Values and Preferences Pneumonia 1. Recommend treatments shown to - - PDF document

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Pneumonia Update 2016

Management of the Hospitalized Patient October, 2016

Scott A. Flanders, M.D., MHM Professor of Medicine Director, Hospital Medicine Program Associate Chair for Quality and Innovation University of Michigan

Disclosure of Financial Relationships Scott A. Flanders, MD

Has disclosed relationships with entities producing, marketing, re-selling, or distributing health care goods or services consumed by, or used on, patients.

Consultant NONE Research and Grant Support CDC Foundation AHRQ Blue Cross Blue Shield, MI Pneumonia Guideline Groups * ATS / IDSA GL panel member Advisory Boards NONE Speakers Bureau NONE Board Member NONE

* non-financial

Key Topics to Cover

• Pneumonia

– Diagnosis: CXR / Etiologies / Procalcitonin – Antibiotics – Steroids

• “Healthcare-Associated Pneumonia”

– Which pneumonia patients are at risk for resistant

• rganisms?

Values and Preferences

• 1. Recommend treatments shown to improve clinical
• utcomes
• 2. Reduce unnecessary antibiotic use
• Use lowest number / “spectrum” of antibiotics
• De-escalate rapidly and shorten durations

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A National Priority

• First attempt to

characterize the annual human toll of antibiotic resistance. Clostridium difficile diagnoses: U.S. Hospitals 1993-2011

Lessa, et al. NEJM 2015

• 450,000 US cases (2011)
• 66% healthcare associated
• 29,000 deaths

Current Challenges

Antibiotic Use in U.S. Hospitals

• CDC: trend analysis over 550 hospitals; 2006-2012

– 55% of patients on antibiotics – Overall use stable; shift to more broad spectrum use

• 30%-50% of use is felt to be inappropriate

Dellit TH, Clin Infect Dis. 2007. Fridkin S, MMWR, 2014 Baggs, J, et al., JAMA IM, 2016.

Conditions Driving Antibiotic Use

The Big Three

• #1 Urinary Tract Infection (UTI)
• #2 Pneumonia
• #3 Skin and Soft Tissue Infection

(UTI and pneumonia account for over half of all inpatient antibiotic use)

• JAMA. 2014; 312(14): 1438-46

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Key Topics to Cover

• Pneumonia

– Diagnosis: CXR / Etiologies / Procalcitonin – Antibiotics – Steroids

• “Healthcare-Associated Pneumonia”

– Which pneumonia patients are at risk for resistant

• rganisms?

Is CXR the Gold Standard?

• French study of 320 patients with suspected CAP
• Excluded very severe cases (ICU, CRB65 >3)
• Performed CXR in all
• Asked ED docs to assess:

– Probability of CAP – Antibiotic plan – Site of care decisions

• Perform Chest CT!
• Ask docs again

Claessens YE, AJRCCM. 2015

Is CXR the Gold Standard?

• 120 pts with – CXR : 30% with CT infiltrates
• 190 pts with + CXR: 30% with NO CT infiltrates
• ED docs modified probability of CAP in 60%

– 80% in line with adjudicated diagnosis

• Modify treatment, drug or site of care : 61%!

Claessens YE, AJRCCM. 2015

CT for Everyone!?

Caveats

• Antibiotics after CT: 15% stopped, 45% started
• CT differed often with clinical / CXR disconnect

– CXR negative but high WBC, CRP, age, crackles – CXR positive but no concerning findings

• Alternate diagnoses: CHF, COPD
• Takehome: CXR is one part of the assessment and

is imperfect

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Case #1

A 64 yo woman with CHF is admitted with 2 days of fever, non- productive cough, and shortness of breath. She has been

• n levofloxacin for 24 hrs per PCP. T 38.8, BP 110/75, HR

90, sats 89% RA. WBC 11 k. CXR shows a patchy RLL

• infiltrate. She is started on Ceftriaxone / Azithro in the ED

and admitted to you. Her respiratory panel is positive for adenovirus and her serum procalcitonin (x2) is 0.05mcg / L. Now what?: 1) Wait for blood and sputum cultures before deciding 2) Stop antibiotics 3) Continue antibiotics for possible bacterial co-infection 4) Stop antibiotics and start Lasix for CHF exacerbation

CAP Etiologies

• Traditional thinking:

– S. Pneumoniae – H. Influenzae – Moraxella catarrhalis – Klebsiella – Atypicals (legionella, Mycoplasma, C. pneumoniae) – S. Aureus

CAP Etiologies

• CDC study in Chicago / Nashville (5 hospitals)
• All hospitalized adults with + CXR (>2000)
• Screened 18 hrs/ d, 7 d / week!
• 2010-2012
• 3-10 week f/u
• Control group without CAP in Nashville
• 80% Ward, 20% ICU

Jain S. NEJM 2015

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Procalcitonin

• Microbial toxins and bacterial-specific pro-

inflammatory mediators stimulate release

• Levels are higher with bacterial infections vs. other
• Rapid rise / fall correlates with clinical response
• Correlates with severity of illness / prognosis
• Not affected by steroids
• Rapid testing available

Procalcitonin: The Algorithm

CHEST 2012

Procalcitonin and Antibiotic Use

RCT/Year Patients with Respiratory Infection Setting Antibiotic Use Christ-Crain, 2004 243 ED Christ-Crain, 2006 302 ED/Inpt. Stolz, 2007 208 ED/Inpt. Briel, 2008 458 Multicenter Nobre, 2008 53 ICU Kristoffeger, 2009 210 ED/Inpt Schuetz, 2009 1359 Multicenter Stolz, 2009 101 Multicenter, ICU Long, 2009 127 ED Burkhardt, 2010 550 ICU Bouadma, 2010 397 ED Long, 2011 156 ED

Procalcitonin and Outcomes

5 10 15 20 25 Mortality Treatment Failure PCT Control

5.7% 6.3% 19% 22%

OR=0.94 (0.71-1.23) OR=0.82 (0.71-0.97) CID 2012 Cochrane 2012

14 Trials, 4221 Patients with Respiratory Infections

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Procalcitonin: Caution Warranted

• 260 CAP pts: Extensive diagnostic testing

– (blood, sputum, urine antigens, PCT, PCR for viral)

• 23% bacterial, 16% viral (+/- bacterial), 46% ?
• Bacterial: 23% with PCT < 0.1 mcg / L (many PSI IV)
• Viral: 23% with PCT > 0.25 mcg / L
• “A low PCT cannot RELIABLY exclude serious

bacterial infection”

Musher, et al. J. Infection 2013

Procalcitonin: Use in Practice

• 200,000 COPD patients; 5% with PCT testing
• Weak association with fewer abx starts
• No association with duration of therapy
• 85% did not get more than 1 PCT test

Lindenauer, In Press, 2016 Vaughn, Submitted, 2016 Lindenauer, In Press, 2016

Procalcitonin: Bottom Line

• It is another less than perfect, but potentially useful

diagnostic test

• Should not be sole variable used to decide whether

to use antibiotics or not

• Most useful when on the fence re giving / stopping

antibiotics

– e.g., infiltrate, positive viral panel AND low PCT

• It can reduce antimicrobial use if protocols for de-

escalation are followed

Key Topics to Cover

• Pneumonia

– Diagnosis: CXR / Etiologies / Procalcitonin – Antibiotics – Steroids

• “Healthcare-Associated Pneumonia”

– Which pneumonia patients are at risk for resistant

• rganisms?

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Key Issues in Antibiotic Management

• Are macrolides (atypical coverage) necessary?
• What regimens are effective for aspiration

pneumonia?

• What duration of treatment is ideal?

Macrolides and Outcomes

Meta-analysis; 23 studies with138,000 patients

Asadi, CID, 2012

Macrolides vs. Nonmacrolides Mortality: RR=0.78 (0.64-0.95)

Macrolides: Immunomodulatory Properties?

Corrales-Medina, Jo Infection, 2011

Antibiotic Therapy

IDSA / ATS 2007 Guidelines + Modifications

• b-lactam* + macrolide (or doxycycline)

(*Ceftriaxone, Cefotaxime, Amp / Sul, Ertapenem, Ceftaroline)

– Or, Respiratory fluoroquinolone

• ICU: ß-lactam+macrolide

– Or ß-lactam+fluoroquinolone – Anti-pseudomonal (many options) or CA-MRSA Rx (Vanco or Linezolid) if risk factors: independent of ICU status

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Macrolides and Outcomes

Asadi, CID, 2012

Meta-analysis; 23 studies with138,000 patients RR=1 Beta-lactam + macro vs. Fluoroquinolone Mortality RR = 1.17 (0.91-1.50) Macrolide vs. Nonmacrolide (RCTs only) Mortality RR = 1.13 (0.65-1.98)

