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1Improving Patient Care: Reducing Antimicrobial Resistance in Respiratory Infections

Improving Patient Care:Reducing AntimicrobialResistance in Respiratory

InfectionsPresentations from a symposium held inChicago, Illinois on Friday, April 29 duringthe 2005 Annual Meeting of the Society of Hospital Medicine Medicine

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




Continuing MedicalEducation

Office of Continuing Medical Education

Madison, Wisconsin

Danielle R. Hanson

University of Wisconsin Medical School

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




Disclosures Dr. Alpesh Amin has received honoraria for speaking from

Ortho-McNeil Pharmaceutical.

Dr. Sanjay Sethi has received grants/research support fromBayer, GlaxoSmithKline, and Pfizer; is a consultant for Abbott,Bayer, Boehringer Ingelheim, GlaxoSmithKline, Pfizer, andSanofi-Aventis; and has received honoraria for speaking fromAbbott, AstraZeneca, Bayer, Boehringer Ingelheim,GlaxoSmithKline, Ortho-McNeil, Pfizer, and Sanofi-Aventis.

Dr. Richard Quintiliani has received honoraria for speakingfrom Ortho-McNeil Pharmaceutical.

Dr. Andrew W. Urban has received grants/research supportfrom Agouron/Pfizer and Amgen, honoraria for speaking fromAbbott and GlaxoSmithKline, and an honorarium for reviewingthis program’s scientific materials.

The University of Wisconsin Medical School and DesignWritehave received a grant from Ortho-McNeil Pharmaceutical toorganize this program.

I would like to take this opportunity on behalf of the University of Wisconsin Medical School and DesignWrite to thankOrtho-McNeil for the educational grant that has allowed us to do this program. In compliance with the ACCME, youwill 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 thissymposium and would appreciate you completing the form and returning it to a staff member at the conclusion of thesymposia.




Learning ObjectivesBy 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 pneumoniapatterns of resistance and treatment

Describe the effect of drug resistance onoutcomes related to nosocomialpneumonia

This program is accredited for 2 category 1 credits toward the AMA Physician’s Recognition Award. Each physicianshould claim only those credits that he or she actually spent in this educational activity. The objectives for thisprogram can be found in your handout materials and also on the screen above.




Welcome and Introductions Alpesh Amin, MD, MBA, FACP

Associate Professor of MedicineExecutive Director, Hospitalist ProgramVice Chair for Clinical Affairs, Department of MedicineUniversity of California, Irvine School of MedicineIrvine, California

I would now like to take this time to introduce our Chairman, Dr. Apesh Amin. Dr. Amin is the Associate ClinicalProfessor at the Department of Medicine at the University of California at Irvine. He is also Executive Director at theHospitalist 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. How’s that? Yes? Okay, good. Well thank youeverybody for coming on a Friday night in Chicago with the weather as good as it is after a long day at the annualmeeting. I hope you’ve enjoyed the meeting so far. I know it’s been – I’ve heard very good feedback about it. So Ihope it’s going well for you all.

I’d like to also welcome you this evening. We’ve got two other wonderful faculty that are going to be joining me. I’d liketo say just a couple of words though. The way our program is going to be tonight is, I’m going to start off with a brief talk and then go into a small Q and A for a couple of minutes and then Dr. Sethi will come up and he’ll do his talk andhave a Q and A and then Dr. Quintiliani will do the same thing.




Program FacultySanjay Sethi, MD

State University of New York at BuffaloBuffalo, New York

Richard Quintil iani, MD, FACP

University of Connecticut School of MedicineFarmington, 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 SleepMedicine at the State University of New York at the Buffalo School of Medicine. He serves as an attending physicianin the Division of Pulmonary and Critical Care and has submitted numerous articles, which you can see in your facultybiographies there.

Dr. Richard Quintiliani is Professor of Medicine and Pharmacology at the University of Connecticut School of Medicinein Connecticut. He is a Senior Consultant in Antibiotic Research Usage of Pharmacoeconomics at Hartford Hospitalwhere again he has submitted over 450 articles and is very well published. You can take a look at the information inthe packet.




Program AgendaWelcome and Introductions Alpesh Amin, MD,

MBA, FACP

Managing Community-Acquired

Pneumonia While Avoiding

Resistance Risks

Alpesh Amin, MD,

MBA, FACP

Questions & Answers Faculty

Acute Exacerbat ion of Chronic

Bronchitis: Strategies for ReducingDrug Resistance

Sanjay Sethi, MD


Ant imicrobial Resistance:

Implication for Nosocomial

Pneumonia Patients

Richard Quintiliani,

MD, FACP


So this is going to be our program for today and without further ado, I’m going to go ahead and get started in talking alittle bit about community-acquired pneumonia while avoiding resistance risk. As you can see, we’re going to start withpneumonia and we’re going to talk a little bit about bronchitis and then about nosocomial pneumonia, all of which areobviously important for the hospitalist’s world.




Managing Community-Acquired Pneumonia WhileAvoiding Resistance Risks

Alpesh Amin, MD, MBA, FACPAssociate Professor of MedicineExecutive Director, Hospitalist ProgramVice Chair for Clinical Affairs, Department of MedicineUniversity of California, Irvine School of MedicineIrvine, California




Community-AcquiredPneumonia (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 patientsrequiring hospitalization

Mortality approaches 40% in patientsrequiring the ICU

Amer ican Thoracic Society. Am J Respir Cri t 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 youas background, there’s about 6 million cases of pneumonia a year, of which 1 million tend to get into the hospital. Andthe mortality range is less than 1% to 5% on the outpatient side, but once they’re in the hospital it goes up to about12%, and once they get to the ICU the rate of mortality jumps up tremendously, to 30% or 40%.




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

Amer ican Thoracic Society. Am J Respir Crit Care Med. 2001;163:1730-54; Vital Statistics Mortality Data, National Center

for Health Statisti cs, Centers for Disease Control and Prevention ; Niederman MS, et al. Clin Ther . 1998;20:820-37.

It’s the sixth leading cause of death in the United States and the number one cause of death from an infectiousetiology in the United States, so it’s a significant cause of mortality amongst our inpatient population. 75% of thesepatients are actually treated as an outpatient, but when you look at the cost of the illness, the cost is on the order of 8billion dollars, of which about 5 billion of that comes from patients above age 65. And we all know that patients abovethe age of 65 are a growing population that come into the hospital setting.




Algorithm For Prediction Model

Fine MJ, et al. N Engl J Med. 1997;336:243-50.

NO

NO

NO

YES

YES

YES

PATIENT WITH CAPPATIENT WITH CAP

OVER 50 YEARS OF AGE?OVER 50 YEARS OF AGE?

ASSIGN PATIENT TO RISK CLASS 1 ASSIGN PATIENT TO RISK CLASS 1

ASSIGN PATIENT TO ASSIGN PATIENT TO

RISK CLASS IIRISK CLASS II--VV

BASED ONBASED ON

PREDICTION MODELPREDICTION MODEL

SCORING SYSTEMSCORING SYSTEM

HISTORY OF ANY OF THESE COMORBID CONDITIONS?HISTORY OF ANY OF THESE COMORBID CONDITIONS?

•• Neoplastic diseaseNeoplastic disease•• Congestive heart failureCongestive heart failure•• Cerebrovascular diseaseCerebrovascular disease

•• Renal diseaseRenal disease•• Liver diseaseLiver disease

ANY OF THESE ABNORMALITIES ON EXAMINATION? ANY OF THESE ABNORMALITIES ON EXAMINATION?

•• Al tered mental status Al tered mental status•• PulsePulse ≥≥125/min125/min•• Respiratory rateRespiratory rate ≥≥30/min30/min

•• Systoli c BP <90 mmHgSystolic BP <90 mmHg•• Temperature <35Temperature <35°°CC

or or ≥≥4040°°CC

Now as hospitalists, I think it’s really important that we take a step back and think about risk stratification of patients.We’re going to be asked more and more and as we work with our emergency medicine colleagues and our primarycare doctors, we should be thinking about risk stratification processes. We had a group of hospitalists that gottogether about a year and a half or two years ago and one of the things we found was that patients sometimes werebeing inappropriately admitted to the floor when they should have possibly been in the ICU and vice versa. So I’mgoing to just give a – even though the literature is kind of loose in this regard, I’m going to give you some thoughts tothink about in terms of risk stratifying your patient.

The first is, Dr. Fine published in the New England J ournal of Medicine a prediction model based on the PSI score, orFine’s criteria, also called the PORT score. What he basically suggested was that for patients over the age of 50years, if they were younger than 50 but they had no comorbid conditions, they had no physical examination findingabnormalities, 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 therewas 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 thesefindings, they were given a certain number of points. What he came up with is, when he added up the points, he wasable 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 aclass.




Pneumonia PORT Risk Class:Mortality and ManagementPredicted Decision to

Risk Class Points Mortality Hospitalize

I NA 0.1% No

II ≤70 0.6% No

III 71-90 2.8% Yes/No

IV 91-130 8.2% Yes

V >130 29.2% Yes

PORT = Pneumonia Patient Outcomes Research Team cohor t 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 beadmitted to the hospital but what he was able to show us is that patients that had a risk classification of 2, say – theirmortality was 0.6%. So if they had a risk classification of 1 or 2, their mortality rate was less than 1% so he made theconclusion – again, not a studied conclusion – but made the conclusion that patients could be managed as anoutpatient 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 uptremendously. 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.




Outpatient Care vs Hospitalizationin 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 orallevofloxacin

Primary endpoint: % of patients with an overallsuccessful outcome at end of treatment* ● Secondary endpoints included patient quality of life

and satisfaction*According to 7 predefined criteria. PSI = Pneumonia Severity Index.

Carratalá 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 waspublished in 2005 whose goal was to say “okay, could I decide whether patients using these criteria should beoutpatient or inpatient management based on – and how should I treat them?” And one of the things – and so thisstudy looked at determining using the PSI score that Dr. Fine came up with and looking at low-risk patients. Thequestion was, do I need to put them in the hospital on IV antibiotics and then switch them over to orals, or could I justtreat them with oral antibiotic and get the same outcome? Now you and I both know that today many hospitals arerunning with capacity issues. We’re running with capacity issues. We have a 95% fill rate right now in our hospital, sorisk stratifying and identifying patients that can be safely treated and appropriately treated is going to be more andmore important for us as hospitalists.

Well what this study did was – it was an unblinded study, randomized and controlled – it looked at about 224 patientsthat were put into class 2 and 3 based on Dr. Fine’s 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 successoutcomes 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.




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 andhospitalization groups

Carratalá 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 weresuccessfully managed as outpatients and 81% that were successfully managed in the hospitalized setting and thatmore patients were satisfied with being managed at home, and could be safely managed at home, and that theirquality of life in terms of adverse drug reactions, medical complications, subsequent hospital admissions, and overallmortality were similar to the hospitalized group versus the outpatient group.




Dependence in Activities of Daily Living

(ADL) Is a Risk Factor for Mortality in NHAP

JAMA

No. of ADL Dependencies

N = 1044

0

5

10

15

20

25

0-3 8-11 12-15 16

Mehr DR, et al. . 2001;286:2427-36.

% M o r t a l i t y

NHAP = nursing home–acquired pneumonia.

4-7

There are other things that have been published in the literature that have looked at potential ways of risk stratifyingyour patients to determine whether these patients should be admitted to the hospital or whether they are evenseverely sick or not, like activities of daily living. There was an article published in J AMA 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 startedgoing up.




CAP: Effect of Pulse and Respiratory

Rate on Mortality in NHAPRapid pulse rate predicts mortality

● Pulse ≥100/min was related to 23.1%30-day mortality (RR 1.91 [95% CI 1.48-2.45])

Rapid respiratory rate predicts mortality

● Respiratory rate ≥30/min was related to21.2% 30-day mortality (RR 1.72 [1.33-2.21])

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 wasa study that looked at patients with a pulse rate of greater than 100, they had a 23% 30-day mortality rate, whereaswhen they had a respiratory rate of greater than 30, they had a 21% 30-day mortality rate. So I’m not saying thatthese are all really good studies. There haven’t been any great studies that try to risk stratify your patients, but whenyou’re a busy hospitalist looking at a patient that the emergency medicine doctor has called you on, hopefully you’llthink about these things as you are thinking about where these patients should be placed and how they should bemanaged.




“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 criteriaNeill 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 versussevere CAP patients and come up with some risks for mortality, and what they found was that respiratory rates above30, diastolic blood pressures below 60, and BUNs of above 19 showed an increased risk of mortality, if you had twoout of the three findings. And then if you had a fourth criteria of confusion, it increased your risk of mortality by two tofour times.




Etiology of CAP: Most Common Causes1 Ambulatory Patients Hospitalized (Non-ICU)2 Severe (ICU)2

S. pneumoniae S. pneumoniae S. pneumoniae

M. pneumoniae M. pneumoniae Legionella species

H. inf luenzae C. pneumoniae H. inf luenzae

C. pneumoniae bacilli H. inf luenzae Gram-negative

S. aureus

Viruses Legionella species

Aspiration

1Based on collective data from recent studies.2Excluding Pneumocystis species.

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

But let’s jump into – so that’s a little bit about risk stratification. Let’s jump into the most common causes of community-acquired pneumonia. We know from Dr. File and many other people who have looked at the commoncauses. Strep pneumonia still continues to be our number one cause of community-acquired pneumonia, making upabout 60% of the patients. And as you can see in ambulatory setting atypicals are common, like Mycoplasma andChlamydia. 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 theyget into the ICU setting you want to start thinking more about gram-negative and Pseudomonas and make sure thatyou’re covering for those appropriately.




