Catching up on Pneumonia - sowega-ahec.org · 2/19/2018 1 Catching up on Pneumonia Daniel B. Chastain, Pharm.D., AAHIVP Clinical Assistant Professor UGA College of Pharmacy ID Pharmacist,

2/19/2018

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Catching up on Pneumonia

Daniel B. Chastain, Pharm.D., AAHIVPClinical Assistant Professor UGA College of Pharmacy

ID Pharmacist, Phoebe Putney Memorial HospitalFebruary 24, 2018

Disclosures

• I have nothing to disclose

Objectives

• Identify major differences in the various types of pneumonia

• Review infectious etiology and risk factors for multidrug‐resistant (MDR) organisms

• Discuss guideline recommendations for treatment and duration

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What is a pneumonia?

• Acute infection of pulmonary parenchyma

• Result of:

– Defect in host defense

– Exposure to virulentorganism

– Overwhelminginoculum

Southwick, F. Infectious Diseases: A Clinical Short Course, 2nd ed.http://www.thevisualmd.com/spaw/uploads/Blausen_0994_Pneumonia.jpg

And then what?

Southwick, F. Infectious Diseases: A Clinical Short Course, 2nd ed.http://nucleus.con.ohio‐state.edu/it/pneumoniacasestudy/pneumonia/Pneumonia_print.html

• Capacity of the alveolar macrophages to ingest/kill the microorganisms is exceeded pneumonia

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How do organisms get there?

1. Inhalation of contaminated droplets

2. Aspiration of oropharyngeal contents

3. Hematogenous spread from extrapulmonarysites

Southwick, F. Infectious Diseases: A Clinical Short Course, 2nd ed.

Diagnosis of pneumoniaDemonstrable infiltrate by chest radiograph or other imaging technique

Clinical signs/symptoms

Microbiological data

Mandell LA, et al. Clin Infect Dis. 2007 Mar 1;44 Suppl 2:S27‐72.Am J Respir Crit Care Med 2005;171(4):388‐416.Kalil AC, et al. Clin Infect Dis 2016;63(5):e61‐e111.

Pneumonia classifications

Community Acquired Pneumonia (CAP)• Community‐dwelling outpatient• Inpatient if diagnosis < 48hrs of admission

Mandell LA, et al. Clin Infect Dis. 2007 Mar 1;44 Suppl 2:S27‐72.Am J Respir Crit Care Med 2005;171(4):388‐416.Kalil AC, et al. Clin Infect Dis 2016;63(5):e61‐e111.

CAP

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CAP epidemiology

• Top 10 most common causes of death among all age groups in US

• Single most common cause of infection‐related mortality

– 30‐40% mortality rate

• Occurs in persons of all ages

– ~6 cases/1000 persons annually

– Most severe in very young, elderly, chronically ill

Mandell LA, et al. Clin Infect Dis. 2007 Mar 1;44 Suppl 2:S27‐72.

He/She has CAP….now what?

• Initial assessment of severityCURB‐65

Confusion (disorientation to person, place, or time) + 1

Uremia (BUN > 20mg/dL) + 1

Respiratory rate (> 30breaths/min) + 1

Blood pressure (SBP < 90mmHgOR DBP < 60mmHg) + 1

Age (> 65 yrs) + 1

• Direct ICU admission:– Septic shock requiring vasopressors– Acute respiratory failure requiring intubation with mechanical ventilation


Score 0‐1

1.5% mortality

Outpatient treatment

Score 2

~10% mortality

Inpatient treatment, non‐ICU

Score > 3

~25+% mortality

Inpatient treatment, ICU

What organisms do we need to cover?

