10 Nov, 2019
Pneumonia

PNEUMONIA 

 
  • Community-acquired pneumonia (CAP) is defined as an acute infection of the lung parenchyma in a patient who has acquired the infection in the community. 
  • Hospital-acquired (or Nosocomial) pneumonia (HAP) is pneumonia that occurs 48 hours or more after admission and did not appear to be present at the time of admission. 
  • Ventilator-associated pneumonia (VAP) is a type of HAP that develops more than 48 to 72 hours after endotracheal intubation. Clinical VAP was defined according to the ATS/IDSA guidelines as a radiographic finding suggestive of a pulmonary infection plus two of the three following signs: temperature >101F or <96F, WBC count >11 or < 4 , and visually mucopurulent tracheal secretions.  
  • Healthcare-associated pneumonia (HCAP) is defined as pneumonia that occurs in a non-hospitalized patient with extensive healthcare contact, as defined by one or more of the following: ( In 2019, IDSA stopped endorsing HCAP terminology). 
  1. Intravenous therapy, wound care, or intravenous chemotherapy within the prior 30 days 
  2. Residence in a nursing home or other long-term care facility 
  3. Hospitalization in an acute care hospital for two or more days within the prior 90 days 
  4. Attendance at a hospital or hemodialysis clinic within the prior 30 days 
 
Pathogenesis — the lungs are constantly exposed to particulate material and microbes that are present in the upper airways and, by micro aspiration, enter the lower respiratory tract. Nevertheless, the lower airways usually remain sterile because of the pulmonary defense mechanisms. The development of pneumonia indicates either a defect in host defenses, exposure to a particularly virulent microorganism, or overwhelming inoculums. 
 
Bacteria are the most common cause of CAP and have traditionally been divided into two groups, “typical” and “atypical” agents: 
  1. Typical organisms : S. pneumoniae, H. influenzae, S. aureus, Group A streptococci, Moraxella catarrhalis, anaerobes, and aerobic gram-negative bacteria. 
  2. Atypical pneumonia:  Chlamydia, Mycoplasma and Legionella  
  3. Gram-negative bacilli : Klebsiella pneumoniae, E.coli, Enterobacter, Serratia, Proteus, Pseudomonas and Acinetobacter are uncommon causes of CAP, except in patients requiring admission to an intensive care unit. 
 
Risk factors: S.Pneumo is the commonest of all CAP and common in COPD, splenectomy, alcoholics and with influenza. Pseudomonas is common in bronchiectasis, prolonged steroid therapy, use of repeated antibiotics, NH residents, debilitation and COPD. S.Aureus is common in elderly and in patients recovering from influenza. Klebsiella is common in alcoholics. Anaerobes are common in aspiration and can cause lung abscess. Legionella is common in air-conditioning facilities like hotels. Risk factors for CAP due to gram-negative bacilli include previous antibiotic therapy, prior hospitalization, immunosuppression, pulmonary comorbidity (eg, cystic fibrosis, bronchiectasis, or repeated exacerbations of COPD, frequent glucocorticoid and/or antibiotic use), probable aspiration, and multiple medical co morbidities (eg, diabetes mellitus, alcoholism). 
 
Signs and symptoms: Common clinical features of CAP include cough, fever, pleuritic chest pain, dyspnea and sputum production. Mucopurulent sputum production is most frequently found in association with bacterial pneumonia, while scant or watery sputum production is more suggestive of an atypical pathogen.  
 
The presence of an infiltrate on plain chest radiograph is considered the gold standard for diagnosing pneumonia when clinical and microbiologic features are supportive. A demonstrable infiltrate by chest radiograph is required for the diagnosis of pneumonia, according to the 2007 IDSA/ATS guidelines. 
 
IDSA/ATS consensus guidelines recognize the limitations of sputum Gram stain and culture. The guidelines recommend that pretreatment sputum Gram stain and culture of expectorated sputum be performed only if good quality sputum can be obtained. Since the oropharynx and upper airway are virtually always colonized with indigenous flora, cultures of expectorated sputum will often grow mixed flora, even in the absence of bacterial lower respiratory tract infection. A “good” sputum sample is one with > 25 polymorphonuclear leukocytes (PMNs) and <10 squamous epithelial cells, usually per low power field (LPF). 
 
