they may get pulmonary emboli. So if you have somebody whose got underlying COPD or chronic bronchitis and comes in with increased dyspnea and sputum and has an infiltrate, hes got a pneumonia so we need to treat the pneumonia. So thats a specific cause of the increased symptoms. The exclusion of those causes you know, the patient who doesnt have the pneumonia, doesnt have the congestive heart failure has a real pure exacerbation. I think thats the kind of patients that we should be focusing on and well be discussing in the subsequent few slides.
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 lets talk about before I kind of so, that was more of the definition issue. So lets move on to before I really get into etiology, I just wanted to point out that Im sure that most of us, and even now in medical schools, that many times there is the perception that is taught to us that exacerbations are a nuisance problem. You know, the patient comes in, feels slightly worse, or much worse, you give him medications to get better, and really its more for like a chest cold or a nuisance problem. Well that perception has changed dramatically in the last 10 years. There is a lot of data, and Ill show you some of it, that as much of one-third or up to 45% of the costs of taking care of patients with COPD is related to exacerbations. Which makes absolute sense, because when is the last time you hospitalized somebody with stable COPD? You dont hospitalize stable COPD; you hospitalize patients with exacerbations. And hospitalization is a big part of the cost of taking care of any disease. There is also good data that exacerbations are actually a major determinate of their loss of quality of life over time in these patients. Its the most common cause of respiratory mortality in these patients. And again, contrary to what we were taught, Im sure many of us were taught or remember from medical school, exacerbations now we have data from the Lung Health Study that they actually do contribute to the progression of lung disease. So their FEV1s, when they get worse over time, proportional worsening, not all of it is related to exacerbations. So we need to be more serious about exacerbations.
56
Outcome After Exacerbations

60 50
47 41 59
Mortality (%)
40
30
30 20 10 0
24
Hospital Hospital stay, all pts stay, pts >65 (n = 362) yrs (n = 167)
90 days
180 days
1 year
Time After Hospitalization (pts >65 years)
Seneff MG, et al JAMA. 1995;274:1852-7.
In fact, if you look at outcomes so this is a study which was done in ICU these are all patients with exacerbations without pneumonia, without congestive heart failure, patients hospitalized for exacerbations in the ICU, and they were able to look at their mortality over time. Its a multi-center study by Seneff, and what they found was that for the hospital stay there was about a 24% mortality in these patients. And then the patients who were more than 65 years of age, they could get the data down the road because they were all Medicare patients. As you can see, theres progressive mortality in these patients. So at one year, its almost at 50%. So thats worse than a lot of malignancies and other problems, so exacerbations have serious consequences.
57
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 thats quite considerable. If you look at outpatients and again there you dont really measure mortality, youre more concerned with relapses, youre 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.
58
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 thats 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.
59
Treatment of AECB
Medical therapy
Bronchodilators Oxygen Antibiotics Systemic corticosteroids
Ventilatory support
Non-invasive ventilation (NIV) Invasive ventilation
So lets 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. Its not, we throw a bunch of things at these patients which includes bronchodilators, which we use in all patients, oxygen and bronchodilators weve always used because there wouldnt be any randomized controlled trials. There are no placebo-controlled trials but I guess well never do that. Oxygen and hypoxic patients again, thats something we always do and presume its of benefit. Antibiotics in the majority of your patients and well 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 dont want to be discussing corticosteroids but I just wanted to mention a point, that there are now a couple of studies showing that we dont 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 dont have slides for that because of time limitations but I can discuss that later. Whats new also in terms of the real severe patients we end up using ventilatory support. Whats 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.
60
Etiology of AECB
Noninfectious H. para Gram-neg Pseudomonas Chlamydia S. pneumoniae
H. influenzae
M. catarrhalis Virus
Obaji A, Sethi S. Drugs Aging. 2001;18:1-11.
So lets get a focus on the antibiotic issue. And when we focus on the antibiotic issue, of course, the first question that comes up is: if there is a need for antibiotics and exacerbations, you know, whats 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. Viruses, about one-third of exacerbations are related to viral infections. Among the bacteria, the pneumococcus and Hemophilus and Moraxella are three major predominant pathogens in these 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. The atypical Chlamydia has been shown to have a role in about 5%-10% of exacerbations, and H. parainfluenza may play a role within the more severely compromised patients. And you know that the sudden proportion of exacerbations are noninfectious. Once you get into a real severe COPD, it doesnt take much to tip those patients over and it may be environmental factors and things like those.
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, et al. Am J Respir Crit Care Med. 1995;152:1316-20; Sethi S, et al. NEJM. 2002; 347;465-71; Sethi S, et al. Am J Respir Crit Care Med. 2004;168:448-53; Sethi S, et al. Chest. 2000;118:1557-65.
The problem we have as clinicians is that you know Ive dealt with this issue for the last, um we have large cohort studies that weve been doing, and I must have treated more than 1000 exacerbations in the last 10 years, and I still dont know in individual patients, is it viral, bacterial, or environmental? Its very difficult to tell. I will give you some hints and then some studies which help us to some extent, but in most patients we dont know. And about 50% of exacerbations are bacterial and we use antibiotics in all the patients, we are overtreating. But on the other hand the consequences of undertreatment are many times worse than overtreatment. So do we have the spectrum of etiology? We still dont have good reliable diagnostic tests that can tell in an individual patient that you are dealing with you know, whats the etiology of the exacerbation in that particular patient. There are some interesting things being developed but none of them have reached clinical utility. Again, 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, we isolate the same bacteria from these patients when they are stable, what does it mean having bacteria when you isolate that from the sputum in patients with exacerbations? Again, 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. If you do studies with bronchoscopy, we can actually culture bacteria from the distal airways in significant concentrations in about half the patients. And we have done some work to show that its not the same strain that these patients are colonized with which gives them exacerbations, its the acquisition of a new strain of a pathogen which gives them exacerbations.
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, et al. Am J Respir Crit Care Med. 1995;152:1316-20; Sethi S, et al. NEJM. 2002; 347;465-71; Sethi S, et al. Am J Respir Crit Care Med. 2004;168:448-53; Sethi S, et al. Chest. 2000;118:1557-65.
We and others have shown development of specific immune responses to the pathogens following exacerbations, and we have also shown that these patients have much more neutrophilic airway inflammation when they have bacterial versus nonbacterial exacerbations. So I think the whole question of do bacteria cause exacerbations? is pretty much settled also within the academic community.
63
Antibiotic Resistance
S. Harris.
So lets get onto resistance issues. So hopefully, we wont live to see that day when mutations will reach a point that well be putting bacteria in cages, but resistance is a problem. And again, some of it has already been mentioned so Ill kind of breeze through it. Ill just focus on the three community-acquired pathogens.
64
H. Influenzae in Sputum from Patient with AECB
Im sure you are all very familiar with Pseudomonas-resistant pathogens and gram-negative resistant pathogens. But Hemophilus influenza these are all sputum smears from a study with patients with exacerbations, so they are always difficult to see, and the little red dot is there. I was enjoying the conversation about sputum in the earlier talk; basically we have kind of given up on microbiology, which is kind of unfortunate in my opinion we should be using more microbiology but anyway thats Hemophilus influenza.
65
H. influenzae -Lactamase Production: US Isolates (n=2,706)