Chlamydia Co-infection ProlongsLength of Stay (LOS) in CAP

N = 125

8.4 10.5

21.9

0

5

10

15

20

25

C. pneumoniae S. pneumoniae Both

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

H o s p i t a l L O S ( d a y s )

This is a little bit of older data that was published inThorax – you know, the whole concept of covering for atypicals. Ithink from a hospitalist’s standpoint, I know that we don’t have length of stay this high usually anymore in the hospitalsetting, but you can see the patients that were treated. [For those] that had Chlamydia pneumonia, length of stays inthis study were in the order of 8 days, but if they had Strep pneumonia, they were on the order of 10 days. But thecombination of the two really increased the morbidity in patients and the risk for mortality in patients as they stayed inthe hospital longer.




Guidelines for CAP Management:The ATS Algorithm of 2001

Outpatient therapyOutpatient therapy Inpatient therapyInpatient therapy

NoNo

C/PC/P

diseasedisease

NoNoYesYes

History of History of

C/PC/P

diseasedisease

No modifiersNo modifiers +/+/-- modifiersmodifiers

Risk for Risk for

PseudomonasPseudomonas

No C/PNo C/P

disease,disease,

nono

modifier modifier

+ C/P+ C/P

disease,disease,

+/or +/or

modifier modifier C/P = cardiopulmonary

Amer ican Thoracic Society.

Am J Respir Cri t Care Med. 2001;163:1730-54.

CAP is presentCAP is present

Mild toMild to

moderatemoderate

illnessillness

Severe CAPSevere CAP

So appropriate coverage for atypical and typical organisms in the management of community-acquired pneumonia isextremely important.

So guidelines that are out there – there are various guidelines that are available. American Thoracic Society haspublished its guidelines, the latest one in 2001. IDSA has published its guidelines, the latest one in 2003. And thereare differences in the guidelines but the concepts are somewhat – are there. If you have community-acquiredpneumonia, for example, ATS basically says take a look at whether you’re thinking about outpatient therapy versusinpatient when you’re thinking about your risk stratification model, and then if they have outpatient therapy, do theyhave any cardiopulmonary disease or not? And do they have any disease modifiers or do they have a risk for drug-resistantStrep 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 you’re dealing with severe CAP, you want to think about the risk for Pseudomonas because they may impact the typeof therapy and whether you need double coverage or not. You also want to kind of think about if they have underlyingcardiopulmonary disease or disease modifiers.




ATS 2001 Recommendations for CAP

OutpatientOutpatient

C/P = cardiopulmonary; PSA = + Pseudomonas; 3GC = third-

generation cephalosporin ; DRSP/GN = drug-resistant S.

pneumoniae/gram negative bacilli; AP = anti-Pseudomonal,

AMG = aminoglycoside; FQ = fluoroquinolone Amer ican Thoracic Society.

Am J Respir Cri t Care Med. 2001;163:1730-54.

CAP is presentCAP is present

No C/PNo C/P

disease,disease,

no modifiersno modifiers

History of C/PHistory of C/P

disease and/or disease and/or

modifiersmodifiers

Beta-lactam OP: cefpodoxime, cefuroxime, amoxicillin1 gm TID, amoxicillin/clavulanate, ceftriaxone

Beta-lactam IP: cefotaxime, ceftriaxone,ampicillin/sulbactam, hi -dose ampicillin

Beta-lactam ICU, non-PSA: cefotaxime, ceftriaxoneBeta-lactam ICU, + PSA: cefepime, imipenem-cilastatin/

meropenem, piperacillin/tazobactam

InpatientInpatient

No C/P or DRSP/GN risk :No C/P or DRSP/GN risk:

IV azithromyci n or IV betaIV azithromyc in or IV beta-lactam + doxycyclinelactam + doxycycline(macrolide(macrolide--allergic) or allergic) or

IV fluoroquinolone aloneIV fluoroquinolone alone

WARDWARD

(mild(mild--moderatemoderate

hospitalized)hospitalized)ICUICU

No risk of No risk of PseudomonasPseudomonas::IV 3GC + IV azithromycinIV 3GC + IV azithromycin

or IV fluoroquinoloneor IV fluoroquinolone

+ C/P or DRSP/GN risk:+ C/P or DRSP/GN risk:IV betaIV beta--lactam + IV/POlactam + IV/PO

macrolide/doxycycline or macrolide/doxycycline or fluoroquinolone alonefluoroquinolone alone

++ PseudomonasPseudomonas::IV AP + IVIV AP + IV ciprocipro or IV AP +or IV AP +IV AMG + IV azithromycinIV AMG + IV azithromycin

or IV FQ (notor IV FQ (not ciprocipro))

Clarithromycin or Clarithromycin or

azithromycinazithromycin

(doxycycline as(doxycycline as

alternate only)alternate only)

BetaBeta

--lactam +lactam +

macrolide/doxycyclinemacrolide/doxycyclineor fluoroquinoloneor fluoroquinolone

alonealone

So this is what ATS – and I know most of you probably already know this but just as a quick reminder. ATS basicallyhas recommended if they have no – if they’re outpatient and they have no cardiopulmonary disease or modifiers, therecommendation was to consider clarithromycin or azithromycin or consider – and then doxycycline was offered as adistant alternative. When you’ve got patients who have had underlying cardiopulmonary disease and/or diseasemodifiers, 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 atdrug-resistant organisms, at drug-resistantStrep 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 analcoholic, or has been on immunosuppressants, or has been treated with an antibiotic in the past 30 days, or has afamily 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 thenappropriately double-cover patients for Pseudomonas.




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-doseamoxicillin/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/clavulanateMandell LA, et al; IDSA. Clin Infect Dis. 2003;37:1405-33.

Now certainly also the other thing I think that’s important that you need to remember is that the IDSA guidelines havecome out, with this guideline in 2003, and they’ve focused on some other things. For example, again, healthy, noprevious antibiotic – you could see a macrolide or doxycycline. If they’re healthy but they’ve had previous antibiotics,the real recommendation in the past 3 months is considered – what they haven’t been on because of the risk of resistance – so you can either do a respiratory fluoroquinolone or combination therapy. If they have comorbidities butthey haven’t been on antibiotics, you could see what the recommendations are there in terms of macrolides andrespiratory fluoroquinolones. But if they’ve had antibiotics in the past 3 months, again use either respiratoryfluoroquinolones or the combination therapy, but use the opposite [combination] is what the recommendation is. Thinkabout at-risk for aspiration because you’ll have to cover for atypical organisms.




IDSA CAP Guidelines: 2003 Inpatient Medical Ward – no recent antibiotics (3 months)

● Respiratory fluoroquinolone or

● Advanced macrolide plus beta-lactam

Medical Ward – recent antibiotic therapy (3 months)● Respiratory fluoroquinolone or

● Advanced macrolide plus beta-lactam

● Regimen selected depends on nature of recent antibiotic therapy

Mandell LA, et al; IDSA. Clin Infect Dis. 2003;37:1405-33.

When they get into the medical ward, again the question about whether they’ve been on antibiotics for the past 3months needs to be asked because you’ll use the other combination. And then again when they get into the hospitalsetting.




IDSA CAP Guidelines: 2003 Inpatient ICU – low risk of P. aeruginosa infection

● No beta-lactam allergy

─ Beta-lactam plus either an advanced macrolideor a respiratory fluoroquinolone

● Beta-lactam allergy

─ Respiratory fluoroquinolone with or w/outclindamycin

ICU – P. aeruginosa is an issue ● No beta-lactam allergy

─ Anti-Pseudomonal agent plus ciprofloxacin

─ Anti-Pseudomonal agent plus an aminoglycosideplus a respiratory fluoroquinolone or a macrolide

● Beta-lactam allergy

─ Aztreonam plus a respiratory fluoroquinolonewith or w/out an aminoglycoside

Mandell LA, et al; IDSA. Clin Infect Dis. 2003;37:1405-33.

In the ICU, the risk for Pseudomonas is raised again, and then whether they have beta-lactam allergies or not in yourchoice of antibiotics appropriately.




JCAHO & CMS: 2004 Pneumonia

Antibiotic Consensus RecommendationNon-ICU Patient ICU Patient Pseudomonal Risk*

Beta-lactam (IV or IM) +macrolide (IV or oral)

Beta-lactam (IV) +macrolide (IV)

In addition to antibioti cs 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 OR These antibio tics would also be cons ideredacceptable:

Quinolone mono therapy(IV or oral)

Beta-lactam (IV) +quinolone (IV)

IV anti-Pseudomonal beta-lactam +IV anti-Pseudomonal quinolone

OR OR OR

Beta-lactam (IV or IM) +doxycycline (IV or oral)

If documented betalactam allergy:quinolone IV +clindamycin (IV)

IV anti-Pseudomonal beta-lactam +IV aminoglycoside +IV antipneumococcal quinolone or IV macrolide

OR OR

Quinolone (IV) +vancomycin (IV)

If documented beta-lactam allergy: Aztreonam + aminoglycoside +antipneumococcal quino lone

http://www.jcaho.org

The interesting thing is that it is not only ATS and IDSA that’s coming up with guidelines. If you look at it, in the past10 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 werepublishing guidelines. Now look at what you’re seeing: J oint Commission and CMS – as was mentioned earlier thismorning in terms of pay-for-performance coming into play and measurements of quality – so this is on the J ointCommission website, their guidelines, and they’re going to make choices and based on what professional societiesand literature comes up with. The payers and the regulatory agencies and the accrediting bodies are starting to comeup with guidelines, and asking us, and they are going to tie payment structures to it based on quality measures and soforth. So I think as hospitalists this is going to be in our area. Nobody is going to be really focusing on this and I thinkwe need to be aware of it.




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 yourantibiotic therapy within 4 hours. So I think you’ve seen in that last study that we’re 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 comeinto the ER, take 2 hours to get evaluated because of wait time, and that you have 4 more hours after that – it’s goingto be that these patients are going to need their antibiotics within 4 hours. The quality measures that we are going toneed 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 wecan 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 abilityto do early switch of antibiotics from oral to IV. There’ve been studies in the literature that have shown that [it] reducescost and shortens length of stay. Switch therapy allows for defervescence and should occur when patients are

potentially defervescing, but you don’t have to wait for the fever to resolve if they’re clinically improving, their GI tract isfunctioning, they are able to tolerate orals, and they’re oxygenating well. There have been studies that have shownthat by doing this you can save patients a number of days on IV therapy. You can do safe and early discharge. And Ithink the latest guidelines are going to focus on switch therapy more and more.




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 strategiesmay significantly and safely reduce mean

LOS when recommended LOS is shorter thanactual LOS

IV to PO switch therapy works: patients getout 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 youcould even reduce your length of stay by 3 or 4 days based on doing appropriate switch therapy.



Improving Patient Care: Reducing Antimicrobial Resistance in Respiratory Infections 29

Clinical EfficacyStudies

Before I get into the clinical efficacy studies, I’m going to throw out [something]. My job here today is to raise somequestions more than anything else, and one of the problems, and you’ll see at the end of the talk some slides onresistance issues that we’re dealing with because there is a fair amount of resistance in the United States that’soccurring. Bactrim, sulfa drugs have a resistance on the order of about 30% right now. Macrolides around the countryare 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 we’re alreadydealing with. We’re talking about in some areas there’s MRSA resistance. Up to as high as 50% in some institutions.So in just 70 years, we’ve come this far in terms of our resistance. Well, what’s the next 70 years look like or the 70years after that look like? What kind of treatment are we going to have and how resistant are antibiotics going to be?So I’m wondering whether there are other ways and modalities of treating patients that would help deal with the

concept of resistance.




Short-Course Therapy for CAP:Role of Fluoroquinolones High cure rates possible with short-course

therapy with a potent, rapidly actingantibacterial agent

Pharmacodynamic principles and efficacy

● Maximize concentration-dependent killing

● Increased AUC and C valuesmax

● Rapid bacterial killing

● Decreased adaptive resistance

Safety considerations of high-dose quinolonetherapy

Dunbar LM, et al. Clin Infect Dis. 2003;37:752-60.

And you’re going to see me show some studies here to try to at least raise that question. I’m not sure I have theanswer today because, still, good head-to-head studies need to be done in this regard, but we do have betterantibiotics today. We have antibiotics that have 80%, 90%, 100% bioavailability, when the first sulfa drugs or the firstpenicillins 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 – there’s no head-to-head good studies that show that patients should be treatedthat long necessarily.

We also know that there’s 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 haveoverusage of antibiotics. Resistance occurs if patients take antibiotics and get off of them before the organism iseradicated. So the question of whether the concept of short-course might be an appropriate thing for us to think aboutas 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 you’re using an antibiotic that had 40% or 50% bioavailability versus an antibiotic that has 80 or 90% bioavailability inthe appropriate patient, maybe you don’t need patients to be on them quite as long. We know that there have beenstudies 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 haspublished a fair number of literatures on that. So the question is – if it can be done in the sicker patient, can it be donein the less sicker patients or what kind of patients can we consider doing it? Well, the concept of short-course, if youwere going to try to design an antibiotic that could fit these principals, you’d be looking to maximize concentration-dependent killing, increasing your area under the curve, hopefully getting rapid bactericidal killing. And the question is,can you do this?




Levofloxacin Short-CourseTherapy for CAP Multicenter, randomized, double-blind, non-

inferiority study

Comparison of 500 mg levofloxacin QD x 10days 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 forat least 24 hours


Well, here was a study that Dr. Dunbar had published. Now there is a problem with this study – they made two changesat the same time during the study – but it still gives us a hint into the concept. It was a multi-center randomized studythat 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 it’s 5000 mg versus 3750 so there’s less total amount of antibiotics that’s used if you follow thisrationale.




