Pneumonia Uremia by mikeholy

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									Rizwana Khan MD

   8 to 15 per 1000 persons per year

   Highest rates are at extremes of age

   There is seasonal variation, with more cases occurring during the winter

   The rates of pneumonia are higher for men than for women, for black persons
    compared with Caucasians

   Defect in host defenses
   Exposure to a particularly virulent microorganism
   An overwhelming inoculum

   Microaspiration is the most common mechanism

   Hematogenous spread from a distant site

   Direct spread from a contiguous focus

   Macroaspiration
Bacterial virulence factors
   Chlamydophila pneumoniae produces a ciliostatic factor

   Mycoplasma pneumoniae can shear off cilia

   Influenza virus reduces tracheal mucus velocity within hours, for up to 12 weeks

   Streptococcus pneumoniae and Neisseria meningitidis produce proteases that
    can split secretory IgA

   Pneumococcus capsule inhibits phagocytosis; pneumolysin, neuraminidase,
    and hyaluronidase

   Mycobacterium spp, Nocardia spp, and Legionella spp, are resistant to the
    microbicidal activity of phagocytes
Predisposing host conditions
   Alterations in the level of consciousness, which predispose to macro/ micro aspiration
   Alcohol consumption, Hypoxemia, Acidosis
   Toxic inhalations
   Pulmonary edema
   Uremia
   Malnutrition
   Solid organ or stem cell transplant recipients, or chemotherapy
   Mechanical obstruction of a bronchus
   Being elderly, there is a marked increase in the rate of pneumonia in persons ≥65 years
   Cystic fibrosis
   Bronchiectasis
   Chronic obstructive pulmonary disease (COPD)
   Previous episode of pneumonia or chronic bronchitis
   Immotile cilia syndrome
   Kartagener's syndrome (ciliary dysfunction, situs inversus, sinusitis, bronchiectasis)
   Young's syndrome (azoospermia, sinusitis, pneumonia)
   Increased risk with gastric acid-suppressive therapy, including proton pump inhibitors
    (PPIs) and H2 blockers

   Antipsychotic drugs associated with an almost 60 percent increase in the risk of
    pneumonia among elderly persons requiring hospitalization

   Current use of atypical (OR 2.61) or typical (OR 1.76) antipsychotic use was
    associated with a dose-dependent increased risk for CAP compared with past use

   Atypical antipsychotic use was also associated with an increase in the risk of fatal
    CAP (OR 5.97)

   Risk of community-acquired pneumonia and use of gastric acid-suppressive drugs. Laheij et al.JAMA.2004;292(16):1955-60
   Use of proton pump inhibitors and the risk of community-acquired pneumonia: a population-based case-control study. Gulmez et al.
    Arch Intern Med. 2007;167(9):950-5.
   Proton-pump inhibitor use and the risk for community-acquired pneumonia. Sarkar et al. Ann Intern Med. 2008;149(6):391-8
   Association of community-acquired pneumonia with antipsychotic drug use in elderly patients: a nested case-control study. Trifir et al.
    Ann Intern Med. 2010;152(7):418-25, W139-40.
   Bacteria are the most common cause of CAP

   "Typical" organisms : S. pneumoniae, Haemophilus influenzae, Staphylococcus
    aureus, Group A streptococci, Moraxella catarrhalis, anaerobes, and aerobic
    gram-negative bacteria

   "Atypical― organisms: Legionella spp, Mycoplasma pneumoniae,
    Chlamydophila pneumoniae, and C. psittaci

   A microbiologic diagnosis is confirmed in about 60 % of cases of CAP in
    research studies
   and in 20 % of cases in everyday practice
Epidemiologic clues
   Know the local epidemiology and the patient's travel history (eg, endemic fungi
    such as Histoplasma, Coccidioides, Blastomyces, and Paracoccidioides spp;

   Elicit history of specific exposures (eg, Histoplasma spp and bat or bird
    droppings, Chlamydophila psittaci and birds)

   Be aware of national and international outbreaks (eg, influenza or severe acute
    respiratory syndrome [SARS])

   Never forget Mycobacterium tuberculosis

   Pneumocystis jirovecii is often forgotten as a cause of CAP

   Methicillin-resistant Staphylococcus aureus is an increasingly recognized cause
    of severe, occasionally necrotizing CAP
   S. pneumoniae — most common cause of CAP but isolated in 5-18%

   H. influenzae — pneumonia in elderly adults and patients with cystic fibrosis and

   M. pneumoniae —Infection rates are highest in school-aged children, military
    recruits, and college students

   Chlamydia pneumoniae — The infection is most common in those aged 65 to 79

   Legionella — Outbreaks associated with exposure to aerosol-producing devices,
    including showers, grocery store mist machine, cooling towers, whirlpool spas, and
    decorative fountains

   Community-associated methicillin-resistant S. aureus (CA-MRSA) is associated with
    severe necrotizing pneumonia
   CA-MRSA pneumonia may be associated with influenza infection
   Group A streptococcus —GAS, S. pyogenes can cause a fulminant pneumonia with
    early empyema formation young, immunocompetent hosts

   Anaerobes — may be the cause of aspiration pneumonia and lung abscess

   Neisseria meningitidis — an uncommon cause of CAP

   Pneumonia due to N. meningitidis should be reported to the health department and
    prophylaxis given as for meningitis or septicemia

   Mycobacterium tuberculosis — an important cause of CAP in developing countries
    and in some regions of the United States

   Other bacteria — Francisella tularensis (tularemia) and Coxiella burnetii (Q fever)
   Gram-negative bacilli — especially K. pneumoniae, Escherichia coli, Enterobacter spp,
    Serratia spp, Proteus spp, P. aeruginosa, and Acinetobacter spp, are uncommon causes
    of CAP except in patients with severe pneumonia requiring admission to an ICU where, as
    a group, they are among the most commonly isolated organisms after S. pneumoniae.