• It depends…


Respiratory viruses: influenza A and B, respiratory syncytial virus, and parainfluenza

Score 0‐1

1.5% mortality

Outpatient treatment

S. pneumoniaeM. pneumoniaeH. influenzaeC. pneumoniaeRespiratory viruses

Score 2

~10% mortality

Inpatient treatment, non‐ICU

S. pneumoniaeM. pneumoniaeC. pneumoniaeH. influenzaeLegionella sp.AspirationRespiratory viruses

Score > 3

~25% mortality

Inpatient treatment, ICU

S. pneumoniaeS. aureusLegionella sp.Gram‐negative bacilliH. Influenzae

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Outpatient Treatment Options


Previously healthy, no antibiotic therapy

< 3 months

Presence of comorbidities* or antimicrobial use < 3 months OR High rate (>25%) of macrolide‐resistant S. pneumoniae

*comorbidities such as chronic heart, lung, liver or renal disease; diabetes mellitus; alcoholism; malignancies; asplenia;

immunosuppressing conditions or use of immunosuppressing drugs

Macrolide • Azithromycin 500mg PO x 1,

then 250mg/d x 4 days or 500mg/d x 3 days

Doxycycline 100mg PO q12hrs

Respiratory FQ• Levofloxacin 750mg PO q24hrs• Moxifloxacin 400mg PO q24hrs

β‐lactam• Amox/Clav 2g PO q12hrs• Cefuroxime 500mg PO q12hrs

PLUSMacrolide (azithromycin)Doxycycline 100mg PO q12hrs

• Macrolides, FQs prolong QTc• FQs associated with ↑ risk of

C. difficile infections, dysglycemias

Microbiologic studies not routinely necessary

Inpatient, non‐ICU Treatment Options


Respiratory FQ• Levofloxacin 750mg IV/PO q24hrs• Moxifloxacin 400mg IV/PO q24hrs

β‐lactam• Ceftriaxone 1‐2g IV q24hrs• Ampicillin/sulbactam 3g IV q6hrs

PLUSMacrolide• Azithromycin 250‐500mg IV/PO q24hrsDoxycycline 100mg PO q12hrs

• Macrolides, doxycycline, FQs‐ IV = PO• Macrolides, FQs prolong QTc• FQs associated with ↑ risk of

C. difficile infections, dysglycemias

Sputum culture performed on all patients admitted with CAP If severe, blood cultures, Legionella urinary antigen, and Pneumococcal urinary antigen

Inpatient, ICU Treatment Options

Respiratory FQ• Levofloxacin 750mg IV/PO q24hrs• Moxifloxacin 400mg IV/PO q24hrs

β‐lactam• Ceftriaxone 1‐2g IV q24hrs• Ampicillin/sulbactam 3g IV q6hrs

PLUS

Macrolide• AzithromycinDoxycycline 100mg IV/PO q12hrs

OR

If MRSA is a concern, add:• Vancomycin 15‐20mg/kg IV q12hrs• Linezolid 600mg IV/PO q12hrsMRSA, 1‐2%• Risk factors: recent influenza‐like

illness, glucocorticoid use, necrotizing or cavitary pneumonia, presence of empyema

If Pseudomonas is a concern, replace above regimens with:• Piperacillin/tazobactam 4.5g IV q6hrs• Cefepime 2g IV q8hrs

PLUS• Antipseudomonal FQ (ciprofloxacin, levofloxacin)

OR• Aminoglycoside + azithromycin or respiratory FQP. aeruginosa, low*• Risk factors: COPD or bronchiectasis, especially those

on glucocorticoids, immunosuppressantsMandell LA, et al. Clin Infect Dis. 2007 Mar 1;44 Suppl 2:S27‐72.Musher DM, et al. N Engl J Med. 2014 Oct 23;371(17):1619‐28.Prina E, et al. Lancet. 2015 Sep 12;386(9998):1097‐108.

Sputum culture Blood culturesLegionella urinary antigenPneumococcal urinary antigen± Bronchoscopy

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The finer points…

• Treatment based on accurate diagnosis

– Differential: CHF, COPD

• Low rates of resistance to empiric therapy

• If an organism is isolated, narrow therapy

– Causative pathogen not identified in ~60%

• Influenza, rhinovirus, coronaviruses, ~30%

– Blood cultures positive 5‐15%

Mandell LA, et al. Clin Infect Dis. 2007 Mar 1;44 Suppl 2:S27‐72.Prina E, et al. Lancet. 2015 Sep 12;386(9998):1097‐108.

