Pneumonia (12 from URI, COVID, PNE)

Risk factors for VAP MDR pathogens

MDR pathogens risk factors IV antibiotics last 90 days Septic Shock = mortality Acute respiratory distress syndrome ARDS preceding VAP 5+ days of hospitalization prior Acute Renal Replacement prior to VAP Pseudomonas risk factors Bronchiectasis Cystic fibrosis IV antibiotics last 90 days Septic Shock Acute respiratory distress syndrome ARDS preceding VAP 5+ days of hospitalization prior Acute Renal Replacement prior to VAP

VAP guided steps

MRSA risk factors? YES to the following: More than 10% S. Aureus isolates are MRSA Risk of Multi Drug resistant pathogens Tx- Vancomycin or Linezolid NO to MRSA: Less than 10% S. Aureus isolates are MRSA No risk of Multi Drug resistant pathogens Tx with - Pip-tazo, cefepime, levofloxacin or meropenem Dual therapy Pseudomonas? YES to the following: More than 10% gram negative isolates resistant to monotherapy or risk of MDR pathogens Combination of: pip-tazo cefepime meropenem or Aztreonam + FQ-Ciprofloxacin, Levofloxacin, Moxifloxacin or Aminoglycoside Amikacin, Gentamicin, Kanamycin, Streptomycin, Tobramycin or Colistin No dual therapy then Tx for antipseudomonal monotherapy pip-tazo cefepime meropenem levofloxacin Aminoglycoside- Amikacin, Gentamicin, Kanamycin, Streptomycin, Tobramycin

HAP guided steps

MRSA risk factors? YES to the following: Prior IV antibiotics last 90 days More than 20% S. Aureus isolates are MRSA Mechanical Ventilation = mortality Septic Shock = mortality Tx- Vancomycin or Linezolid NO to MRSA: Tx for MSSA coverage Tx with - Pip-tazo, cefepime, levofloxacin or meropenem Dual therapy Pseudomonas? YES to the following: Prior IV antibiotics last 90 days Mechanical ventilation= mortality Septic Shock = mortality Combination of: pip-tazo cefepime meropenem Plus FQ Ciprofloxacin, Levofloxacin, Moxifloxacin or Aminoglycoside Amikacin, Gentamicin, Kanamycin, Streptomycin, Tobramycin No dual therapy then Tx for antipseudomonal monotherapy pip-tazo cefepime meropenem levofloxacin Aminoglycoside- Amikacin, Gentamicin, Kanamycin, Streptomycin, Tobramycin

Community Acquired Pneumonia (CAP) Microbiology

Outpatient Streptococcus pneumoniae (75%) Mycoplasma pneumoniae Haemophilus influenzae Chlamydophila pneumoniae Viral Inpatient Streptococcus pneumoniae Mycoplasma pneumoniae Chlamydophila pneumoniae Haemophilus influenzae Legionella spp Aspiration Viral Inpatient (severe category bugs to cover) Streptococcus pneumoniae Staphylococcus aureus Legionella spp Gram-negative bacilli (Klebsiella, Pseudomonas) Haemophilus influenzae

Resistance Rates to S. pneumoniae

Penicillins Amoxicillin/clavulanate 4% Penicillin 21% Cephalosporins Cefepime <1% Ceftriaxone 2% Cefuroxime 25% Fluoroquinolones Levofloxacin <1% Moxifloxacin <1% Macrolides Azithromycin 23% Clindamycin 9% Vancomycin 0%

Pathogen Risk Factors

Pseudomonas aeruginosa Structural lung disease Frequent steroid and antibiotic use Prior antibiotic therapy Gram-negative pathogens such as Klebsiella spp or Acinetobacter spp Chronic alcoholism Staphylococcus aureus End-stage renal disease on Dialysis Injection drug use Prior viral influenza often get Prior antibiotic therapy

Initial Empiric Therapy

Antibiotic (IV) Cefepime (4th gen cephlasporin) G+/G- cidal Ceftazidime (3rd gen cephlasporin) G+/G- cidal Imipenem (Carbapenems) G+/G- cidal Meropenem (Carbapenems)G+/G- cidal Piperacillin-tazobactam (Anti-pseud PCN) G+/G- cidal Gentamicin/tobramycin (Aminoglycoside) G- cidal Amikacin (Aminoglycoside) G- cidal Levofloxacin (Fluoroquinolones) G+/G- cidal Ciprofloxacin (Fluoroquinolones) G+/G- cidal Vancomycin- 10% lung penetration (G+) Linezolid- 100% lung penetration (G+)