0

20

40

60

80

100

92.4n=198

91.1n=192

93.2n=103

92.4n=92

)

CAP: Clinical and Microbiologic Results

Clinical Success* Microbiologic Eradication

750 mg

500 mg

% o f P a t i e n t s

(Clinically evaluable population (Microbiologically

evaluable population)

Levofloxacin Short-Course Therapy for

*Clinical success includes cured and improved.


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.




Levofloxacin Short-Course

Therapy for CAP: SafetyNo. (%) of Patients

750 mg 500 mg

(N=256) (N=265) 95% CI

≥1 treatment-emergent* AE 148 (57.8) 158 (59.6) (-6.8, 10.5)

≥1 treatment-related† AE 18 (7.0) 15 (5.7)

≥1 serious‡ AE 25 (9.8) 37 (14.0)

Discontinuation due to AE 18 (7.0) 22 (8.3)

Deaths§ 5 (1.9) 9 (3.4)

*Any adverse event that was new in onset or increased in intensity or frequency during the study period.† Any tr eatment-em ergent adverse even t assessed b y in vest igator as p robably o r ver y li kely related t o st udy drug.‡ Any tr eatment-emergent ad verse event that was fatal , immediately li fe-th reaten ing, req ui red o r prolonged inpatient

hospitalization, caused permanent or significant disability, was a congenital anomaly, or was deemed medically important.§ Any death t hat occur red f rom study ent ry to the post - study vi si t is inc luded.


And when she looked at adverse events, the adverse events were less in the 750 group compared to the 500 groupand the number of deaths were also less in those groups.




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 perday 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 = .03Schrag SJ, et al. JAMA. 2001;286:49-56. PRSP = penicillin-resistant S. pneumoniae

There’ve been studies looking at short courses of amoxicillin also for community-acquired pneumonia patients to dealwith resistant pneumococcal carriage analysis, and this also showed in penicillin-resistantStrep pneumonia thatpotentially short-course therapy as compared to standard course might actually show some beneficial outcomes.Again, higher doses but shorter courses.




Azithromycin vs ClarithromycinShort-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 wereeradicated, compared with 91% (32/35) isolated fromclarithromycin group

Incidences of treatment-related adverse events were similar for thetwo groups (P =0.815)

O’Doherty 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 theoutcomes are also comparable in both groups. Again, the concept of short-course raised again.




0

20

40

60

80

100

89.3n=159

88.8n=161

91.8n=146

95.8 96.7

88.5

Telithromycin vs ClarithromycinShort-Course Therapy for CAP

Tellier G, et al.

Clinical Cure Rates Bacteriological eradication rates

for S. pneumoniae

5-day telithromycin 7-day telithromycin 10-day clarithromycin

% o f

P a t i e n t s

23/24 29/30

23/26

J Anti microb 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 it’sgotten the recommendation for sinusitis and bronchitis for 5-day therapy for telithromycin compared to 7-10 daytherapy for pneumonia.




S. pneumoniae Resistance* to Penicillin

and Macrolides, USA 1992–1998

(n=125) (n=149)(n=124)(n=79)(n=81)(n=147)(n=185)

µg/mL.

0

10

20

30

40

50

1992 1993 1994 1996 1997 1998

PenI

PenR

*Resistance defined as erythromycin MIC >1

% o

f I s o l a t e s

Felmingham D, Washington J. J Chemother . 1999;11(suppl 1):5-21; Felmingham D, Gruneberg RN.

J Antimicrob Chemother . 2000;45:191-203.

1995

EryR

I raised this question today only because look at what’s happening to the resistance of Strep pneumonia to penicillinand macrolide. You can see it continuously. It’s been on the rise for the last decade or so.




S. pneumoniae Resistance Rates for Selected Agents, 1999–2000*

Antimicrobial % Resistance

Macrolides 25.9

Clindamycin 8.8

Tetracycline 16.4

Chloramphenicol 8.4

Trimethoprim/sulfamethoxazole 30.3

Fluoroquinolones 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 I’ve mentioned before, macrolides have a resistance of almost 20%-30% and Bactrim to 30%.




Antimicrobial Resistance Trend: S. pneumoniae, USA, 2002-2003

Antimicrobial Agent,% Resistant

TRUST 6(2002)

TRUST 7(2003)

Penicillin* 18.4 17.3

Azithromycin 27.5 27.5

Trimeth/sulfa 26.0 24.0

Ceftriaxone (nonmeningitis) 1.7 1.5Levofloxacin 0.9 0.9

No. of institutions 239 227

No. of isolates 7671 4456

Levofloxacin MIC90 (µg/ml) 1.0 1.0

*Penicill in-resistant = MIC >2µg/ml; NCCLS broth mic rodilu tion – 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 seeagain there, penicillins are shown to be in the order of 18% or so. Still we’re lucky with some of the fluoroquinolonesthat have resistances of less than 1%. Again, look at Bactrim, you’re on the order of 24% and 26%. Othercomparative industry-sponsored studies are showing the same results. In fact, the PROTECT study had shown thatthe resistance in the Far East may be as high as 60% or 70%, in J apan or Korea, to macrolides and penicillin-resistantStrep pneumonia.




S. pneumoniae Antimicrobial Resistance TRUST 7 (2002–2003)S. pneumoniae S. pneumoniae

Penicill in Resistance Azithromycin Resistance(Resis tant, MIC ≥2 µg/mL) (Resis tant, MIC ≥2 µg/mL)

DCDC

≥20% RNational Rate: 12%-19.9% R National Rates:

Penicil lin = 17.3% R Azi thromycin = 27.5% R<12% 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 I’d be very concernedabout. They’ve already shown a greater than 20% resistance. Look at how much of the United States we’re dealingwith for penicillin and azithromycin across the board.




Antimicrobial % Susceptibility:P. aeruginosa , USA, 2002-2003 Antimicrobial Agent, TRUST 6 TRUST 7% Resistant (2002) (2003)

Ceftazidime 79.7 80.6

Cefepime NT 79.5

Gentamicin 76.7 72.3

Pip/Tazo 85.8 87.0Imipenem 81.9 78.8

Ciprofloxacin 67.4 68.8

Levof loxacin 67.7 65.3

Isolates (labs) 998 (36) 882 (36)

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).

Also, antimicrobial susceptibility to Pseudomonas where we don’t have that many great agents that are up in the 90%or 100% efficacy. That’s part of the reason we have to consider double coverage, and more and more we’re startingto worry about resistance issues. In terms of the fluoroquinolones, really the only thing we have are cipro andLevaquin. We have gentamicin and piperacillin but again, nothing there above 90%.




Pay-for-Performance Initiative Hospital Quality Initiative requires hospitals

to report on 17 quality measures

Failure to report performance date willresult in 0.4% reduction in annual paymentfrom CMS

Measures related to pneumonia include:smoking cessation, initial antibiotic within4 hrs of hospital arrival, blood culturebefore first antibiotic, oxygenationassessment

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 leadingcause of death and the most common infectious cause of death in the hospital setting and the numbers that we have –we’re certainly going to be tied to quality and efficiency and performance issues by our employers and by the public.

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 that’s beingthrown around that failure to report performance may result in a 0.4% reduction in payments from CMS. Measuresrelated to pneumonia, as I mentioned earlier in this talk, include smoking cessation, antibiotics within 4 hours, bloodcultures, oxygenation assessment, vaccination – Pneumovax and H. influenza. The top 20% of hospitals may actuallyget a financial bonus for doing the appropriate job and I think that’s going to fall on our shoulders as hospitalists todeal with.




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 effectiveas hospitalization in low-risk patients with CAP, and alsoincreases patient satisfaction

Short-course, higher-dose therapy for CAP offers anumber of potential advantages: rapid eradication of pathogen, increased patient compliance, and reducedresistance rates

● Short-course therapy with levofloxacin,azithromycin, or telithromycin has shown promise

So I’m going to wrap up today by saying that community-acquired pneumonia is relatively common and a seriousrespiratory tract infection that is really being managed by hospitalists on a day-to-day basis with our infectious diseaseand pulmonary colleagues. There is no universal consensus for the treatment of community-acquired pneumonia, butthere are guidelines by ATS and IDSA. They vary a little bit, but the good thing is that both organizations are actuallycoming together and they’ve already produced a combined guideline for hospital acquired-pneumonia, and thecommunity-acquired guideline is suspected to come out soon. Recent data suggests that outpatient care could beeffective 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 beone of the new ways of looking at the management of this common disease state.




Questions & Answers

How many of the pneumonias actuallyare viral? What personally do you feel are the util ity of sputum and blood cultures, in terms of whatwe actually end up doing?

Studies that I’ve seen in terms of viral pneumonias have ranged anywhere from 10% to 30%-40%, in that range.

As far as sputum utility – it’s interesting because I’ll even tell you just a personal experience of my institution. Therewas a strong demand by our infectious disease specialist and chief of infection control during the first time I put out theguidelines on community-acquired pneumonia that they absolutely need to get sputums done. The problem is thatgetting sputums is not always easy because you’ve got to collect it and you’ve got to get it down to the lab. And if thepatient is dehydrated to get the sputum it is more difficult. And the best thing to do is get the sputum, get it down to thelab immediately. If it sits around, you run into problems of getting inappropriate results. Now even though we aredoing it for academic reasons, I think that people are understanding that getting the sputum is not the easiest thing inthe world. Now does that mean that we shouldn’t do it? The answer is no. That doesn’t mean we shouldn’t do it,because it still has a utility. If you see gram-positive cocci on your sputum, you can de-escalate therapy andappropriately 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 tothe sputum, one other comment that I wanted to make in regards to getting the sputum is that there are differences inthe two guidelines. You know, IDSA strongly in the past – I will see what the combined guidelines show – but in thepast, it was highly recommended to get the sputum sample. ATS was kind of equivocal on it.




Questions & Answers

And our hospital didn’t rank as well for the antibiotics. Given that as a hospitalist,I’m called when I can’t do anything aboutthe 4 hours –

Any suggestions?

Yes, you know, the 4-hour issue is actually starting to come into question today. It’s still there and I need to say thatwe need to be pushing that agenda today still, but I think it’s starting to be raised nationally about whether 1) it’spossible, and 2) whether it’s really truly effective, does it really change outcomes. That’s being raised as a question.

In any case, as that’s being discussed on a national scale, what can you do I think is the next question. I think we allwould agree that the very first thing is that we should be giving antibiotics appropriately. This to me is an opportunityfor us as hospitalists to look and to first define the problem in our institution. Why can’t it be done? Work with andtake 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 performanceimprovement process. I think that’s what really the regulatory agencies that are recommending this are trying to getus to try to do. We should try to go about doing that.




Questions & Answers

What about, JACHO has their antibiotics butsince ATS and IDSA can vary, what happensif JACHO picks – oh, you need to do sputumcultures and –

It becomes a pay-for-performance.

Right. And that’s the reason I brought this up today at this talk is because I think we all need to be aware that theremay 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 what’s going to happen is that IDSA and ATScombine and release their guidelines. J ACHO and so forth will use the similar guidelines. This variability inrecommendations needs to be worked through a little bit.




Questions & Answers

… we need to develop therapeutic approacheswith those two background sort of notionsand then observe the effectiveness over time,because if we are trying to apply a nationalapproach in a local scene I think it’s fraughtwith 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 inyour own institution to apply the principles of those but you may have to tweak them and make them apply to yourlocal institution. And certainly, you know, even if you compare my MRSA rate to a hospital 30 minutes away from meis a huge difference, so you’ve got to take all of those factors into account, I agree with you. And that should be yourtake-home message, and I think that’s what you’re seeing us starting to do is really try to give ideas of how toimplement things. The resource rooms that I was telling everybody to look at the Cybernet Café is that whole process.What we’re trying to do is not necessarily give every detail of what should be done but the process of how to go aboutdoing it and the tools that can be used to develop your process.




Questions & AnswersIs it possible to legislate that people shouldwear masks if they are coughing?

I assume it’s possible. I don’t know whether – I think this is maybe something – I could be something that you couldtry to think about at your own local institution and see how to implement it. It’s a tough thing. I think you’re also goingto need to think about this in terms of infection control issues within your setting.

And the other question here was – Is there a role for gene therapy? – I can’t quite read this question. I’ll be in the backfor whoever asked it, you can stop by and see me in the back.

With that, I want to say thank you, and I’d like to invite Dr. Sethi up here to give his talk.




Acute Exacerbation of ChronicBronchitis: Strategies forReducing Drug Resistance

Sanjay Sethi, MD

Associate ProfessorPulmonary, Critical Care and Sleep MedicineUniversity at Buffalo, SUNY

Good evening here and thanks for being here. My job is to discuss acute exacerbations of chronic bronchitis, whichhas been my area of research for the last 10 years or so, and it’s a nice opportunity to talk to a different audience. Alot of what I will present is actually based on outpatient studies. Unfortunately, there is not a lot of data about antibioticuse and exacerbations in the inpatient setting. I think I will try to point out those areas which do relate to inpatientsettings and I’d also like to point out some of the information that we have in that situation.




Confronting the Challenge of Microbial Resistance Bacteria have a remarkable ability to develop

antibiotic resistance

Antibiotic use exerts selective pressure thatfavors proliferation of resistant bacteria

Drug-resistant pathogens are a growingmenace

Resistance is associated with poor outcomesand 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 byDr. Amin also – that microbial resistance has become a problem and has become a challenge, and there are somefacts 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 aremarkable ability to develop antibiotic resistance, as we have learned over the years, and the fact that the majorreason they develop resistance is because of antibiotic use. I mean there is no reason why if a bacterial speciesthat had previously been sensitive would expend its energies to develop resistance unless there is antibioticpressure. So obviously one way to confront the challenge of resistance is to use less antibiotics and to use themappropriately.