   Klebsiella pneumonia —in patients who have COPD, diabetes, and alcohol abuse

   Pseudomonas aeruginosa — Risk factors include bronchiectasis and the use of repeated
    antibiotic courses or prolonged glucocorticoids and in patients with COPD and pulmonary

   Immunocompromise (eg, neutropenia, HIV infection, solid organ or hematopoietic stem
    cell transplantation) and previous hospitalization are other risk factors

   Acinetobacter spp —A. baumannii is emerging as a cause of severe CAP with high
   Multidrug resistance is an increasing problem with Acinetobacter infection

   Moraxella catarrhalis —70% have predisposing factors such as neutropenia, malignancy,
    or COPD or malnutrition

   S. aureus — in elderly adults and in younger patients who are recovering from influenza
    (postinfluenza pneumonia)
   Influenza virus — Influenza A or B viruses cause an acute respiratory illness that
    occurs in outbreaks and epidemics, mainly in the winter season

   Influenza pneumonia occurs most frequently in patients with heart or lung disease,
    diabetes mellitus, renal disease, hemoglobinopathy, or immunosuppression;
    residents of nursing homes or chronic care facilities; and otherwise healthy
    individuals over age 65

   Parainfluenza virus — in immunocompromised adults

   Respiratory syncytial virus —causes acute respiratory tract illness in persons of all

   Adenovirus — Adenoviral pneumonia was first described among military recruits in
    whom it causes an "atypical pneumonia―

   Human metapneumovirus — (HMPV) was first described in 2001 in the Netherlands.
    Symptomatic disease most often occurs in the young children or older adults
   Severe acute respiratory syndrome (SARS) — In November 2002, an outbreak
    started in Guangdong Province in southern China and spread worldwide affecting
    more than 8,000 persons.
   SARS was due to a novel coronavirus that jumped the species barrier from civet cats
    to man.
   The case fatality rate of the 2003 Hong Kong outbreak was 11%, but higher mortality
    was seen in elderly adults (≥60 years of age) and pregnant women

   Hantavirus — The illness is preceded by prodromal flu-like symptoms followed by
    noncardiogenic pulmonary edema and ARDS-like picture
   The virus is spread to humans from infected mice

   Avian influenza — The first association of avian influenza H5N1 with clinical
    respiratory disease occurred in Hong Kong in 1997, when 18 human cases occurred
    during a poultry outbreak of highly pathogenic H5N1 influenza in live-bird markets
   The WHO and the CDC consider avian influence a potential source for the next
    global influenza pandemic

   Varicella — Varicella pneumonia is the most frequent complication of varicella
    infection in normal healthy adults
   The case fatality rate is between 10 and 30 percent
   More common in the immunocompromised patient, particularly those with neutropenia, on
    chronic immunosuppressive therapy (eg, organ transplant recipients), and those infected
    with HIV

   Cryptococcus spp — found in the soil throughout the world
   In immunocompetent individuals, primary infections are usually discovered as an incidental
    finding on chest radiograph
    Cryptococcal pneumonia in immunocompromised patients is symptomatic with cough,
    fever, and dyspnea

   Histoplasma capsulatum — infection is most common in the Midwestern states located in
    the Ohio and Mississippi River valleys
    H. capsulatum proliferates best in soil contaminated with bird or bat droppings
   Symptomatic patients with acute histoplasmosis generally present with a flu-like illness with
    pulmonary complaints and radiographic abnormalities

   Coccidioides spp — endemic to certain lower deserts of the western hemisphere including
    southern Arizona, central California, southwestern New Mexico, and west Texas.
   They are also found in parts of Mexico, Central, and South America

   Other fungi — include Aspergillus spp and Pneumocystis jirovecii (formerly P. carinii)
Clinical evaluation
   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

   Gastrointestinal symptoms (nausea, vomiting, diarrhea), and mental status changes

   Chest pain occurs in 30 %, chills in 40 to 50%, and rigors in 15%

   On physical examination, approximately 80% are febrile

   A respiratory rate above 24 breaths/minute is noted in 45 to 70 % and may be the most
    sensitive sign in elderly patients; tachycardia is also common

   Chest examination reveals audible rales in most patients, while approximately one-third
    have evidence of consolidation

   The major blood test abnormality is leukocytosis (typically between 15,000 and 30,000 per
    mm3) with a leftward shift. Leukopenia can occur, and generally connotes a poor prognosis
Radiologic evaluation
   A n infiltrate by chest radiograph or other imaging technique is required for the diagnosis

   Recommendations are less clear in what appears to be a viral infection with nasal
    congestion and cough; one approach in these cases is to obtain a chest x-ray when there is
    an abnormal vital sign with particular emphasis on a respiratory rate >20/min or a fever