Management considerations

• Corticosteroids, decrease instability by 1 day, no difference in mortality– Prednisone 50mg/day x 5 days

• Switch to PO therapy once stable– Amoxicillin (or amox/clav) ± azithromycin

• 5 days for low‐severity• 7 days for severe

• Pneumococcal, influenza vaccinations!


Patient outcomes

• Clinical improvement < 48‐72 hours– Cough < 8 days

– Auscultatory crackles < 21 days

• Radiographic improvement < 4‐12 weeks

• Failure to improve, resistant pathogen, parapneumonic effusion or empyema, noninfectious etiology

• < 12% readmitted < 30 days due to comorbidities


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CAP

HAP

Mandell LA, et al. Clin Infect Dis. 2007 Mar 1;44 Suppl 2:S27‐72.Am J Respir Crit Care Med. 2005 Feb 15;171(4):388‐416.Kalil AC, et al. Clin Infect Dis. 2016 Sep 1;63(5):e61‐e111.

Hospital‐acquired pneumonia (HAP)• > 48hrs after hospital admission

Epidemiology of HAP

• ~50% occur in < 66 YOA outside of ICU

• Leading cause of infection‐related deaths

– Prolongs hospitalization by 7‐9 days

– Attributable mortality: 20‐33%

– Serious complications in < 50% HAPs

• Respiratory failure, pleural effusions, septic shock, etc.

Kalil AC, et al. Clin Infect Dis. 2016 Sep 1;63(5):e61‐e111.Baker D, et al. Am J Infect Control. 2018 Jan;46(1):2‐7.

The ever‐changing microbiome

• Complex interaction

– Naso/oropharyngeal flora

– Duration of hospitalization

– Previous antimicrobial therapy

– Comorbid conditions

• Community hospital acquired ~ 2 days

Am J Respir Crit Care Med. 2005 Feb 15;171(4):388‐416.Kalil AC, et al. Clin Infect Dis. 2016 Sep 1;63(5):e61‐e111.

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Infectious Etiology

• Wide variety of pathogens– Aerobic Gram negative bacilli

• Escherichia coli, Klebsiella pneumoniae, etc.

• Pseudomonas aeruginosa, Acinetobacter sp., etc.

– Gram positive cocci• Streptococcus sp.

• Staphylococcus aureus, including methicillin susceptible (MSSA) and methicillin resistant (MRSA)

– Viral or fungal, rare in immunocompetent

• Influenced by host and hospital factors

Kalil AC, et al. Clin Infect Dis. 2016 Sep 1;63(5):e61‐e111.

Microbiologic Evaluation

• Blood and respiratory cultures in all patients

– Typically, lower respiratory tract samples

• Expectorated sputum, tracheal secretions of limited use due to colonization

• Reserve invasive sampling (e.g. bronchoscopy) if clinically worsening


HAP Treatment Options

• Piperacillin/tazobactam 4.5g IV q6hrs• Cefepime 2g IV q8hrs• Levofloxacin 750mg IV/PO q24hrs

• Linezolid, FQs‐ IV = PO• FQs associated with ↑ risk of C. difficile infections,

dysglycemias• *Verify penicillin allergies (true allergy < 1%)• **Reserve carbapenems for severely ill patients

• Piperacillin/tazobactam 4.5g IV q6hrs• Cefepime 2g IV q8hrs• Levofloxacin 750mg IV/PO q24hrs• Aztreonam 2g IV q8hrs*

PLUS• Vancomycin 15‐20mg/kg IV q12hrs• Linezolid 600mg IV/PO q12hrs

• If structural lung disease (bronchiectasis or CF), COPD, or respiratory culture with Gram negative bacilli, add FQ (if not used above) or aminoglycoside)

1. Patients not at increased risk of mortality (e.g. not on MV, not in septic shock)

2. No IV antibiotics < 90 days

Low risk of MRSA (prevalence < 10‐20%)

> 20% or unknown prevalence of MRSA


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HAP Treatment Options

• Linezolid, FQs‐ IV = PO• FQs associated with ↑ risk of C. difficile

infections, dysglycemias• *Verify penicillin allergies (true allergy < 1%)• **Reserve carbapenems for severely ill patients