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 isactually the best data for community-acquired pneumonia and ventilator-associated pneumonia, but there is alsosome data now on exacerbations that more resistance is associated with more and more increased costs and pooroutcomes in these patients. And so basically we need to do something. We need some timely action. I think in myarea what I will be discussing is how to use antibiotics appropriately. I think that’s one of the best things we can dowhen we treat exacerbations.




Acute Exacerbations of ChronicBronchitis (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, butyou’ll be surprised that every time I meet with a group of COPD specialists we are still discussing what exactly is anexacerbation. I will make some comments about etiology. I think that’s important and that has been my area of interest. We will talk a little bit about resistance and I’ll mention a couple of studies and then discuss thisstratification approach. You saw that for community-acquired pneumonia and that’s becoming advocated for acuteexacerbations, for AECB, also.




COPD

Bronchiectasis Emphysema

Chronic Bronchitis

AECB

Increased sputum volume

Increased sputum purulence

Definition of COPD Ai rf low l imitation/obstruction present

Increased dyspnea

Barnes PJ. N Engl J Med. 2000;343:269-80; Sethi S. Clin Pulm Med. 1999; 6:327-32.

Let’s start with definition and essentially we know that COPD comprises patients with chronic bronchitis and/oremphysema. A fair number of those patients may even have a touch of bronchiectasis, which seems to be now anatural part of the history of the disease, and then they have increased symptoms. I’ll point out these three symptomsup there – dyspnea – an increase in dyspnea, an increase in sputum volume or sputum production, and an increase insputum purulence. Now these are the three classical cardinal symptoms which define a patient with underlying COPDor chronic bronchitis, which make us suspect that the patient has an exacerbation. So that’s the bottom line of thediagnosis. It’s a symptomatic diagnosis and it’s based on change in the baseline symptoms of these patients.




Definition of COPD Exacerbation (AECB)

Duration of 24 hours to 2 weeks

Increased symptoms greater thanday-to-day variation

Exclusion of other causes

● Pneumonia

● Congestive heart failure

● Pulmonary embolism

● OthersSethi S. J Resp Dis. 2002;23:217-25.

But that’s not all to the definition. There are other aspects that we need to pay attention to as physicians and thoseare that, first of all, how long have there been increased symptoms? I mean, patients with COPD and chronicbronchitis are always symptomatic. They always have some extent of dyspnea, cough, and sputum. The questioncomes up, how long have they been having those increased symptoms? Generally, we’d like to define a time periodof at least 24 hours and maybe up to about 2 weeks of increased symptoms. So it’s an acute or subacute illness interms 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 don’t know how many of you do outpatient management of these patients but if you do, you’ll see it all the time: Well, how are you doingtoday? Well, it’s a bad day. Yesterday, I was fine. Today, I’m bad. Tomorrow, I’ll be fine again. So they have thisday-to-day variability in symptoms. So the increase in symptoms to diagnose an exacerbation has to be more thanthe day-to-day variation.

And I think the third important aspect, which is often ignored, is that patients with COPD also have other reasons toget more dyspnea. Many of them have coexistent cardiac disease, they are prone to pneumonia, they may getpulmonary emboli. So if you have somebody whose got underlying COPD or chronic bronchitis and comes in withincreased dyspnea and sputum and has an infiltrate, he’s got a pneumonia so we need to treat the pneumonia. Sothat’s a specific cause of the increased symptoms. The exclusion of those causes – you know, the patient who doesn’thave the pneumonia, doesn’t have the congestive heart failure – has a real pure exacerbation. I think that’s the kindof patients that we should be focusing on and we’ll be discussing in the subsequent few slides.




AECB Perception vs Reality

Perception Reality

A nuisance Contributes toproblem with

● Cost of health care

no serious ● Poor quality of lifeconsequences

● Mortality

● Progression of lung disease

But let’s talk about – before I kind of – so, that was more of the definition issue. So let’s move on to – before I reallyget into etiology, I just wanted to point out that I’m sure that most of us, and even now in medical schools, that manytimes there is the perception that is taught to us that exacerbations are a nuisance problem. You know, the patientcomes in, feels slightly worse, or much worse, you give him medications to get better, and really it’s more for like achest cold or a nuisance problem. Well that perception has changed dramatically in the last 10 years.

There is a lot of data, and I’ll 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 youhospitalized somebody with stable COPD? You don’t hospitalize stable COPD; you hospitalize patients withexacerbations. And hospitalization is a big part of the cost of taking care of any disease. There is also good data thatexacerbations are actually a major determinate of their loss of quality of life over time in these patients. It’s the mostcommon cause of respiratory mortality in these patients. And again, contrary to what we were taught, I’m 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 weneed to be more serious about exacerbations.




Outcome After Exacerbations

24

30

41

47

59

0

10

20

30

40

50

60

stay, all pts

90 days 180 days 1 year

( % )

JAMA. 1995;274:1852-7.

Hospital

(n = 362)

Hospital

stay, pts >65

yrs (n = 167)

M

o r t a l i t y

Time After Hospitalization

(pts >65 years)

Seneff MG, et al

In fact, if you look at outcomes – so this is a study which was done in ICU – these are all patients with exacerbationswithout pneumonia, without congestive heart failure, patients hospitalized for exacerbations in the ICU, and they wereable to look at their mortality over time. It’s a multi-center study by Seneff, and what they found was that for thehospital stay there was about a 24% mortality in these patients. And then the patients who were more than 65 yearsof age, they could get the data down the road because they were all Medicare patients.

As you can see, there’s progressive mortality in these patients. So at one year, it’s almost at 50%. So that’s worsethan a lot of malignancies and other problems, so exacerbations have serious consequences.




Outcome of AECBIn ICU Patients

Hospital mortality: 24%

In Hospitalized Patients

Hospital mortality: 6%-12%

In ER Patients Relapse (repeat ER visit): 22%-32%

In Outpatients

Treatment failure rate: 13%-33%

Seneff MG, et al JAMA. 1995;274:1852-7; Murata GH, et al. Ann Emerg Med .1991;20:125-9;

Adams SG, et al. Chest. 2000;117:1345-52.

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




Pneumonia

S. Harris.

AECB

Cartoon - Pneumonias

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




Treatment of AECB Medical therapy

● Bronchodilators

● ● Antibiotics

● Systemic corticosteroids

Ventilatory support

● Non-invasive ventilation (NIV)

● Invasive ventilation

Oxygen

So let’s get into treatment issues. The approach to treatment, and this applies definitely to inpatients and in mostoutpatients, too, that the treatment of an acute exacerbation of chronic bronchitis or COPD is the multi-modalityapproach. It’s not, we throw a bunch of things at these patients which includes bronchodilators, which we use in allpatients, oxygen – and bronchodilators we’ve always used because there wouldn’t be any randomized controlledtrials. There are no placebo-controlled trials but I guess we’ll never do that. Oxygen and hypoxic patients – again,that’s something we always do and presume it’s of benefit. Antibiotics in the majority of your patients and we’ll discussthat subsequently. Corticosteroids in most hospitalized patients, we should be using them; there are a couple of goodstudies now, showing that corticosteroids compared to placebo are of benefit. Not a huge benefit but at least a 10% or15% improvement over placebo in terms of outcome.

I really don’t want to be discussing corticosteroids but I just wanted to mention a point, that there are now a couple of studies showing that we don’t need the big asthma doses of steroids in these patients. Many times, 40-60mg of

prednisone or equivalent for 7 to 10 days is adequate. Oral or IV, whichever way you want to use it. I don’t haveslides for that because of time limitations but I can discuss that later. What’s new also in terms of the real severepatients – we end up using ventilatory support. What’s new with that is non-invasive ventilation. COPD exacerbationsare very amenable to noninvasive ventilation and a lot of good studies showing that it actually reduces mortality andlength of stay.




Etiology of AECB

Virus

H. inf luenzae

S.

pneumoniaeNoninfectious

H. para

Pseudomonas

Obaji A, Sethi S. Drugs Aging. 2001;18:1-11.

M. catarrhalis

Gram-neg

Chlamydia

So let’s get a focus on the antibiotic issue. And when we focus on the antibiotic issue, of course, the first question thatcomes up is: if there is a need for antibiotics and exacerbations, you know, what’s causing it? Are bacteria reallycausing 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 andHemophilus and Moraxella are three major predominant pathogens in these patients. As you get into more severepatients – 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 about5%-10% of exacerbations, and H. parainfluenza may play a role within the more severely compromised patients. Andyou know that the sudden proportion of exacerbations are noninfectious. Once you get into a real severe COPD, itdoesn’t take much to tip those patients over and it may be environmental factors and things like those.




Evidence for Bacterial Etiologyof AECB

Bacteria can be cultured from the distalairways in significant concentrations in>50% of patients

Acquisition of strains of bacteria newto the patient is associated with agreater than 2-fold increase in the riskof 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 Cri t 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 – I’ve dealt with this issue for the last, um – we have large cohortstudies that we’ve been doing, and I must have treated more than 1000 exacerbations in the last 10 years, and I stilldon’t know in individual patients, is it viral, bacterial, or environmental? It’s very difficult to tell. I will give you somehints and then some studies which help us to some extent, but in most patients we don’t know. And about 50% of exacerbations are bacterial and we use antibiotics in all the patients, we are overtreating. But on the other hand theconsequences of undertreatment are many times worse than overtreatment.

So do we have the spectrum of etiology? We still don’t have good reliable diagnostic tests that can tell in an individualpatient that you are dealing with – you know, what’s the etiology of the exacerbation in that particular patient. Thereare 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 – alot of debate about, do bacteria really cause exacerbations? You know, we isolate the same bacteria from thesepatients when they are stable, what does it mean having bacteria when you isolate that from the sputum in patientswith 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 theexacerbations. If you do studies with bronchoscopy, we can actually culture bacteria from the distal airways insignificant concentrations in about half the patients. And we have done some work to show that it’s not the same strainthat these patients are colonized with which gives them exacerbations, it’s the acquisition of a new strain of apathogen which gives them exacerbations.




Evidence for Bacterial Etiologyof AECB (cont)

Specific immune responses developto infecting bacterial strains followingexacerbation

Neutrophilic airway inflammation isassociated with recovery of bacterialpathogens 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 Cri t 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, andwe have also shown that these patients have much more neutrophilic airway inflammation when they have bacterialversus nonbacterial exacerbations. So I think the whole question of “do bacteria cause exacerbations?” is pretty muchsettled also within the academic community.




S. Harris.

Antibiotic Resistance

So let’s get onto resistance issues. So hopefully, we won’t live to see that day when mutations will reach a point thatwe’ll be putting bacteria in cages, but resistance is a problem. And again, some of it has already been mentioned soI’ll kind of breeze through it. I’ll just focus on the three community-acquired pathogens.




H. Influenzae in Sputum fromPatient with AECB

I’m sure you are all very familiar with Pseudomonas-resistant pathogens and gram-negative resistant pathogens. ButHemophilus influenza – these are all sputum smears from a study with patients with exacerbations, so they are alwaysdifficult to see, and the little red dot is there. I was enjoying the conversation about sputum in the earlier talk; basicallywe have kind of given up on microbiology, which is kind of unfortunate in my opinion – we should be using moremicrobiology – but anyway that’s Hemophilus influenza.




H. influenzae β-Lactamase

Production: US Isolates (n=2,706)Northwest North Central

100

100

80

60

40

20

0

β L+ β L- BLNAR β L+ β L- BLNAR

β β

β β β β

β β

0

0

20

40

60

80

L+ L-

L+ L-

1

0

20

40

60

80

100

0

20

40

60

80

100

L+ L-

0

20

40

60

80

100

L+ L-

0

20

40

60

80

100

NortheastSouthwest

South Central Southeast

www.protektus.org

34.5

65.5

BLNAR

0.9

74.3

24.9

BLNAR

70.3

28.7

68.6

1.2

30.2

BLNAR

0.4

70.9

28.7

BLNAR

0.3

74.5

25.2

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) – that’s the blue bars over here – are beta lactamase producing, andthat means that amoxicillin will not work for these patients.




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 bitabout the pneumococcal resistance. Again, about 20%-25%, up to 35% – depending upon where you are – have whatwe call high-grade penicillin resistance: the one that really matters in respiratory infections.




S. pneumoniae Resistance:

US Isolates (n=10,103)North Central

0

20

40

60

80

100

Penl

0

20

40

60

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100

Penl

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80

100

Penl

0

20

40

60

80

100

Penl

0

20

40

60

80

100

NortheastSouthwest

South Central Southeast

Northwest

www.protektus.org

17.3

33.923.2

PenR MacR

29.327.126.5

PenR MacR

18.1

32.7 38.6

26.4 31.825.4

PenR MacR

26.521.724.6

PenR MacR

40.236.5

27.5

Penl PenR MacR Penl 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.




Changing Resistance Patterns for S. pneumoniae and H. influenzae (1977-2001)

Jacobs MR. Am J Med. 1999;106:19S-25S; Doern GV, et al. Emerg Infect Dis. 1999;5:757-65; Thornsberr y 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. Ant imicrob Agents Chemother . 1998;42:3313-14; Jones ME, et al. IJAA. 1999;19:119-123; Doern GV, et al. Ant imi crob 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.

0

5

10

15

20

25

30

35

40

1 9 7 7

1 9 7 9

1 9 8 1

1 9 8 4

1 9 8 5

1 9 8 9

1 9 9 0

1 9 9 3

1 9 9 5

1 9 9 6

- ‘ 9 7

1 9 9 7

- ‘ 9 8

1 9 9 8

- ‘ 9 9

1 9 9 9

- 2 0 0

0

2 0 0 0

- ’ 0 1

I s o l a t e s ( % )

Year

Penicillin-resistant S. pneumoniae

Macrolide-resistant S. pneumoniae

β-Lactamase + H. influenzae

The problem is that many times the resistances go together. The pneumococcus has learned how to put all theseresistance genes into what they call a transposon so that many times, strains that are resistant to one antibiotic areresistant to the others – and [you have] so-called multi-drug resistance strains. This is an example.