100 80 60 40 20 0 34.5 0
Northwest
65.5
100 80 60 40 20 0 BLNAR
North Central
68.6 30.2 1.2
L+
L-
L+
L-
BLNAR
Southwest
100 80 60 40 20 0 24.9 0.9 74.3 100 80 60 40 20 0
Northeast
70.9 28.7 0.4
L+
L-
BLNAR
L+
L-
BLNAR
South Central
100 80 60 40 20 0 28.7 1 100 70.3 80 60 40 25.2 20 0
Southeast
74.5
0.3
L+
L-
www.protektus.org
BLNAR
L+
L-
BLNAR
This is actually the PROTECT study, which again is one of the industrial studies industry-responsive studies. Essentially the biggest problem with Hemophilus influenza is beta lactamase production. About 30%-35% of strains (depending on which part of the country you are) thats the blue bars over here are beta lactamase producing, and that means that amoxicillin will not work for these patients.
66
S. pneumoniae in Sputum from Patient with AECB
This is the pneumococcus, again from a sputum smear in a patient with exacerbation, and again you heard a fair bit about the pneumococcal resistance. Again, about 20%-25%, up to 35% depending upon where you are have what we call high-grade penicillin resistance: the one that really matters in respiratory infections.
67
S. pneumoniae Resistance: US Isolates (n=10,103)

100 80 60 40 20 0 Penl PenR MacR 33.9 17.3 23.2
Northwest
100 80 60 40 20 0
North Central
31.8
25.4
26.4
Penl
PenR
MacR
Southwest
100 80 60 40 20 0 Penl PenR MacR 26.5 27.1 100 80 29.3 60 40 20 0 24.6
Northeast
21.7
26.5
Penl
PenR
MacR
South Central
100 80 60 40 20 0 Penl PenR MacR 18.1 32.7 38.6 100 80 60 40 20 0 Penl 27.5
Southeast
36.5 40.2
www.protektus.org
PenR
MacR
We also have issues of macrolide resistance. This is showing trends in macrolide resistance development. And again, in the 30%-35% range for the pneumococcus in the United States at this point in time.
68
Changing Resistance Patterns for S. pneumoniae and H. influenzae (1977-2001)

40
Penicillin-resistant S. pneumoniae
35 30
Macrolide-resistant S. pneumoniae -Lactamase + H. 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. Am J Med. 1999;106:19S-25S; Doern GV, et al. Emerg Infect Dis. 1999;5:757-65; Thornsberry C, et al. Clin Infect Dis. 2002;34:S4-16; Farrar GE. Clin Ther. 1989;11:555-6; Forward KR. Semin Respir Infect. 1999;4:243-54; Jones RN. Diagn Microbiol Infect Dis. 1997;27:75-83; Hogan PA. Antimicrob Agents Chemother. 1998;42:3313-14; Jones ME, et al. IJAA. 1999;19:119-123; Doern GV, et al. Antimicrob Agents Chemother. 1999;4:385-389; Thornsberry C, et al. J Antimicrob Chemother. 1999;44:749-59; Hoban D, et al. Diagn Microbiol Infect Dis. 2003;45:251-9.
The problem is that many times the resistances go together. The pneumococcus has learned how to put all these resistance genes into what they call a transposon so that many times, strains that are resistant to one antibiotic are resistant to the others and [you have] so-called multi-drug resistance strains. This is an example.
69
Penicillin-Resistant S. 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, et al. Antimicrob Agents Chemother. 2001;45:1721-9.
Here you have penicillin-resistant pneumococci, and you can see that, if they are resistant to penicillin, they are many of the times resistant to a lot of the other antibiotics at the same time. So thats a problem, again you know, many times because of the lack of microbiology we dont even know what were dealing with.
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, et al. N Engl J Med. 1999;341:233-9.
Fluoroquinolones are great drugs, and still remain good drugs, but we also have to be careful about how we use them because otherwise resistance will develop to the quinolones also. This is data from Canada, which shows that over the 1990s there was a lot of quinolones use, and there still is in Canada. Then with the last period, there was the emergence of quinolone resistance. Thats from 1998. The good news is that it seems to have plateaued out in Canada and in the US also, its about a 3%-4% range of pneumococcal resistance to the fluoroquinolones. Its about the same number in the US and it seems to be plateauing out, which is good, but again, I think we have to be cautious and circumspect about how we use quinolones in these patients.
71
M. catarrhalis in Sputum from Patient with AECB
Moraxella catarrhalis again, the red dots are there.
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. catarrhalis
Pfaller MA, et al. Am J Med. 2001;111:4S-12S.
And with that, the major problem again is the beta lactamase production and resistance and because of that to penicillin and amoxicillin, and there is some emerging resistance to trimethoprim sulfa.
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 thats about resistance. The question that was again raised by Dr. Amin is, what is the clinical relevance of this resistance? You know, there is much more in vitro data for resistance than there is in vivo data. Part of the problem is the kind of studies that are done. If you examine this question on the surface, youll say that all these studies seem to show equivalent efficacy with all the antibiotics, but the problems with the studies there are several problems with the studies which could explain that. Many of the studies actually exclude the kind of patients who have resistant strains. So as well discuss later, the most common cause for the individual patient to have a resistant strain is having been exposed to antibiotics in the previous 3 months. Most of the studies exclude those patients. So many of the times, thats why they dont pick up resistant strains. Many times, the dont do good diagnostics to document microbiologic failures. We all have clinical failures when you treat these patients, and Im sure a portion of those are because of resistance, but we never do microbiology so we never know. So I think thats the kind of problems we have in trying to show clinical relevance.
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, et al. Chest. 2000;117:1345-52.
There are a couple of studies in exacerbations which have shown clinical relevance, 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.
75
Antibiotics and Relapse of AECB

60 50
P < 0.05
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, et al. Chest. 2000;117:1345-52.
Again, this is just looking at what antibiotics they got. They didnt have microbiology in these patients, but what was interesting was that, yes, the antibiotics decreased the rate of relapse in these patients, so thats the antibiotics with the relapse rate of about 19%. Without antibiotics, it was about 30%. Then when they broke down this group into what antibiotic was used, the highest relapse rate was the amoxicillin, so its kind of interesting I think. What it shows is that when you give an ineffective antibiotic when the patient, you think, needs an antibiotic, you will actually have high rates of relapse. So these kind of studies which hint at that resistance is relevant in these patients.
76
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, Id talk a little bit about the stratification approach. Where instead of whats happened with all of this resistance emergence is that obviously we cant 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.
77
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 lets look at severity of disease. And as Ive said there is again, there is one study which helps us kind of define the severity of an exacerbation. Again, we dont 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, Im coughing more sputum, and its more yellow and its a type 1 exacerbation. On the other hand, if the patient came in and said you know, theres only al little bit of change in my sputum color and everything else is fine and I have a bit of a cold thats a type 3 exacerbation.
78
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
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 dont seem to make a difference, and also there is a very high rate of spontaneous resolution in those patients.
79
Antibiotics in AECB: Results

35 30
P < 0.05
% Deterioration
25 20 15 10 5 0 All Type 1 Type 2 Type 3
Placebo Antibiotic
Type of Exacerbation
In fact, its more dramatic when you look at failures. As you see over here, there was about an 18% failure rate on placebo versus about half of that with antibiotics, and again the predominant benefit was in type 1 exacerbations and some in type 2. So essentially, what this tells us is that the real mild exacerbations mild symptoms, single symptoms maybe they dont need antibiotics, but there is a much more substantial benefit with antibiotics in type 2 and 3 exacerbations.
80
Relapse After Outpatient AECB: A Multivariate Regression Model

Prospective study 268 general practices
Odds Ratios
1.8 1.6 1.4 1.2 1.0 0.8 0.6 0.4 0.2 0.0 Dyspnea IHD Visits/yr
2414 patients Relapse in 507 patients in 1 month (21%)

262 (11%) return visit 161 (7%) ER visit 84 (3.5%) hospitalization
Miravitlles M, et al. Eur Respir J. 2001;17:928-33.
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, and this is a study done from Spain, again in the outpatient setting, looking at a bunch of patients and looking at their relapse rates, and again it was about 21% relapse rate in those patients. Again, relapses result in ER visits and hospitalizations, but then they looked at what predicted relapse which caused the patient to relapse in a multivariate model, and it showed that patients with more underlying severe lung disease with comorbid conditions, especially cardiac problems and frequent visits with frequent exacerbations, are the ones who tend to relapse.
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, et al. CMAJ. 1994;151(10 suppl):1-23.
FEV1 = Forced expiratory volume in 1 second.
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, do not have frequent exacerbations, and have relatively preserved lung function (defined as an FEV1 of more than 50%) those patients are classified as simple chronic bronchitis. The presence of one or more of these risk factors and those patients are then called complicated chronic bronchitis or complicated COPD.
82
Proposed Therapies for AECB According to Patient Subsets