1. Patients at increased risk of mortality (e.g. on MV, in septic shock)

2. IV antibiotics < 90 days

• Piperacillin/tazobactam 4.5g IV q6hrs• Cefepime 2g IV q8hrs• Aztreonam 2g IV q8hrs*• Meropenem 2g IV q8hrs**

• Vancomycin 15‐20mg/kg IV q12hrs• Linezolid 600mg IV/PO q12hrs

PLUS • Antipseudomonal FQ (cipro, levo)OR

• Aminoglycoside (tobra, gent, amikacin)

PLUS

• High rate of mortality – mechanical ventilation or septic shock• Cover MRSA if prior IV antibiotic use < 90 days, > 20% or unknown S. aureus isolates are MRSA• Risk factors associated with MDR organisms – prior IV antibiotic use < 90 days


Who needs coverage for MRSA?

• Anti‐MRSA agent (vancomycin, linezolid)

– High risk of mortality (MV support, septic shock)

– Prior IV antibiotic use < 90d

– > 20% or unknown S. aureus isolates are MRSA

• Anti‐MSSA agent (PTZ, cefepime, carbapenem)

– No risk factors, not at high risk of mortality

– < 20% S. aureus isolates are MRSA


Gram negative bacilli in HAP

• Double cover (β‐lactam, cephalosporin, carbapenem, monobactam + FQ)

– High risk of mortality (MV support, septic shock)


• Single agent therapy (β‐lactam, cephalosporin, carbapenem, monobactam)

– Everyone else


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CAP

VAP

HAP


Ventilator‐associated pneumonia (VAP) • > 48‐72hrs after endotracheal intubation

Epidemiology of HAP/VAP

• VAP in 10% of MV patients

– Highest risk early in MV

• Prolongs MV by 7‐12 days, hospitalization by 11‐13 days

• VAP all‐cause mortality: 20‐50%

Cook DJ, et al. Ann Intern Med. 1998 Sep 15;129(6):433‐40.Kalil AC, et al. Clin Infect Dis. 2016 Sep 1;63(5):e61‐e111.

3% risk/day for days 1‐5

2% risk/day for days 6‐10

1% risk/day for > 10 days

Diagnosis of pneumoniaDemonstrable infiltrate by chest radiograph or other imaging technique

Clinical signs/symptoms

Microbiological data

Fàbregas N, et al. Thorax. 1999 Oct;54(10):867‐73.Mandell LA, et al. Clin Infect Dis. 2007 Mar 1;44 Suppl 2:S27‐72.Am J Respir Crit Care Med 2005;171(4):388‐416.Kalil AC, et al. Clin Infect Dis 2016;63(5):e61‐e111.

• VAP: CXR infiltrate + ≥ 2 signs (↑ WBC, purulent secre ons, fever)

• Signs/symptoms without CXR infiltrate: nosocomial tracheobronchitis

Sensitivity 69%, specificity 75%

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VAP Treatment Options

• Piperacillin/tazobactam 4.5g IV q6hrs• Cefepime 2g IV q8hrs• Levofloxacin 750mg IV/PO q24hrs

• Piperacillin/tazobactam 4.5g IV q6hrs• Cefepime 2g IV q8hrs• Levofloxacin 750mg IV/PO q24hrs• Aztreonam 2g IV q8hrs*• Meropenem 2g IV q8hrs**

PLUS• Antipseudomonal FQ (cipro, levo)

OR• Aminoglycoside (tobra, gent, amikacin)

If ALL answers are no…1. IV antibiotics < 90 days?2. Septic shock at time of VAP diagnosis?3. ARDS preceding VAP diagnosis?4. > 5 days of hospitalization prior to VAP diagnosis?5. Need for acute renal replacement therapy prior to VAP diagnosis?

< 10% Gram negative isolates resistant to monotherapy agent

> 10% Gram negative isolates resistant to monotherapy agent

Add vancomycin 15‐20mg/kg IV q12hrs or linezolid 600mg IV/PO q12hrs if > 20% or unknown prevalence of MRSA


VAP Treatment OptionsIf ANY answers are yes…1. IV antibiotics < 90 days?2. Septic shock at time of VAP diagnosis?3. ARDS preceding VAP diagnosis?4. > 5 days of hospitalization prior to VAP diagnosis?5. Need for acute renal replacement therapy prior to VAP diagnosis?