Sputum culture results must be interpreted with caution because many respiratory pathogens can colonize the upper and/or lower respiratory tracts. In addition, microorganisms that do not cause pulmonary disease, such as Candida species, coagulase-negative staphylococci, and enterococci are commonly isolated in culture and should not be treated. 
 
Cultures: 
  • Obtain empiric gram stain, sputum culture and blood cultures only for severe pneumonia or suspected MRSA/Pseudomonas or hospitalized with IV antibiotics in the last 90 days
  • Check urine for Legionella and strep pneumo only in severe community-acquired pneumonia.
 
Procalcitonin AND CRP - Biologic markers are sometimes used to try to distinguish between bacterial and non-bacterial causes of pneumonia. The two most promising are procalcitonin (PCT) and C-reactive protein (CRP). 
 
Procalcitonin is a peptide precursor of calcitonin that is released by parenchymal cells in response to bacterial toxins, leading to elevated serum levels in patients with bacterial infections; in contrast, procalcitonin is down-regulated in patients with viral infections.  Procalcitonin should not be used to withhold therapy but rather to deescalate antibiotics.
 
The CURB-65 score is based upon five easily measurable factors. Patients with scores ≥2 require more intensive treatment. 
  • Confusion
  • Urea (BUN> 20 mg/dL)
  • Respiratory rate ≥30 breaths/minute 
  • Blood pressure – (systolic <90 mmHg or diastolic ≤60 mmHg) 
  • Age ≥65 years 
Pneumonia Severity Index- Based on various variables,  PSI stratifies patients into 5 mortality risk classes. Class I and II patients should be treated as outpatients, risk class III patients should be treated in an observation unit or with a short hospitalization, and risk class IV and V patients should be treated as inpatients. PSI is much more extensively studied and validated than CURB-65. 
  • Age >50 years 
  • The presence of coexisting conditions: 
    • Neoplastic disease 
    • Heart failure 
    • Cerebrovascular disease 
    • Renal disease 
    • Liver disease 
  • The presence of physical examination abnormalities: 
    • Altered mental status 
    • Pulse ≥125/minute 
    • Respiratory rate ≥30/minute 
    • Systolic blood pressure <90 mm Hg 
    • Temperature <35°C or ≥40°C 
 
SMART -COP: A maximum 11 points can be accrued based on the following criteria: SBP less than 90 mm Hg, multilobar infiltrates, albumin less than 35 g/L, tachypnea, tachycardia > 125 beats/min, acute confusion, low oxygenation (based on age-adjusted PaO2,SpO2, and P/F ratios), and pH less than 7.35. A score of 3 or more suggest ICU admission. Clin Infect Dis. 2008 Aug 1;47(3):375-84
 
IDSA/ ATS Pneumonia Severity —  Pneumonia is considered severe if at least 1 major criteria or 3 minor criteria are present. 
 
Major criteria include Respiratory failure needing mechanical ventilation, septic shock. Minor criteria include RR>30, P/F ratio <250, multilobar infiltrates, confusion, BUN>20, leukopenia with WBC<4000, Platelet count less than 100, Temperature <36, sepsis induced hypotension. 
 
 
Both IDSA/ATS criteria and SMART-COP criteria outperformed PSI and CURB-65 in meta analysis. IDSA also recommends PSI in preference to CURB-65.
 
Treatment of CAP: 
Outpatients 
  1. Amoxicillin 1 g t.i.d. or doxycycline 100 mg b.i.d. or Zithromax for 5 days.
  2. If any comorbidities, Augmentin + zithromax / doxycycline or monotherapy with respiratory fluoroquinolones.