Simple, uncomplicated AECB 4 exacerbations/yr No comorbid illness FEV1 >50% Complicated AECB >4 exacerbations/yr Complicated AECB at risk for P. aeruginosa Patients with chronic bronchial sepsis Serious comorbid illness Need for chronic FEV1 <50% corticosteroid therapy Home oxygen and frequent (>4/yr) courses of antibiotics Chronic oral steroids FEV1 <35% Advanced macrolide Selected cephalosporins Doxycycline TMP/SMX New fluoroquinolones Amoxicillin/clavulanate Fluoroquinolone with anti-Pseudomonal activity
ODonnell DE, et al. Can Respir J. 2003;10(suppl A):11A-33A.
FEV1 = Forced expiratory volume in 1 second; TMP/SMX = Trimethoprim/sulfamethoxazole
So this is all being put together in a set of guidelines. Now there are again several guidelines for treatment of exacerbations with antibiotics, and again most of those guidelines differ or disagree with each other. 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, so lets forget about all this resistance emergence and outcome issues and still treat everyone with amoxicillin to start with or Bactrim. But again, thats like saying because we dont have the data and placebo-controlled trials that nobody wants to do, we should be ignoring a large body on resistance and outcome. The Canadian guidelines have kind of incorporated those issues, and of the guidelines that are out there I like these ones the best so Ill present those. What they did in these guidelines was to classify the patients, as I showed you, into simple or uncomplicated exacerbations, complicated and complicated ones at risk for Pseudomonas. Youre going to start seeing the similarity to the pneumonia set-up. With simple uncomplicated, as I mentioned, in patients without comorbid illness and without frequent exacerbations and relatively preserved lung function in those patients you can use a macrolide, selective cephalosporins with good pneumococcal activity, or even doxy or trimethoprim sulfa. Again, these are the not patients that most probably you are going to see in the hospital setting. These are mostly 99% of these patients are outpatients. I mean, if they get admitted, its by mistake. Complicated exacerbations are the kind of patient that youre going to see and these are patients who have any one or more of these risk factors. I think the first three are the important ones frequent exacerbations, serious comorbid illness, or an FEV1 of less than 50%. Home oxygen and steroids kind of correlate with having bad lung disease. And in those patients, the recommendation is that we should, up front, be using either one of the new fluoroquinolones or amoxicillin. The idea being that in those patients we need more aggressive therapy up front to minimize the risk of failure in those patients. Then theres a third group, which is complicated and at risk for Pseudomonas. These are patients defined by very severe underlying COPD, with a need for chronic steroids, and again in those patients, the recommendation is to stick with a fluoroquinolone with some anti-Pseudomonal activity in an outpatient setting. In an inpatient setting, we dont know. I mean Im reluctant to throw three antibiotics at these patients, so I still tend to use a single agent with anti-Pseudomonal activity in these patients in the inpatient setting. I think the best thing to do in these patients is to get sputum cultures because then you know if youre dealing with Pseudomonas or not and then you can guide your therapy. Again, these guidelines havent been tested in evidence-based situations, but they are based on the best knowledge or the best science that we have right now.
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, clarithromycin) Ketolide (telithromycin) Cephalosporin (cefuroxime, cefpodoxime, cefdinir) Doxycycline
Complicated COPD
Fluoroquinolone (moxifloxacin, gemi floxacin, gatifloxacin, levofloxacin) Amoxicillin-clavulanate If at risk for Pseudomonas, consider ciprofloxacin and obtain sputum culture
Worsening clinical status or inadequate response in 72 hrs Reevaluate Consider sputum culture
Sethi S, Murphy TF. Infect Dis Clin N Am. 2004;18:861-82.
This is something that I wrote last year in the Infectious Disease Clinics. Its kind of based on the same one. I will try to simplify it even more and incorporate the idea of Anthonisen and when can we not use antibiotics. So in patients who are mild, again, patients you wont see in the hospital setting, maybe antibiotics are not indicated. Once they have a moderate to severe exacerbation based on having two of the three cardinal symptoms at least, then again simple and complicated we kind of discussed that already and its pretty much based on the same kind of break-up. But I think Pseudomonas patients fall into this group and those kinds of patients should receive sputum cultures to guide their therapy.
84
Antibiotic Steak
S. Harris.
So thats 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 youll get cured.
85
Approaching Antibiotic Therapy of RTI

Severity of acute illness Expected outcome Expected resistance Adverse effects Overall cost
Just kind of to summarize, I think approaching antibiotic therapy of exacerbations, 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 way I like to say it is it wont apply so much to you folks, but its like cholesterol therapy has become much more complicated. We have to worry about LDL and HDL and all those things the same thing with antibiotic use. You need to start taking into account the severity of the acute illness, expected resistance, and outcomes issues, and also adverse effects and costs.
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, et al Chest. 2002;121:1449-55.
But I think when it comes to costs, we should look at the overall cost of treatment rather than just the cost of the antibiotic acquisition. And I think its a famous quote that the most expensive therapy is one which does not work. And this is well exemplified this is data again from the study Ive shown you, the Spanish study. They looked at the costs of the failures and showed that 21% of failures were responsible for almost two-thirds of the costs. 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 doesnt get appropriate treatment, the chances are is that the hospitalization is going to be prolonged and they are going to develop complications. So I think saving a few dollars on the initial antibiotic therapy and being conservative, in this situation, can be harmful many times.
87
Antibiotic Treatment of RTI: Ideal Approach

Accurate diagnosis Syndrome Etiology Susceptibility Therapy Focused Narrow-spectrum
What we would like to have is this. This would be the ideal approach to treating any respiratory tract infection we have a very accurate diagnosis of what the syndrome is, whats causing it, and the therapy has to be right on the dot.
88
Antibiotic Treatment of RTI: Pragmatic Approach

Educated guess Syndrome Etiology Susceptibility Therapy Empiric Risk stratification
The problem is is that we dont have the tools to do that. Right now, the best we can do is an educated guess as to whats going on with this patient, whats causing for example the exacerbation, and then base the therapy in an emphatic way on a risk stratification approach that we discussed.
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, most patients get better anyway Antibiotics reduce morbidity, mortality and health care costs for several diseases
Again, theres some philosophical viewpoints about antibiotic treatment of respiratory tract infections that a lot of the paradigms that we were brought up with are changing. 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. But now the approach is that we should use the risk stratification approach and choose initial therapy based on that. Not everyone has to fail the first-line therapy to get second-line antibiotics. Using low doses for long duration that was alluded to. Now you know, use high doses for short duration. Thats becoming the approach that may be the best way to decrease antibiotic exposure. The concept that antibiotics are pretty harmless is also not true. I think we have to be more circumspect about antibiotics. Besides the issue of adverse affects, also the issues of resistance emergence because of antibiotic use. On the other hand, we had this other approach or the other extreme people have that most patients get better anyway, and that may not be based on fact. And antibiotics are known to reduce mortality, morbidity and health care costs of exacerbations in a lot of other diseases.
90
Elegant Solutions
S. Harris.
So again, it gets more complicated. As it says over there, Whatever happened to elegant solutions? It does get more complicated with time. . . .
91
Research at the VA
But if you fix those patients up there, they can go back to doing what they should be doing thats playing golf. Thats the VA and thats the research building I work in. . . .
92
A Must See in Buffalo
I always like to put us this to show that theres more things in Buffalo besides snow.
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, there are hundreds of studies. There are literally hundreds of studies. The problem is that all the antibiotic comparison studies are industry-sponsored and were done for only one purpose, and that is to get FDA approval for the new drug thats coming on. And what the FDA wanted and thats changing, which is good in a way was show us that youre as good as whats available in the market and approved for that particular indication. So every study was designed to show non-inferiority to a competitor, which is existing in the market, and thats exactly what it did. Because all the studies are designed very carefully that they fall within 10% or 15%, and the studies take on generally simpler patients so that all the results about 80% to 90% of the patients get better, which is not true when you look at the few placebo-controlled trials. There is a move now by the FDA that they want to look at superiority again. Theyre bringing about some change, which is a painful change for many companies, but may be actually worthwhile down the road. All right? Sure.
94
Questions & Answers