Penicillin-Resistant S. pneumoniae Is

Often Resistant to Other Antimicrobials

0

20

40

60

80

100

ifl f

%

Azi thr omycin Clari thr omycin Cefuroxime TMP/SMX Amo x/clav Gat oxacin Levo loxacin

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 manyof the times resistant to a lot of the other antibiotics at the same time.

So that’s a problem, again – you know, many times because of the lack of microbiology we don’t even know whatwe’re dealing with.




Fluoroquinolone Use and

Pneumococcal Resistance in Canada

Year

0

1

2

3

4

5

1988 1989 1990 1991 1992 1993 1994 1995 1996 1997 19980

1

2

3

4

5

6

≥

Chen DK, et al.

% C

i p r o f l o x a c i n -

R e s i s t a n t P n e u m o c o c c i

P r e s c r i p t i on s

p er 1

0 0

P er s on s

15-64 years

65 years

Quinolone use

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 thembecause otherwise resistance will develop to the quinolones also. This is data from Canada, which shows that overthe 1990s there was a lot of quinolones use, and there still is in Canada. Then with the last period, there was theemergence of quinolone resistance. That’s from 1998. The good news is that it seems to have plateaued out inCanada and in the US also, it’s about a 3%-4% range of pneumococcal resistance to the fluoroquinolones. It’s aboutthe same number in the US and it seems to be plateauing out, which is good, but again, I think we have to be cautiousand circumspect about how we use quinolones in these patients.




M. catarrhalis in Sputum from

Patient with AECB

Moraxella catarrhalis – again, the red dots are there.




Prevalence of Antimicrobial Resistance

in the Community Among Adults

0

20

40

60

80

M. catarrhalis

%

Amox/Clav

TMP/SMX

Am J Med

100

R e s i s t a n t

Penicillin

Macrolide

Tetracycline

Gatifloxacin

Pfaller MA, et al. . 2001;111:4S-12S.

And with that, the major problem again is the beta lactamase production and resistance – and because of that topenicillin and amoxicillin, and there is some emerging resistance to trimethoprim sulfa.




Clinical Relevance of Antimicrobial Resistance Difficulties in demonstrating clinical relevance

● Exclusion criteria in antibiotic comparisontrials

● Observational studies ─

Low-level resistance

─ Use of newer antimicrobial agents● Immune response can cause resolution of

infection over time in spite of ineffectiveantibiotics

● Inadequate diagnostic methods to documentmicrobiologic failures

So that’s about resistance. The question that was again raised by Dr. Amin is, what is the clinical relevance of thisresistance? You know, there is much more in vitro data for resistance than there is in vivo data. Part of the problem isthe kind of studies that are done. If you examine this question on the surface, you’ll say that all these studies seem toshow equivalent efficacy with all the antibiotics, but the problems with the studies – there are several problems withthe studies which could explain that. Many of the studies actually exclude the kind of patients who have resistantstrains. So as we’ll discuss later, the most common cause for the individual patient to have a resistant strain is havingbeen exposed to antibiotics in the previous 3 months. Most of the studies exclude those patients. So many of thetimes, that’s why they don’t pick up resistant strains. Many times, the don’t do good diagnostics to documentmicrobiologic failures. We all have clinical failures when you treat these patients, and I’m sure a portion of those arebecause of resistance, but we never do microbiology so we never know. So I think that’s the kind of problems we havein trying to show clinical relevance.




Antibiotics and Relapse of AECB Retrospective chart analysis

VA Emergency Department charts over 18mos

Relapse defined as patient returning within14 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 mostinteresting of all. This was done in a VA in the emergency department and they looked at patients who got treated forexacerbations and how many of them relapsed in the next 2 weeks and they found that about 22% of them relapsedover the next 2 weeks.




Antibiotics and Relapse of AECB

P < 0.05

Chest

0

10

20

30

40

50

60

(270)

) ( )

(63)

(9)

(20)

Adams SG, et al. . 2000;117:1345-52.

None (92) Antibiotics Amoxici l lin (37 Amox/Clav 59 Macrolides TMP/SMX (82) Cipro Cephalosoprin

R e l a p s e R a t e ,

%

Again, this is just looking at what antibiotics they got. They didn’t have microbiology in these patients, but what wasinteresting was that, yes, the antibiotics decreased the rate of relapse in these patients, so that’s the antibiotics withthe relapse rate of about 19%. Without antibiotics, it was about 30%. Then when they broke down this group intowhat antibiotic was used, the highest relapse rate was the amoxicillin, so it’s kind of interesting I think. What it showsis that when you give an ineffective antibiotic when the patient, you think, needs an antibiotic, you will actually havehigh rates of relapse. So these kind of studies which hint at that resistance is relevant in these patients.




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 HRor RR

Anthonisen NR, et al. Ann In tern Med. 1987:106:196-204.

So let’s look at severity of disease. And as I’ve said there is – again, there is one study which helps us kind of definethe severity of an exacerbation. Again, we don’t have a Fine classification but we have an Anthonisen typing of exacerbations. So let me show you that.

This is a study done by Nick Anthonisen way back in the 1980s. It was a placebo-controlled trial of antibiotics, andthey basically defined the exacerbation by the three symptoms and they classified the exacerbations as type 1, 2, or 3based on the number of symptoms present. So a very simple system. So the patient came in and said, “my breathingis worse, I’m coughing more sputum, and it’s more yellow” – and it’s a type 1 exacerbation. On the other hand, if thepatient came in and said “you know, there’s only al little bit of change in my sputum color and everything else is fineand I have a bit of a cold” – that’s a type 3 exacerbation.




Antibiotics in AECB: Results

P < 0.01

0

10

20

30

40

50

60

70

80

Placebo

Antibiot ic


% S u c c e s s

Type of Exacerbation

Al l Type 1 Type 2 Type 3

So they went ahead and classified. They prospectively classified their exacerbations and, again, this was comparingplacebo versus antibiotics – and what they found was that antibiotics helped, with about 15% difference between thetwo 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 thatsetting, antibiotics don’t seem to make a difference, and also there is a very high rate of spontaneous resolution inthose patients.




Antibiotics in AECB: Results

35P < 0.05

0

5

10

15

20

25

30

Placebo

Antibiot ic

% D e t e r i o r a t i o n

Type of Exacerbation

Al l Type 1 Type 2 Type 3


In fact, it’s more dramatic when you look at failures. As you see over here, there was about an 18% failure rate onplacebo versus about half of that with antibiotics, and again the predominant benefit was in type 1 exacerbations andsome in type 2. So essentially, what this tells us is that the real mild exacerbations – mild symptoms, singlesymptoms – maybe they don’t need antibiotics, but there is a much more substantial benefit with antibiotics in type 2and 3 exacerbations.




Relapse After Outpatient AECB:

A Multivariate Regression Model 268 general practices

2414 patients

Relapse in 507

patients in 1 month(21%)

● ● ●

Eur Respir J

O d d

s R a t i o s

0.0

0.2

0.4

0.6

0.8

1.0

1.2

1.4

1.6

1.8Prospective study

262 (11%) return visit

161 (7%) ER visit

84 (3.5%)hospitalization

Miravit lles M, et al. . 2001;17:928-33.

Dyspnea IHD Visits/yr

How are the patients themselves? How was their underlying disease? Can we predict or can we tell which patientsare not going to do well? There are studies to show that, and this is a study done from Spain, again in the outpatientsetting, looking at a bunch of patients and looking at their relapse rates, and again it was about 21% relapse rate inthose patients.

Again, relapses result in ER visits and hospitalizations, but then they looked at what predicted relapse which causedthe patient to relapse in a multivariate model, and it showed that patients with more underlying severe lung diseasewith comorbid conditions, especially cardiac problems and frequent visits with frequent exacerbations, are the oneswho tend to relapse.




Important New QuestionsExpected Outcome Risk factors for poor

outcome

● ●

exacerbations

● 1

FEV1

Comorbid conditions(cardiac disease)

Frequent

(>4 / past year)

Severe obstructivedisease (FEV <50%)

Simple

Chronic Bronchitis

No risk factors

Complicated

Chronic Bronchitis

Risk factors +

Chronic Bronchitis

Balter MS, et al. CMAJ. 1994;151(10 suppl):1-23. = 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 twogroups – patients who do not have comorbid conditions, do not have frequent exacerbations, and have relativelypreserved lung function (defined as an FEV1 of more than 50%) – those patients are classified as simple chronicbronchitis. The presence of one or more of these risk factors and those patients are then called complicated chronicbronchitis or complicated COPD.




Proposed Therapies for AECBAccording to Patient Subsets

≤

1

1

Home oxygen

Doxycycline

TMP/SMX

Fluoroquinolone

AECB AECB

FEV1

bronchial sepsis

1

Can Respir J )

4 exacerbations/yr

No comorbid illness

FEV >50%

>4 exacerbations/yr

Serious comorb id il lness

FEV <50%

Chronic oral steroids

Advanced macro lide

Selected cephalosporinsNew fluoroquinolones

Amoxic il li n/clavulanate with anti -Pseudomonal

activity

Simple, uncomplicated Complicated Complicated AECBat risk for P. aeruginosa

= Forced expiratory volume in 1 second;

TMP/SMX = Trimethoprim/sulfamethoxazole

Patients with chronic

Need for chronic

corticosteroid therapy

and frequent (>4/yr)

courses of antibiotics

FEV <35%

O’Donnell DE, et al. . 2003;10(suppl A :11A-33A.

So this is all being put together in a set of guidelines. Now there are again several guidelines for treatment of exacerbations withantibiotics, and again most of those guidelines differ or disagree with each other. There are still guidelines from the AmericanCollege of Physicians that would say that the last good placebo-controlled study was the Anthonisen study from the 1980s, so let’sforget about all this resistance emergence and outcome issues and still treat everyone with amoxicillin to start with or Bactrim. Butagain, that’s like saying “because we don’t have the data and placebo-controlled trials” that nobody wants to do, we should beignoring 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 bestso I’ll present those. What they did in these guidelines was to classify the patients, as I showed you, into simple or uncomplicatedexacerbations, complicated and complicated ones at risk for Pseudomonas. You’re going to start seeing the similarity to thepneumonia set-up. With simple uncomplicated, as I mentioned, in patients without comorbid illness and without frequentexacerbations and relatively preserved lung function – in those patients you can use a macrolide, selective cephalosporins withgood pneumococcal activity, or even doxy or trimethoprim sulfa. Again, these are the not patients that most probably you aregoing to see in the hospital setting. These are mostly – 99% of these patients are outpatients. I mean, if they get admitted, it’s bymistake.

Complicated exacerbations are the kind of patient that you’re going to see and these are patients who have any one or more of these risk factors. 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, therecommendation is that we should, up front, be using either one of the new fluoroquinolones or amoxicillin. The idea being thatinthose patients we need more aggressive therapy up front to minimize the risk of failure in those patients.

Then there’s a third group, which is complicated and at risk for Pseudomonas. These are patients defined by very severeunderlying COPD, with a need for chronic steroids, and again in those patients, the recommendation is to stick with afluoroquinolone with some anti-Pseudomonal activity in an outpatient setting. In an inpatient setting, we don’t know. I mean I’mreluctant to throw three antibiotics at these patients, so I still tend to use a single agent with anti-Pseudomonal activity in thesepatients in the inpatient setting. I think the best thing to do in these patients is to get sputum cultures because then you know if you’re dealing with Pseudomonas or not and then you can guide your therapy. Again, these guidelines haven’t been tested inevidence-based situations, but they are based on the best knowledge or the best science that we have right now.




Risk Stratification and Acute

Exacerbations of COPD

•

••

•

Consider sputum culture

••

•

MILD

••

•

•

••If at risk for , consider

Exacerbations

No antibiotics Simple COPD Complicated COPD

Advanced macrolide

(azithromycin, clarithromycin)

Ketolide (telithromycin)

Cephalosporin (cefuroxime,

cefpodoxime, cefdinir)

Doxycycline

Worsening cli nical status o r inadequate response in 72 hrs

Reevaluate

MODERATE OR SEVERE

At least 2 of the 3 card inal symptoms:

Increased dyspnea



Only 1 of the 3 cardinal symptoms:

Increased dyspnea



Fluoroquinolone (moxifloxacin, gemi

floxacin, gatifloxacin, levofloxacin)

Amoxici ll in-clavulanate

Pseudomonas

ciprofloxacin and obtain 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. It’s kind of based on the same one. I will tryto simplify it even more and incorporate the idea of Anthonisen and when can we not use antibiotics. So in patientswho are mild, again, patients you won’t see in the hospital setting, maybe antibiotics are not indicated. Once they havea moderate to severe exacerbation based on having two of the three cardinal symptoms at least, then again simpleand complicated – we kind of discussed that already and its pretty much based on the same kind of break-up. But Ithink Pseudomonas patients fall into this group and those kinds of patients should receive sputum cultures to guidetheir therapy.




S. Harris.

Antibiotic Steak

So that’s in terms of guidelines of treatment And of course if nothing else works, you can tell them to eat a steak thathas so many antibiotics in it that you’ll get cured.




Approaching AntibioticTherapy of RTI

Severity of acute

illness

Expected outcome

Expected resistance

Adverse effects

Overall cost

J ust kind of to summarize, I think approaching antibiotic therapy of exacerbations, and even other respiratory tractinfections, has become somewhat complicated by the whole resistance emergence issues and we have to become abit more careful.