Macrolides and Pneumonia

RCT: Beta Lactam + Macrolide vs. Beta Lactam

• RCT of 580 CAP pts; 6 Swiss hospitals
• Excluded: Severe Pneumonia, HCAP risk factors
• Legionella urine antigen performed in all
• Day7 Stability: HR < 100, SBP > 90, T < 38, RR < 24,

Oxygen Sat > 90% RA by day 7

• Macrolide: 67%

No Macrolide: 59%

Garin, et al. JAMA IM, 2014

Macrolides and Pneumonia

RCT: Beta Lactam + Macrolide vs. Beta Lactam Hazard Ratio for Instability Atypical pathogens 0.33 (0.13-0.85) PSI Class IV 0.81 (0.59-1.10) No atypical pathogens 0.99 (0.80-1.22) PSI Class I-III 1.06 (0.82-1.36)

(No diff at 90 days: mortality, ICU admits, LOS, complications, recurrence) Garin, et al. JAMA IM, 2014

Macrolides and Pneumonia

Pragmatic, Cluster, Randomized,Non-Inferiority Trial

Beta-lactam Beta-lactam + macro Fluoro Patients 656 739 888 Adherence 93% 88% 93% 90 d Mort. 9% 11% 8.8% Days to oral 4 4 3 LOS 6 6 6

Beta-lactam monotherapy: Non-inferior!

(for non-ICU patients without legionella) Postma DF, et al. NEJM, 2015

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Azithromycin: The Downside

• Excess CV mortality during treatment

– Based on large registries; due to QT prolongation? – 1 per 5000 courses: high CV risk patients

• Increasing resistance (S. Pneumo, others)
• Adverse drug events
• C. difficile

NEJM 2012

Fluoroquinolones: The Downside

• Very broad spectrum drugs

– Broad GNR coverage – Declining activity against Pseudomonas, E. Coli

• Adverse drug events

– FDA warnings against use in “uncomplicated infections” – Tendon rupture, neuropathy / CNS effects, etc.

• A major driver of C. difficile

Risk for C. Difficile

• High Risk

– Clindamycin – Fluoroquinolones – Cephalosporins / Carbepenems

• Low(er) Risk

– Penicillins, Macrolides, TMP/SMX

• No risk

– Tetracyclines

• Clearance of Colonization?

– Beta lactam / lactamase, metronidazoleDubberke, AAC, 2015

Brown, AAC, 2013

Ceftriaxone + Doxycycline?

Does Doxycycline Protect against C. difficile?

(Doernberg, et. al. CID, 2012)

• Observational, single center study
• Ceftriaxone + doxy vs. ceftriaxone +(levo or azithro)
• HR for C. diff = 0.15
• 27% lower rate of C. difficile for each day of doxy
• Doxycycline

– Has some activity against C.difficile – Inhibits protein synthesis (and C. diff toxin production) – Absorbed in the upper GI tract (less colonic delivery)

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Antibiotics for Pneumonia: Options

• Beta lactam + macrolide vs. beta lactam alone

– More benefit demonstrated in sicker patients – May not be necessary in some ward patients – (Assuming they do not have legionella)

• Fluoroquinolones vs. beta lactam + macrolide

– Ward patients: comparable outcomes to beta + macrolide – beta + macrolide favored for sicker patients – Important downsides exist

• Beta-lactam/lactamase+macrolide; beta-lacta + doxy

– Potentially beneficial if C. difficile is a local problem – Less outcome data

Case # 2

A 78 y.o. woman is admitted from assisted living with 2 days of somnolence / confusion and 1 day of fever, cough, and sputum production. She was recently started on hydrocodone for acute low back pain. T 38.5, HR 115, BP 110-70, sat 89%. Her CXR shows a RLL infiltrate, “concerning for aspiration”. In addition to stopping her narcotics, the most appropriate treatment is: 1) Supportive care only 2) Ceftriaxone + Azithromycin 3) Ceftriaxone + Azithromycin + Clindamycin 4) Clindamycin

Aspiration Pneumonia

• 15% of CAP hospitalizations called “aspiration

pneumonia”, but……

• All pneumonia is essentially aspiration pneumonia

– 50% of healthy adults aspirate during sleep

• Are the elderly unique?