Inpatients, Non-severe Pneumonia treatment 

  1.  Ceftriaxone + Zithromax 
  2.  Respiratory fluoroquinolone (moxifloxacin, or levofloxacin) alone
  3.  Can add MRSA/Pseudomonas coverage, if risk factors present ( Usually h/o previous infections or hospitalized with IV antibiotics in the last 90 days). 
Inpatients, Severe pneumonia treatment 
  1. Ceftriaxone + Zithromax
  2. Ceftriaxone + Respiratory fluoroquinolone (moxifloxacin, or levofloxacin).  
  3.  If PCN allergic, a respiratory fluoroquinolone (moxifloxacin, or levofloxacin) + aztreonam 
  4.  Can add MRSA/Pseudomonas coverage, if risk factors present ( Usually h/o previous infections or hospitalized with IV antibiotics in the last 90 days). 
Patients should be switched from intravenous to oral therapy when they are hemodynamically stable and improving clinically, are able to ingest medications, and have a normally functioning gastrointestinal tract. Patients should be discharged as soon as they are clinically stable, have no other active medical problems, and have a safe environment for continued care. Inpatient observation while receiving oral therapy is not necessary.​
 
Patients with CAP should be treated for a minimum of 5 days (level I evidence), should be afebrile for 48–72 h, and should have no more than 1 CAP-associated sign of clinical instability before discontinuation of therapy. 
 
In CAP-START study, a strategy of preferred empirical treatment with beta-lactam monotherapy was noninferior to strategies with a beta-lactam–macrolide combination or fluoroquinolone monotherapy with regard to 90-day mortality. N Engl J Med 2015; 372:1312-1323 , JAMA Intern Med. 2014 Dec;174(12):1894-901
 
Even though some studies showed that ceftriaxone alone is non inferior to ceftriaxone+zithromax combination, IDSA strongly recommends a combination approach.  Azithromycin could also does play some role  due to its immunomodulator properties rather than atypical coverage alone. BMJ Open. 2013 Jun 20;3(6
 
Aspiration Pneumonia: The diagnosis of acid pneumonitis is usually presumptive based upon the clinical features and course noted. After a suspected aspiration, chest x-ray abnormalities typically appear within two hours.  Aspiration pneumonitis is a chemical / inflammatory reaction, does not need antibiotic coverage and typically resolves within 24 hours.
 
The most common form of aspiration pneumonia is caused by bacteria that normally reside in the upper airways. True aspiration pneumonia usually refers to an infection caused by less virulent bacteria, primarily anaerobes and streptococci, which are common constituents of the normal flora in a susceptible host prone to aspiration. Anaerobic bacteria are the dominant organisms in the upper airways. IDSA recommends that no routine anaerobic coverage is needed for aspiration pneumonia, unless empyema or lung abscess is suspected.
 
Clindamycin (600 mg IV every eight hours followed by 300 mg orally four times daily or 450 mg orally three times daily) is the first-line therapy. Alternative agents are amoxicillin-clavulanate; or a combination of metronidazole plus beta-lactam; or Unasyn/zosyn/imipenem/aztreonam/Avelox. 
 
Non Resolving Pneumonia: Alternative pathogens in addition to the usual bacterial causes of pneumonia need to be considered in the patient who fails to respond to treatment. They include fungal infections, TB, malignancy, resistant bacteria, presence of empyema or lung abscess, inflammatory diseases, and interstitial pneumonia. 
 
Take away points from 2019 IDSA guidelines:
  • Obtain empiric gram stain, sputum culture and blood cultures only for severe pneumonia or suspected MRSA/Pseudomonas or hospitalized with IV antibiotics in the last 90 days
  • Check urine for Legionella and strep pneumo only in severe community-acquired pneumonia.
  • Procalcitonin should not be used to withhold therapy but rather to deescalate antibiotics.
  • IDSA recommended not using the term HCAP anymore.
  • Can stop MRSA coverage, if nasal PCR screen is negative or cultures negative after 48 hours.
  • No routine anaerobic coverage is needed for aspiration pneumonia, unless empyema or lung abscess is suspected.
  • Duration of antibiotics for outpatient and non severe inpatient community-acquired pneumonia is 5 days , if patient achieves clinical stability.
  • It is reasonable to treat patients with severe pneumonia or MRSA or Pseudomonas with 7 days of antibiotics or until clinical stability, whichever is later.
 