The way I like to say it is – it won’t apply so much to you folks, but it’s like cholesterol therapy has become much morecomplicated. We have to worry about LDL and HDL and all those things – the same thing with antibiotic use. Youneed to start taking into account the severity of the acute illness, expected resistance, and outcomes issues, and alsoadverse effects and costs.




Cost of Therapy

therapy is one whichdoes not work

responsible for 63%

of the costs Reduction in failures

by 50% will translateto a 33% reductionin costs

Chest

C

o s t ( $ )

Cost of AECB Treatment

0

100

200

300

400

500

600

Average Failure

The most expensive

Failures (21%) were

Miravit lles M, et al . 2002;121:1449-55.

Success

But I think when it comes to costs, we should look at the overall cost of treatment rather than just the cost of theantibiotic acquisition. And I think – it’s 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 I’ve shown you, the Spanish study. They looked at thecosts of the failures and showed that 21% of failures were responsible for almost two-thirds of the costs. It goes overthe patients who got hospitalized and required additional diagnostic testing. I think this really applies again to thesetting in which you work in – that if a patient comes in initially and doesn’t get appropriate treatment, the chances areis that the hospitalization is going to be prolonged and they are going to develop complications. So I think saving afew dollars on the initial antibiotic therapy and being conservative, in this situation, can be harmful many times.




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, what’s causing it, and the therapy has to be right on the dot.




Antibiotic Treatment of RTI:Pragmatic Approach

Educated guess

● Syndrome

● Etiology

● Susceptibility

Therapy

● Empiric

● Risk stratification

The problem is is that we don’t have the tools to do that. Right now, the best we can do is an educated guess as towhat’s going on with this patient, what’s causing for example the exacerbation, and then base the therapy in anemphatic way on a risk stratification approach that we discussed.




Antibiotic Treatment of RTI:Changing Paradigms

Initial therapy is Antibiotics do no harmalways first-line

We have to be more Choose initial therapy circumspect about

based on risk antibiotics

stratification Antibiotics do little Use low doses for long good, most patients

duration get better anyway

Use high doses for Antibiotics reduceshort duration morbidity, mortality

and health care costs for several diseases

Again, there’s some philosophical viewpoints about antibiotic treatment of respiratory tract infections that a lot of theparadigms that we were brought up with are changing. We would always talk to the patient and always give the mostsimple 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 – thatwas alluded to. Now you know, use high doses for short duration. That’s becoming the approach that may be thebest way to decrease antibiotic exposure.

The concept that antibiotics are pretty harmless is also not true. I think we have to be more circumspect aboutantibiotics. 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 betteranyway, and that may not be based on fact. And antibiotics are known to reduce mortality, morbidity and health carecosts of exacerbations in a lot of other diseases.




S. Harris.

Elegant Solutions

So again, it gets more complicated. As it says over there, “Whatever happened to elegant solutions?” It does get morecomplicated with time. . . .




Research at the VA

But if you fix those patients up there, they can go back to doing what they should be doing – that’s playing golf.

That’s the VA and that’s the research building I work in. . . .




A Must See in Buffalo

I always like to put us this to show that there’s more things in Buffalo besides snow.




Questions & AnswersWhy 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 that’s coming on. And what the FDA wanted – and that’s changing,which is good in a way – was show us that you’re as good as what’s available in the market and approved for thatparticular indication.

So every study was designed to show non-inferiority to a competitor, which is existing in the market, and that’s exactlywhat it did. Because all the studies are designed very carefully that they fall within 10% or 15%, and the studies takeon generally simpler patients so that all the results – about 80% to 90% of the patients get better, which is not truewhen you look at the few placebo-controlled trials. There is a move now by the FDA that they want to look atsuperiority again. They’re bringing about some change, which is a painful change for many companies, but may beactually worthwhile down the road. All right?

Sure.




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 it’s just a matter of time. You know, the discussion with the 4 hours and the 8 hours was very interesting. If you look at thedata that it’s based on, it’s terrible data. It’s a retrospective analysis of a large database in which they do a multivariate analysisand 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 slightlyabove 1. So that’s why I think they are going back to the 8 hours because really the difference in the 8 hours and 4 hours isminimal. But can I go back to your question? Yes, so it’s analogous to the 4 hours, 8 hours, the data was soft for that. The datafor pneumococcal vaccine is soft but it’s a core measure that they’re measuring. They are defending it – the hospitaladministrators defend it by saying that, hey, if you were giving the vaccine right then that means you were doing other things right.So that’s why it’s still a core measure. But I think it’s more of a quality measure than anything else. In terms of the data for adults,it’s actually – you’re right – it’s very soft data.




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 I’ve heard through the grapevine theadult 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 didn’t have any dramatic effects as they had in the kids. So there is development – there areattempts to develop better vaccines. We obviously need a better pneumococcal vaccine. What I do is I use it in my patients. Imay 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 beokay 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 arefair?

All right. Thank you very much.




Antimicrobial Resistance:Implication for NosocomialPneumonia Patients

Richard Quintiliani, MD,, FACP

Professor of Medicine and PharmacologyUniversity of Connecticut School of MedicineFarmington, Connecticut

As it is shown on the program, I’m the last speaker, so I hope that everybody is alive enough to hang in here with mypresentation. I promise I will try to end it as indicated. No later than 9:30. I suspect if I speak much longer than that, Iprobably will have to strike a deal and I’ll have to pretend I’m talking and you’d have to pretend you’re listening and soI don’t want to get into that issue.

My background is shown on the pamphlet that’s been distributed as a blend of infectious diseases and pharmacology.So I will use both of those backgrounds in this brief presentation.




Antimicrobial Resistance:Implication for Hospital-Acquired, Ventilator-

Associated, and Healthcare-Associated Pneumonia

I’ll be focusing mainly on nosocomial pneumonia, which used to be viewed as pneumonia that develops in a hospitalsetting. I will try to show to you in this talk that the term nosocomial is no longer going to become very popularbecause 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 dealingwith this type of infection.




Hospital-Acquired, Ventilator-Associated, and Healthcare-Associated Pneumonia Hospital-acquired pneumonia (HAP)

● Pneumonia occurring ≥48 hours after admission that was notincubating at the time of admission (some patients withsevere HAP may require intubation and should be managedsimilar to patients with VAP)

Ventilator-associated pneumonia (VAP)

● Pneumonia that arises >48 hours after endotrachealintubation

Healthcare-associated pneumonia (HCAP)

● Pneumonia in patients who have resided in a nursing homeor long-term care facility

● Patients who were hospitalized for at least 2 days in anacute care hospital within 90 days prior to the onset of thepneumonia

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 that’s acquired in a hospital but alsoacquired outside of a hospital. For instance, we now talk about hospital-acquired pneumonia – so called HAP – andthese are persons who develop pneumonia at 48 hours or longer after being admitted to a hospital. Moreover theyshould not have any evidence of incubating a pneumonia at the time of their admission. So this is now hospital-acquired 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 referredto as VAP, or ventilator-associated pneumonia. And again, the definition according to the new ATS guidelines ispneumonia 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 havea 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 hospitalfor at least 2 days and 90 days prior to the onset of this new pneumonia. So this is the new breakdown of pneumoniain the high-risk category. Usually the term nosocomial was an encompassing term for all of these three.




HAP and VAP

Early-onset: pneumonia that occurs within the first 4 days after hospitalization or incubation

Late-onset: pneumonia that occurs ≥5days 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 it’s very important to do this because it really willdetermine the choice of antimicrobials – now when we talk about ventilator-associated pneumonia or hospital-acquiredpneumonia its being broken down into two very distinctive types, of which one is referred to as early-onset whereasthe other is referred to as late-onset. Early-onset is a pneumonia that occurs within the first 4 days afterhospitalization or incubation. The late-onset are the ones that occur 5 days or later. Now we are going to see in amoment that the antibiotic approach really varies tremendously whether the patient has this early- or late-onset type of pneumonia.




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-onsetHAP 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 antibiotictherapy

*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, healthcareassociated pneumonia – and again, these are the patients from the chronic care facilities, nursing homes – shouldreally be treated similar to hospital-acquired or VAP of the late-onset. So they really are viewing these people whoreside 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 morecomplicated ones. Also, just like in community-acquired pneumonia, we do not want a delay in therapy once a patientdevelops any of those three types of pneumonias that I mentioned. It is important to get initial cultures. But it’s alsogoing to be important that after we get those, if we have some negative reports, we are going to use this informationvery heavily to decide how to simplify or de-escalate therapy. In my mind, sputum cultures actually have more valuefor their negative than their positive value. Unfortunately, many organisms will often colonize, but if we can’t find themthey are almost certainly not the source of that lung infection.




ATS/IDSA 2005 Guidelines* Early, appropriate, broad-spectrum

antibiotic therapy should be prescribedwith adequate doses

Empiric therapy should include agentsfrom a different antibiotic class than the

patient has recently received De-escalation of antibiotics should be

considered based on results of culturesand patient’s clinical response

*ATS/IDSA. Am J Respir Crit Care Med. 2005;171:388-416.

Also, we’re back to making sure – if you’re going to prescribe an antibiotic, make sure it’s 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 aswe heard earlier – the right dose and obviously the right way to dose that drug. Also initial therapy should includeagents from different antibiotic classes that the patient has recently received and again back into this concept of de-escalation should be considered on the basis of the information that comes from the initial culture reports.




Traditional Empiric Antimicrobial

Therapy in HAP, VAP, and HCAP

Start simple (narrow-spectrum)

Reserve the “big guns”

Add other Abx

Suspect

infection

Isolate susceptible

pathogen

Patient deteriorates or

pathogen identif ied as

resistant to therapy

against suspected pathogens

Successful outcome!

Initiate narrow-spectrum AbxDetermine most

likely pathogen

Abx = ant ib iotics

Now it’s interesting that there’s quite a paradigm shift. We always used to think in this traditional way – to try to getour cultures, initiate therapy with very narrow-spectrum antibiotics, and then once we get this information, then wewould change the antibiotic regimen accordingly. But unfortunately, this concept of starting simple and getting a betterbasis delays the appropriate therapy. If you initiate therapy inappropriately, there’s a high mortality and of course thisis now what’s being recognized, particularly in these hospital-associated pneumonias.




Reasoning Behind Traditional(Conservative) Approach

Avoid need for an ID consult

Reduce the development of resistanceto the “big guns”

Reason that not everything that lookslike 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 westart simple, we probably don’t need an ID consult, which could be expensive. Perhaps if we do not use the so-called“big-gun” antibiotics, we won’t see as much resistance developing to them, and often we see a lung infiltrate – andmaybe it’s not a lung infection at all. And of course again, the pharmacists are always nagging us to keep the costsdown, so they are always upset if we start with some of these big guns, which tend to be typically a lot more expensivethan the more narrow-spectrum agents.




New Concepts About Empiric Antimicrobial

Therapy in HAP, VAP, and HCAP

Suspect

infection

Isolate pathogen Patient deteriorates or

pathogen identif ied as

resistant to therapy

Initiate broad-spectrum Abx

(often multiple drugs)

Determine potential

pathogens and

resistance rates

Successful outcome! Change Abx

Narrow (de-escalate)

Abx coverage based on

susceptibility results

The new concept, the new paradigm – and this applies definitely to the hospital-acquired, ventilator-associated and thehealthcare-associated pneumonias – is that we want to start initially with big guns. We want to cover all the suspectedor target pathogens, and once we get the information from our culture reports – hopefully do get some informationthat will now allow us to de-escalate or simplify therapy.

We are really learning quite nicely now that we also don’t have to go very long to cure many causes of lung infections.Many of the newer antibiotics that we have are very rapid eliminators of microorganisms. We’ve been hearing aboutshort-course therapy for community-acquired pneumonia – 5 days, for instance, with some of the respiratoryfluoroquinolones. We’ve already heard in the past about 3-day therapy, particularly in Europe, with 3 days of azithromycin for mild to moderate pneumonia. So there’s a big movement in the area of respiratory tract infections toabbreviate duration of therapy, and one of the main reasons for this actually is to avoid so-called collateral damage tothe 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.




Reasoning Behind New Approach Get it right up front (aggressive approach)

Reduce mortality associated with inappropriateempiric antimicrobial therapy

Streamline antibiotic therapy once susceptibility data are available

Avoid prolonged and unnecessary use of “bigguns,” which avoids “collateral damage” toGI flora and development of resistant organisms

Costs saved by avoiding treatment failure greaterthan 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 don’t get it right right up front there’s excessive mortality. And of course, indirectly that leads toexcessive costs as well. So it’s 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.




Initial Inappropriate Therapy in Patients

with Serious Infections: Mortality

Rello et alInitial appropr iate therapy

Infection-related mortalityInitial inappropriate therapy

Kollef & WardCrude mortality

Ibrahim et al

Infection-related mortalityLuna et al

Crude mortality0 20 40 60 80 100

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. Thereis a tremendous increase in mortality if you do not choose a proper antimicrobial for whatever happens to be theresponsible pathogen in that patient. Now here again is the reason behind breaking down these pneumonias intoearly- and late-onset. Now the early-onset again applies to the hospital-acquired or the ventilator pneumonia. Wedon’t use those terms for the healthcare-associated because you really can’t do that, because they’re there for weeksor months or whatever.




Common Potential Pathogens for Early-Onset (≤4 days) HAP or VAP Usually caused by

non-multidrug resistant pathogens that commonly colonizethe oropharynx

Treatment similar toagents used forcommunity-acquiredpneumonia(eg, monotherapy with

●Streptococcus

“respiratory quinolone”pneumoniae or ceftriaxone + macrolide)

● Haemophilus species For early-onset, one can

● Oropharyngealstill use “traditional” oranaerobes

(not B. fragilis ) “conservative” approach;

● Legionella species however, for all HCAP uselate-onset treatment

Richards MJ, et al. Crit Care Med. 1999;27:887-92.

