The Bacterial Pneumonias: A New Treatment Paradigm




(1)
Division of Pulmonary and Critical Care Medicine, Eastern Virginia Medical School, Norfolk, VA, USA

 




Keywords
PneumoniaCommunity acquired pneumonia (CAP)Severe community acquired pneumoniaHealthcare associated pneumonia (HCAP)Nursing-home acquired pneumoniaLong term acute care associated pneumoniaHospital acquired pneumonia (HAP)Ventilator associated pneumonia (AP)Aspiration pneumoniaMulti-drug resistant pathogen (MDR)


PneumoniaThe old mans best friendCaptain of the Men of Death

Sir William Osler, Physician (1849–1919)


Pneumonia is a common disease and a leading cause of death. Indeed, William Osler recognized that most old people die from pneumonia rather than from old age itself [1]. Pneumonia is therefore a leading cause of hospitalization and amongst the most common reasons for admission to the ICU. Indeed, over 50 % of patients with severe sepsis have pneumonia. Most bacterial pneumonias, with the notable exception of Legionella Pneumonia, Tuberculosis and Leptospiral Pneumonia are caused by the aspiration of oropharyngeal material colonized with the causative pathogen. This implies that the “causative” pathogen together with low-virulence oral flora are aspirated in most pneumonia. Appropriate initial antimicrobial therapy, defined as the use of at least one antibiotic active in vitro against the causative bacteria, is associated with reduced length of hospitalization, reduced morbidity and reduced mortality when compared with patients receiving initial inappropriate therapy [24]. As inappropriate initial antibiotic therapy is usually associated with infection with a drug-resistant pathogen (DRP), and as DRPs are usually acquired in specific settings, the treatment of pneumonia has traditionally been based on the setting in which the pneumonia develops. The number of individuals receiving health care outside the hospital setting, including home wound care and infusion therapy, dialysis, nursing homes and long-term acute care (LTAC) facilities is increasing. One of the most frequent causes of hospitalization and mortality in these patients is pneumonia. Hence a new class of pneumonia was identified; healthcare associated pneumonia (HCAP). Consequently, the 2005 and 2007 guidelines for the management of pneumonia by the American Thoracic Society and the Infectious Diseases Society of America recommend that pneumonia should be classified into one of three categories at diagnosis: (1) community-acquired pneumonia (CAP), (2) healthcare-associated pneumonia (HCAP), and (3) hospital-acquired pneumonia (HAP) [5, 6]. These three categories of pneumonias are further subdivided into the following “word-soup” subtypes according to the setting where the pneumonia develops, the severity of illness and the risk of aspiration, namely:



  • Community Acquired Pneumonia (CAP)


  • Severe Community Acquired Pneumonia (S-CAP)


  • Healthcare Associated Pneumonia (HCAP)


  • Nursing-Home acquired pneumonia (NHP)


  • Long Term Acute Care Associated Pneumonia (LTAC-P)


  • Hospital Acquired Pneumonia (HAP)


  • Early Ventilator Associated Pneumonia (E-VAP)


  • Late Ventilator Associated Pneumonia (L-VAP)


  • Aspiration pneumonia (AP)

The mortality of patients with HCAP is higher than that of patients with CAP (about 30 % vs 5 %); this is likely related to the comorbidities and poor-functional status of patients with HCAP rather than the virulence of the pathogen or the prescription of initial inappropriate antibiotic therapy [79].

It has been argued that patients with HCAP and HAP are at a higher risk of infection with DRP’s such as Pseudomonas aeruginosa and methicillin–resistant Staphylococci (MRSA) and therefore require an initial broad spectrum multidrug antibiotic regimen. It has been assumed that the three major categories of pneumonia are distinct clinical entities that require specific antimicrobial regimens. However, increasing evidence suggests that there is much overlap between these conditions and that a more unified approach to the treatment is more practical. In essence these pneumonias differ by the spectrum of colonizing organisms which are aspirated and it may therefore be more useful to risk stratify patients according to the likelihood of developing infection with gram-negative and DRPs. The traditional approach assumes that patients with HCAP are infected with DRPs while CAP patients are infected with multi-sensitive organisms (MSO). However, a small percentage of patients with CAP are infected with DRPs while a significant percentage of patients with HCAP are infected with MSO (see Fig. 17.1). Indeed, only 10–30 % of patients with HCAP are infected with DRPs [7, 10, 11]. A more useful schema is to assess the risk of infection with a pathogen not susceptible to ceftriaxone, ampicillin-sulbactam, macrolide or a respiratory fluoroquinolone; these known as CAP drug-resistant pathogens (CAP-DRPs) [8]. In a large prospective observational study Shindo et al. reported infection with CAP-DRPs in 26.6 % of patients with HCAP and 8.6 % of patients with CAP. Remarkably, the risk factors for CAP-DRPs were almost identical in patients with CAP and HCAP. Based on this concept, the following have been identified as risk factors for infection with a CAP-DRPs in both community and healthcare associated pneumonia [8, 10, 12]:

A69851_3_En_17_Fig1_HTML.gif


Fig. 17.1
Traditional classification of bacterial pneumonias with percentage of CAPDRPs (in black)




  • Hospitalization for >2 days during the previous 90 days


  • Antibiotic use during the previous 90 days


  • Non-ambulatory status


  • Tube feeds


  • Immunocompromised status


  • Use of acid suppressive therapy


  • Chronic hemodialysis during the preceding 30 days


  • Positive MRSA history within previous 90 days


  • Present hospitalization >2 days

The risk of a CAP-DRPs increases with the number of risk factors being about 3 % with no risk factors, 10 % with one risk factor and greater than 80 % for 5 or more risk factors [8]. According to this revised treatment approach a patient with pneumonia and one or more risk factors for a CAP-DRP (irrespective of where the patient develops the pneumonia) should receive broad spectrum antibiotics, while all others should be treated with narrow spectrum antibiotics (traditional CAP antibiotics) [8, 9]. It may be also reasonable to tailor the “aggressiveness” of the CAP-DRPs regimen according to the number of risk factors for a CAP-DRP. Poor functional status (Barthel Index score <50) is a major factor increasing the risk of infection with a CAP-DRP; these patients usually have multiple other risk factors for infection with a CAP-DRP [9, 13, 14]. The antibiotic regimen for those likely to be infected with a CAP multi-sensitive organism (CAP-MSO) is further stratified according to severity of illness (see algorithm below). In patients risk stratified to treatment with a CAP-DRP regimen, monotherapy is adequate once a known pathogen is identified. This strategy of initiating broad spectrum cover with two or more antibiotics and then narrowing the spectrum to a single agent when a pathogen is identified is known as “antimicrobial de-escalation” [15]. The de-escalation approach has been demonstrated to be associated with a reduction in mortality [16]. The exception to this “monotherapy” rule is patients with “severe-CAP” in whom combination therapy with ceftriaxone and a macrolide is recommended (see below)


Unified Treatment Algorithm



No Risk Factors for a CAP-DRP


Low Acuity of illness



  • Macrolide


  • Fluoroquinolone


  • Ampicillin-sulbactam


  • Doxycycline

High Acuity of illness (ICU admission)



  • Ceftriaxone and macrolide


Risk Factors for CAP-DRPs






  • Piperacillin/Tazobactam + vancomycin + ciprofloxacin


  • Carbapenem + vancomycin


  • Cefepime + vancomycin


  • Piperacillin/Tazobactam + vancomycin + aminoglycoside (once daily)


  • Etc, etc…


Influenza (Co-Existent or Influenza Pneumonia)






  • Early treatment (within 48 h of the onset of symptoms) with oseltamivir or zanamivir is recommended for influenza A.


  • Use of oseltamivir and zanamivir is not recommended for patients with uncomplicated influenza with symptoms for >48 h, but these drugs may be used to reduce viral shedding in hospitalized patients or for influenza pneumonia.


  • S. pneumoniae and S. aureus, the most common causes of secondary bacterial pneumonia in patients with influenza.

Patients with severe pneumonia are best managed in the ICU. Patients with the following criteria require ICU admission [6].


Major Criteria






  • Requirement for mechanical ventilation or


  • Septic shock (SBP < 90 despite fluids)


Minor Criteria (3 or More)






  • 30 < white blood cell count < 4 × 109/L


  • Blood urea nitrogen > 20 mg/dL


  • PaO2/FiO2 < 250


  • Multilobe involvement


  • Respiratory rate >30/min


  • Platelet count < 100,000 × 109/L


  • Confusion/disorientation


  • Hypothermia (temperature <36o)


  • Hypotension requiring fluid resuscitation

The classically described “atypical” pathogens that cause CAP include Chlamydia pneumoniae, Mycoplasma pneumoniae, and Legionella species. The “atypical” moniker is an inaccurate description of the clinical features of the pneumonia associated with these organisms and is retained more as a classification than a specific descriptor of the disease process or clinical presentation. M. pneumoniae has been shown to be the most common of the atypical pathogens and accounts for 17–37 % of outpatient CAP and 2–33 % of CAP requiring hospitalization. C. pneumoniae is more common than Legionella species; however, Legionella species can lead to rapidly progressive and fatal pneumonia.