 
 
Nosocomial Pneumonia 
Nosocomial Pneumonia is defined as lower respiratory infection that develops in a hospitalized patient after 48 hours of admission, and was not present or incubating at the time of admission.  Nosocomial pneumonia includes Hospital-acquired pneumonia (HAP) , Ventilator associated pneumonia (VAP) , and Health care–associated pneumonia (HCAP). 
 
CDC Definition : A new, persistent, or progressive infiltrate or cavitation should be seen on 2 or more serial chest radiographs. Clinically the patient should show either fever  with no other recognized cause, leukopenia or leukocytosis . The patient also should exhibit at least 2 of the following signs: new onset of purulent sputum, change in character of sputum, increased respiratory secretions, or increased suctioning requirements. Finally, the patient should exhibit worsening gas exchange (decreased P /F ratio or increased ventilation demand). The microbiological criteria include at least 1 of the following: a positive blood culture not related to another source of infection; positive growth in culture of pleural fluid; a positive quantitative culture from a bronchoalveolar lavage (BAL) (>1000 cfu/mL).  
 
Etiology: 
Most common bacteria for nosocomial pneumonia are Pseudomonas aeruginosa, Acinetobacter, Staphylococcus aureus, Escherichia coli, ESBL Klebsiella and Enterobacter, all of which caused 80% of all infections. These are also the most common late onset infections (after 4 days of admission). They also have increased risk of having multi drug resistance. 
 
Early-onset infections (within 4 days after admission) are usually caused by a group of “core” organisms: Streptococcus pneumoniae, Haemophilus influenzae, MSSA, and nonresistant gram-negatives (E coli, Klebsiella , Enterobacter , Proteus and Serratia marcescens).  
 
Fungal and rare pathogens such as Aspergillus , Pneumocystis jiroveci, Candida , Nocardia , and viruses such as cytomegalovirus should be suspected in immunosuppressed and transplant patients. 
 
Pathogenesis of VAP:
The presence of an endotracheal tube is by far the most important risk factor, resulting in a violation of natural defense mechanisms (the cough reflex of glottis
and larynx) against microaspiration around the cuff of the tube. Infectious bacteria obtain direct access to the lower respiratory tract via:
  1. Microaspiration, which can occur during intubation itself
  2. Development of a biofilm laden with bacteria (typically Gram-negative bacteria and fungal species) within the endotracheal tube
  3. Pooling and trickling of secretions around the cuff
  4. Impairment of mucociliary clearance of secretions with gravity dependence of mucus flow within the airways.
 
Diagnosis:
VAP must be distinguished from tracheo-bronchitis. Clinical features of these diseases can overlap, but only VAP will demonstrate the presence of hypoxia and the presence of infiltrate/consolidation on chest radiography. Curr Opin Infect Dis. 2013 Apr;26(2):140-50 . Per CDC criteria, a period of at least 2 days of stable or decreasing ventilator settings (daily minimum PEEP or FiO2]) followed by consistently higher settings for at least 2 additional calendar days is required before a patient can be said to have a ventilator-associated condition (VAC). Most VACs are attributable to pneumonia, pulmonary edema, atelectasis or ARDS. 
 
