4.1 Lower Respiratory Tract Infections & Sepsis Syndromes

Infectious pulmonary and systemic diseases constitute a major percentage of inpatient admissions and critical care consultations. Mastery of clinical prediction rules (CURB-65, PSI), empiric antimicrobial selection, sepsis resuscitation bundles, antiviral pharmacology, and antimycobacterial therapy is vital for the ABIM Internal Medicine Board Examination.

1. Community-Acquired Pneumonia (CAP)

Community-Acquired Pneumonia (CAP) is defined as an acute infection of the pulmonary parenchyma acquired outside of a healthcare facility or diagnosed within <48 hours of hospital admission.

Microbiology

• Typical Bacterial Pathogens: Streptococcus pneumoniae (most common bacterial cause across all age groups; classically causes lobar consolidation, rusty sputum, lancet-shaped Gram-positive diplococci), Haemophilus influenzae (frequent in COPD and smokers), Moraxella catarrhalis, Staphylococcus aureus (post-viral influenza, cavitary/necrotizing pneumonia), and Klebsiella pneumoniae (alcohol use disorder, currant-jelly sputum, upper lobe cavitation).
• Atypical Pathogens: Mycoplasma pneumoniae (young adults, cold agglutinins, autoimmune hemolytic anemia, erythema multiforme), Chlamydia pneumoniae (subacute presentation, pharyngitis, hoarseness), and Legionella pneumophila (contaminated water aerosols, air conditioning cooling towers, presents with high fever, relative bradycardia [Faget sign], gastrointestinal symptoms/diarrhea, hyponatremia, and elevated transaminases; diagnosed via urine antigen test for serogroup 1).
• Respiratory Viruses: Influenza A and B, Respiratory Syncytial Virus (RSV), SARS-CoV-2, Metapneumovirus, and Adenovirus.

Clinical Risk Stratification & Site-of-Care Triage

Determining outpatient versus inpatient versus intensive care unit (ICU) admission is the critical initial decision in CAP management.

Empiric Antimicrobial Regimens for CAP (IDSA/ATS Guidelines)

A. Outpatient Regimens

1. Healthy Adults Without Comorbidities or Risk Factors for Resistant Pathogens:
   • Amoxicillin 1 g PO TID (preferred high-dose beta-lactam) OR
   • Doxycycline 100 mg PO BID OR
   • Macrolide (Azithromycin 500 mg day 1, then 250 mg daily; or Clarithromycin 500 mg BID) ONLY IF local pneumococcal macrolide resistance is documented to be <25%.
2. Adults with Chronic Comorbidities (COPD, HF, DM, Chronic Kidney/Liver Disease, Alcoholism, Asplenia, Malignancy):
   • Combination Therapy (Beta-lactam + Atypical Coverage):
     • Amoxicillin-clavulanate (Augmentin) 875/125 mg PO BID or 2000/125 mg PO BID, OR Cefuroxime 500 mg PO BID, OR Cefpodoxime 200 mg PO BID PLUS
     • Azithromycin 500 mg daily (or Clarithromycin 500 mg BID) OR Doxycycline 100 mg PO BID.
   • Monotherapy with Respiratory Fluoroquinolone:
     • Levofloxacin 750 mg PO daily OR Moxifloxacin 400 mg PO daily.

B. Inpatient Regimens (Non-ICU Medical Ward)

1. Standard Dual Therapy (Class I Recommendation):
   • IV Beta-lactam (Ceftriaxone 1–2 g IV daily, Ampicillin-sulbactam 1.5–3 g IV q6h, or Cefotaxime 1–2 g IV q8h) PLUS
   • IV/PO Macrolide (Azithromycin 500 mg IV/PO daily).
2. Monotherapy Alternative:
   • Respiratory Fluoroquinolone (Levofloxacin 750 mg IV/PO daily or Moxifloxacin 400 mg IV/PO daily).

C. Inpatient Regimens (ICU / Severe CAP)

• Core Backbone: IV Beta-lactam (Ceftriaxone 2 g IV daily or Ampicillin-sulbactam 3 g IV q6h) PLUS IV Azithromycin 500 mg daily OR IV Levofloxacin 750 mg daily.
• Risk Factors for MRSA (Prior isolation, post-influenza necrotizing infiltrates, cavitary lesions, end-stage renal disease):
  • Add Vancomycin (15–20 mg/kg IV q8–12h targeting AUC/MIC 400–600 or trough 15–20 mcg/mL) OR Linezolid 600 mg IV/PO q12h.
  • Clinical Pearl: Nasal MRSA PCR screening has a Negative Predictive Value (NPV) >96–98%; a negative nasal PCR allows rapid discontinuation/de-escalation of anti-MRSA therapy.
• Risk Factors for Pseudomonas aeruginosa (Prior isolation, bronchiectasis, severe structural lung disease, frequent systemic corticosteroid/antibiotic courses):
  • Replace Ceftriaxone with an Antipseudomonal Beta-lactam (Piperacillin-tazobactam 4.5 g IV q6h, Cefepime 2 g IV q8h, Ceftazidime 2 g IV q8h, or Meropenem 1 g IV q8h) PLUS Levofloxacin 750 mg IV daily or Ciprofloxacin 400 mg IV q8h.