Silent Aspiration Elderly with CAP 70% Elderly w/o CAP 10% – Pneumonia if reduced host defenses / high bacterial load

Marik, Curr Op Pulm Med. 2011

Aspiration Pneumonia

A Distinct Clinical Phenotype?

• “At risk”:

– Chronic neurologic / swallowing disorders – Altered consciousness / alcohol or drugs – Vomiting / witnessed choking – Gravity dependent radiographic changes

• Older, more co-morbidity
• Higher 1 year mortality / higher recurrence
• Adds to mortality in CAP and HCAP

Taylor, Am J Med. 2013 Komiya, Respirology. 2013

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Aspiration Pneumonia: Anaerobes

• El Sohl, et al. Am J Crit Care 2003

– 95 elderly NH patient with “severe aspiration” – Quantitative bronchial sampling – 67 pathogens isolated

• 50% GNRs
• 15% staph
• 15% anaerobes (over half also had GNR); low virulence orgs

– Poor functional status associated with anaerobes – 85% of patients with an anaerobe isolated improved on regimens without dedicated anaerobic coverage

Aspiration Pneumonia: Anaerobes

When to cover anaerobes

• Indolent symptoms
• Severe periodontal disease
• Putrid sputum
• Necrotizing / cavitary lesions / post-obstructive
• Large effusions (is it an empyema?)
• Elderly + poor functional status?
• Alcoholics

Aspiration Pneum(onitis vs. onia)

Jaoude, Emerg Med, 2012 Aspiration Pneumonia CAP

Time to Symptom Resolution Pneumonitis?

Aspiration Pneumonia

Time to Clinical Stability < 2 days > 2 days

Patients 102 227 Nursing home 67% 64% ICU transfer 23%* LOS (d) 4 6.5* 30 d mortality 9% 37%* β-lactam+macro 73% 70% Added clinda 2% 6% Authors propose stopping antibiotics in aspiration patients whose symptoms resolve in <48 hrs

* = significant difference Jaoude, Emerg Med, 2012

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Aspiration Pneumonia

Treatment

• Most do well with routine “CAP treatment”
• Risk stratify for anaerobes
• If concerned:

– Ceftriaxone / Levo are active against most oral anaerobes (but may miss B. Fragilis, some clostridia) – Ceftriaxone + Metronidazole: all anaerobes – Ceftriaxone + Clindamycin: all anaerobes, but also gets your pt C. Difficile

Treatment Duration: 5 Days

5 Days Rx and Stop if: T < 37.8 for 48 hrs and: No More than 1 of: SBP < 90 HR > 100 RR > 24 Sat < 90% Control Physician discretion

Uranga, JAMA IM 2016

Treatment Duration: 5 Days

5 Days and Stop Control Patients 162 150 30 Day Success 92% 89% Abx Days (Median) 5 10 30 Day Readmission 1.4% 6.6%

70% of the intervention group received 5 days of treatment

Uranga, JAMA IM 2016

Appropriate Duration: How well do we do?

30.8% 53.4% 15.9% 0% 10% 20% 30% 40% 50% 60% Appropriate Duration Excess Duration Excluded from logic

10 Michigan Hospitals 1400 Pneumonia Patients

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The First 5 Days

Ann Intern Med, 1964

Steroids for Pneumonia

Siemieniuk R, et. al. Ann Intern Med. 2015

13 RCTS with > 2000 pts Outcome Risk Ratio Absolute Effect NNT Mortality 0.67 (0.45-1.01) 3% fewer 33

(Severe CAP)

0.39 (0.2-0.77) Need MV 0.45 (0.26-0.79) 5% fewer 20 ARDS 0.24 (0.10-0.56) 6.2% fewer 16 LOS(d)

• 2.9 (-5.2- -.75)

1 d shorter Stability(d)

• 1.2 (-2.1- -0.4)

1.2 d sooner Hyperglyc 1.5 (1.01-2.2) 3.5% more 29

Steroids for Pneumonia

ISSUES

• Mortality most affected in severe CAP

– Driven by one small study stopped early – Variable definitions of “severe”

• Multiple steroid doses; from 1 dose to 10 days
• Excluded patients at risk for steroid adverse effects

– h/o GI bleed, immune suppression, etc.

• Hyperglycemia is associated with higher mortality?

Await Ongoing Trials

Key Topics to Cover

• Pneumonia Update

– Diagnosis: CXR / Etiologies / Procalcitonin – Macrolides for everyone: necessary and safe? – Steroids for pneumonia

• “Healthcare-Associated Pneumonia”

– Which pneumonia patients are at risk for resistant

• rganisms?