In diagnosing VAP, 2016 IDSA guidelines recommend using non invasive sampling like endotracheal cultures to invasive sampling like BAL. Also, a Canadian Clinical Trials showed that similar clinical outcomes and overall use of antibiotics is observed when either BAL with quantitative culture or endotracheal aspiration with non-quantitative culture is used for diagnosis. N Engl J Med 2006; 355:2619-2630 , Cochrane Database Syst Rev. 2014 Oct 30;(10):CD006482
 
Treatment: 
Key points of 2016 IDSA guidelines for HAP/VAP treatment are:
  1. In patients with suspected VAP, include coverage for S. aureus, Pseudomonas aeruginosa, and other gram-negative bacilli in all empiric regimens. Most common drugs used are zosyn, cefepime, levaquin, imipenem or meropenem. 
  2. Including an agent active against MRSA for the empiric treatment of suspected VAP only in patients with any of the following: a risk factor for antimicrobial resistance (septic shock, previous antibiotic use in last 90 days, ARDS, more than 5 days since admission, AKI needing dialysis), patients being treated in units where >10%–20% of S. aureus isolates are methicillin resistant, and patients in units where the prevalence of MRSA is not known. Either a vancomycin or linezolid is reasonable.
  3. Include an agent active against MSSA and not MRSA for the empiric treatment of suspected VAP in patients without risk factors for antimicrobial resistance, who are being treated in ICUs where <10%–20% of S. aureus isolates are methicillin resistant. Regimens include zosyn, cefepime, imipenem, levofloxacin or meropenem. In straighforward MSSA pneumonia, drugs like cefazolin, nafcillin or oxacillin are preferred. 
  4. Prescribing two antipseudomonal antibiotics from different classes for the empiric treatment of suspected VAP only in patients with any of the following: a risk factor for antimicrobial resistance (septic shock, previous antibiotic use in last 90 days, ARDS, more than 5 days since admission, AKI needing dialysis), patients in units where >10% of gram-negative isolates are resistant to an agent being considered for monotherapy, and patients in an ICU where local antimicrobial susceptibility rates are not available. Common second antibiotic that is added for double gram negative coverage are aminoglycosides, flouroquinolones, colistin and polymyxin. 
  5. For patients with VAP due to gram-negative bacilli that are susceptible to only aminoglycosides or polymyxins (colistin or polymyxin B), both inhaled and systemic antibiotics, rather than systemic antibiotics alone should be used
  6. In patients with HAP/VAP caused by Acinetobacter species, we recommend against the use of tigecycline
  7. For patients with HAP/VAP, a 7-day course of antimicrobial therapy rather than a longer duration is recommended (strong recommendation)
  8. For patients with HAP/VAP, PCT levels plus clinical criteria should be used to guide the discontinuation of antibiotic therapy, rather than clinical criteria alone.
  9. For patients with suspected VAP whose BAL CFU count is less than 104/ml, IDSA suggest that antibiotics be withheld rather than continued. Also, for patients with suspected HAP/VAP, IDSA recommend using clinical criteria alone, rather than using serum procalcitonin/CRP plus clinical criteria, to decide whether or not to initiate antibiotic therapy. 
  10. IDSA do not recommend antibiotics for ventilator associated tracheobronchitis. 

Patients with either late-onset infection or the presence of any of the other MDR risk factors should have empiric coverage for MDR gram-negative and gram-positive pathogens, in addition to the core pathogens already mentioned. Thus a combination of an antipseudomonal b-lactam (imipenem, meropenem, Zosyn, aztreonam, or cefepime) plus an aminoglycoside or quinolone is commonly used.  

 
Combination therapy with an aminoglycoside is usually the judicious first step, reserving quinolones for subsequent ICU infection. Aminoglycosides may have more intrinsic activity than antipseudomonal quinolones. In fact, in recent years the activity of quinolones against pseudomonas has declined.  
 
When aminoglycosides and quinolones are used, they kill bacteria in a concentration-dependent fashion, and once-daily dosing can optimize the killing of organisms. 
 
