Lec 13- HAP & VAP Part 1

Okay, I will update the study notes based on the provided lecture objectives and the content about nosocomial pneumonia, HAP (Hospital-Acquired Pneumonia), and VAP (Ventilator-Associated Pneumonia).

• Lecture Objectives:
  • List likely organisms responsible for HAP/VAP
  • List risk factors associated with resistant organisms in HAP/VAP
  • Discuss key guideline-based recommendations for adults with HAP/VAP
  • Assess the type of pneumonia based on a patient's presentation
  • Select the most appropriate empiric or pathogen-directed pharmacotherapeutic plan and stewardship strategies
  • Recommend the most appropriate modifications of a patient's treatment plan based on efficacy, adverse events, and follow-up assessment

Definitions of Pneumonia

- Community-Acquired Pneumonia (CAP): Occurs outside the healthcare setting and less than 48 hours from hospital admission.
- Hospital-Acquired Pneumonia (HAP): Occurs ≥48 hours after hospital admission in patients not intubated at admission.
- Ventilator-Associated Pneumonia (VAP): Occurs ≥48 hours after endotracheal intubation.

Epidemiology of Nosocomial Pneumonia

- Nosocomial pneumonia is among the most common hospital-acquired infections.
- HAP is more common than VAP.
- HAP is associated with a higher cost than VAP but a similar mortality rate.
- Nosocomial pneumonia is associated with increased cost of care, hospital length of stay, and mortality.
- Mortality ranges from 15% to 50%, depending on the severity of illness.
- Excess cost is approximately $40,000 per patient.
- Hospital stay is prolonged by nearly 2 weeks.
- Mechanical ventilation is prolonged by about 10 days.

Etiology of Nosocomial Pneumonia

- The organisms that cause HAP and VAP are generally the same but occur in different percentages.
- HAP:
    - Pseudomonas aeruginosa (19%)
    - Acinetobacter spp. (13%)
    - Enterobacter spp. (9%)
    - Klebsiella spp. (8%)
    - Serratia spp. (5%)
    - Staphylococcus aureus (16-36%), MRSA (10%)
- VAP:
    - Pseudomonas aeruginosa (20%)
    - Acinetobacter baumannii (5-10%)
    - Enterobacter spp. (9%)
    - Klebsiella spp. (6%)
    - Serratia spp. (6%)
    - Staphylococcus aureus (30%), MRSA (n/a)
- Prevalence of pathogens varies across studies, temporally, and geographically.

Diagnosis of Nosocomial Pneumonia

- Diagnosis is challenging because findings are usually non-specific.
- Diagnosis is based on clinical criteria alone.
- Biomarkers are not recommended due to a lack of clinical outcomes data and sensitivity/specificity <90% by expert panel. These include:
    - Procalcitonin (PCT).
    - Soluble triggering receptor expressed on myeloid cells (sTREM-1).
    - C-reactive protein (CRP).
- Modified clinical pulmonary infection score (CPIS) is not recommended.
- Chest radiography/imaging is used.
- Blood cultures are taken for all patients.
- Non-invasive respiratory cultures are taken for all patients, including:
    - Spontaneous expectoration.
    - Sputum induction.
    - Nasotracheal suctioning.
    - Endotracheal aspiration.

General Principles for Treatment

- Determine mortality risk (high vs. low) based on:
    - Need for ventilator support due to pneumonia.
    - Presence of septic shock (patients in shock require vasopressors).
- Selection of antibiotics should be tailored based on local antibiogram and patient's prior cultures.
    - Hospital-specific.
    - Unit-specific (Inpatient, Outpatient, ED, ICU).
    - Patient-specific.
- All patients should receive coverage for MSSA, P. aeruginosa, and Gram-negative bacilli.
    - Consider risk factors for MRSA and/or multi-drug resistance (MDR).
    - This impacts whether to add MRSA coverage or double antipseudomonal coverage.
- Therapy should be modified based on culture results.

Risk Factors for MRSA or MDR

- Risk factors for MRSA:
    - HAP: IV antibiotic in prior 90 days, hospitalization in a unit where >20% MRSA or % unknown.
    - VAP: IV antibiotic in prior 90 days, hospitalization in a unit where >10-20% MRSA or % unknown.
- Risk factors for MDR:
    - HAP: IV antibiotic in prior 90 days, structural lung disease (bronchiectasis, cystic fibrosis).
    - VAP: IV antibiotic in prior 90 days, septic shock at the time of VAP, ARDS preceding VAP, ≥5 days of hospitalization prior to VAP, acute renal replacement therapy prior to VAP onset.

