Lec 11- CAP Part 2

Lecture Objectives

• Identify the physiologic mechanisms of defense that play a role in Community- Acquired Pneumonia (CAP).
• Recognize the common organisms associated with CAP.
• List the risk factors that can increase the likelihood of CAP.
• List factors to consider for the selection of appropriate treatment of CAP.
• Enumerate the recommended treatments for CAP.
• Be able to select the most appropriate treatment for CAP, based on a specific case.

Lecture Outline

• The lecture will cover host respiratory system defense mechanisms.
• It will cover impairment of pulmonary defenses.
• It will cover the epidemiology of CAP.
• It will cover the risk factors involved in CAP.
• The lecture will cover etiology of CAP, the clinical presentation, and diagnosis of CAP.
• The lecture covers the treatment of bacterial CAP.
• It will cover the epidemiology of bacterial and viral co-CAP in an epidemic/pandemic setting.
• It will cover the prevention and treatment of viral CAP (influenza).

Host Defense Mechanisms

• Host defense mechanisms are split into the upper airways, conducting airways, and lower respiratory tract.

Upper Airways

• The upper airways consists of the nasopharynx and oropharynx.
• Nasopharynx:
  • Includes nasal hair, turbinates, and the mucociliary apparatus.
  • It is also important for IgA secretion.
• Oropharynx:
  • Composed of saliva, sloughing of epithelial cells, coughing, and complement production.

Conducting Airways

• Conducting airways include the trachea and bronchi.
• Coughing and epiglottic reflexes are important.
• Sharp-angled branching airways are included.
• Mucociliary apparatus and airway surface liquid is important.
• Immunoglobulin production (IgG, IgM, IgA) occurs here.
• Dendritic cells and bronchus-associated lymphoid tissue (BALT) are important for defense.

Lower Respiratory Tract

• The lower respiratory tract consists of the terminal airways and alveoli.
• The alveolar lining fluid is important, as it contains surfactant, fibronectin, Ig, complement, free fatty acids, and Fe-binding proteins.
• Alveolar macrophages and neutrophils are also included.
• Dendritic cells and bronchus-associated lymphoid tissue (BALT) are included.

Pneumonia Development

• Pneumonia can occur because of the impairment of host defenses.
• Pneumonia can occur when virulent organisms or a large inoculums overwhelm host defenses.
• Pneumonia can also occur via colonization of the upper respiratory tract.
• It can occur through hematogenous or iatrogenic spread.

Impairment of Pulmonary Defenses: Factors and Effects

• Altered levels of consciousness can compromise epiglottic closure, leading to aspiration of oropharyngeal flora.
  • This can be due to stroke, seizures, drug intoxication, alcohol abuse, or normal sleep.
• Cigarette smoke disrupts mucociliary function and macrophage activity.
• Alcohol impairs epiglottic and cough reflexes.
  • It's associated with increased colonization of the oropharynx with aerobic Gram-negative bacilli.
  • It decreases mobilization of neutrophils and blocks TNF response to endotoxin.
  • Alcohol enhances monocyte production of IL-10.
• Mycoplasma pneumoniae or Haemophilus influenzae can interfere with normal ciliary function.
• Respiratory viruses destroy respiratory epithelium and disrupt normal ciliary activity.
  • They interfere with neutrophil function via chemotaxis, phagocytosis, and oxidative metabolism.
  • They can also inhibit alveolar macrophage function.
• Sepsis from extrapulmonary infections undermines lung defense mechanisms.
  • In animal models, lipopolysaccharide or endotoxin decreases lung clearance of bacteria.
• Human Immunodeficiency Virus (HIV) can cause a decreased quantitative and qualitative CD4 T-cell response.
  • It can also result in BALT dendritic cell and degeneration of lymphoid follicles, defective antigen-presenting cells, and abnormal chemotaxis, phagocytosis, and oxidative metabolism.
• Iatrogenic manipulation interferes with usual host defenses and predisposes one to infection.
  • This includes endotracheal tubes, nasogastric tubes, and respiratory therapy equipment.
• Medications, such as proton pump inhibitors and H2-blockers, are a factor.
• Congenital defects and diseases such as Young's syndrome or cystic fibrosis.
• Myasthenia gravis and dementia can increase aspiration, as can esophageal reflux, strictures, and diverticula.

Community-Acquired Pneumonia

• Community-acquired pneumonia (CAP) is an acute infection of the pulmonary parenchyma that is acquired outside of the hospital/health-care setting.
• CAP is supported by clinical signs or symptoms, radiologic findings, and auscultatory findings.