 
PEARLS: 
  • Combination therapy for a specific pathogen should be used judiciously in the therapy of HCAP, and consideration should be given to short-duration (3-5 days) aminoglycoside therapy, when used in combination with a Beta-lactam to treat P. aeruginosa pneumonia. 
  • The endotracheal tube cuff pressure should be maintained at greater than 20 cm H2O to prevent leakage of bacterial pathogens around the cuff into the lower respiratory tract 
  • A sterile culture of respiratory secretions in the absence of a new antibiotic in the past 72 hours virtually rules out the presence of bacterial pneumonia, but viral or Legionella infection is still possible. 
  • In mechanically ventilated patients, the endotracheal cuffs are effective at preventing macro-aspiration but small folds on the surface of the cuff act as conduits for micro aspiration of secretions pooled above the cuff. In older patients, who may have tracheomalacia, there may be a leak around the cuff despite high intra-cuff pressure. 
  • Measures for preventing VAP include HOB elevated to 30-45degrees, daily chlorhexidine mouth wash, stress ulcer prophylaxis, sub-glottic secretion drainage, maintain ETT cuff pressure or 20-30cm H2O,  endotracheal suction and extubation if not necessary. 
  • HCAP risk factors include hospitalization for > 48 hrs  in the last 90 days, a residence in SNF, chronic dialysis, wound care, home infusion therapy, family members with MDR organism.
  • Presence of bacteria in expectorated sputum or endotracheal aspirate cultures usually represents colonization only, and does not itself justify a diagnosis of HCAP / VAP
  • Severe pneumonia with bilateral infiltrates: think of ARDS due to secondary sepsis, atypical pneumonia, PCP, and blastomycosis. Consider antifungals on admission. 
  • Compared with betalactam+macrolides, combination of betalactam+ fluoroquinolones are associated with similar mortality rates but increased length of stay. (Crit Care Med. 2012 Aug; 40(8): 2310–2314). 
  • In severely ill population with clinically suspected VAP and negative quantitative BAL cultures, early discontinuation of antibiotics did not affect mortality and was associated with a lower frequency of MDR super infections. BAL or mini-BAL was defined as negative if there was less than 104 CFU/mL of growth from the culture. (Crit Care Med. 2013 Jul;41(7):1656-63) 
  • Less than 50% neutrophils in a pulmonary specimen makes VAP less likely 
  • A good respiratory specimen should have less than 10 epithelial cells and more than 25 WBC. 
  • Common contaminants in sputum are candida, enterococci, and coagulase negative staph. 
  • CURB 65:  Treatment is outpatient for a score of 1, inpatient for 2 and ICU for 3 or more. 
  • In VAP, a 7-8 day therapy is equally efficacious as 10-15 day therapy. There was no difference in mortality rates or ventilator free days. JAMA. 2003 Nov 19;290(19):2588-98 , 
  • Oral chlorhexidine is active against staph, MRSA and VRE. 
  • Oral chlorhexidine wash 4 times a day decreased the incidence of VAP. However, the mortality rates and ICU length of stay was the same. Am J Respir Crit Care Med. 2006 Jun 15;173(12):1348-55
  • In the intial treatment of VAP, choosing broad coverage instead of relying on previous endotracheal cultures and sensitivities have shown to be better, unless the endotracheal aspirate is taken in last 48 hours. Chest. 2013;144(1):63-71 
  • Inhaled antibiotics like colistin or tobramycin have improved 30 day survival in pneumonia caused by pseudomonas and acinetobacter. However, when patients who are transitioned to palliative care are included, there was no mortality benefit. In essence, this study only talked about patients who are alive and not switched to palliative care.  Also, it resulted in increased ventilator days, longer ICU stay and hospital stay. Respir Care. 2012 Aug;57(8):1226-33 
  • IDSA gave a strong recommendation for amoxicilllin and weak recommendation for doxycycline / zithromax for the outpatient treatment of pneumonia. 
  • VAP and gastric residuals: Among adults requiring mechanical ventilation and receiving early enteral nutrition, the absence of gastric volume monitoring was not inferior to routine residual gastric volume monitoring in terms of development of VAP. JAMA. 2013;309(3):249-256
  • Empyema drainage can be achieved via tube thoracostomy (large bore chest tubes are required due to high viscosity) with or without intrapleural tissue plasminogen activator administration. Decortication may be required if tube thoracostomy is not successful. For lung abscess or necrotizing pneumonia, thoracotomy and wedge resection is occasionally required.​​ 
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Infections