Do you see a role for a better pneumococcal vaccine in adults?
We are. And you know, I would love to comment on that that. Fortunately, there are no core measures for exacerbations as of yet, but its just a matter of time. You know, the discussion with the 4 hours and the 8 hours was very interesting. If you look at the data that its based on, its terrible data. Its 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 thats why I think they are going back to the 8 hours because really the difference in the 8 hours and 4 hours is minimal. But can I go back to your question? Yes, so its analogous to the 4 hours, 8 hours, the data was soft for that. The data for pneumococcal vaccine is soft but its a core measure that theyre measuring. They are defending it the hospital administrators defend it by saying that, hey, if you were giving the vaccine right then that means you were doing other things right. So thats why its still a core measure. But I think its more of a quality measure than anything else. In terms of the data for adults, its actually youre right its very soft data.
95
Questions & Answers

Are they working on a better vaccine?
Yes, there actually has been some adult studies and this is totally unofficial, but from what Ive 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. When they tried that in adults, they didnt have any dramatic effects as they had in the kids. So there is development there are attempts to develop better vaccines. We obviously need a better pneumococcal vaccine. What I do is I use it in my patients. I may not use it every 5 years and do all those things but I think, you know, if you look at the overall safety/benefit ratio it may be okay to use it at least once. To impose it as a quality measure I think is a bit unfair, but who said that our federal authorities are fair? All right. Thank you very much.
96
Antimicrobial Resistance: Implication for Nosocomial Pneumonia Patients

Richard Quintiliani, MD,, FACP
Professor of Medicine and Pharmacology University of Connecticut School of Medicine Farmington, Connecticut
As it is shown on the program, Im the last speaker, so I hope that everybody is alive enough to hang in here with my presentation. I promise I will try to end it as indicated. No later than 9:30. I suspect if I speak much longer than that, I probably will have to strike a deal and Ill have to pretend Im talking and youd have to pretend youre listening and so I dont want to get into that issue. My background is shown on the pamphlet thats been distributed as a blend of infectious diseases and pharmacology. So I will use both of those backgrounds in this brief presentation.
97
Antimicrobial Resistance:
Implication for HospitalAcquired, VentilatorAssociated, and HealthcareAssociated Pneumonia
Ill be focusing mainly on nosocomial pneumonia, which used to be viewed as pneumonia that develops in a hospital setting. 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, as mentioned, hospital-acquired pneumonia into different subsets of patients. Several months ago, the ATS and the IDSA published actually their 2005 guidelines as to how one should be dealing with this type of infection.
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Hospital-Acquired, Ventilator-Associated,
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. Am J Respir Crit Care Med. 2005;171:388-416; Craven DE, et al. Infect Dis Clin North Am. 2004;18:939-62.
Now on the first slide, this is really the new way to break down pneumonia thats acquired in a hospital but also acquired outside of a hospital. For instance, 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. Moreover they should not have any evidence of incubating a pneumonia at the time of their admission. So this is now hospitalacquired pneumonia, often referred to in the past as nosocomial pneumonia. Now also viewing perhaps one of the most difficult types of hospital-associated pneumonia and this is now referred to as VAP, or ventilator-associated pneumonia. And again, the definition according to the new ATS guidelines is pneumonia that arises 48 hours or longer after endotracheal intubation. And lastly kind of a brand new kind of definition here is referred to healthcare-associated pneumonia or HCAP, 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. Also now, 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. So this is the new breakdown of pneumonia in the high-risk category. Usually the term nosocomial was an encompassing term for all of these three.
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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. Am J Respir Crit Care Med. 2005;171:388-416; Craven DE, et al. Infect Dis Clin North Am. 2004;18:939-62.
Also to make it further, and perhaps maybe even more difficult, but its 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, 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. The late-onset are the ones that occur 5 days or later. Now we are going to see in a moment that the antibiotic approach really varies tremendously whether the patient has this early- or late-onset type of pneumonia.
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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. Am J Respir Crit Care Med. 2005;171:388-416.
Now also from the guidelines, the following point should really be underscored, that hospital, um, healthcare associated pneumonia and again, 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. So they really are viewing these people who reside in chronic care facilities as being really a very high-risk group of patients. The reason is pretty obvious. They are usually colonized not with a common oropharyngeal pathogens but the more complicated ones. Also, just like in community-acquired pneumonia, we do not want a delay in therapy once a patient develops any of those three types of pneumonias that I mentioned. It is important to get initial cultures. But its also going to be important that after we get those, if we have some negative reports, we are going to use this information very heavily to decide how to simplify or de-escalate therapy. In my mind, sputum cultures actually have more value for their negative than their positive value. Unfortunately, many organisms will often colonize, but if we cant find them they are almost certainly not the source of that lung infection.
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ATS/IDSA 2005 Guidelines*
Early, appropriate, 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 patients clinical response
*ATS/IDSA. Am J Respir Crit Care Med. 2005;171:388-416.
Also, were back to making sure if youre going to prescribe an antibiotic, make sure its given in adequate doses. 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. 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.
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Traditional Empiric Antimicrobial Therapy in HAP, VAP, 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 its interesting that theres quite a paradigm shift. We always used to think in this traditional way to try to get our cultures, initiate therapy with very narrow-spectrum antibiotics, and then once we get this information, then we would change the antibiotic regimen accordingly. But unfortunately, this concept of starting simple and getting a better basis delays the appropriate therapy. If you initiate therapy inappropriately, theres a high mortality and of course this is now whats being recognized, particularly in these hospital-associated pneumonias.
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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, which is what it is being referred to in these guidelines, is that, hey, if we start simple, we probably dont need an ID consult, which could be expensive. Perhaps if we do not use the so-called big-gun antibiotics, we wont see as much resistance developing to them, and often we see a lung infiltrate and maybe its not a lung infection at all. And of course again, the pharmacists are always nagging us to keep the costs down, so they are always upset if we start with some of these big guns, which tend to be typically a lot more expensive than the more narrow-spectrum agents.
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New Concepts About Empiric Antimicrobial Therapy in HAP, VAP, 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, ventilator-associated and the healthcare-associated pneumonias is that we want to start initially with big guns. We want to cover all the suspected or target pathogens, 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 dont have to go very long to cure many causes of lung infections. Many of the newer antibiotics that we have are very rapid eliminators of microorganisms. Weve been hearing about short-course therapy for community-acquired pneumonia 5 days, for instance, with some of the respiratory fluoroquinolones. Weve already heard in the past about 3-day therapy, particularly in Europe, with 3 days of azithromycin for mild to moderate pneumonia. So theres a big movement in the area of respiratory tract infections to abbreviate duration of therapy, 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. So short-term therapy is less likely to be disruptive to gut flora.
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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, 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, called an aggressive approach is to try to get it right up front, because if you dont get it right right up front theres excessive mortality. And of course, indirectly that leads to excessive costs as well. So its kind of a reverse of things. Start with the combination therapy, powerful antibiotics, and then try to simplify therapy hopefully when we get further information.
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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, et al. Am J Respir Crit Care Med. 1997;156:196-200; Kollef MH, Ward S. Chest. 1998;113:412-20; Ibrahim EH, et al. Chest. 2000;118:146-55; Luna CM, et al. Chest. 1997;111:676-85.
Here for example back up here this slide just shows what inappropriate therapy does in a serious infection. 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. Now here again is the reason behind breaking down these pneumonias into early- and late-onset. Now the early-onset again applies to the hospital-acquired or the ventilator pneumonia. We dont use those terms for the healthcare-associated because you really cant do that, because theyre there for weeks or months or whatever.
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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. fragilis) Legionella species
Richards MJ, et al. Crit Care Med. 1999;27:887-92.
Treatment similar to agents used for community-acquired pneumonia (eg, monotherapy with respiratory quinolone or ceftriaxone + macrolide)
For early-onset, one can still use traditional or conservative approach; however, 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, the usual responsible pathogen is a typical organism that colonizes in the oropharynx. So very similar to what we see in community acquired-pneumonia. So what these new guidelines are suggesting is that in early onset of hospital-acquired pneumonia, you might want to treat them just like you do for community acquired-pneumonia, with combination therapy of a macrolide and a third-generation cephalosporin, or monotherapy with one of the respiratory fluoroquinolones. But again, I want to underscore that, according to these new guidelines, that any patient coming from a chronic care facility, nursing home, or long-term care facility is not looked upon as somebody who warrants early-onset type of antibiotic therapy. Theyre viewed as patients who have late-onset.
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Common Etiologies for Late-Onset (5 days) HAP, VAP and HCAP