Duration of Therapy

Bottom line: HAP/VAP duration of 7 days of treatment. Could consider 14 days if P. aeruginosa or Acinetobacter spp. •Prospective randomized controlled trial of 401 patients with VAP •Randomized to receive 8 days or 15 days of antibiotics •Found No difference in mortality, recurrent infections, or length of ICU stay •Found Group who received 8 days overall received less antibiotics •Found Infections caused by non-lactose fermenting gram negative bacilli had more recurrences if treated for 8 days

IDSA Severity Index (know the major)

Defining Severe Community-acquired Pneumonia Validated definition includes either one major criteria or three or more minor criteria Major criteria Septic shock with need of vasopressors Respiratory failure requiring mechanical ventilation Minor criteria Respiratory Rate greater than or equal to 30 PaO2/FiO2 ratio greater than or equal to 250 Multilobar infiltrates Confusion/disorientation Uremia (Blood urea Nitrogen (BUN) greater than or equal to 20 mg/dL Leukopenia (white blood cell count) greater than 4,000 cells/uL due to infection Thrombocytopenia (platelet count) greater than 100,000/uL Hypothermia (core temp less than 36*C or 96.8F) Hypotension needing aggressive fluid resuscitation

Risk factors for Multidrug resistant VAP/HAP/ VAP& HAP/and Psurdomonas VAP/HAP

Risk factors for Multi Drug resistant VAP -Prior IV antibiotics last 90 days (3 months) -Septic shock at time of VAP -Acute Respiratory distress syndrome (ARDS) preceding VAP -Five days or more of hospitalization prior to VAP -Acute renal replacement therapy prior to VAP Risk factors for Multi Drug resistant HAP Prior IV antibiotic use within 90 days Risk factors for MRSA VAP or HAP Prior IV antibiotic use within 90 days Risk factors for Multi Drug resistant Pseudomonas VAP/HAP Prior IV antibiotic use within 90 days

CAP patient change from IV to PO

•1-Hemodynamically stable •2-Improving clinically •3-Able to ingest medications •4 Normal function of GI tract •5 Hemodynamically stable •Clinical stability guideline •Temp ≤ 37.8C •HR ≤ 100 bpm •RR ≤ 24 breaths/min •SBP ≥ 90 mmHg •O2 Sat ≥ 90% •Normal mental status •Use same agent or same drug class as IV antibiotic •If received IV Beta-lactam + macrolide, switch to macrolide alone is safe if no drug resistant S. pneumoniae or gram-negative enteric pathogens •Respiratory fluoroquinolones have good bioavailability IV Azithromycin to PO Azithromycin IV Doxycycline to PO Doxycycline IV Moxifloxacin to PO Moxifloxacin IV Levofloxacin to PO Levofloxacin IV Ceftriaxone to PO Cefdinir IV Ampicillin-sulbactam to PO Amoxicillin-clavulanate

Duration of therapy

•5 days for most appropriate for most patients •If confirmed MRSA or Pseudomonas, then extend 7 days •Septic shock •Grown MRSA or pseudomonas in past •Longer if: •meningitis, endocarditis, or other deep-seated infection •infection with other, less-common pathogens (i.e. tuberculosis)

Community Acquired Pneumonia (CAP) Risk Factors

•Age > 65 years •Immunocompromised •Recent treatment with antibiotics •Comorbidities (any) •Asthma/COPD •Cerebrovascular disease •Chronic renal failure •Diabetes •Heart failure Hepatic disease

Initial Empiric Therapy for HAP or VAP

•Antipseudomonal Beta-lactam + •Antipseudomonal cephalosporin Ceftazidime and cefepime •Antipseudomonal carbapenem imipenem, meropenem, and doripenem •Beta-lactam/beta-lactamase inhibitor Antipneumococcal/Antipseudomonal β-lactam = Cefepime, Imipenem, Meropenem, Piperacillin/Tazobactam, Doripenem •Anti-MRSA + •Linezolid or vancomycin •Consider double coverage fluoroquinolone or aminoglycoside •Antipseudomonal fluoroquinolone Ciprofloxacin, levofloxacin, Moxifloxacin •Aminoglycoside amikacin, gentamicin, kanamycin, streptomycin, Tobramycin

Community Acquired Pneumonia (CAP) Epidemiology

•Approximately 4 million people develop CAP annually •Over 80% treated as outpatient •Leading cause of infection-related death •Cost of $40 billion annually