   If the clinical syndrome favors pneumonia but the radiograph is negative, the radiograph
    may represent a false negative result. CT scan has higher sensitivity and accuracy for
    detecting CAP

   Volume depletion may produce an initially negative radiograph, which "blossoms" into
    infiltrates following rehydration (7% of patients )

   For hospitalized patients with suspected pneumonia and a negative chest radiograph, it is
    reasonable to initiate empiric presumptive antibiotic therapy and repeat the chest
    radiograph in 24 to 48 hours

   Alternatively, a CT scan could be performed in patients with a negative chest radiograph
    when there is a high clinical suspicion for pneumonia

   Mandell, LA, Wunderink, RG, Anzueto, A, et al. Infectious Diseases Society of America/American Thoracic Society consensus
    guidelines on the management of community-acquired pneumonia in adults. Clin Infect Dis 2007; 44 Suppl 2:S27
Diagnostic testing for microbial etiology

   For outpatients with CAP, routine diagnostic tests are optional

   Hospitalized patients with specific indications should have blood cultures and
    sputum Gram stain and culture, or other tests as indicated
   diagnostic tests are optional for other hospitalized patients without severe CAP
   Patients with severe CAP requiring ICU admission should have blood cultures,
    urinary antigen tests, and sputum

   Some microbes are critical to detect because they require treatment different
    from standard empiric regimens:
   Legionella species
   Influenza, including avian influenza
   Community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA)
   Agents of bioterrorism

   Mandell, LA, Wunderink, RG, Anzueto, A, et al. Infectious Diseases Society of America/American Thoracic Society
    consensus guidelines on the management of community-acquired pneumonia in adults. Clin Infect Dis 2007; 44
    Suppl 2:S27
Hospitalized patients
Diagnostic yield of microbiologic tests in hospitalized patients with CAP:

   Pathogen identified -- 60 percent patients
   Adequate sputum samples obtained --15 percent
   Gram stain positive -- 82 percent
   Urinary pneumococcal antigen test positive -- 54 percent patients with
    pneumococcal pneumonia
   Blood cultures positive -- 16 percent

   Bronchoscopy is of additive diagnostic value – in 49 percent who do not
    expectorate sputum and 52 percent who fail treatment within 72 hours

   Mandell, LA, Wunderink, RG, Anzueto, A, et al. Infectious Diseases Society of America/American Thoracic Society
    consensus guidelines on the management of community-acquired pneumonia in adults. Clin Infect Dis 2007; 44
    Suppl 2:S27
     Blood cultures
Pretreatment blood cultures are positive -- 7 to 16 percent of hospitalized patients

   Blood cultures are commonly advocated in hospitalized patients with CAP because:

   The microbial diagnosis is established
   This is the only diagnostic test done, in most cases
   The isolates identified are used for tracking resistance patterns of S. pneumoniae and to determine
    serotypes of S. pneumoniae to evaluate contemporary and future vaccines

   Counter arguments for not obtaining these tests are that:

   The blood culture positivity rate is relatively low
   There is a high rate of false positive blood cultures (10%)
   Positive cultures rarely lead to modification or narrowing of antibiotic therapy
   Variables associated with bacteremia included absence of prior antibiotic use, chronic liver disease,
    pleuritic pain, tachycardia (>125 beats per minute), tachypnea (>30 breaths per minute), and systolic
    hypotension (<90 mm Hg)

   The guidelines recommend blood cultures for hospitalized patients with specific indications, including all
    patients who require admission to the ICU for CAP, and consider them optional for other patients

   Mandell, LA, Wunderink, RG, Anzueto, A, et al. Infectious Diseases Society of America/American Thoracic Society consensus guidelines on the
    management of community-acquired pneumonia in adults. Clin Infect Dis 2007; 44 Suppl 2:S27
Sputum specimens are recommended for hospitalized patients with any of the following criteria:
   Intensive care unit admission
   Failure of antibiotic therapy (either outpatients or hospitalized patients)
   Cavitary lesions
   Active alcohol abuse
   Severe obstructive or structural lung disease
   Positive urine antigen test for pneumococcus
   Positive urine antigen test for Legionella (special culture needed)
   Pleural effusion

   The sensitivity of Gram stain compared to culture ranged from 15 to 100% and specificity 11 to

   Culture results should be interpreted based upon the following findings:
   Quantitation of growth (heavy, moderate or light)
   Clinical correlation
   Correlation with the Gram stain
   Specimens collected after antibiotics are given are more likely to grow S. aureus or gram-
    negative bacilli (GNB), which usually represent early airway contaminants

   Mandell, LA, Wunderink, RG, Anzueto, A, et al. Infectious Diseases Society of America/American Thoracic Society consensus guidelines
    on the management of community-acquired pneumonia in adults. Clin Infect Dis 2007; 44 Suppl 2:S27
    Urine antigen
  More sensitive and specific than Gram stain and culture of sputum
  Urine specimens are usually available in the 30 to 40 % of patients who cannot supply sputum
  Results of urine antigen testing are immediately available
  The test retains validity even after the initiation of antibiotic therapy
  The test has high sensitivity compared with blood cultures and sputum studies
  The urinary antigen tests for Legionella and S. pneumoniae are FDA-cleared and provide results
   in minutes