Pseudomonas aeruginosa S. aureus (~50% methicillinresistant S. aureus [MRSA]) Enterobacter species Klebsiella species, including expanded-spectrum -lactamase producing organisms (ESBLs) Acinetobacter species
Richards MJ, et al. Crit Care Med. 1999;27:887-92.
Now how about the late-onset? Theres tremendous change in the target organisms if you develop your pneumonia 5 days or later, these are the major pathogens we want to make sure we cover in our initial empiric therapy, and thats why we require these so-called very broad-spectrum drugs. Here are the major causes of late-onset hospital-acquired pneumonia, ventilator-associated or HCAP: Pseudomonas ranks among the worst; however, there has been a tremendous increase now in Staph areus as a cause of hospital-associated pneumonia, and unfortunately one half of these now exhibit resistance to methicillin. But also remember, this is somewhat of a misnomer. These so-called MRSAs are resistant to all beta-lactam antibiotics, so no beta-lactam antibiotics whether youre talking about Primaxin or Zosyn have any activity against MRSA, and usually you have to resort to drugs like vancomycin or linezolid. Interestingly, the community-acquired MRSAs are not infrequently susceptible to some of the older remedies like Bactrim, clindamycin, and tetracyclines. However, paradoxically, 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. And of course, Klebsiella ranks high, as does Enterobacter, but now we are seeing what is called expanded-spectrum beta-lactamase, the so-called ESBLs. These are organisms that will hydrolyze the beta-lactam ring of third-generation cephalosporins, and often fourth-generation as well. Again, Im going to display some of the drugs that are the best choices. Right at the end, Im going to come up with what I think is going to make the best sense in terms of treating patients with late-onset, hospital-acquired or ventilator-associated pneumonia or HCAP. Also Enterobacter species and then lastly Acinetobacter. These are our major targets and these are the reasons for all this new stratification. 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. So as mentioned earlier, we have to chose the right drug and weve got to give it at the right time. Weve got to give it at the right dose but we also have to give it by the right mode of administration.
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Pharmacokinetic/Pharmacodynamic Parameters Affecting Antibiotic Potency

Peak/MIC (concentration-dependent) Goal: peak/MIC 10 Concentration AUC/MIC Goal: 30 for gram +; 125 for gram Time > MIC (time-dependent) Goal: 50% dosing interval MIC
0
Quintiliani R. Infect Med. May 2004:219-32.
Time (Hours)
Just quickly, this one slide it sums up the three basic pharmacokinetic concepts that are now being used to dose antibiotics in the best way. For instance, this just shows blood levels on antibiotics after a dose. Obviously at some time, the drug has to drop below its MIC the concentration thats necessary to kill the target organism. Now interestingly, certain classes of antibiotics kill bacteria the same, where the levels just exceed their MIC for that pathogen way down here just above the MIC, and where they do not kill any better if they are way up at the peak concentration, so these antibiotics are now referred to as concentration-independent or time-dependent killing, 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. Now on the other hand, 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. And the rule here is that with these kind of antibiotics, you get the best killing if the levels are roughly ten times above the MIC for the target organism. Lastly, there is the so-called AUC, which is a measurement of how high and how long levels stay above the MIC this is the area right there, the area under the serum concentration curve after a dose of antibiotics. The AUC is nothing more than a measurement of the exposure of the organism to that antibiotic through any one dosing interval. Its kind of fascinating that certain organisms require very little exposure to be rapidly inhibited. For instance, the pneumococcus is rapidly killed with an AUC of about 30 whereas organisms like Pseudomonas require very high and long exposure. 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. I mean you can use them but you have to use them in combination with another anti-Pseudomonas drug.
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Pharmacokinetic/Pharmacodynamic Parameters of Antimicrobial Classes

Concentration-Independent (Time-Dependent)
Beta-lactams (penicillins, cephalosporins,
penems, monobactams) Clindamycin Erythromycin Clarithromycin Linezolid Vancomycin
Concentration-Dependent (Dose-Dependent)
Fluoroquinolones
Aminoglycosides
Amphotericin B
Metronidazole
Daptomycin
And so its on your handout here these are antibiotics that use mainly time to kill organisms and these are the ones that use mainly concentration. In fact the observation that for these time-dependent antibiotics oops, were going to go back here for a second well 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. So thats 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. This has been tremendously useful in the dosing of beta-lactams that have relatively short half-lives, that typically have to be given very often, and therefore result in laws of labor and supply costs. At Hartford Hospital, for instance, we dose Zosyn by constant infusion. We dose ceftazidime frequently by constant infusion, thereby saving all kinds of monies from avoidance of labor and supplies. For instance, constant infusion turns out to be once-daily dosing.
111
Empiric Antibiotic Combination Therapy Choices for Late-Onset HAP, VAP, 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, modest activity against ESBL-producing Klebsiella and Acinetobacter baumannii Concerns over nephrotoxicity and ototoxicity Use once-daily dosing method
Now lets first look at possible choices I mean, what are we going to use? And it turns out that were probably going to have to end up using three antibiotics. Thats like back to the future when we used to do that in overwhelming intra-abdominal sepsis well, aminoglycosides like genta- and tobramycin have remained very active against most aerobic enterics and includes Pseudomonas. Unfortunately they have very poor activity against MRSA, and so certainly we cant use them alone and they have very modest activity against these expanded-spectrum betalactamaseproducing Klebsiella and Acinetobacter. And of course, were always concerned about do we have nephro- and ototoxicity.
112
Aminoglycoside Dosing Methods
20
Concentration (g/mL)
18 16 14 12 10 8 6
4
2 0 4 8 12 16 20 24
Once-daily (7 mg/kg) Conventional (1.5 mg/kg q8h)
Time (hours)
But if youre going to use them, 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- and nephrotoxicity. 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. Now why did we use that dose? Because the Pseudomonas is the usual most difficult target organism. It usually requires around 1.5 to 2 mcg loading at ten times above that and thats the only way you do it. And then the levels drop to zero at the end of 12 hours and then you go to a drug-free period. A few challenges a neutropenic animal with a potential lethal dose of Pseudomonas. 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. No one thought we could do this. They thought wed have undue oto- and nephrotoxicity but you dont, you get less. 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 1.5 or 2. When you go above that, you cant drive any more drug into those sites. The thing thats associated with toxicity with aminoglycosides is how much accumulates in the ears and kidneys and you actually accumulate more with intermittent dosing because you dont have a large wash out period. So thats the way these drugs should be given. So its back to the point that if youre going to give this drug, lets dose it in the best possible way.
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Bacterial Killing as a Function of MIC