• Piperacillin/tazobactam 4.5g IV q6hrs• Cefepime 2g IV q8hrs• *Aztreonam 2g IV q8hrs• **Meropenem 2g IV q8hrs




PLUS


Diagnosis…not always straightforward

• Cardinal signs neither sensitive nor specific

• Concomitant pulmonary complications

• Absence of new infiltrate, diagnosis unlikely

• Stable ventilator settings, diagnosis unlikely

• No improvement after 48‐72hrs of empiric antibiotics, alternative diagnosis


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The role of MRSA in VAP

• Anti‐MRSA agent (vancomycin, linezolid)


– > 20% or unknown S. aureus isolates are MRSA

• Anti‐MSSA agent (PTZ, cefepime, carbapenem)

– No risk factors

– < 20% S. aureus isolates are MRSA


Gram negative bacilli in VAP

• Double cover (β‐lactam, cephalosporin, carbapenem, monobactam + FQ)– Prior IV antibiotic use < 90d, septic shock, ARDS, > 5d of hospitalization, acute RRT

– > 10% isolates resistant to monotherapy agent

• Single agent therapy (β‐lactam, cephalosporin, carbapenem, monobactam)– No risk factors

– < 10% isolates resistant to monotherapy agent


Double Coverage vs. GNR

1. Increase probability that empiric regimen has activity

2. Achieve synergy between multiple agents

3. Decrease probability of acquired resistance

• Appropriate for those at high risk of MDR

• No difference in outcome once susceptibilities available

– Increased risk of ADEs, resistance, etc.


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Aerosolized antibiotics: Theoretical value?

• Improve pulmonary penetration, limiting systemic toxicities

– Enhanced microbiologic clearance

– No impact on duration of MV, LOS, mortality

• Useful as adjunct against MDR GNR

– Susceptible only to aminoglycosides or polymyxins

– Last resort


Managing HAP/VAP

• Inadequate/delayed therapy = poor outcomes, ↑ mortality

• If an organism is isolated, narrow therapy– S. aureus and P. aeruginosa EASY to isolate in culture if not isolated from quality respiratory specimen, then discontinue MRSA coverage and MDR Gram negative coverage

• Switch to PO therapy once stable


The Art of Deescalation

• Continued broad/double coverage– Expensive, promotes resistance, harmful

• Gram stain from respiratory specimen

• Negative cultures– Clinical judgment

– Proportion unlikely to have pneumonia

• Positive cultures– Definitive therapy based on susceptibility


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How long do they really need?

• 7 days!!!

– Regardless of pathogen

– Shorter or longer depending on clinical, laboratory, radiologic parameters

• No difference in MV‐free days, ICU LOS, mortality, or recurrent infection



Healthcare‐associated pneumonia (HCAP)Community‐dwelling patient admitted with recent healthcare contact:• Recent hospitalization (> 2d within 90d)• Residence in NH or LTCF• Home infusion, wound care, HD within 30d• Family member with MDR pathogen

CAP

VAP

HAP


Guidelines…before

Am J Respir Crit Care Med. 2005 Feb 15;171(4):388‐416.

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Guidelines…and after


HCAP

• Increased risk for MDR organisms

– Nursing homes/long‐term care facilities

– Hemodialysis centers

– Outpatient clinics

– Recent hospitalization

• Not included in 2016 HAP/VAP guidelines…but why?


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Antibiotic Use in HCAP, 2006‐2012

Jones BE, et al. Clin Infect Dis 2015;61(9):1403‐10.

Proportion with positive cultures

Jones BE, et al. Clin Infect Dis 2015;61(9):1403‐10.

So what does this mean?