2. Hospital-Acquired Pneumonia (HAP) & Ventilator-Associated Pneumonia (VAP)

• Hospital-Acquired Pneumonia (HAP): Pneumonia occurring >=48 hours after hospital admission that was not incubating at the time of admission.
• Ventilator-Associated Pneumonia (VAP): Pneumonia arising >48–72 hours following endotracheal intubation.
• Microbiology: Gram-negative bacilli (Pseudomonas aeruginosa, Klebsiella pneumoniae, Escherichia coli, Enterobacter cloacae, Acinetobacter baumannii, Stenotrophomonas maltophilia) and Staphylococcus aureus (MRSA and MSSA).

Empiric Treatment Strategy

• Single Antipseudomonal Beta-Lactam (Cefepime 2 g IV q8h, Piperacillin-tazobactam 4.5 g IV q6h, or Meropenem 1 g IV q8h).
• Add MRSA Coverage (Vancomycin 15–20 mg/kg IV q8–12h or Linezolid 600 mg IV q12h) if patient has prior IV antibiotic exposure within 90 days, hospitalization in a unit where MRSA prevalence is >20% or unknown, or high risk of mortality.
• Add Second Antipseudomonal Agent (Aminoglycoside: Amikacin/Tobramycin, or Fluoroquinolone: Ciprofloxacin/Levofloxacin) if high mortality risk, septic shock, or prior IV antibiotics within 90 days.
• Duration: Standard course is 7 days for responding patients with clinical improvement and resolving procalcitonin.

3. Sepsis & Septic Shock (Surviving Sepsis Campaign 2021 Guidelines)

Definitions (Sepsis-3 Criteria)

• Sepsis: Life-threatening organ dysfunction caused by a dysregulated host immune response to infection. Organ dysfunction is clinically identified by an acute increase in the Sequential Organ Failure Assessment (SOFA) score >= 2 points.
• Septic Shock: A subset of sepsis in which underlying circulatory and cellular/metabolic abnormalities are profound enough to substantially increase mortality. Defined clinically as: Persisting hypotension requiring vasopressors to maintain Mean Arterial Pressure (MAP) >= 65 mmHg AND serum lactate > 2.0 mmol/L (18 mg/dL) despite adequate volume resuscitation.

The Surviving Sepsis Hour-1 Bundle

All 5 elements should be initiated immediately within the first 60 minutes of triage or recognition:

1. Measure Serum Lactate Level: Remeasure within 2–4 hours if initial lactate is elevated (>2.0 mmol/L) to guide resuscitation and clearance kinetics.
2. Obtain Blood Cultures Prior to Antibiotics: Obtain at least 2 sets of blood cultures (aerobic and anaerobic bottles from distinct venipuncture sites). Do not delay antibiotic administration by >45 minutes if blood cultures are difficult to draw.
3. Administer Broad-Spectrum IV Antimicrobials: Initiate full-dose empiric IV antimicrobials within 1 hour of recognition.
4. Administer Rapid IV Crystalloid Resuscitation: Administer 30 mL/kg of IV balanced crystalloid (Lactated Ringer's or Plasma-Lyte preferred over 0.9% Normal Saline to reduce hyperchloremic metabolic acidosis and acute kidney injury) within 3 hours for hypotension (MAP <65 mmHg) or initial serum lactate >= 4.0 mmol/L.
5. Apply Vasopressors for Refractory Hypotension:
   • First-Line Vasopressor: Norepinephrine (potent alpha-1 and modest beta-1 agonist) titrated to maintain MAP >= 65 mmHg.
   • Second-Line Vasopressor: Vasopressin (fixed continuous infusion of 0.03 units/min) added to norepinephrine when high-dose norepinephrine is required, allowing norepinephrine dosage reduction.
   • Third-Line Inotrope/Vasopressor: Epinephrine (if MAP remains inadequate) or Dobutamine (added if myocardial dysfunction or persistent hypoperfusion despite adequate volume and MAP).
   • Avoid Dopamine: Associated with significantly higher incidence of tachyarrhythmias compared to norepinephrine.
   • Refractory Septic Shock Corticosteroids: Initiate IV Hydrocortisone 200 mg/day (given as 50 mg IV q6h or continuous infusion) ONLY IF blood pressure remains refractory to fluid resuscitation and moderate-to-high dose vasopressor therapy (e.g., Norepinephrine >=0.25 mcg/kg/min).