BACTERIAL POPULATION
Number of Organisms
MIC 50%
MIC 90%
10x MIC
Minimum Inhibitory Concentration

Moreover, the emergence of resistance is less. In any population of bacteria, you have a bell-shaped curve where some organisms are less and some more susceptible, and often what can happen is, that if you suboptimally dose with typical intermittent dosing, the organisms way out here on the end can survive.
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

When that happens, they begin growing, they form a whole new population, much higher MIC 50 to 90 thats referred to as emergence of bacterial killing the resistance. If you actually start out with a dose ten times above the MIC, the chance of that happening is over zero. So aminoglycoside is one of the drugs were going to be using right at the end and so lets at least dose it in the best way.
12 18 17 15
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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%; moxifloxacin 93%, gatifloxacin 94%; ciprofloxacin 70%
What about the quinolones? The quinolones are fine in the urine but again systemically you cant use them alone for systemic Pseudomonas. Moreover, only around 65% of Pseudomonas now will test susceptible to either levo or cipro. There is no difference, by the way, between these two drugs in terms of the activity against that bacterium. The common mistake as a clinician look only at the MIC, and the amount needed to kill an organism, and assume that the drug with a low MIC is the best choice. Not so. You have to integrate blood levels and its a wash between these two drugs. You cant use amox or lactam, or moxifoxacin because it has very modest Pseudomonas activity and has not even been tested in the laboratory. And for Tequin gatifloxacin its only tested for urine isolates. So were not going to be able to use fluoroquinolones alone for Pseudomonas. They have no core activity against MRSA, modest against Acinetobacter and ESBLs. Nicely, though, they have no significant oto- or nephrotoxicity. The oral formulations really have excellent bioavailability, approaching 100% with levo and 93 or 94 with gati, and cipro was a little less down around 70%.
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Pharmacodynamics of LEV, IMP, and LEV-IMP Combination against P. 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 g/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 g/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, Wolter DJ. Clin Infect Dis. 2005;40(suppl 2):S105-14.
But theyre good potential drugs for this de-escalation because if you get an aerobic gram-negative other than Pseudomonas, you can use monotherapy with them as long as the gram-negative is not an Acinetobacter, ESBL as mentioned. We get often asked is there any synergy between these respiratory quinolones and any other anti-Pseudomonas drugs. You know, this has been done with levofloxacin and imipenem. These are what we call time kill curves. We measure the rate of bacterial kill after exposing the organism to the drug. This is the killing with levo right here. It kills for about 6 hours and then it breaks through. If you expose that organism just to Primaxin, imipenem, 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, then you get very good killing for 24 hours. Whether this type of study has been done with cipro, I dont know. I know its been done with the levo and with the imipenem. Again, this is information well need to justify the final conclusions.
117
The Carbapenems (Imipenem, Meropenem)

Anti-Pseudomonas activity closely similar to that of an aminoglycoside, but for best synergistic activity should be given with non-beta lactam antibiotic (eg, aminoglycoside, anti-Pseudomonas fluoroquinolone) Most active class of drugs against ESBL-producing Klebsiella and Acinetobacter baumannii No significant activity against MRSA and Stenotrophomonas maltophilia Ertapenem, another carbapenem, should not be used in the empiric treatment of HCAP since it has poor Acinetobacter and P. aeruginosa activity
Now the carbapenems. They, like imipenem and meropenem, there is another carbapenem out there called ertapenem (Invanz) you cant use that one. Be careful with that drug because it has very poor Pseudomonas and Acinetobacter activity. 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. So they probably have the best overall antiPseudomonas activity. They are very closely similar to that of aminoglycosides, but again for the best you need new therapy and for the best synergetic activity, you want to give it usually with a nonbeta-lactam antibiotic like an aminoglycoside or an anti-Pseudomonas fluoroquinolone. It is by far the most active class of drugs against ESBLproducing Klebsiella and Acinetobacter. The problem here, however, is no activity against MRSA and really modest against Stenotrophomonas maltophilia. Now one of the things that you have to recognize although certain organisms we grow out, it doesnt mean they are the significant pathogen theres another organism. Unfortunately, Stenotrophomonas is a very difficult bug to treat, and one other organism, cepacia although you not uncommonly grow them out, they are very seldom invasive. Also we see that when we isolate Candida from sputums, you often see it, but how often do you see Candida pneumonia? Almost zero. So theres a difference in different organisms in terms of their virulence.
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 3.375 g q6h Pip/Taz 3.375 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; indicates not tested; EC = E. coli; KP = K. pneumoniae; AB = A. baumannii; PSA = P. aeruginosa
Kuti JL, et al. Antimicrob Agents Chemother. 2004;48:2464-70.
Now [comment from faculty member: What do you treat that with?] Bactrim is a very good drug. Yes, sometimes the old remedies come back. In fact we dont have time because of timelines here tonight, but probably the best anti-Pseudomonas drug is polymyxin or Colistin. If you have a Pseudomonas aeruginosa that tests resistant to everything, test polymyxin theyre coming back very fast. It has a lot of nephrotoxicity but no ototoxicity, so theres a lot of interest in that drug again. Again, this shows you that I think youre going to have to have a carbapenem as one of your three choices. This is E. coli. This is Klebsiella. This is Acinetobacter and Pseudomonas. To compare these two carbapenems and again theyre the same. If you look above, these two drugs are the same. They have very good activity against major pathogens of late-onset pneumonia.
119
MYSTIC Americas Results P. aeruginosa (193)

100
Cumulative % Inhibited
90 80 70 60 50 40 30 20 10 0 0.016
Meropenem Piperacillin/Tazobactam Cefepime Imipenem
0.03
0.06
0.12
0.25
0.5
16
MIC (mg/L)
Pfaller MA, Jones RN. J Antimicrob Chemother. 2000;46(topic T2):25-37.
Again, between the two meropenem and imipenem, this is meropenem, this is the MICs, theyre very low for both. So there are really no major difference, but they are more intensely active as compared with cefepime or piperacillin/tazobactam.
120
Appropriate Therapy
Antibiotic
Third-generation cephalosporins Cefepime Quinolones Piperacillin/tazobactam Carbapenems
ESBLs
+/ +/ +++
AmpC
+++ + +/ +++
Lets skip this because of the time.
121
Linezolid vs Vancomycin in the Treatment of NP Due to MRSA

Clinical Cure (% of Patients)
Data from 2 Double-Blind, Randomized Controlled Trials, n=116 80 P = .009 P = .182

60 40 20 0
59.0 51.5 43.4 35.5
Linezolid Vancomycin
S. aureus
MRSA
Linezolid therapy was 3.3 times as likely as vancomycin (95% CI: 1.38.3, P = .011) to result in a clinical cure
Wunderink RG, et al. Chest. 2003;124:1789-97.
The other question is what are we going to do with these MRSA? And when you read the guidelines by the ATS, they bring up an observation that the failure rate with vancomycin is rather high at 40%. And so weve got to reconsider that maybe we should be thinking about an alternative drug, and I think linezolid could be that choice. This was the study that was actually done by Richard Wunderink, whos from Chicago, where he compared outcomes and nosocomial pneumonia here we see the term again due to MRSA and the cure rate was higher with linezolid. Why?
122
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 theres very high penetration quantities into the lung.
123
Penetration of Vancomycin Into Human Lung Tissue