Empiric Treatment for HAP

- Low risk for mortality and MRSA: Monotherapy with BL or FQ.
    - Piperacillin-tazobactam, cefepime, imipenem, meropenem + Levofloxacin.
- Low risk for mortality, high risk for MRSA: (BL or FQ) + MRSA.
    - Piperacillin-tazobactam, cefepime, imipenem, meropenem, aztreonam + Levofloxacin, ciprofloxacin + Vancomycin, linezolid.
- High risk for mortality or MDR: 2 agents from different classes (BL, FQ, AG) + MRSA.
    - Piperacillin-tazobactam, cefepime, imipenem, meropenem, aztreonam + Levofloxacin, ciprofloxacin + Amikacin, gentamicin, tobramycin + Vancomycin, linezolid.

Empiric Treatment for VAP

- No risk for MDR, GN-r <10%, and MRSA <10%: Monotherapy with BL or FQ.
    - Piperacillin-tazobactam, cefepime, imipenem, meropenem + Levofloxacin.
- No risk for MDR, GN-r <10%, MRSA >10% or unknown: (BL or FQ) + MRSA.
    - Piperacillin-tazobactam, cefepime, imipenem, meropenem, aztreonam + Levofloxacin, ciprofloxacin + Vancomycin, linezolid.
- No risk for MDR, GN-r >10%, MRSA >10% or unknown: 2 agents from different classes (BL, FQ, AG, PMX) + MRSA.
    - Piperacillin-tazobactam, cefepime, imipenem, meropenem, aztreonam + Levofloxacin, ciprofloxacin + Amikacin, gentamicin, tobramycin + Colistin, polymyxin B + Vancomycin, linezolid.
- Risk for MDR: 2 agents from different classes (BL, FQ, AG, PMX) + MRSA.
    - Piperacillin-tazobactam, cefepime, imipenem, meropenem, aztreonam + Levofloxacin, ciprofloxacin + Amikacin, gentamicin, tobramycin + Colistin, polymyxin B + Vancomycin, linezolid.

Pathogen-Specific, Definitive Therapy for MRSA

- Vancomycin:
    - Guidelines suggest maintaining AUC/MIC ≥ 400 for complicated S. aureus infections, including pneumonia.
    - Target trough concentration 15-20 mg/L as a surrogate for AUC ≥ 400mg*hr/L.
    - Loading dose 25-30 mg/kg (actual body weight) in seriously ill.
    - Maintenance doses 15-20 mg/kg (actual body weight) every 8 to 12 hours.
    - Draw trough concentration at steady-state (5 x t1/2, usually before the 4th dose).
    - Adverse effects:
        - Nephrotoxicity.
        - Ototoxicity.
        - Red-Man Syndrome: rate-dependent infusion reaction (not true allergy), vancomycin direct activation of mast cells to release histamine.
        - Symptoms: flushing, erythema, pruritus (upper body, neck, face > lower body).
        - Management: Stop infusion, administer antihistamine, restart infusion at a slower rate.
- Linezolid:
    - 600 mg IV q12h
    - Drug-drug interactions: SSRIs and tricyclic antidepressants increase the risk for serotonin storm syndrome.
    - Adverse effects: Myelosuppression, serotonin syndrome.
    - Traditionally more expensive than vancomycin.
- Other agents:
    - Daptomycin: NEVER use for pneumonia because it is inactivated by surfactant.
    - Limited evidence with teicoplanin, telavancin, ceftaroline, tedizolid.

Pathogen-Specific, Definitive Therapy for Pseudomonas aeruginosa

- Based on antibiotic susceptibility testing:
    - Routine antimicrobial susceptibility testing should include assessment of the sensitivity of P. aeruginosa isolate to polymyxins (colistin or polymyxin B) in settings that have a high prevalence of extensively resistant organisms.
- Septic shock resolves or not at high risk for mortality, and susceptibility known:
    - Monotherapy with an agent to which the patient isolate is susceptible.
    - Monotherapy with aminoglycosides is NOT recommended.
- In septic shock or at high risk for death, even if susceptibility is known:
    - Combination therapy (2 agents).
    - If the septic shock resolves, de-escalate to monotherapy.

Pathogen-Specific, Definitive Therapy for Acinetobacter spp.

- Based on antibiotic susceptibility testing:
    - Carbapenem or ampicillin/sulbactam if patient isolate susceptible to either.
    - If only susceptible to polymyxins, IV polymyxin + adjunctive inhaled colistin.
    - If only susceptible to colistin, the use of rifampicin is not recommended.
    - Use of tigecycline not recommended.

Pathogen-Specific, Definitive Therapy for Carbapenem-Resistant Organisms

- Based on antibiotic susceptibility testing:
    - If only susceptible to polymyxins, IV polymyxin + adjunctive inhaled colistin.
    - Inhaled polymyxin B not recommended due to a lack of supporting clinical evidence.

Pathogen-Specific, Definitive Therapy for Extended-Spectrum Beta-Lactamase (ESBL)-Producing Gram-Negative Bacilli

- Based on antibiotic susceptibility testing:
    - Consider allergies and comorbid conditions that increase the risk for side effects.

Other Treatment Strategies for Nosocomial Pneumonia

- Newer drugs: Ceftazidime/avibactam, Ceftolozane/tazobactam.
- Off-label investigational agents: Meropenem/vaborbactam, imipenem/cilastatin/relebactam.
- Older drugs: Colistin (colistimethate sodium), polymyxin B.
- Inhaled antibiotics.