Disadvantages of the urine antigen assay for the diagnosis of pneumococcus :
   The sensitivity and specificity may be less in patients without bacteremia
   There is no microbial pathogen available for antibiotic sensitivity testing
   These tests require a licensed technician and cannot be done by the provider

Disadvantage of the urine antigen assay for the diagnosis of Legionella
   Only useful for the diagnosis of L. pneumophila group 1 infection (accounts for 80 % CAP)
   Nosocomial Legionella infections often involve other serotypes, so sensitivity is decreased

   Pneumococcal urinary antigen test sensitivity and specificity of 82 and 97%, respectively

   Mandell, LA, Wunderink, RG, Anzueto, A, et al. Infectious Diseases Society of America/American Thoracic Society consensus guidelines
    on the management of community-acquired pneumonia in adults. Clin Infect Dis 2007; 44 Suppl 2:S27
   Diagnosis determined in 50 % patients by conventional techniques vs 76 %patients by RT-PCR

   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
   In two trials, clinicians were strongly recommended not to prescribe antibacterials in patients with
    a procalcitonin level <0.1 mcg/L, but were encouraged to in patients with levels >0.25 mcg/L
   The analysis suggested the correct decision in 83 percent.

   In one small study, procalcitonin levels increased over time in non-survivors but decreased in

   CRP has shown more limited utility, due in part to the paucity of studies
   One study showed a CRP >40 mg/L had a sensitivity and specificity for bacterial pneumonia of
    70 and 90%, respectively
   Another report indicated particularly high CRP levels in patients with pneumococcal pneumonia
    (mean 178 mg/L)

   Mandell, LA, Wunderink, RG, Anzueto, A, et al. Infectious Diseases Society of America/American Thoracic Society consensus guidelines
    on the management of community-acquired pneumonia in adults. Clin Infect Dis 2007; 44 Suppl 2:S27
    Indications for hospitalization
   The two most commonly used prediction rules are the Pneumonia Severity Index (PSI)
    and CURB-65

   CURB-65 uses five prognostic variables:

   Confusion (based upon a specific mental test or disorientation to person, place, or time)
   Urea (blood urea nitrogen in the United States) >7 mmol/L (20 mg/dL)
   Respiratory rate >30 breaths/minute
   Blood pressure (systolic <90 mmHg or diastolic <60 mmHg)
   Age >65 years

   score of 0 to 1 are at low risk and could be treated as outpatients
   score of 2 should be admitted to the hospital
   score of 3 or more should be assessed for ICU care, particularly if the score was 4 or 5

   Mandell, LA, Wunderink, RG, Anzueto, A, et al. Infectious Diseases Society of America/American Thoracic Society consensus guidelines
    on the management of community-acquired pneumonia in adults. Clin Infect Dis 2007; 44 Suppl 2:S27
   Defining community acquired pneumonia severity on presentation to hospital: an international derivation and validation study. Lim ET AL.Thorax.
   CRB-65 predicts death from community-acquired pneumonia. Bauer ET AL. J Intern Med. 2006;260(1):93-101
Principles of antimicrobial therapy

    Empiric therapy

    The selection of antimicrobial regimens is based upon:

    The most likely pathogen(s)

    Clinical trials proving efficacy

    Risk factors for antimicrobial resistance

    The choice of empiric therapy must take into account the emergence of
     antibiotic resistance among Streptococcus pneumoniae

    Medical comorbidities

    Potential for inducing antimicrobial resistance, pharmacokinetic and
     pharmacodynamic properties, safety profile, and cost

    Mandell, LA, Wunderink, RG, Anzueto, A, et al. Infectious Diseases Society of America/American Thoracic Society consensus guidelines on
     the management of community-acquired pneumonia in adults. Clin Infect Dis 2007; 44 Suppl 2:S27
      Risk factors for drug-resistant S.
      pneumoniae in adults
    Age >65 years

    Beta-lactam, macrolide, or fluoroquinolone therapy within the past three to six

    Alcoholism

    Medical comorbidities

    Immunosuppressive illness or therapy

    Exposure to a child in a day care center

    Recent therapy or a repeated course of therapy with beta-lactams, macrolides, or
     fluoroquinolones is a risk factor for pneumococcal resistance to the same class of

Mandell, LA, Wunderink, RG, Anzueto, A, et al. Infectious Diseases Society of America/American Thoracic Society consensus guidelines on
    the management of community-acquired pneumonia in adults. Clin Infect Dis 2007; 44 Suppl 2:S27

   Mandell, LA, Wunderink, RG, Anzueto, A, et al. Infectious Diseases Society of
    America/American Thoracic Society consensus guidelines on the management of
    community-acquired pneumonia in adults. Clin Infect Dis 2007; 44 Suppl 2:S27
No comorbidities or recent antibiotic use

   Azithromycin (500 mg on day one followed by four days of 250 mg a day)
   500 mg a day for three days, or 2 g single dose (microsphere formulation) are
    acceptable alternative regimens

   Clarithromycin XL (two 500 mg tablets once daily) for five days or until afebrile
    for 48 to 72 hours

   Doxycycline (100 mg twice a day) for 7 to 10 days

   The use of fluoroquinolones is discouraged unless there is a high prevalence
    of macrolide-resistant S. pneumoniae
Comorbidities or recent antibiotic use

•   A respiratory fluoroquinolone (gemifloxacin 320 mg daily, levofloxacin 750 mg
    daily, or moxifloxacin 400 mg daily)