Epidemiology of CAP (United States)

• Incidence of CAP is 25 episodes per 10,000 adults in the United States.
• Incidence is higher for older ages.
  • 65–79 years: 63 cases per 10,000 adults
  • ≥80 years: 164 cases per 10,000 adults
• There are an estimated 1.5 million hospitalizations and 10,000 deaths annually due to CAP.
• The mortality rate for CAP ranges from <1% to 50% depending on the severity.
• CAP causes billions of dollars in healthcare costs annually.

Risk Factors for CAP

• Risk factors include older age.
  • The incidence is approximately 3x higher than the general population in those ≥65 years of age.
• Chronic comorbidities raise the risk of CAP.
  • COPD is the highest risk factor, but also chronic lung diseases, asthma, bronchiectasis, chronic heart diseases, stroke, diabetes, malnutrition, and immunocompromise.
• Viral respiratory infections are a risk.
  • Influenza virus is the most common but is not considered a comorbidity of COVID.
• Impaired airway protection, smoking and alcohol abuse, and living conditions are also risk factors.
  • Risk is increased with crowded living conditions, low-income settings, and environmental toxins.

Etiology of CAP

• In 40–60% of cases of CAP, the causative organism is not identified.
• When isolated, bacterial or viral agents can include:
  • Typical bacteria: Streptococcus pneumoniae (most common bacterial cause, 33-50%), Haemophilus influenzae (7-16%), Moraxella catarrhalis (1.2-3.5%), Staphylococcus aureus, Group A streptococci, aerobic gram-negative bacteria (e.g., Enterobacteriaceae such as Klebsiella spp or Escherichia coli), microaerophilic bacteria, and anaerobes (associated with aspiration).
  • Atypical Bacteria: Legionella spp (3-8%), Mycoplasma pneumoniae (4-11%), Chlamydia pneumoniae (2-7%), Chlamydia psittaci, and coxiella burnetii.
  • Respiratory Viruses: Coronaviruses, Influenza A and B viruses (6-14%), Rhinoviruses (4-12%), Respiratory syncytial virus (RSV), Human metapneumovirus (0.4-5%), Parainfluenza viruses, Adenoviruses, and Human bocaviruses.

Etiology of CAP Breakdown

• Outpatients
  • S. pneumoniae
  • Mycoplasma pneumoniae
  • Haemophilus influenzae
  • Chlamydia pneumoniae
• Inpatient non-ICU:
  • S. pneumoniae
  • Staphylococcus aureus
  • Mycoplasma pneumoniae
  • Chlamydia pneumoniae
  • Haemophilus influenzae
  • Legionella spp.
• Inpatient ICU:
  • S. pneumoniae
  • Staphylococcus aureus
  • Legionella spp
  • Gram-negative bacilli
  • Haemophilus influenzae

Clinical Presentation in CAP

• Respiratory findings include cough, sputum production, dyspnea, and chest discomfort.
• Auscultatory findings include lung sounds such as rales and ronchi and dullness on percussion.
• Systemic findings include fatigue, sweats, headache, nausea, myalgia, fever (60-90%), chills/rigors, and tachycardia.
• Radiographic findings include lobar consolidation, interstitial infiltrates, and cavitations.
• A chest X-ray may be required. In addition, computed tomography (CT) may be required.

CAP Diagnosis

• CAP diagnosis consists of:
  • Radiographic evidence.
  • Signs and symptoms.
• Compatible clinical syndrome and imaging findings consistent with pneumonia are sufficient to establish an initial clinical diagnosis of CAP.
  • However, the combination of findings is nonspecific and shared among many cardiopulmonary disorders.
• Severity of disease and whether the patient can be assessed/treated as an outpatient vs inpatient are important considerations.