Inpatient CAP (all PO meds as IV)

•Beta-lactam + macrolide •Preferred beta-lactams: ampicillin-sulbactam cefotaxime ceftriaxone ceftaroline Macrolide: Erythromycin Azithromycin Clarithromycin Fidaxmicin •Alternative to macrolide: doxycycline •OR •Respiratory fluoroquinolone monotherapy (moxifloxacin, gemifloxacin, and levofloxacin) OR •Beta-lactam + macrolide Beta-lactam + Doxycycline Beta-lactam + Respiratory fluoroquinolone

Procalcitonin (PCT) in CAP

•Biomarker elevated in presence of bacterial infection, unaffected by viral infection or use of steroids •Sensitivity ranges from 38-91% in CAP• Rises within 6-12 hrs of infection •Normal < 0.05 ng/mL •Pneumonia •Antibiotics strongly discouraged: <0.1 ng/mL •Antibiotics discouraged: 0.1-0.25 ng/mL •Antibiotics encouraged: > 0.25 ng/mL •Septic shock level of 120 •Take at initial presentation, monitor days 3, 5, 7 for de-escalation •"Empiric abx should be initiated in clinically suspected & radiographically confirmed CAP regardless of initial serum PCT level"

Supportive Care for CAP

•Bronchodilators •Albuterol •Ipratropium •Often nebulizers while inpatient •Oxygen support (very common at elevation) •Nasal cannula or face mask •Mechanical ventilation •Corticosteroids (hard stand) •Controversial •Potential benefit in severe CAP based on 2015 review/meta-analysis •NOT recommended in 2019 guideline for CAP alone (just the bronchodilators and oxygen support •Only in COPD patients

Severity of Illness Scores Community-Acquired Pneumonia (CAP)

•CURB-65 •Confusion •Uremia •Respiratory rate •Low Blood pressure •Age 65 years or greater -CURB Score of 2 = home treatment Score of 3-4 = admission Score of 4-5 = inpatient admission • Pneumonia Severity Index (PSI) •Validated in 50,000 patients with pneumonia •Contains 20 variables •Gender, comorbidities, laboratory values, physical exam findings •Preferred over CURB-65 by IDSA 20 different variables

Outpatient Treatment of CAP

•Previously healthy, no comorbidities or risk factors for drug-resistant S. pneumoniae •Amoxicillin 1g PO TID (preferred as monotherapy) OR •Doxycycline 100 mg PO BID (less data to support Doxy) •Z-packs (Azithromycin) •Macrolides only recommended if resistance rates < 25% and almost everywhere in US has resistance rates >25% Risk factors for drug-resistant S. pneumoniae •Chronic heart, lung, liver, or renal disease •Diabetes Mellitus •Alcoholism •Malignancy •Asplenia-absence of normal spleen function •If risk factors for drug-resistant S. pneumoniae •Beta-lactam + macrolide (oral) •Amoxicillin-clavulanate, cefpodoxime, or cefuroxime preferred •PLUS •Macrolide or doxycycline •OR •Respiratory fluoroquinolone (oral) (have a lot of adverse effect) •Moxifloxacin or levofloxacin •Lack of randomized control trial (RCT) data in outpatient setting •Limited data for doxycycline in pnemonia •Amoxicillin does not have presumed activity against atypical organisms •Recommend patients w/ recent exposure to one class of abx receive treatment from a different class, given increased risk for resistance to the initial treatment regimen

De-Escalation

•Reevaluate antibiotics by day 3 or sooner •Biomarkers such as procalcitonin (at this point) recommended to assist with de-escalation •Microbiological cultures and antigen results •If MDR pathogen is not present, may be able to simplify therapy

Ventilator Associated Pnemonia (VAP) Epidemiology

•Second most common nosocomial infection in United States •Most common infectious cause of death in United States •5-10 cases per 1,000 hospital admissions •Incidence increases 6-20x in mechanically ventilated •Accounts for > 50% antibiotics prescribed •Mortality rate of 20-50%

Aerosolized Antibiotics

•Theoretical advantage of providing high concentration of drug at target site and lower risk of systemic toxicity •Approved for use in cystic fibrosis •In HAP or VAP, used in combination with systemic therapy •Variations: •Aminoglycosides Gentamicin/tobramycin •Colistin- also known as polymyxin E, is an antibiotic used as a last-resort for multidrug-resistant Gram negative infections including pneumonia. •Vancomycin •Adverse Effects •Bronchospasm •Mucosal irritation •Emergence of resistance •Recommended if MDR organism susceptible to only aminoglycoside or colistin