Vancomycin Concentration (g/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 heres 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 dont 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, youll probably have to dose it every 8 hours, and were going to worry more about oto- and nephrotoxicity. So well be hearing more about linezolid. Unfortunately, its rather pricey, even by the oral formulation; however, linezolid is again another one of those antibiotics thats almost 100% absorbed, so you obtain concentrations essentially the same as you would if you had the patient on IV formulation. So its another good drug like respiratory fluoroquinolones for de-escalation.
124
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 dont have to do serum assays with linezolid, you dont 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 cant give by mouth. Theres 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.
125
Aminoglycoside Combination Therapy for HCAP and Late-Onset HAP and VAP
1. Combination therapy based on unit-specific antibiogram
Imipenem Imipenemor or Meropenem Meropenem + + Tobramycin Tobramycin + + Vancomycin Vancomycin or Linezolid orLinezolid
2. Modify therapy within 48 hours based on micro biological data
3. Established criteria for duration of therapy: try to avoid more than 7 days
So well end here with what I would think would make some sense, and if youll read in depth the ATS guidelines, 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 dont really finally say, well, heres what we think is probably the most reasonable approach. My view is that you have two options here. You can decide which one makes more sense. There is one way you have to use an aminoglycoside gentamicin, tobramycin. You also have to use a MRSA drug theres no way around that and so you have to choose between vancomycin or linezolid and then I think we need a carbapenem. So that would be an approach to the three types of pneumonia the hospital, um, healthcare-associated, which is always managed identical to the late-onset hospital-acquired or the ventilator-associated pneumonia.
126
Non-aminoglycoside Combination Therapy

Protocol (Nonnephrotoxic, Nonototoxic) for
HCAP and Late-Onset HAP and VAP
1. Combination therapy based on unit-specific antibiogram
Imipenem Imipenemor or Meropenem Meropenem + + Levofloxacin Levofloxacinor or ciprofloxacin ciprofloxacin + + Linezolid Linezolid
2. Modify therapy within 48 hours based on micro biological data
3. Established criteria for duration of therapy: try to avoid more than 7 days. For clinically stable patients who can eat, consider oral quinolone or oral linezolid
Now theres another possibility here, and this is what I would call the nonoto-, nonnephrotoxic drug. Again, we need a carbopenem either Primaxin or meropenem. You need an MRSA drug. If we want a nonnephrotoxic/ototoxic, it would have to be linezolid, and then you combine it with one of the respiratory fluoroquinolones, either levofloxacin or ciprofloxacin.
127
Questions & Answers

Are any antibiotics in your opinion more inducers of ESBL or no?
So we have about three minutes. Any questions on this? A lot of people are unfamiliar with these guidelines because they have been so recently published. Yes? Ive gone to a few talks and it seems like one antibiotic the question is, 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. Yes, Ive heard literally just like zilch and it doesnt do it. Also in terms because of timelines here lets now approach de-escalation, okay? So if you had Klebsiella that produced ESBLs, maybe 60% to 70% are susceptible to cefepime thats the next good drug or even Zosyn. So you could then move down to one of those and get away from a more expensive agent like Primaxin or meropenem. If you isolated a non-ESBL producing Klebsiella or E. coli, you could move down to, lets say, monotherapy with one of the fluoroquinolones. I guess that the whole view is that when you get the new data, we should be able to simplify. And then in fact with the respiratory fluoroquinolones, you can then move them down to their oral formulation and again with linezolid, you can do that as well. So theres a need as I mentioned for an approach on how to de-escalate as well as how to start with. But there is no question, the initial approach is going to be triple therapy. I dont see anyway around that.
128
Questions & Answers

I just wanted to know if there are certain antibiotics that induce ESBL more than others?
No. Im often asked if certain antibiotics can induce or cause the emergence of MRSA and basically, any antibiotic that is not active against MRSA can do this. The quinolones get blamed more than anyone else, but any antibiotic that has minimal to no activity against MRSA will encourage the emergence of that pathogen. So its all beta-lactams, all fluoroquinolones, its all except the two that I mentioned. There is a last one there is a drug called daptomycin one thing as a note of caution, although that drug is very active against MRSA, very low MICs, it should never ever be used in lung infection. They have a black box its called Cubicin. Youve probably have seen it. Its a drug by Aventis. Its daptomycin. It has no penetration into lung tissue. And theres a concern because that drug alone, good against MRSA and skin, soft tissue, and bone, it should never be used for lung and in fact the package insert says that but often it is not noticed.
129
Questions & Answers
On resistance, our nephrologists have us convinced that Zosyn will induce resistant enterococcus and theyve requested that we dont use it because it becomes a problem with their access infections.
Piperacillin is very good against enterococci, okay? I dont see why that would be an issue. It would seem a lot more vancomycin-resistant enterococci, VRE, okay? Again, that organism is often resistant to many classes but is susceptible to linezolid, okay? Here again though, its kind of a fascinating observation its now felt that you dont die from VRE. You die with VRE. As a marker, you get really sick, probably youre not going to last much longer it is not a very invasive organism, and thats why you rarely see proven serious infection from VRE. The hospital epidemiologists go crazy. They want to burn down the hospital when they see that. But its really not that bad. The question is why? Well, Dr. Patrice Courvalin from the Pasteur Institute, hes the most famous guy on enterococci, and he spoke recently at our hospital. And he said that the reason is that when you have these antibiotics that have multiple drug resistance, you know, the MVR organisms, okay? They can do that but its at the expense of a whole bunch of metabolic processes, and by messing with many metabolic processes, it ends up with less virulence. And thats true. Remember the hospitalacquired MRSA are not as virulent as the ones that are community-associated. And actually, penicillin-resistant pneumococci are not as virulent as penicillin-susceptible. We do a lot of animal research and so we often try to produce, say, pneumococcal infection in an animal. 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. So thats a generalization that has held up very well, and multidrug-resistant pathogens tend to be not that invasive. I already mentioned Stenotrophomonas maltophilia as another example of that observation.
130
Questions & Answers

How about chloramphenicol?
Well chloramphenicol well it depends upon a lot of your training in infectious diseases. Its no longer available in the United States except on a compassion and plea basis, okay? I think that was a great mistake. Its a tremendous antibiotic. Good anaerobic, good aerobic and good penetration characteristics. Still used extensively in the world. Cheap as can be as well. Also 100% absorbed. You know, we love those drugs that are totally absorbed like that. Yeah, it produces, occasionally, thrombocytopenia or aplastic anemia. But theres a fascinating observation in fact I wrote an article on this with data give to me by Parke-Davis. When we have seen aplastic anemia, at that time, just about 10 years ago, there were only around 500 reports in the United States. Every one of those patients had received chloramphenicol except one by the oral route of administration. 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 - but the strange observation that IV chloramphenicol is very safe. Oral is also quite safe, but unfortunately one out of every maybe 40,000 will develop aplastic anemia. And so the answer to that drug was, dont give it by mouth if at all possible. But even then, its a rare complication of that drug. But unfortunately, we cant get it now in the United States. I think its kind of a major loss to our armamentarium as they say. We may want to comment on whats ahead. Somebody asked me during the coffee break. I dont know if Im allowed to do that, if Im allowed to talk about with all these regulations, you have to stay within this little path here. Its definitely not a commercial, you might want to know whats ahead. As far as I can tell, theres no more quinolones. Theyll come maybe but not for a long time, okay? The aminoglycosides, nothing new there. No new sulfa drugs. What about cephalosporins? There is one being studied for MRSA. We may in time, within a year or two hopefully, have a cephalosporin to treat MRSA. But well see. (continued)
131
Questions & Answers
How about chloramphenicol?
Um, theres an analog of minocycline coming in fact if you go to Lederle, I was out there today, they have analogs of minocycline called glycylcyclines, which are also good against MRSA. Were getting more and more drugs against MRSA because thats becoming a common pathogen. But the class of antibiotics that most people are talking about that are probably two or three years off are the peptides. These have been recently discovered although known about forever and explained why amphibians are resistant to skin infections. Frogs and toads they dont get skin infections. Why? Because they excrete through their pores long-chain amino acids and therefore theyre called peptides, and they carry a positive electronic charge (a strong one) that is attractive to negative charges in the cell wall. You talk about rapid cure within 30 minutes they kill the organism. It is now known that all forms of life on this planet have those. We have them. 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. Again, there is a bit of clinical observation that patients with severe eczema are very prone to secondary bacterial infections people with psoriasis, no. The reason is that psoriasis patients secrete normal amounts of these peptides. Eczema patients do not. And there is already a pharmaceutical company interested in development of these new class they are called magainins. The word magainin is a Hebrew word which means shield of protection. So the senior researcher spoke Hebrew, he knew that, and so hes named these peptides that theyre developing as magainins. I was recently a visiting professor in New Orleans where they see a lot of tropical diseases. A lot of people train there and go through there from South America, and one of the senior ID physicians got up in the audience and said he, you know, was born in a small village just outside of Lima, Peru, and as long as he could remember as a child, when people used to get wound infections, they used to capture a frog, paste the poor frog over the wound, wrap it up, and they noted very impressive improvement. To me, its always amazing some of the old, old observations that no ones taken advantage of until the last 5 or 10 years.
132
Questions & Answers