Diagnosis of CAP Severity

• There are pneumonia severity indices that can be used to assess severity.
• Indices include pneumonia severity index( PSI)
  • CURB-65: Confusion, Urea, Respiratory rate etc
• IDSA/ ATS Severity Criteria can be applied

Minor Criteria

• Respiratory rate ≥30 breaths/min
• PaO2/FIO2 ratio ≤250
• Multilobar infiltrates
• Confusion or disorientation
• Uremia (blood urea nitrogen level ≥20 mg/dl)
• Leukopenia* (white blood cell count <4,000 cells/ml)
• Thrombocytopenia (platelet count <100,000/ml)
• Hypothermia (core temperature <36°C)
• Hypotension requiring aggressive fluid resuscitation

Major Criteria

• Septic shock with need for vasopressors
• Respiratory failure requiring mechanical ventilation
• A validated definition of severe is:
  • ≥ 1 major criterion
  • ≥ 3 minor criteria

Diagnosis of CAP: Recommendations

• Outpatient:
  • Signs and symptoms
  • Radiology (chest X-ray)
  • Blood or sputum Gram-stain and culture is NOT recommended (optional).
• Inpatient:
  • Signs and symptoms
  • Imaging (chest X-ray, CT)
  • Blood or sputum Gram-stain and culture if:
    • Severe CAP (especially if intubated).
    • Risk for resistant organisms.
    • Empiric treatment for MRSA.
    • Previous treatment for MRSA, PA.
    • Prior hospitalization with IV antibiotics.
  • Pathogen-specific tests may be run.

Factors for Considering a Drug Regimen: CAP

• General Factors:
  • Severity: Inpatient vs outpatient.
  • Most likely pathogens.
  • Clinical experience/evidence.
  • Formulary/cost.
  • Antibiotic characteristics; including PK/PD, spectrum of activity, side effects, and lung penetration.
  • Patient-specific factors: tolerance and allergies.
  • Ease/convenience of administration.
• CAP Specific Factors:
  • Based on PSI or CURB-65, IDSA/ATS criteria.
  • S. pneumoniae, atypical organisms, and viral causes.
  • Doxycycline or omadacycline.
  • Doxycycline $ vs omadacycline $$$$.
  • Age.
  • Drug-drug/-disease interactions: QT-prolongation with fluoroquinolones and bone toxicity.
  • Smoking, recent antibiotic use: beta-lactam/beta-lactamase inhibitor.
  • Legionella outbreak: macrolide or fluoroquinolone.

Empiric Therapy for Adult Outpatients

• No comorbidities or no risk factors for MRSA or Pseudomonas aeruginosa
  • Prior isolation of MRSA or P. aeruginosa
  • Recent hospitalization with IV antibiotics
  • Use Amoxicillin or Doxycycline
  • Use a Macrolide is local pneumococcal resistance is <25%:
    • Azithromycin
    • Clarithromycin
• With comorbidities
  • Chronic heart, lung, liver, or renal disease
  • Diabetes mellitus
  • Alcoholism
  • Malignancy
  • Asplenia
  • Immunosuppression
    • Use a Monotherapy with a respiratory fluoroquinolone
      • Levofloxacin, moxifloxacin, gemifloxacin
    • Or Use a Combination Therapy with:
      • Amoxicillin/clavulanate or cefpodoxime or cefuroxime + macrolide or doxycycline

Empower Therapy for Adults Inpatients -Nonsevere

• Use a Combination therapy: beta-lactam + macrolide.
  • Options include ampicillin/sulbactam, cefotaxime, ceftriaxone, or ceftaroline + azithromycin or clarithromycin.
  • Or
• Monotherapy with a respiratory fluoroquinolone (levofloxacin or moxifloxacin)
  • Or
• Combination therapy with beta-lactam + doxycycline (if unable to tolerate fluoroquinolones or macrolides)
• If there is Prior MRSA respiratory isolation
  • Conduct cultures/nasal PCR, and add MRSA coverage (vancomycin or linezolid).
• Validated local risk factor for MRSA and recent hospitalization with IV antibiotics
  • Conduct cultures/nasal PCR. Only add MRSA coverage if PCR positive or culture is positive.

Empirical Therapy for Adults Inpatients - Severe

• Standard treatment
  • Combination treatment: beta-lactam [ampicillin/sulbactam, cefotaxime, ceftriaxone, or ceftaroline] + macrolide [azithromycin or clarithromycin].
  • Combination treatment with beta-lactam + respiratory fluoroquinolone [levofloxacin or moxifloxacin].
• For cases involving prior respiratory isolation of MRSA.
  • Obtain cultures/nasal PCR and add MRSA coverage with vancomycin or linezolid.
• Validated local risk factor for MRSA, and recent hospitalization with IV antibiotics
  • Obtain cultures/nasal PCR and add MRSA coverage. De-escalate to discontinue based on PCR or cultures.
• Prior respiratory isolation of P. aeruginosa
  • Obtain cultures and add PA coverage with piperacillin/tazobactam, cefepime, ceftazidime, imipenem, meropenem, or aztreonam.
• Validated local risk factor for PA and recent hospitalization with IV antibiotics
  • Obtain cultures and add PA coverage. Deescalate or discontinue based on cultures.