VAP or HAP will get Double Coverage for Pseudomonas

•Use of one antipseudomonal antibiotic is recommended in all cases of HAP or VAP •Double coverage is the use of two antipseudomonal antibiotics from different classes •In institutions with high susceptibility rates to Pseudomonas, routine double coverage is not necessary •Multi-drug resistant Pseudomonas is associated with prior antibiotic exposure •During critical illness and in patients at risk for severe infections, empiric double coverage may improve the probability of having at least 1 active agent in the patient's regimen until susceptibility is known •Most commonly treatment is antipseudomonal Beta-lactam + aminoglycoside (•Preferred beta-lactams: ampicillin-sulbactam cefotaxime, ceftriaxone, ceftaroline + aminoglycoside (Amikacin, Gentamicin, kanamycin, streptomycin, tobramycin) •Very Controversial

Ventilator Associated Pnemonia (VAP) Microbiology

•Wide spectrum of bacteria-recommended to treat based on local institution antibiogram susceptibilities •Can be polymicrobial •Rarely due to viruses or fungi •Anaerobes possible if due to aspiration •Gram-negative pathogens •Pseudomonas aeruginosa •E. coli •Klebsiella pneumoniae •Acinetobacter spp •Gram-positive pathogens •Staphylococcus aureus

•Community-Acquired Pneumonia (CAP)

•Pnemonia that does not meet any of the other definitions

•Hospital Acquired Pneumonia (HAP)

•Pnemonia that occurs ≥ 48 hrs after admission, not incubating at admission- patient comes in for some other reason

Community Acquired Pneumonia (CAP) Diagnosis

•Clinical symptoms (classic symptoms) typically unilateral Aytipical pneumonia can be bilateral •New onset of fever, chills, dyspnea, and productive cough •Tachypnea/tachycardia •Rust-colored sputum or hemoptysis •Hypoxia (especially at altitude) •Pleuritic chest pain (coughing a lot) •+/-microbiologic data (guidline shy away) •"Lack of high-quality evidence that routine diagnostic testing improves individual patient outcomes" •Chest radiograph or other imaging technique demonstrating infiltrate •Blood cultures (less than 10%) (often just a contaminant) •Only 2-9% yield •Most commonly S. pneumoniae •False-positive can lead to extended hospital stay awaiting results •Sputum cultures (given cup just spit) •Over 40% patients cannot produce sufficient sputum prior to antibiotics •Variable yield, depends on quality of sample •Best sample is bronchoalveolar lavage, but invasive •Broncho alvelor lavage is gold standard, but not done in ER •When to obtain blood or sputum cultures? •Recommend not obtaining in outpatient setting •Only in inpatient if: •Severe •Empirically treated for MRSA/Pseudomonas •Previously infected w/ MRSA/Pseudomonas •Received IV abx within previous 90 days (at higher risk for MRSA/Pseudomonas) •Urinary antigens (other diagnositcs) •Legionella and S. pneumoniae •S. pneumoniae antigen not routinely recommended •Legionella antigen recommended if suspecting Legionella: •Epidemiologic factors such as recent outbreak or travel to location with outbreak •Severe CAP

Objectives

•Discuss the clinical presentation of pneumonia as well as diagnostic strategies that should be evaluated. •Classify a patient case of pneumonia as community-acquired, hospital-acquired, or ventilator-associated. •Identify common pathogens associated with each classification of pneumonia. •Design an empiric antimicrobial regimen based on patient admission status and severity. •Develop an antimicrobial regimen based on risk factors for multi-drug resistant pathogens.

VAP and Other Pathogens (rare)

•Fungal: •Rare in immunocompetent •Often isolate Candida spp from respiratory cultures, but usually colonization rather than pneumonia (candida are in lungs) •Viral: •Influenza •SARS-CoV-2 •Other respiratory viruses (RSV, parainfluenza, rhinovirus, etc)

Prevention of CAP

•Immunizations •Influenza •Pneumococcal •Tdap •Smoking cessation •Greatest risk for invasive pneumococcal disease in immunocompetent nonelderly adults •Screened while hospitalized and provided information •Respiratory hygiene in healthcare settings •Hand hygiene and masks for patients with cough