•   Combination therapy with a beta-lactam effective against S. pneumoniae
•   High-dose amoxicillin, 1 g three times daily or amoxicillin-clavulanate 2 g twice
    daily or cefpodoxime 200 mg twice daily or cefuroxime 500 mg twice daily)

•   PLUS

•   A macrolide (azithromycin 500 mg on day one followed by four days of 250 mg
    a day or clarithromycin 250 mg twice daily or clarithromycin XL 1000 mg once

•   Or doxycycline (100 mg twice daily)
Treatment duration and response

   Ambulatory patients with CAP should be treated for a minimum of five days

   A meta-analysis of RCT of 2800 patients with mild to moderate CAP, found
    comparable clinical outcomes with less than seven days compared to more
    than seven days of antimicrobial therapy

   Antibiotic therapy should not be stopped until the patient is afebrile for 48 to 72
    hours and is clinically stable

   Persistence of some symptoms is not an indication to extend the course of
    antibiotic therapy as long as the patient has demonstrated some clinical
    response to treatment

   Efficacy of short-course antibiotic regimens for community-acquired pneumonia: a meta-analysis. Li et al. Am J Med. 2007;120(9):783-90.
   Time course of symptom resolution in patients with community-acquired pneumonia. Metlay et al. Respir Med. 1998;92(9):1137-42.
   Routine chest x-rays for patients who are responding clinically are unnecessary

   Some recommend a follow-up chest x-ray at 7 to 12 weeks, for patients over
    age 40 years or smokers, to document resolution of the pneumonia and
    exclude malignancy

   Among patients with CAP, nonresponse is primarily seen in those who require
    hospitalization, occurring in 6 to 15% of such patients

   VACCINATION — Patients with CAP should be appropriately vaccinated for
    influenza and pneumococcal infection

   SMOKING CESSATION — Smoking cessation should be a goal for patients
    with CAP who smoke

   Practice guidelines for the management of community-acquired pneumonia in adults. Bartlett at al. Infectious Diseases Society
    of America. Clin Infect Dis 2000; 31:347
Hospitalized patients
   In the general wards -- an antipneumococcal fluoroquinolone (eg, levofloxacin,
   or
   the combination of a beta-lactam plus a macrolide

   ICU admission -- a beta-lactam (ceftriaxone, cefotaxime, ampicillin-sulbactam)
   plus
   either intravenous azithromycin
   Or
   an antipneumococcal fluoroquinolone

   If Pseudomonas is a concern, an antipseudomonal agent (piperacillin-tazobactam,
    imipenem, meropenem, or cefepime)
   PLUS
   an antipseudomonal fluoroquinolone (ciprofloxacin or high-dose levofloxacin) should be

   If MRSA is a concern, either vancomycin or linezolid should be added
       Not in the ICU
Combination therapy

   ceftriaxone (1 to 2 g IV daily),cefotaxime (1 to 2 g IV every eight hours), or ampicillin-
    sulbactam (1.5 to 3 g IV every six hours)


   a macrolide (azithromycin [500 mg IV or orally daily] or clarithromycin XL [two 500
    mg tablets once daily])

   Doxycycline (100 mg orally or IV twice daily) may be used as an alternative to a

   Oral therapy with a macrolide or doxycycline is appropriate only for selected patients
    without evidence of or risk factors for severe pneumonia

   Monotherapy with a respiratory fluoroquinolone given either IV or orally
    (levofloxacin 750 mg daily or moxifloxacin 400 mg daily or gemifloxacin 320 mg daily
    Admitted to an ICU
   Intravenous combination therapy with an anti-pneumococcal beta-lactam (ceftriaxone 2 g daily,
    cefotaxime 2 g every eight hours, or ampicillin-sulbactam 1.5 to 3 g every six hours)

   either an advanced macrolide (azithromycin 500 mg daily) or a respiratory fluoroquinolone
   (levofloxacin 750 mg daily or moxifloxacin 400 mg)

   In patients (particularly those with bronchiectasis or COPD and frequent antimicrobial or
    glucocorticoid use) who may be infected with Pseudomonas aeruginosa or other resistant

   therapy with a beta-lactam and a fluoroquinolone, such as the following regimens:

   Piperacillin-tazobactam (4.5 g every six hours) OR
   Imipenem (500 mg IV every six hours) OR
   Meropenem (1 g every eight hours) OR
   Cefepime (2 g every eight hours) OR
   Ceftazidime (2 g every 8 hours)

  Ciprofloxacin (400 mg every 8 hours) OR
  Levofloxacin (750 mg daily)
    For beta-lactam allergic patients, options include:
    aztreonam (2 g every 6 hours) plus levofloxacin (750 mg daily)

    or aztreonam plus moxifloxacin plus an aminoglycoside

    If the Gram stain suggests S. aureus,treat MRSA with the addition of
     vancomycin (15 mg/kg every 12 hours, adjusted for renal function)


    linezolid (600 mg intravenously twice daily) until the results of culture and
     susceptibility testing are known

    empiric therapy of MRSA in patients with severe CAP who have risk factors for
     CA-MRSA (prior antimicrobial therapy or recent influenza-like illness)

   CA-MRSA is susceptible to more antibiotics than HA-MRSA, but is more virulent
   TX with Vancomycin or linezolid is recommend
   Increasing MICs of MRSA may reduce the efficacy of vancomycin in pulmonary
   Linezolid has been shown to reduce toxin production