Newer Treatment therapies for CAP

• Omadacycline is an aminomethylcycline.
  • Trialed in OPTIC: omadacycline vs moxifloxacin.
• Delafloxacin is a fluoroquinolone.
  • It was trialed in DEFINE-CABP: delafloxacin vs moxifloxacin.
• Lefamulin is a pleuromutilin.
  • It was trialed in LEAP-2: lefamulin vs moxifloxacin.
• Ceftaroline a 5th generation cephalosporin
  • It was trialed in FOCUS-1 and 2: ceftaroline vs ceftriaxone.

IV-to-PO Transition and Duration of Therapy in Adults

• Patients should be switched from IV to PO therapy when hemodynamically stable.
  • They must be improving clinically, be able to ingest medications, and have a normally functioning GI tract.
  • The treatment can be the same agent or the same class of medication.
• Patients should be stable and afebrile for 48 to 72 hours with a minimum duration of 5 days.
  • Resolution of vital sign abnormalities (HR, RR, BP, O₂Sat, T).
  • Ability to eat.
  • Have mental awareness.
• Most studies in support of 5-day treatment duration included patients without severe CAP.
• Duration increases to 7 days in:
  • Patients with suspected or proven MRSA.
  • Patients with P. aeruginosa.

Viral CAP Prevention & Treatment

• Primary prevention: Vaccination.
• Influenza vaccines contain hemagglutinin (HA) derived from viruses projected to be responsible for that year's season.
  • All influenza vaccines for the 2024–2025 season are quadrivalent.
• The influenza vaccine comes in Egg-based or Cell- or recombinant-based forms.
• Universal annual vaccination recommended in 2010 by the Advisory Committee on Immunization Practices (ACIP) in the United States.
  • Inactivated influenza vaccine (IIV) is for ≥6 months of age.
  • Recombinant influenza vaccine (RIV).
  • Live attenuated influenza vaccine (LAIV) is for 2–49 years of age who are not pregnant and do not have chronic medical conditions.
  • High-dose inactivated influenza vaccine (HD-IIV) is for adults ≥65 years of age or SOT 18–64 years.
  • Adjuvanted inactivated influenza vaccine (allV) is for adults ≥65 years of age or SOT 18–64 years.
• Other prevention includes infection control.
  • Hygiene, social distancing.

Influenza A & B Vaccine: Contraindications and Precautions

• Vaccine types Inactivated (IIV) and Recombinant (RIV)
  • You can not administer to someone with severe allergy to vaccine or components (including egg products).
• For Live attenuated (LAIV)
  • You can not administer to someone with Severe allergy to vaccine or components.
  • Concomitant aspirin or salicylate use in children or adolescents.
  • If they are Age 2 - 4 years and have a history of asthma/wheezing.
  • Immune compromise or have close contact with immunosuppressed person
  • Pregnancy or Anti-influenza medication in past 48 hr.
• Inactivated (IIV) and Recombinant (RIV) Precautions:
  • History of Guillain-Barre Syndrome within 6 weeks after influenza vaccine.
• Live attenuated (LAIV) precations:
  • History of Guillain-Barre Syndrome within 6 weeks after influenza vaccine.
  • Comorbidity predisposing them to influenza complications (including immunocompromise, pregnancy and many other)
  • Age ≥ 5 years & history of asthma/wheezing.

Influenza: A & B Treatment and Chemoprophylaxis

• Oseltamivir is administered via PO.
  • For treatment it can be taken 5 days at Any age.
  • For Chemoprophylaxis, can be used at ≥3 months, x 7 days.
  • Known adverse effects: Nausea, vomiting, headache. post marketing reports of serious skin reactions and sporadic, transient neuropsychiatric events.
• Zanamivir is administered via Inhaled.
  • Treatment: ≥7 years, x 5 days.
  • Prophylaxis: ≥5 years, x 7 days.
  • known side effects: bronchiospasm, sinuitis, and dizziness. Reports of skin ractions and neuropsychiatric events.
• Peramivir is administered: IV
  • Treatment: ≥6 months, x 1 day.
  • Adverse effects : Diarrhea. Post marketing reports of serious skin reactions and sporadic, transient neuropsychiatric events.
• Baloxavir is administered PO. -Treatment: ≥5 years, x 1 day
  • Common adverse effects in clinical trials: none.
• Treatment ideally should be initiated within 48 hours.