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Healthcare Associated Pneumonia

• Home Therapy

– IV – Wound Care – Nursing care through health agency

• Hospital or Dialysis Clinic in past 30 days for

– Dialysis / Any IV therapy

• Hospitalized ≥ 2 days in past 90? days
• Nursing Home or Long-Term Care Facility

At Risk for Multidrug-Resistant Organisms (MDROs)

IDSA / ATS Guidelines: Am J Resp Crit Care 2005

Vanco: 16% to 31% Pip-Tazo: 16% to 27% 2006 2010 Jones, BE. CID, 2015 MRSA: 2.5% to 2% Pseudomonas: 1.9% to 2% Jones, BE. CID, 2015

Pseudomonal Coverage for Pneumonia

21.6% 10.9% 44.4% 14.0% 1.0% 0.6% 2.1% 0.0% 0% 5% 10% 15% 20% 25% 30% 35% 40% 45% 50% All CAP HCAP PNA? Positive Pseudomonas No Pseudomonas

11.5%

46.5% 22.6%

10 Michigan Hospitals 1400 Pneumonia Patients

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HCAP: Diagnostic Performance

• From 2006-2010:

– Sensitivity increased (a little) – Specificity decreased ( a lot) – Diagnostic odds no better

• Meaning?

– The percentage of patients covered for MRSA and Pseudomonas without MRSA / Pseudomonas doubled – 1/3 of patients with positive cultures did not get coverage – Our current approach really sucks

Predicting Drug Resistant Organisms

An Evolving Story

• “HCAP” risk factors not all associated with MDROs
• Prior MRSA / pseudomonal infection : Important!
• Treatment for MDROs and Outcomes

– Severity adjusted outcomes not worse with HCAP – Risk stratification for MDROs necessary – Low risk: outcomes good with CAP treatment – High risk: outcome better? with broad spectrum rx

JHM, JGIM: 2012

Predicting Drug Resistant Organisms

Risk Scores: %Accuracy

ATS HCAP Criteria 69% DRIP 81% Schreiber 68% Shorr 56% Niederman 65% Shindo 67% Aliberti 66% Park 73% (Tested in culture positive patients, NPV >>> PPV)

Webb, AAC. 2016

Predicting MRSA and Pseudomonas

MRSA

More Likely Prior MRSA IVDU Dialysis High MRSA prevalence Prior hospital Less Likely No nasal colonization

Pseudomonas

More Likely Prior pseudomonas COPD Bronchiectasis Prior fluroquinolones Inhaled steroids Prior hospital

Metersky, Resp 2016 Waterer, Resp 2016

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Putting it All Together

• Strong Risk Factors for Resistant Organisms

– Prior Hospitalization in past 90 days / prior broad abx – LTAC / SNF if prior antibiotics, poor functional status – Critically Ill patients – Prior MRSA / Pseudomonas – Bronchiectasis / COPD (recurrent abx / chronic steroids)

• Weaker, Unclear

– Nursing home (alone) – Dialysis (may be MRSA risk) – Wound Care / Home Health / Feeding tubes / PPI/ H2

• Too heterogeneous (but important)

– Immunosuppressed

A General Approach

Evaluate MDRO Risk Factors

Quantity Risk 1 2 3 4 5 6 Higher Illness Severity Lower Illness Severity

If Broad Spectrum Rx

• Blood/Sputum CX
• De-escalate if negative at 48-72
• 7 day treatment is sufficient for most

Legend: Threshold for broad spectrum Rx

High MDRO Prevalence / Prior MDRO Low MDRO Prevalence

Conclusions

• CXR / Etiologies / PCT

– CXR is imperfect and most CAP is viral – Following PCT protocols will help reduce abx overuse

• Macrolides

– Data still supports use in sicker pts – Ward patients: benefit unclear? if no legionella

• Steroids

– May hold some promise – Need further study to identify a target population, dosing

• Patients at risk for resistant organisms

– Risk stratify and target broad spectrum treatment – De-escalate if cx negative; treat for 1 week

THANK YOU!

QUESTIONS?

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De-escalation: “HCAP”

Oral Antibiotic Options Augmentin Respiratory Fluoroquinolone (Levofloxacin, Moxifloxacin) Oral 3rd generation cephalosporin