1. Patients with HCAP are not at high risk for MDR organisms

2. HCAP poor predictor for infection with MDR organisms

3. Underlying patient comorbidities > interaction with healthcare system as determinants for MDR organisms

4. No evidence supporting improved outcomes if HCAP treated the same as HAP

Attridge RT, et al. Am J Med. 2011 Aug;124(8):689‐97. Lopez A, et al. Eur J Intern Med. 2012 Jul;23(5):407‐11.Yap V, et al. Infect Dis Clin North Am. 2013 Mar;27(1):1‐18.Shorr AF, et al. Clin Infect Dis. 2012 Jan 15;54(2):193‐8. Jones BE, et al. Clin Infect Dis 2015;61(9):1403‐10.Webb BJ, et al. Antimicrob Agents Chemother. 2016 Apr 22;60(5):2652‐63.

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What happened to HCAP?

The future of HCAP?

Shindo Y, et al. Am J Respir Crit Care Med. 2013 Oct 15;188(8):985‐95.

Risk factors of antimicrobial resistance in CAP

Univariate AnalysisOR(95% CI)

Multivariate analysisOR(95% CI)

Hospitalization for >2 days in the preceding 90 days

4.63 (3.03‐7.09) 2.06 (1.23‐3.43)

Immunosuppression 2.68 (1.40‐5.13) 2.31 (1.05‐5.11)

Use of antibiotics in previous 90 days

3.60 (2.40‐5.40) 2.45 (1.51‐3.98)

Tube feeding 6.15 (3.41‐11.10) 2.43 (1.18‐5.00)

Non‐ambulatory status 3.89 (2.60‐5.84) 2.45 (1.40‐4.30)

Rethinking HCAP treatment

Brito V, et al. Curr Opin Infect Dis. 2009 Jun;22(3):316‐25.

HCAP is present: from a nursing home, recent hospitalization, hemodialysis, home infusion therapy

Assess severity of illness (need for MV, ICU admit)AND

Presence of risk factors for MDR organisms(recent antibiotics, recent hospitalization,

poor functional status, immune suppression)

Severe pneumonia?

0‐1 risksTreat for common CAP

organisms, PO β‐lactam + macrolide or FQ

> 2 risksConsider hospitalTreat for MDR

organisms with HAP therapy

0 risksTreat for severe

pneumonia in hospitalPO/IV β‐lactam + macrolide or FQ

> 1 risksTreat for MDR

organisms with HAP therapy

No Yes

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We are stuck, for now…

• Linezolid, FQs‐ IV = PO• FQs associated with ↑ risk of C. difficile

infections, dysglycemias• *Verify penicillin allergies (true allergy < 1%)• **Reserve carbapenems for severely ill patients

• Piperacillin/tazobactam 4.5g IV q6hrs• Cefepime 2g IV q8hrs• *Aztreonam 2g IV q8hrs• **Meropenem 2g IV q8hrs




PLUS

Am J Respir Crit Care Med. 2005 Feb 15;171(4):388‐416.

Managing HCAP

• If an organism is isolated, narrow therapy– S. aureus and P. aeruginosa EASY to isolate in culture if not isolated from quality respiratory specimen, then discontinue MRSA coverage and MDR Gram negative coverage

• Switch to PO therapy once stable– If on FQ, then change to same FQ PO

– Amoxicillin/clavulanate

• 7 day duration extrapolated from HAP/VAP

Am J Respir Crit Care Med. 2005 Feb 15;171(4):388‐416.Boyce JM, et al. Antimicrob Agents Chemother. 2013 Mar;57(3):1163‐8.

Conclusion

• Potentially life‐threatening illnesses

• Ensure symptoms and radiographic findings support diagnosis

• Correctly classify type of pneumonia

• Limit unnecessary use of dual agents against Gram negative pathogens and anti‐MRSA therapy

• Emphasize antimicrobial deescalation

• Short course antimicrobial therapy

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Questions?Daniel B. Chastain, Pharm.D., AAHIVP

Clinical Assistant Professor

UGA College of Pharmacy

ID Pharmacist, Phoebe Putney Memorial Hospital

[email protected] or [email protected]

Documents

Catching up on Pneumonia - sowega-ahec.org · 2/19/2018 1 Catching up on Pneumonia Daniel B. Chastain, Pharm.D., AAHIVP Clinical Assistant Professor UGA College of Pharmacy ID Pharmacist,