   Risk factors for CA-MRSA colonization:
   contact sport participants, injection drug users, those living in crowded conditions,
    men who have sex with men, prisoners

   CA-MRSA pneumonia should be suspected in young, previously healthy adults with
    a recent influenza-like illness

   Factors associated with rapid mortality include infection with influenza, the need for
    ventilator or inotropic support, onset of respiratory distress syndrome, hemoptysis,
    and leukopenia
Timing of antimicrobial

   The United States National Pneumonia Medicare Quality Improvement Project
    and the National Quality Forum have changed the recommended target for
    initial administration of antimicrobial therapy from four to six hours after arrival
    at the hospital

   The previously recommended four hour window resulted in the unintended
    consequence of overuse of antimicrobials before the diagnosis of pneumonia
    could be definitively established

   Timing of antibiotic administration and outcomes for Medicare patients hospitalized with community-acquired pneumonia. Houck ET
    AL.Arch Intern Med. 2004;164(6):637-44.
   TI
   JCAHO tweaks emergency departments' pneumonia treatment standards. Mitka ET AL. JAMA. 2007;297(16):1758-9.
Clinical response to therapy
   Improvement in the patient's clinical course is seen within 48 to 72 hours

   Patients who do not demonstrate some clinical improvement within 72 hours
    are considered nonresponders

   The time to resolution of all symptoms and radiographic findings is more

   With pneumococcal pneumonia, for example, the cough usually resolves within
    eight days and auscultatory crackles clear within three weeks

   As many as 87% of inpatients with CAP have persistence of at least one
    pneumonia-related symptom at 30 days compared to 65% by history in the
    month prior to the onset of CAP

   Processes and outcomes of care for patients with community-acquired pneumonia: results from the Pneumonia Patient Outcomes
    Research Team (PORT) cohort study. Fine ET AL.Arch Intern Med. 1999;159(9):970-80.
   Reaching stability in community-acquired pneumonia: the effects of the severity of disease, treatment, and the characteristics of
    patients. Menndez ET AL.Clin Infect Dis. 2004;39(12):1783-90.
Radiographic response
   At day 7, 56% have clinical improvement but only 25% have resolution of CXR

   At day 28, 78% have attained clinical cure but only 53% have resolution of CXR

   Delayed radiographic resolution was independently associated with multilobar

   The chest x-ray usually cleared within four weeks in patients younger than 50
    years of age without underlying pulmonary disease

   Resolution could be delayed for 12 weeks or more in older individuals and in
    those with underlying lung disease
Duration of hospitalization

   It is not necessary to observe stable patients overnight after switching from
    intravenous to oral therapy

   No significant difference in 14-day hospital readmission rate OR 30-day
    mortality rate
   On the last day of hospitalization seven parameters of instability should be
   temperature >37.8 ºC [100 ºF]
   respiratory rate >24/min
   heart rate (HR) >100 beats/min
   systolic BP ≤90 mmHg
   oxygen saturation <90 percent on room air
   inability to receive oral nutrition
   change of mental status from baseline

   At 60 days post discharge, patients with at least one parameter of instability at
    discharge ARE significantly more likely to have died or required readmission

   (death rates, 14.6 versus 2.1 percent; readmission rates, 14.6 versus 6.5
Duration of therapy
a minimum of five days

Before stopping therapy, the patient should be:
   afebrile for 48 to 72 hours
   breathing without supplemental oxygen (unless required for preexisting disease)
   have no more than one clinical instability factor (defined as heart rate [HR] >100
    beats/min, respiratory rate [RR] >24 breaths/min, and systolic blood pressure [SBP]
    ≤90 mmHg)

Longer durations of therapy are needed in the following settings:
   If the initial therapy was not active against the subsequently identified pathogen
   If extrapulmonary infection is identified (eg, meningitis or endocarditis)
   If the patient has documented P. aeruginosa or S. aureus pneumonia, or pneumonia
    caused by some unusual and less common pathogens (eg, Burkholderia
    pseudomallei, fungus)

   Efficacy of short-course antibiotic regimens for community-acquired pneumonia: a meta-analysis. Li ET AL, Am J Med. 2007;120(9):783-90.
The nonresponding patient
   The absence or delay in achieving clinical stability after 72 hours of antibiotic

noninfectious entities to be considered:
   drug fever
   Malignancy
   interstitial lung disease
   inflammatory conditions
   heart failure
   hospital-acquired infection of another body system (eg, intravascular catheter
    infection, urinary tract infection or Clostridium difficile infection)
   The upper airway of hospitalized patients receiving antibiotics may become
    colonized, and repeat sputum cultures should be interpreted with caution
Risk factors for Tx failure
   Multilobar pneumonia
   Pneumonia caused by Legionella or gram-negative organisms
   Pneumonia Severity Index (PSI) >90
   Treatment with an antimicrobial agent to which the causative organism was not

   Further evaluation —
   repeating the history (including travel and pet exposures to look for unusual
    pathogens), chest x-ray, and sputum and blood cultures

   further diagnostic procedure, such as chest CT, bronchoscopy, and, lung biopsy
    can be performed
   Whether or not there is a benefit of glucocorticoids in severe CAP is presently
    being evaluated in a large Veteran Administration cooperative study
   Pending these results, glucocorticoids are not recommended as adjunctive
    therapy for CAP

   VACCINATION — Patients with CAP should be appropriately vaccinated for
    influenza and pneumococcal infection

   SMOKING CESSATION — Smoking cessation should be a goal for hospitalized
    patients with CAP who smoke

   Glucocorticoid treatment in community-acquired pneumonia without severe sepsis: no evidence of efficacy. Meduri ET AL. Am J Respir
    Crit Care Med. 2010;181(9):880-2.