Diagnostic Testing of Hospitalized Patients with Pneumonia






  • Blood cultures


  • Urinary antigen tests for Legionella pneumophila and Streptococcus pneumonia


  • Expectorated sputum for culture


  • Intubated patients require endotracheal aspirate or m-BAL with quantitative culture


  • Screening for HIV in at risk patients


  • Nasopharyngeal swab for influenza during seasonal influenza (rapid Ag test and viral PCR)


Non-Infectious Diseases Masquerading as Pneumonia






  • Cryptogenic organizing pneumonia (COP)


  • Eosinophilic pneumonia


  • Hypersensitivity pneumonia


  • Drug induced pneumonitis: methotrexate, nitrofurantoin, gold, amiodarone


  • Pulmonary vasculitis


  • Pulmonary embolism/infarction


  • Pulmonary malignancy


  • Radiation pneumonitis


  • Tuberculosis


Special Considerations



Severe CAP with no MDR Risk Factors


Streptococcus pneumoniae remains the most common and important pathogen causing “Classic CAP”. Although monotherapy is considered standard for “classical CAP”, a survival benefit of combination β-lactam and macrolide has been suggested. Waterer et al. found that patients with bacteremic pneumococcal CAP who receive at least two effective antibiotic agents within the first 24 h after presentation had a significantly lower mortality than patients who received only one effective antibiotic agent [17]. The most common combination was a third generation cephalosporin with a macrolide or quinolone. Using a large hospital database Brown et al. demonstrated a lower mortality, shorter LOS and lower hospital charges for patients with CAP treated with dual therapy using macrolides as the second agent [18]. Rodriguez et al. undertook a secondary analysis of data obtained from a prospective observational cohort study of cases in 33 ICUs in Spain. Overall, 270 patients required vasoactive drugs and were characterized as having shock. In the cases with shock, combination antibiotic therapy was associated with a significantly higher adjusted 28-day in-ICU survival (hazard ratio 1.69: 95 % CI 1.09–2.60; P = 0.01) [19]. Another study investigated outcome of patients with severe CAP, comparing patients treated with β-lactam/macrolide combination versus those treated with fluoroquinolone monotherapy [20]. Lower 30-day mortality rates were seen for those treated with β-lactam/macrolide combination (18.4 versus 36.6 % (P = 0.05). In a systemic review by Sligl et al. which included almost 10,000 critically ill patients with CAP macrolide use was associated with a significant 18 % relative reduction in mortality compared with non-macrolide therapies [21].

The possible explanations for the benefits of dual coverage (esp. with a macrolide) include antibiotic synergy, coverage of unrecognized atypical pathogens, immunomodulating effects and the effect on bacterial quorum sensing. Macrolides, at sub-minimum inhibitory (MIC) concentrations, are potent inhibitors of the production of pneumolysin (a potent virulence factor) by macrolide-susceptible strains of the pneumococcus, whereas the beta-lactam agent, ceftriaxone, as well as amoxicillin, ciprofloxacin, moxifloxacin, and tobramycin are relatively ineffective [22]. Although they also antagonize various pro-inflammatory activities of neutrophils, macrolides primarily target the synthesis of interleukin (IL)-8 by bronchial epithelial cells, eosinophils, monocytes, fibroblasts and airway smooth muscle cells [23].


Community-Acquired MRSA Pneumonia (CA-MRSA)


In the United States, some patients with CAP have been affected by a severe necrotizing bilateral pneumonia caused by community-acquired methicillin-resistant Staphylococcus aureus (CA-MRSA), a pathogen that seems more common in the United States than in Europe [24]. Initially reports of CA-MRSA were of patients with severe pneumonia and a high mortality, but more recently the spectrum of illness caused by this pathogen has expanded to include patients with milder illness [2426]. CA-MRSA is resistant to fewer antimicrobials than are hospital acquired MRSA strains and often contain a novel type IV SCCmec gene. In addition, most contain the gene for Panton-Valentine leukocidin, a toxin associated with the clinical features of necrotizing pneumonia, shock, as well as formation of abscesses and empyemas [27]. Because the clinical presentation of this infection is disproportionately exotoxin-mediated, treatment is recommended with antibiotics that suppress toxin production, such as linezolid or clindamycin (added to vancomycin); these regimens have been associated with reduced mortality [28, 29].

Clinical Features suggesting CA-MRSA [30]
Oct 12, 2016 | Posted by in CRITICAL CARE | Comments Off on The Bacterial Pneumonias: A New Treatment Paradigm

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