Interestingly, in the patients who have developed hospital-acquired pneumonia in this short time period of around 4days, the usual responsible pathogen is a typical organism that colonizes in the oropharynx. So very similar to whatwe 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, withcombination therapy of a macrolide and a third-generation cephalosporin, or monotherapy with one of the respiratoryfluoroquinolones.

But again, I want to underscore that, according to these new guidelines, that any patient coming from a chronic carefacility, nursing home, or long-term care facility is not looked upon as somebody who warrants early-onset type of antibiotic therapy. They’re viewed as patients who have late-onset.




Common Etiologies for Late-Onset(≥5 days) HAP, VAP and HCAP

Pseudomonas aeruginosa

S. aureus (~50% methicillin-resistant S. aureus [MRSA])

Enterobacter species

Klebsiella species, includingexpanded-spectrum β-lactamaseproducing organisms (ESBLs)

Acinetobacter speciesRichards MJ, et al. Crit Care Med. 1999;27:887-92.

Now how about the late-onset? There’s tremendous change in the target organisms if you develop your pneumonia 5days or later, these are the major pathogens we want to make sure we cover in our initial empiric therapy, and that’swhy we require these so-called very broad-spectrum drugs. Here are the major causes of late-onset hospital-acquiredpneumonia, ventilator-associated or HCAP: Pseudomonas ranks among the worst; however, there has been atremendous 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-calledMRSAs are resistant to all beta-lactam antibiotics, so no beta-lactam antibiotics – whether you’re talking aboutPrimaxin or Zosyn – have any activity against MRSA, and usually you have to resort to drugs like vancomycin orlinezolid.

Interestingly, the community-acquired MRSAs are not infrequently susceptible to some of the older remedies likeBactrim, 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-spectrumbeta-lactamase, the so-called ESBLs. These are organisms that will hydrolyze the beta-lactam ring of third-generationcephalosporins, and often fourth-generation as well.

Again, I’m going to display some of the drugs that are the best choices. Right at the end, I’m going to come up withwhat I think is going to make the best sense in terms of treating patients with late-onset, hospital-acquired orventilator-associated pneumonia or HCAP. Also Enterobacter species and then lastly Acinetobacter . These are ourmajor targets and these are the reasons for all this new stratification. Also you do have to know a little bit aboutpharmacokinetics to understand how to dose antibiotics in the best way to maximize bacterial killing. So as mentionedearlier, we have to chose the right drug and we’ve got to give it at the right time. We’ve got to give it at the right dosebut we also have to give it by the right mode of administration.




C o n c e

n t r a t i o n

Time (Hours)

MIC

Peak/MIC (concentration-dependent)

Goal: peak/MIC ≥10

AUC/MIC

Goal: ≥30 for gram +; ≥125 for gram ─ Time > MIC (time-dependent)

Goal: ≥50% dosing interval

Pharmacokinetic/Pharmacodynamic

Parameters Affecting Antibiotic Potency

0Quintiliani R. Infect Med. May 2004:219-32.

J ust quickly, this one slide – it sums up the three basic pharmacokinetic concepts that are now being used to doseantibiotics in the best way. For instance, this just shows blood levels on antibiotics after a dose. Obviously at sometime, the drug has to drop below its MIC – the concentration that’s necessary to kill the target organism. Nowinterestingly, certain classes of antibiotics kill bacteria the same, where the levels just exceed their MIC for thatpathogen way down here just above the MIC, and where they do not kill any better if they are way up at the peakconcentration, so these antibiotics are now referred to as concentration-independent or time-dependent killing, and thegoal is to try to keep the levels of that time-dependent antibiotic to be equal or greater than 50% of any one dosinginterval.

Now on the other hand, certain antibiotics do kill better if the concentrations are quite high in relationship to the MICtowards the pathogen and so they are referred to as a concentration-dependent or dose-dependent antibiotics. Andthe 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 – thisis the area right there, the area under the serum concentration curve after a dose of antibiotics. The AUC is nothingmore than a measurement of the exposure of the organism to that antibiotic through any one dosing interval. It’s kindof fascinating that certain organisms require very little exposure to be rapidly inhibited. For instance, thepneumococcus is rapidly killed with an AUC of about 30 whereas organisms like Pseudomonas require very high andlong exposure. High AUCs of around 125 and actually there is no single fluoroquinolone that should be used alone totreat serious systemic Pseudomonas infection because you cannot attain this target of equal or greater than an AUCof 125. I mean you can use them but you have to use them in combination with another anti-Pseudomonas drug.




Pharmacokinetic/Pharmacodynamic

Parameters of Antimicrobial ClassesConcentration-Independent Concentration-Dependent

(Time-Dependent) (Dose-Dependent)

Beta-lactams Fluoroquinolones(penicillins,

Aminoglycosidescephalosporins, penems, monobactams) Amphotericin B

Clindamycin Metronidazole Erythromycin Daptomycin

Clarithromycin

Linezolid

Vancomycin

And so it’s on your handout here – these are antibiotics that use mainly time to kill organisms and these are the onesthat use mainly concentration. In fact the observation that for these time-dependent antibiotics – oops, we’re going togo back here for a second – we’ll go back just one here – these antibiotics that kill the same when the level is justabove the MIC are way up at the peak – this is the explanation of the constant infusion of beta-lactam is coming back.So that’s going to be all the penicillins and cephalosporins kill in that fashion and so our goal is really just to get thelevels just above the MIC and try to keep it there for at least 50% or more of the dosing interval. This has beentremendously useful in the dosing of beta-lactams that have relatively short half-lives, that typically have to be givenvery often, and therefore result in laws of labor and supply costs. At Hartford Hospital, for instance, we dose Zosyn byconstant infusion. We dose ceftazidime frequently by constant infusion, thereby saving all kinds of monies fromavoidance of labor and supplies. For instance, constant infusion turns out to be once-daily dosing.




Empiric Antibiotic Combination Therapy

Choices for Late-Onset HAP, VAP, or HCAPAminoglycosides

(gentamicin/tobramycin)

● Good aerobic gram-negative activity butmust be given in combination withanother anti-Pseudomonas drug

● Poor activity against MRSA, modestactivity against ESBL-producingKlebsiella and Acinetobacter baumannii

● Concerns over nephrotoxicity andototoxicity

● Use once-daily dosing method

Now let’s first look at possible choices – I mean, what are we going to use? And it turns out that we’re probably goingto have to end up using three antibiotics. That’s like back to the future – when we used to do that in overwhelmingintra-abdominal sepsis – well, aminoglycosides like genta- and tobramycin have remained very active against mostaerobic enterics and includes Pseudomonas. Unfortunately they have very poor activity against MRSA, and socertainly we can’t use them alone and they have very modest activity against these expanded-spectrum beta-lactamase–producingKlebsiella and Acinetobacter . And of course, we’re always concerned about do we havenephro- and ototoxicity.




Aminoglycoside Dosing Methods

C o n c

e n t r a t i o n ( µ g / m L )

20

18

16

14

12

10

8

642

0 4 8 12 16 20 24

Time (hours)

Quintiliani R. Infect Med. May 2004:219-32.

But if you’re going to use them, you use the once-daily dosing method. There is no question that that dosing approachis associated with much more rapid killing and paradoxically much less oto- and nephrotoxicity. The once-a-dayprogram that we developed at Hartford that is used now in around 90% of the hospital is that we give a large dose of 7mg/kg and above those peak around 20. Now why did we use that dose? Because the Pseudomonas is the usualmost difficult target organism. It usually requires around 1.5 to 2 mcg loading at ten times above that and that’s theonly 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. Afew challenges – a neutropenic animal with a potential lethal dose of Pseudomonas. Many more animals survive thatchallenge if they get the dose this way as opposed to the intermittent dosing technique where the levels only peakaround 4 or 5 and go down to 1 at the end of 8 hours. No one thought we could do this. They thought we’d haveundue oto- and nephrotoxicity but you don’t, you get less. The reason why is that in humans there exists a saturationcapacity to move aminoglycoside from serum into the renal tubular cells or the inner ear cells and it occurs way downhere around 1.5 or 2. When you go above that, you can’t drive any more drug into those sites. The thing that’sassociated with toxicity with aminoglycosides is how much accumulates in the ears and kidneys and you actuallyaccumulate more with intermittent dosing because you don’t have a large wash out period. So that’s the way thesedrugs should be given. So it’s back to the point that if you’re going to give this drug, let’s dose it in the best possibleway.

Conventional (1.5 mg/kg

Once-daily (7 mg/kg)

q8h)




Bacterial Killingas a Function of MIC

BACTERIAL POPULATION

Minimum Inhibitory Concentration

N u m b e r o f O

r g a n i s m s

MIC 50% MIC 90% 10x MIC


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 moresusceptible, and often what can happen is, that if you suboptimally dose with typical intermittent dosing, the organismsway out here on the end can survive.




Bacterial Killingas a Function of MIC

BACTERIAL POPULATION

N u m b e r o f O r g a n i s m s

MIC 50% MIC 90% 10x MICNew MIC 90%

Minimum Inhibitory Concentration


When that happens, they begin growing, they form a whole new population, much higher MIC – 50 to 90 – that’sreferred to as emergence of bacterial killing the resistance. If you actually start out with a dose ten times above theMIC, the chance of that happening is over zero. So – aminoglycoside is one of the drugs we’re going to be using rightat the end and so let’s at least dose it in the best way.




Fluoroquinolones ~65% of Pseudomonas aeruginosa

susceptible to levofloxacin andciprofloxacin and therefore they must beused with other anti-Pseudomonas drugs

Poor activity against MSRA and modest

activity against Acinetobacter species andESBL-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 can’t use them alone forsystemic 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. Thecommon mistake as a clinician – look only at the MIC, and the amount needed to kill an organism, and assume thatthe drug with a low MIC is the best choice. Not so. You have to integrate blood levels and it’s a wash between thesetwo drugs. You can’t use amox or lactam, or moxifoxacin because it has very modest Pseudomonas activity and hasnot even been tested in the laboratory. And for Tequin – gatifloxacin – it’s only tested for urine isolates. So we’re notgoing to be able to use fluoroquinolones alone for Pseudomonas. They have no core activity against MRSA, modestagainst Acinetobacter and ESBLs. Nicely, though, they have no significant oto- or nephrotoxicity. The oralformulations really have excellent bioavailability, approaching 100% with levo and 93 or 94 with gati, and cipro was alittle less – down around 70%.




Pharmacodynamics of LEV, IMP, and LEV-IMP

Combination against P. aeruginosa 236

µ

mex opr

µ

LEV

IMP

0

1

2

3

4

5

6

7

8

9

10

0 4 8 12 16 20 24 36

Time (h)

L o g

C F U / m L

1 0

Levofloxacin (LEV) Alone

Rapid 3-log kill by 6 hr followed byregrowth between 6 and 24 hrs

Emergence of resistant subpopulation(MIC of 10 mutants was 16 g/mL)

One mutant (444LEV) exhibited dualresistance to imipenem andoverexpressed the EF- N effluxpump

Imipenem (IMP) AloneRapid 3-log kill by 6 hr with levelremaining constant between 6 and 24 hr

Emergence of resistant subpopulation(MIC of 10 mutants was 16 g/mL)

LEV-IMP Combination

Rapidly bactericidal (4-log decrease by2-hr time point)

Bacterial eradication observed by 12 hr

No emergence of resistant isolatesLister PD, Wolter DJ. Clin Infect Dis. 2005;40(suppl 2):S105-14.

LEV-IMP

But they’re good potential drugs for this de-escalation because if you get an aerobic gram-negative other thanPseudomonas, you can use monotherapy with them as long as the gram-negative is not an Acinetobacter , ESBL asmentioned.

We get often asked is there any synergy between these respiratory quinolones and any other anti-Pseudomonasdrugs. You know, this has been done with levofloxacin and imipenem. These are what we call time kill curves. Wemeasure the rate of bacterial kill after exposing the organism to the drug. This is the killing with levo right here. It killsfor about 6 hours and then it breaks through. If you expose that organism just to Primaxin, imipenem, you also getkilling for about 8 to 12 hours but then it begins to break through so neither one can be used alone. However if you putthem together, then you get very good killing for 24 hours. Whether this type of study has been done with cipro, I don’tknow. I know it’s been done with the levo and with the imipenem. Again, this is information we’ll need to justify thefinal conclusions.




The Carbapenems(Imipenem, Meropenem) Anti-Pseudomonas activity closely similar to that of

an aminoglycoside, but for best synergistic activityshould 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 beused in the empiric treatment of HCAP since ithas poor Acinetobacter and P. aeruginosa activity

Now the carbapenems. They, like imipenem and meropenem, there is another carbapenem out there calledertapenem (Invanz) – you can’t 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 toencourage resistance of Pseudomonas to imipenem or meropenem. So they probably have the best overall anti-Pseudomonas activity. They are very closely similar to that of aminoglycosides, but again for the best – you need newtherapy – and for the best synergetic activity, you want to give it usually with a non–beta-lactam antibiotic like anaminoglycoside or an anti-Pseudomonas fluoroquinolone. It is by far the most active class of drugs against ESBL-producing Klebsiella and Acinetobacter . The problem here, however, is no activity against MRSA and really modestagainstStenotrophomonas maltophilia. Now one of the things that you have to recognize – although certain organismswe grow out, it doesn’t mean they are the significant pathogen – there’s another organism. Unfortunately,Stenotrophomonas is a very difficult bug to treat, and one other organism, cepacia – although you not uncommonlygrow them out, they are very seldom invasive. Also we see that when we isolate Candida from sputums, you oftensee it, but how often do you see Candida pneumonia? Almost zero. So there’s a difference in different organisms interms of their virulence.