Other Treatment Strategies: Ceftazidime/Avibactam vs Ceftolozane/Tazobactam

- Ceftazidime/Avibactam:
    - FDA Indication for HAP/VAP: Yes
    - Activity against most ESBL: Yes
    - Activity against AmpC beta-lactamase: Yes
    - Activity against some carbapenemases: No
    - Efficacy data: REPROVE trial showed non-inferiority to meropenem
- Ceftolozane/Tazobactam:
    - FDA Indication for HAP/VAP: Yes
    - Activity against most ESBL: Yes
    - Activity against AmpC beta-lactamase: Yes
    - Activity against some carbapenemases: No
    - Efficacy data: ASPECT-NP trial showed non-inferiority to meropenem

Other Treatment Strategies: Meropenem/Vaborbactam Vs. Imipenem/Cilastatin/Relebactam

- Meropenem/Vaborbactam:
    - FDA Indication for HAP/VAP: No
    - Activity against most ESBL: Yes
    - Activity against AmpC beta-lactamase: Yes
    - Activity against some carbapenemases: Yes
    - Efficacy data: TANGO-II trial showed superiority vs best available therapy for CRE
- Imipenem/Cilastatin/Relebactam:
    - FDA Indication for HAP/VAP: No
    - Activity against most ESBL: Yes
    - Activity against AmpC beta-lactamase: Yes
    - Acitivity against some carbapenemases: NO
    - Efficacy data: RESTORE-IMI trial showed superiority vs colistin in HAP/VAP

Other Treatment Strategies: Colistin (Polymyxin E) vs. Polymyxin B

- Colistin (Polymyxin E):
    - FDA Indication for HAP or VAP: No.
    - Activity against most ESBL: Yes.
    - Activity against AmpC beta-lactamase: Yes.
    - Activity against some cabapenemases: Yes.
    - Administration routes: IV, inhaled (off-label).
    - Elimination: Primarily renal.
    - Renal adjustment: Yes.
    - Formulation: Inactive prodrug hydrolyzed to active colistin.
    - Nephrotoxicity: RR 1.55 (95% CI: 1.36, 1.78).
    - Neurotoxicity: Yes.
- Polymyxin B:
    - FDA Indication for HAP or VAP: No.
    - Activity against most ESBL: Yes.
    - Activity against AmpC beta-lactamase: Yes.
    - Activity against some carbapenemases: Yes.
    - Administration routes: IV, inhaled (off-label).
    - Elimination: Primarily non-renal.
    - Renal adjustment: No.
    - Formulation: Active metabolite.
    - Nephrotoxicity: Yes.
    - Neurotoxicity: Yes.

Other Treatment Strategies: Inhaled Antibiotics

- Recommendations:
    - Use combinations of inhaled and systemic antibiotics for VAP due to MDR gram-negative bacilli susceptible only to aminoglycosides or polymyxins.
    - For HAP/VAP with Acinetobacter spp., if only susceptible to polymyxins, IV polymyxin + adjunctive inhaled colistin.
    - For HAP/VAP with carbapenem-resistant organisms, if only susceptible to polymyxins, IV polymyxin + adjunctive inhaled colistin.
- Inhaled options: Colistin, gentamicin, tobramycin.
    - Inhaled polymyxin B lacks clinical evidence.
- Advantage: Increased clinical cure rate (potential?).
- Disadvantage: Increased burden and cost.
- Clinical evidence: No proven effects on mortality, adverse reaction, or antibiotic resistance.
- Unknown: Optimum dosing, delivery method, patient population with the greatest benefit.

Duration of Therapy

- For both HAP and VAP, a 7-day course is recommended.
- Benefits of short courses (7-8 days) vs. long courses (10-15 days) of antibiotic therapy:
    - Increased antibiotic-free days.
    - Reduced rates of recurrent VAP due to MDR organisms.
- No difference between short courses (7-8 days) vs. long courses (10-15 days) of antibiotic therapy with respect to:
    - Mortality.
    - Recurrence of pneumonia.
    - Ventilator-free days.
    - Duration of mechanical ventilation.
    - ICU length of stay.

Antibiotic Stewardship

- De-escalation is recommended:
    - Switch from empiric broad-spectrum therapy to therapy with a narrower spectrum of activity.
    - Recommendation based on expert clinical experience and clinical rationale.
- Procalcitonin concentration + clinical criteria to guide discontinuation:
    - Procalcitonin is a precursor of calcitonin that rises in response to bacterial infections.
    - Best-established to guide early discontinuation of antibiotics in VAP.
    - Evidence predominantly from VAP, extrapolated to HAP.
    - Can lead to shorter duration of antibiotic therapy.
    - No significant differences in mortality, pneumonia recurrence, mechanical ventilation, ICU/hospital length of stay, development of resistance.