Guidelines for the management of adults with hospital-acquired, ventilator-associated, and healthcare-
associated pneumonia. American Thoracic Society, Infectious Diseases Society of America. Am J Respir Crit
Care Med. 2005;171(4):388-416
   HAP occurs 48 hours or more after admission

   VAP is a type of HAP that develops more than 48 to 72 hours after
    endotracheal intubation

   HCAP occurs in a non-hospitalized patient with extensive healthcare contact:

      Intravenous therapy, wound care, or intravenous chemotherapy within the
    prior 30 days
     Residence in a nursing home or other long-term care facility
     Hospitalization in an acute care hospital for two or more days within the prior
    90 days
     Attendance at a hospital or hemodialysis clinic within the prior 30 days
   HAP is the Leading cause of death with mortality ranging from 20 to 50%

   Most cases of HAP occur outside of intensive care units

   However, the highest risk for HAP is in patients on mechanical ventilation (ie,

   Estimates of incidence range from four to seven episodes per 1000
    hospitalizations, accounting for 13 to 18% of all nosocomial infections
   The primary route of infection of the lungs is through microaspiration of
    organisms that have colonized the oropharyngeal tract or GIT

   45% healthy subjects aspirate during sleep, and an even higher proportion of
    severely ill patients aspirate

   Endotracheal tube permits the aspiration of oropharyngeal material or bacteria
    of gastrointestinal origin

   Hospitalized patients often become colonized with microorganisms acquired
    from the hospital environment

   75% of severely ill patients will be colonized within 48 hours
Microbiology of VAP/HAP

   There is a paucity of data regarding whether the pathogens that cause VAP differ
    from those that cause HAP in patients who are not mechanically ventilated

   The infecting flora in patients with VAP includes MSSA, MRSA , P. aeruginosa ,
    Stenotrophomonas maltophilia , Acinetobacter spp , and other spp

   The infecting flora in non-ventilated patients with HAP was similar, except non-
    Enterobacteriaciae gram-negative bacilli (P. aeruginosa, Acinetobacter, and S.
    maltophilia) were less likely

   Clinical characteristics and treatment patterns among patients with ventilator-associated pneumonia. Kollef et al. Chest.
   Clinical characteristics and treatment patterns among patients with ventilator-associated pneumonia. Kollef et al. Chest.
   The clinical and microbiologic features of HCAP are more similar to HAP and VAP
    than to CAP

   The incidence of S. aureus in the HCAP and HAP groups are comparable (47%) and
    significantly higher than in the CAP group (26%)

   The rate of MRSA infection is also higher in HCAP and HAP; 27 and 23 versus 9%
    for CAP

   P. aeruginosa is the only other pathogen with a significant occurrence (25%) in
    HCAP patients

   Patients with HCAP had higher mortality (18 versus 7%) and longer length of
    hospitalization (19 versus 15%) compared with CAP patients

   Health care-associated pneumonia (HCAP): a critical appraisal to improve identification, management, and outcomes--proceedings of
    the HCAP Summit. Kollef et al. Clin Infect Dis. 2008;46 Suppl 4:S296-334; quiz 335-8.
   Epidemiology and outcomes of health-care-associated pneumonia: results from a large US database of culture-positive pneumonia. Kollef et al.
    Chest. 2005;128(6):3854-62.
MDR risk factors

Host risk factors for infection with MDR pathogens include :

   Receipt of antibiotics within the preceding 90 days
   Current hospitalization of ≥5 days
   High frequency of antibiotic resistance in the community or in the
    specific hospital unit
   Immunosuppressive disease and/or therapy

   The risk factor of long-term care facility residence applies specifically
    to those who have more severe illness, prior antibiotic therapy in the
    preceding six months, or poor functional status

   Indicators of potentially drug-resistant bacteria in severe nursing home-acquired pneumonia. El Solh et al.
    Clin Infect Dis. 2004;39(4):474-80.
   HAP, VAP, or HCAP should be suspected in patients with a new or progressive
    infiltrate on lung imaging as well as clinical characteristics such as:
   Fever
   Purulent sputum
   Leukocytosis
   Decline in oxygenation

   The presence of a new or progressive radiographic infiltrate plus at least two of the
    three clinical features (fever >38ºC, leukocytosis or leukopenia, and purulent
    secretions) represents a clinically relevant combination of criteria for starting empiric
    antimicrobial therapy

   When findings at autopsy are used as a standard of reference, this combination of
    findings resulted in 69% sensitivity and 75% specificity for pneumonia

   Clinical diagnosis of ventilator associated pneumonia revisited: comparative validation using immediate post-
    mortem lung biopsies. Et al. Thorax. 1999;54(10):867-73.
   Appropriate antibiotic therapy significantly improves survival for patients with
    HAP, VAP, or HCAP

   When therapy is given, antimicrobial selection should be based upon risk
    factors for MDR pathogens