What about Synercid.
Synercid I find no longer an acceptable drug. Thats the combination of quinupristin and dalfopristin the problem with the drug is not that its not a good active drug against MRSA, it is, but it has a huge side effect profile. About 25% get line sepsis, QTc prolongation, all kinds of interference with other drugs that are handled by the CP450 system, and so its a very unpopular drug. Its when you say you cant use vanco, you cant use linezolid, cant use daptomycin, then you might want to use Synercid.
133
Questions & Answers

Whats the role of ertapenem?
Ertapenem is actually a it could be used, okay? Its being use mostly which I think is more appropriately in intraabdominal problems, particularly in prophylaxis. When you have someone with diverticulitis undergo an elective surgery of appendix, gall bladder, you want activity against three target gram-negatives E. coli, Proteus, and Klebsiella, but you need aerobic activity, and its very good against bacteria, and you give it once a day its kind of nice. Unfortunately, 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. So youve got to watch that drug and thats why a lot of ID people have troubles with it.
134
Questions & Answers
What about Telithromycin?
Again, somebody asked me, what about telithromycin? That wasnt mentioned for a brief moment. And any discussion with respiratory tract infections should also address that drug. Well, its kind of a fascinating drug. Its called a ketolide. Its still a macrolide. What they did was that they took the 14-membered ring lactone structure, which is a classic macrolide, and they detached a sugar side chain its called cladinose put in a ketone root, hence ketolide. When they did that, they basically created a macrolide that was highly active against penicillin-resistant pneumococci, macrolide all the macrolide-resistant pneumococci so its a very impressive drug when it comes to the pneumococcus. Unfortunately, it has modest activity against H. flu and thats a potential problem. Thirdly, theres no IV formulation. Why? Because its very hard to create a well-tolerated IV macrolide. We have no IV clarithromycin in the United States. Erythromycin, yes, we have it, but about 25% of the people get like a chemical phlebitis, so we dont have that. Thirdly, it has some disturbance in combination. Thats a problem. It typically occurs about one hour after its administration. It lasts about an hour. You have to go through a lot of discussion with a patient about this potential. Fourthly, a lot of GI side effects, which is typical of all macrolides. And fifthly, a lot of interaction with the CP450, so statins should be used. So its complicated. By accumulation, my own view is that its not going to be that popular. I mean why not use a respiratory quinolones? Thats my view instead of that drug, and bioavailability is now about 60%. But when we were talking about community acquired pneumonia to make it a balanced talk, youve got to address that drug, which is recently being marketed in the United States fairly heavily.
135

Presentations aa symposium held in Presentationsfrom from symposium held in Chicago, Illinois on Friday, Friday, April Chicago, 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. Thank you hanging in here, and I hope you have a good night. Thank you.

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Improving Patient Care: Reducing Antimicrobial Resistance in Respiratory Infections

Improving Patient Care: Reducing Antimicrobial Resistance in Respiratory Infections

Good evening everyone and welcome to this evenings program.

Improving Patient Care: Reducing Antimicrobial Resistance in Respiratory Infections

Continuing Medical Education

Improving Patient Care: Reducing Antimicrobial Resistance in Respiratory Infections

Improving Patient Care: Reducing Antimicrobial Resistance in Respiratory Infections

Improving Patient Care: Reducing Antimicrobial Resistance in Respiratory Infections

Alpesh Amin, MD, MBA, FACP

Improving Patient Care: Reducing Antimicrobial Resistance in Respiratory Infections

Sanjay Sethi, MD State University of New York at Buffalo

Improving Patient Care: Reducing Antimicrobial Resistance in Respiratory Infections

Faculty Richard Quintiliani, MD, FACP Faculty

Improving Patient Care: Reducing Antimicrobial Resistance in Respiratory Infections

Managing CommunityAcquired Pneumonia While Avoiding Resistance Risks

Improving Patient Care: Reducing Antimicrobial Resistance in Respiratory Infections

Community-Acquired Pneumonia (CAP)

Improving Patient Care: Reducing Antimicrobial Resistance in Respiratory Infections

CAP Is a Serious Illness

Costs of treating CAP exceed $8 billion

Improving Patient Care: Reducing Antimicrobial Resistance in Respiratory Infections

Algorithm For Prediction Model

ASSIGN PATIENT TO RISK CLASS 1

Improving Patient Care: Reducing Antimicrobial Resistance in Respiratory Infections

Pneumonia PORT Risk Class: Mortality and Management

PORT = Pneumonia Patient Outcomes Research Team cohort study.

Improving Patient Care: Reducing Antimicrobial Resistance in Respiratory Infections

Outpatient Care vs Hospitalization in Low-Risk Patients with CAP

Improving Patient Care: Reducing Antimicrobial Resistance in Respiratory Infections

Outpatient Care vs Hospitalization in Low-Risk Patients with CAP

Improving Patient Care: Reducing Antimicrobial Resistance in Respiratory Infections

No. of ADL Dependencies

Improving Patient Care: Reducing Antimicrobial Resistance in Respiratory Infections

CAP: Effect of Pulse and Respiratory Rate on Mortality in NHAP

Rapid respiratory rate predicts mortality

Improving Patient Care: Reducing Antimicrobial Resistance in Respiratory Infections

Mild to Moderate vs Severe CAP: British Thoracic Society (BTS) Rule

Revision of the BTS rule Add a fourth criterion

Define increased mortality risk

Improving Patient Care: Reducing Antimicrobial Resistance in Respiratory Infections

Severe (ICU)2 S. pneumoniae Legionella species H. influenzae Gram-negative S. aureus

on collective data from recent studies.

File et al, Am J Med Continuing Education Series, 1997.

Improving Patient Care: Reducing Antimicrobial Resistance in Respiratory Infections

Chlamydia Co-infection Prolongs Length of Stay (LOS) in CAP

Kauppinen MT, et al. Thorax. 1996;51:185-9.

Improving Patient Care: Reducing Antimicrobial Resistance in Respiratory Infections

Guidelines for CAP Management: The ATS Algorithm of 2001

American Thoracic Society. Am J Respir Crit Care Med. 2001;163:1730-54.

Improving Patient Care: Reducing Antimicrobial Resistance in Respiratory Infections

ATS 2001 Recommendations for CAP

History of C/P disease and/or modifiers

No risk of Pseudomonas: IV 3GC + IV azithromycin or IV fluoroquinolone

Improving Patient Care: Reducing Antimicrobial Resistance in Respiratory Infections

IDSA CAP Guidelines: 2003 Outpatient

Healthy & no previous antibiotic therapy (3 months)

Healthy but has had previous antibiotic therapy

Comorbidities present (COPD, CHF, diabetes, etc)

Improving Patient Care: Reducing Antimicrobial Resistance in Respiratory Infections

IDSA CAP Guidelines: 2003 Inpatient

Improving Patient Care: Reducing Antimicrobial Resistance in Respiratory Infections

IDSA CAP Guidelines: 2003 Inpatient

ICU low risk of P. aeruginosa infection No beta-lactam allergy