Aspiration Pneumonia

•Infection of lungs due to aspiration of orophargyneal or gastric contents •Aspiration pneumonitis: chemical injury to lungs caused by acidic gastric contents (inflammatory not infectious) •Inflammatory •Burn to the lung •Not infectious •Can occur in community or hospital setting •Risk factors •Altered mental status (intoxication, stroke/seizure/brain injury) •Dysphagia (dementia, stroke, Parkinson disease, MS) •Esophageal disorders/GERD/ineffective cough reflex •Enteral tube feeding •PPIs •Suggest not routinely adding anaerobic coverage for suspected aspiration pneumonia unless lung abscess or empyema suspected •Patients who aspirate gastric contents are considered to have aspiration pneumonitis •Many have resolution of symptoms within 24-48 hours and require only supportive treatment, without antibiotics •No clinical trials comparing treatment regimens with and without anaerobic coverage for patients hospitalized with suspected aspiration

Viral CAP

•Influenza most common between October and March (more in upcoming lecture) Get flu shot •SARS-CoV-2 2020

Clinical Controversy: Linezolid vs. Vancomycin

•Lung tissue penetration •Vancomycin: 10-20% •Linezolid: 100% •2 large multicenter trials found linezolid noninferior to vancomycin, but vancomycin not dosed based on levels •Zephyr trial of 2012 •1184 patients with HAP or HCAP randomized to linezolid or vancomycin •Greater clinical & microbiological success with linezolid •No difference in mortality •Increased nephrotoxicity with vancomycin •Average vancomycin trough of 12 mcg/mL

CAP Summary

•Minimize microbiology diagnostics •For Healthy outpatient: amoxicillin or later doxycycline •Outpatient w/ comorbidities: augmentin or cefpodxime or cefuroxime PLUS macrolide (erythromycin, azithromycin, clarithromycin, Fidamicin) OR FQ (Ciprofloxacin, Levofloxancin, Moxifloxicin alone •HCAP is not a thing-evaluate risk for MRSA or Pseudomonas based on personal history and recent IV abx •Inpatient, non-severe: B-lactam + macrolide OR FQ on own •Inpatient, severe: B-lactam + macrolide OR B-lactam + FQ •Steroids not recommended •Additional coverage not recommended for aspiration •Duration: 5 days for most, 7 days if MRSA/Pseudomonas

CAP: Risk for MRSA or Pseudomonas

•Most consistent risk factors: •Prior isolation of these organisms, especially from the respiratory tract •Recent (last 90 days) hospitalization and exposure to parenteral antibiotics Concerned with •MRSA: •Treat with vancomycin or linezolid or •Pseudomonas (Tx with anti-psudo b-lactams) piperacillin-tazobactam cefepime ceftazidime aztreonam meropenem imipenem Prior resp isolation of MRSA (past)? Nonsevere -Add MRSA coverage, obtain cultures Severe- Add MRSA coverage, obtain cultures Prior resp isolation of PA (past_? Nonsevere- Add PA coverage, obtain cultures Severe- Add PA coverage, obtain cultures Recent IV abx and local risk factors? Nonsevere Obtain culture, but do not start coverage Severe Add MRSA and PA coverage, obtain culture Obtain cultures (cx) in all cases if suspecting MRSA or Pseudomonas (PA) -Most concerned if patient has had MRSA or PA in the past or if they have severe CAP No valid scoring system for id, tx, or pt. outcomes, go to local data

Ventilator Associated Pnemonia (VAP) Diagnosis

•New or progressive radiographic infiltrate •Clinical findings •Fever (Temp > 38°C) •Purulent sputum •Leukocytosis/leukopenia •Positive culture from sputum or tracheal aspirate •Use Respiratory cultures to diagnos •Tracheal aspirate (noninvasive) •Sputum (noninvasive) •Bronchoalveolar lavage (gold standard but invasive) •Clinical findings and microbiologic data recommended for diagnosis over biomarkers such as procalcitonin or C reactive protein

Ventilator Associated Pnemonia (VAP) Risk Factors

•Patient-related risk factors •Male gender •Preexisting pulmonary disease •Multiple organ system failure •Treatment-related risk factors •Intubation •Enteral feeding •Modifiable risk factors •Infection control •Hand hygiene •Early removal of invasive devices •Patients kept at 30-45° position •Oral decolonization with chlorhexidine rinse to prevent

•Ventilator-Associated Pneumonia (VAP)

•Pnemonia that arises > 48 hrs after intubation