   Once the results of pretherapy cultures are available, therapy should be

   Mortality is significantly higher among patients who received inappropriate initial
    therapy compared with patients who received appropriate coverage (30 versus
    18%); switching to an appropriate regimen did not reduce the risk of death

   Mortality is significantly lower among patients in whom therapy was
    deescalated compared to those whose therapy was either escalated or
    unchanged (17 versus 43 and 24%, respectively)

   Antimicrobial therapy escalation and hospital mortality among patients with health-care-associated pneumonia: a single-center
    experience. Zilberberg ET AL.Chest. 2008;134(5):963-8.
Emperic treatment
    with no known risk factors for MDR pathogens
    with no known risk factors for MDR pathogens
    Ceftriaxone (2 g intravenously daily)

    Ampicillin-sulbactam (3 g intravenously every six hours)
     piperacillin-tazobactam (4.5 g intravenously every six hours) if there is concern based on
     prevailing pathogens within an institution for gram-negative bacilli not treated by
     ampicillin-sulbactam (eg, Enterobacter spp, Serratia spp, Pseudomonas spp)

    Levofloxacin (750 mg intravenously daily) or moxifloxacin (400 mg intravenously daily)

    Ertapenem (1 g intravenously daily).
With known mdr risk factors
   Empiric three-drug combination therapy including:

   Antipseudomonal cephalosporin:
cefepime (2 g intravenously every eight hours) or ceftazidime (2 g intravenously every 8

   Antipseudomonal carbapenem:
imipenem (500 mg intravenously every six hours) or meropenem (1 g intravenously
    every eight hours) or doripenem (500 mg intravenously every eight hours;
    administered over one hour for HAP or HCAP, administered over four hours for VAP)

   Piperacillin-tazobactam (4.5 g intravenously every six hours)

   For patients who are allergic to beta-lactam antibiotics:
   aztreonam (2 g intravenously every six to eight hours)
   PLUS

   Antipseudomonal fluoroquinolone, preferred regimen if Legionella is likely:
    ciprofloxacin (400 mg intravenously every eight hours) or levofloxacin (750 mg
    intravenously daily)

   Aminoglycoside:
   gentamicin or tobramycin (7 mg/kg intravenously per day adjusted to a trough level
    <1 mcg/mL) or amikacin (20 mg/kg intravenously per day adjusted to a trough level
    <4-5 mcg/mL)
   The aminoglycoside can be stopped after five to seven days in responding patients

   PLUS (if MRSA is suspected, there are MRSA risk factors, or there is a high
    incidence of MRSA ):

   Linezolid (600 mg intravenously every 12 hours; may be administered orally)
   Vancomycin (15 to 20 mg/kg intravenously every 8 to 12 hours for patients with
    normal renal function, with a target serum trough concentration of 15 to 20 mg/L.)
   In seriously ill patients, a loading dose of 25 to 30 mg/kg can be used to facilitate
    rapid attainment of the target trough
   If patients have recently received antibiotics, empiric therapy should generally
    be with a drug from a different class since earlier treatment may have selected
    pathogens resistant to the initial class

   Colistin, polymyxin, or inhaled aminoglycosides may be considered as
    potential additional antibiotics in patients with MDR gram-negative bacilli

   Aerosolization may increase antibiotic concentrations at the site of infection,
    and may be particularly useful for treatment of organisms that have high MICs
    to systemic antimicrobial agents

   Aerosolized antibiotics to treat ventilator-associated pneumonia. Luyt et al. Curr Opin Infect Dis.
   There is no significant difference between patients treated for eight compared to 15
    days in mortality or recurrent infection at 28 days

   Among patients who developed recurrent infections, MDR pathogens were isolated
    less frequently in those treated for eight days (42 versus 62% for those treated for
    15 days)

   However, patients with VAP caused by nonfermenting gram-negative bacilli (eg,
    Pseudomonas spp) had a higher pulmonary infection recurrence rate when treated
    for eight versus 15 days (41 versus 25% with 15 days of treatment), although
    mortality was not different

   In patients who had S. aureus isolated, there was no significant difference based on
    treatment duration (8 or 15 days) for 28-day mortality or VAP recurrence

   Comparison of 8 vs 15 days of antibiotic therapy for ventilator-associated pneumonia in adults: a randomized
    trial. Chastre et al. JAMA. 2003;290(19):2588-98.
   Short-course empiric antibiotic therapy for patients with pulmonary infiltrates in the intensive care unit. A proposed
    solution for indiscriminate antibiotic prescription. Singh et al. Am J Respir Crit Care Med. 2000;162(2 Pt 1):505-11.
   The all-cause mortality rate for HAP and VAP is in the range of 33 to 50%

   Variables associated with increased mortality include:

   Serious illness at the time of diagnosis (eg, high APACHE score, shock, coma,
    respiratory failure, ARDS)
   Bacteremia
   Severe underlying comorbid disease
   Infection caused by an organism associated with multidrug resistance
    (Pseudomonas aeruginosa, Acinetobacter spp)
   Multilobar, cavitating, or rapidly progressive infiltrates on lung imaging
   Delay in instituting effective antimicrobial therapy

   Outcomes of patients hospitalized with community-acquired, health care-associated, and hospital-acquired
    pneumonia. Venditti et al. Ann Intern Med. 2009;150(1):19-26.

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