OPTAMA (Optimizing Pharmacodynamic Target

Attainment Using the MYSTIC Antibiogram)Regimen Probability of Target Attainment (%)

EC KP AB PSA

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

─

100

100

90

─ 99

─ 89

─ 80

─

88 91

92 89

59 84

69 89

50 82

67 93

56 70

65 85

41 53

46 59

MYSTIC = Meropenem Yearly Susceptibil ity 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 don’t have time because of timelines here tonight, but probably the best anti-Pseudomonas drug is polymyxin or Colistin. If you have aPseudomonas aeruginosa that tests resistant to everything, test polymyxin – they’re coming back very fast. It has alot of nephrotoxicity but no ototoxicity, so there’s a lot of interest in that drug again.

Again, this shows you that – I think you’re going to have to have a carbapenem as one of your three choices. This isE. coli. This is Klebsiella. This is Acinetobacter and Pseudomonas. To compare these two carbapenems and again –they’re the same. If you look above, these two drugs are the same. They have very good activity against major

pathogens of late-onset pneumonia.




MIC ( )

MYSTIC Americas ResultsP. aeruginosa (193)

0

10

20

30

40

50

60

70

80

90

100

1 2 4 8

/

C u m u l a t

i v e % I n h i b i t e d

mg/L

Pfaller MA, Jones RN. J Antimicrob Chemother . 2000;46(topic T2):25-37.

0.016 0.03 0.06 0.12 0.25 0.5 16

Meropenem

Piperacillin Tazobactam

Cefepime

Imipenem

Again, between the two – meropenem and imipenem, this is meropenem, this is the MICs, they’re very low for both.So there are really no major difference, but they are more intensely active as compared with cefepime orpiperacillin/tazobactam.




Appropriate Therapy

Antibiotic ESBLs AmpC

Third-generation cephalosporins – –

Cefepime – +++

Quinolones +/– +

Piperaci ll in/tazobactam +/– +/–

Carbapenems +++ +++

Let’s skip this because of the time.




Linezolid vs Vancomycin in the

Treatment of NP Due to MRSA

P

Chest

(

) P = .182 P = .009

0

20

40

60

80

MRSA

Linezolid

Linezolid therapy was 3.3 times as likely as vancomycin(95% CI: 1.3–8.3, = .011) to result in a clinical cure

Wunderink RG, et al. . 2003;124:1789-97.

Data from 2 Double-Blind, Randomized Controlled Trials, n=116

C l i n i c a l C u r e

% o

f P a t i e n t s

51.5

43.4

59.0

35.5

S. aureus

Vancomycin

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 we’ve got toreconsider that maybe we should be thinking about an alternative drug, and I think linezolid could be that choice. Thiswas the study that was actually done by Richard Wunderink, who’s from Chicago, where he compared outcomes andnosocomial pneumonia here – we see the term again – due to MRSA and the cure rate was higher with linezolid.Why?




Penetration of Vancomycin IntoHuman Lung Tissue

J Antimicrob Chemother

0

5

10

15

20

25

30

35

40

45

1 2 3.5 6 12

Time (hours)

)

Serum

Lung

MIC

30 patients administered1 g IV vancomycin

Lung tissue:serumconcentration ratio ranged from0.24 to 0.41 at 1 and 12 h,respectively

1/6 patients observed at 6 h

and 3/7 patients at 12 h didnot have detectable levelsof vancomycin in lung tissue

1 g dose of vancomycin doesnot achieve sustained lungconcentrations > MIC forsusceptible staphylococciover a dosing interval of 12 h

Cruciani M, et al. . 1996;38:865-9.

V a n c o m y c i n C o n

c e n t r a t i o n ( µ g / m L

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




Linezolid vs Vancomycin Linezolid Vancomycin

Serum assays No Yes

Need renal-adjust dose No Yes

Oral bioavailability 100% 0%

Adverse potential Thrombocytopenia, Ototoxicity andInteraction with nephrotoxicity

SSRIs

MRSA activi ty Excellent Excellent

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



Imipenem or

Meropenem

+

Tobramycin+

Vancomycin

or Linezolid


Aminoglycoside Combination Therapy

for HCAP and Late-Onset HAP and VAP1. Combination therapy

based on unit-specific antibiogram

based on microbiological data

Imipenem or

Meropenem

+

Tobramycin+

Vancomycin

or Linezolid

2. Modify therapywithin 48 hours

3. Established criteria for duration of therapy:try to avoid more than 7 days

So we’ll end here with what I would think would make some sense, and if you’ll read in depth the ATS guidelines, theytalk about all of these things and they kind of scramble it a bit and they say – well you probably should do this or that –but they don’t really finally say, well, here’s what we think is probably the most reasonable approach. My view is thatyou have two options here. You can decide which one makes more sense. There is one way you have to use anaminoglycoside – gentamicin, tobramycin. You also have to use a MRSA drug – there’s no way around that and soyou have to choose between vancomycin or linezolid and then I think we need a carbapenem. So that would be anapproach to the three types of pneumonia – the hospital, um, healthcare-associated, which is always managedidentical to the late-onset hospital-acquired or the ventilator-associated pneumonia.



Imipenem or

Meropenem

+

Levofloxacin or ciprofloxacin

+

Linezolid


Non-aminoglycoside Combination Therapy Protocol (Nonnephrotoxic, Nonototoxic) for HCAP and Late-Onset HAP and VAP

1. Combination therapybased on unit-specific antibiogram

Imipenem or

Meropenem

+

Levofloxacin or ciprofloxacin

+

Linezolid

2. Modify therapywithin 48 hours

based on microbiological data

3. Established criteria for duration of therapy: try to avoidmore than 7 days. For c linically stable patients who caneat, consider oral quinolone or oral linezolid

Now there’s another possibility here, and this is what I would call the nonoto-, nonnephrotoxic drug. Again, we need acarbopenem – either Primaxin or meropenem. You need an MRSA drug. If we want a nonnephrotoxic/ototoxic, itwould have to be linezolid, and then you combine it with one of the respiratory fluoroquinolones, either levofloxacin orciprofloxacin.




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 havebeen so recently published.

Yes?

I’ve gone to a few talks and it seems like one antibiotic – the question is, are any antibiotics in your opinion more inducers of ESBLor no?

The question was – is any antibiotic more prone to induce these ESBLs? No.

Yes, I’ve heard literally just like “zilch” and it doesn’t do it.

Also in terms – because of timelines here – let’s now approach de-escalation, okay? So if you had Klebsiella that producedESBLs, maybe 60% to 70% are susceptible to cefepime – that’s the next good drug – or even Zosyn. So you could then movedown to one of those and get away from a more expensive agent like Primaxin or meropenem. If you isolated a non-ESBLproducing Klebsiella orE. coli, you could move down to, let’s 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 there’s a need as Imentioned for an approach on how to de-escalate as well as how to start with. But there is no question, the initial approach isgoing to be triple therapy. I don’t see anyway around that.




Questions & Answers

On resistance, our nephrologists have us

convinced that Zosyn will induce resistant

enterococcus and they’ve requested that we don’t

use it because it becomes a problem with their access infections.

Piperacillin is very good against enterococci, okay? I don’t see why that would be an issue. It would seem a lot morevancomycin-resistant enterococci, VRE, okay? Again, that organism is often resistant to many classes but issusceptible to linezolid, okay?

Here again though, it’s kind of a fascinating observation – it’s now felt that you don’t die from VRE. You die with VRE.As a marker, you get really sick, probably you’re not going to last much longer – it is not a very invasive organism, andthat’s why you rarely see proven serious infection from VRE. The hospital epidemiologists go crazy. They want toburn down the hospital when they see that. But it’s really not that bad. The question is “why?” Well, Dr. PatriceCourvalin from the Pasteur Institute, he’s 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, theMVR organisms, okay? They can do that but it’s at the expense of a whole bunch of metabolic processes, and bymessing with many metabolic processes, it ends up with less virulence. And that’s true. Remember the hospital-

acquired MRSA are not as virulent as the ones that are community-associated. And actually, penicillin-resistantpneumococci are not as virulent as penicillin-susceptible. We do a lot of animal research and so we often try toproduce, say, pneumococcal infection in an animal. Very easy to do it if we challenge the animal with a penicillin-sensitive Strep pneumoniae but not easy at all when it is penicillin-resistant. So that’s a generalization that has heldup very well, and multidrug-resistant pathogens tend to be not that invasive. I already mentioned Stenotrophomonasmaltophilia as another example of that observation.




Questions & Answers

How about chloramphenicol?

Well chloramphenicol – well it depends upon a lot of your training in infectious diseases. It’s no longer available in theUnited States except on a compassion and plea basis, okay? I think that was a great mistake. It’s a tremendousantibiotic. 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 there’s a fascinating observation – in fact I wrote an article on this with data give to me by Parke-Davis. When wehave seen aplastic anemia, at that time, just about 10 years ago, there were only around 500 reports in the UnitedStates. Every one of those patients had received chloramphenicol except one by the oral route of administration. Theone exception – some kind of psychotic patient who was using eye drops over and over – you know 30 cc a day andwas 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,

don’t give it by mouth if at all possible. But even then, it’s a rare complication of that drug. But unfortunately, we can’tget it now in the United States. I think it’s kind of a major loss to our armamentarium as they say.

We may want to comment on what’s ahead. Somebody asked me during the coffee break. I don’t know if I’m allowedto do that, if I’m allowed to talk about – with all these regulations, you have to stay within this little path here. It’sdefinitely not a commercial, you might want to know what’s ahead. As far as I can tell, there’s no more quinolones.

They’ll 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 we’ll see. (continued)




Questions & Answers

How about chloramphenicol?

Um, there’s 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. We’re getting more and more drugs againstMRSA because that’s becoming a common pathogen. But the class of antibiotics that most people are talking aboutthat are probably two or three years off are the peptides. These have been recently discovered – although knownabout forever – and explained why amphibians are resistant to skin infections. Frogs and toads – they don’t get skininfections. Why? Because they excrete through their pores long-chain amino acids and therefore they’re calledpeptides, and they carry a positive electronic charge (a strong one) that is attractive to negative charges in the cellwall. You talk about rapid cure – within 30 minutes they kill the organism. It is now known that all forms of life on thisplanet 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 thatpsoriasis patients secrete normal amounts of these peptides. Eczema patients do not. And there is already apharmaceutical company interested in development of these new class – they are called magainins. The wordmagainin is a Hebrew word which means “shield of protection.” So the senior researcher spoke Hebrew, he knewthat, and so he’s named these peptides that they’re 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 thereand go through there from South America, and one of the senior ID physicians got up in the audience and said he, youknow, was born in a small village just outside of Lima, Peru, and as long as he could remember as a child, whenpeople used to get wound infections, they used to capture a frog, paste the poor frog over the wound, wrap it up, andthey noted very impressive improvement. To me, it’s always amazing some of the old, old observations that no one’staken advantage of until the last 5 or 10 years.




Questions & AnswersWhat about Synercid.

Synercid I find no longer an acceptable drug. That’s the combination of quinupristin and dalfopristin – the problemwith the drug is not that it’s 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, andso it’s a very unpopular drug. It’s when you say you can’t use vanco, you can’t use linezolid, can’t use daptomycin,then you might want to use Synercid.




Questions & Answers

What’s the role of ertapenem?

Ertapenem is actually a – it could be used, okay? It’s being use mostly – which I think is more appropriately – in intra-abdominal problems, particularly in prophylaxis. When you have someone with diverticulitis undergo an electivesurgery of appendix, gall bladder, you want activity against three target gram-negatives – E. coli, Proteus, andKlebsiella, but you need aerobic activity, and it’s very good against bacteria, and you give it once a day – it’s kind of nice. Unfortunately, if it gets to be overused in the hospital, the resistance mechanism is such that you cantheoretically see ertapenem encouraging Pseudomonas-developed resistance to Primaxin and to meropenem. Soyou’ve got to watch that drug and that’s why a lot of ID people have troubles with it.




Questions & Answers

What about Telithromycin?

Again, somebody asked me, what about telithromycin? That wasn’t mentioned for a brief moment. And anydiscussion with respiratory tract infections should also address that drug. Well, it’s kind of a fascinating drug. It’scalled a ketolide. It’s 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 – it’s 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 it’s a very impressive drug when it comes to thepneumococcus. Unfortunately, it has modest activity against H. flu and that’s a potential problem. Thirdly, there’s noIV formulation. Why? Because it’s very hard to create a well-tolerated IV macrolide. We have no IV clarithromycin inthe United States. Erythromycin, yes, we have it, but about 25% of the people get like a chemical phlebitis, so wedon’t have that. Thirdly, it has some disturbance in combination. That’s 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 thispotential. Fourthly, a lot of GI side effects, which is typical of all macrolides. And fifthly, a lot of interaction with theCP450, so statins should be used. So it’s complicated. By accumulation, my own view is that it’s not going to be thatpopular. I mean why not use a respiratory quinolones? That’s my view instead of that drug, and bioavailability is nowabout 60%. But when we were talking about community acquired pneumonia – to make it a balanced talk, you’ve gotto address that drug, which is recently being marketed in the United States fairly heavily.




Improving Patient Care:Reducing AntimicrobialResistance in Respiratory

InfectionsPresentations from a symposium held inPresentations from a symposium held inChicago, Illinois on Friday, April 29 during the 2005 AnnualChicago, Illinois on Friday, April 29 during the 2005 AnnualMeeting of the Society of Hospital MedicineMeeting of the Society of Hospital Medicine

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