Hospital-Acquired Pneumonia (Nosocomial Pneumonia) and

Ventilator-Associated Pneumonia

Overview
The term healthcare-associated pneumonia (HCAP) was defined as pneumonia in
nonhospitalized patients who had significant experience with the healthcare system. Such contact
could include (1) intravenous therapy for wound care within the preceding 30 days, (2) residence
in a long-term care facility, (3) hospitalization in an acute-care hospital within the preceding 90
days, and/or (4) outpatient treatment in a hospital or hemodialysis clinic within the preceding 30
days. These individuals were believed to be at an increased risk for infection with multidrugresistant (MDR) organisms because of such contact. [1] However, more recent studies have
indicated that many individuals who met the criteria for HCAP were not infected with MDR
pathogens. [2] The risk of infection with MDR organisms appears to depend much more on
specific risk factors of the given patient than on contact with various aspects of the healthcare
system. Patients who would have met the criteria for HCAP should not be empirically treated
with antibiotics to cover MDR bacteria unless they have valid risk factors for acquiring MDR
organisms (see below). [3]
Pneumonia is defined as "new lung infiltrates plus clinical evidence that the infiltrate is of an
infectious origin, which include the new onset of fever, purulent sputum, leukocytosis, and
decline in oxygenation." [4] Hospital-acquired pneumonia (HAP), or nosocomial pneumonia, is a
lower respiratory infection that was not incubating at the time of hospital admission and that
presents clinically 2 or more days after hospitalization. Pneumonia that presents sooner should be
regarded as community-acquired pneumonia. Ventilator-associated pneumonia (VAP) is defined
as pneumonia that presents more than 48 hours after endotracheal intubation.
Clinicians should understand that many of these findings are often shared with mimics of
nosocomial pneumonia, such as congestive heart failure (CHF), pulmonary emboli, pulmonary
hemorrhage, primary or metastatic lung carcinomas, leukemias/lymphomas, pulmonary drug
reactions, and radiation pneumonitis, among others. VAP refers to nosocomial pneumonia that
develops among patients on ventilators. [4, 1]

Typical chest radiograph of a patient

with nosocomial pneumonia.
HAP is a common nosocomial bacterial infection and is most prevalent in medical and surgical
intensive care units (ICUs). As such, HAP adds significantly to the cost of hospital care and to
the length of hospital stays.
Patients with HAP develop fever and leukocytosis. These findings are a requisite for its
presumptive diagnosis. Respiratory tract symptoms include an increase in respiratory rate and
shortness of breath.
Go to Mycoplasma Pneumonia, Bacterial Pneumonia, and Viral Pneumoniafor more complete
information on this topic.

Pathophysiology
Inhalation, aspiration, and hematogenous spread are the 3 main mechanisms by which bacteria
reach the lungs. The primary route by which organisms enter the lower airways is aspiration of
oropharyngeal secretions into the trachea.
Primary inhalation pneumonia develops when these organisms bypass normal respiratory defense
mechanisms or when the patient inhales aerobic gram-negative organisms that colonize the upper
respiratory tract or respiratory support equipment.
Aspiration pneumonia is due to the aspiration of colonized upper respiratory tract secretions.

The stomach appears to be an important reservoir of gram-negative bacilli that can ascend and
colonize the respiratory tract. A prospective observational study found that patients who used
acid-suppressive medications were more likely to develop hospital-acquired pneumonia (HAP)
than were patients who did not (5% vs 2%). The risk for pneumonia was significantly increased
with proton pump inhibitors, but not with histamine 2blocking agents. [5]
Hematogenously acquired infections originate from a distant source and reach the lungs via the
bloodstream.

Etiology
The development of hospital-acquired pneumonia (HAP) represents an imbalance between
normal host defenses and the ability of microorganisms to colonize and then invade the lower
respiratory tract.
Because aerobic gram-negative bacilli (eg, Pseudomonas aeruginosa) are the major pathogens
associated with HAP, the pathophysiology of nosocomial pneumonia relates to the destructive
effect on lung tissue. Aerobic gram-negative pathogens may be divided into 2 categories. The
first category includes organisms that cause necrotizing pneumonia with rapid cavitation,
microabscess

formation,

aeruginosa). [6] Alternatively,

blood-vessel
other

invasion,

nonnecrotizing

and

hemorrhage

gram-negative

bacilli

(eg, P

(eg, Serratia

marcescens) may be responsible for nosocomial pneumonia.

Common causes of hospital-acquired pneumonia
Common bacteria involved in hospital-acquired pneumonia (HAP) include the following: [7]

P aeruginosa

Staphylococcus

aureus, including

methicillin-susceptible S

aureus (MSSA)

and

methicillin-resistant S aureus (MRSA)

Klebsiella pneumoniae

Escherichia coli

Non-Enterobacteriaceae

bacteria

such

as S

marcescens,

Stenotrophomonas

maltophilia, and Acinetobacter species are less common causes

Acinetobacter species commonly colonize respiratory tract secretions in patients in the ICU.
HAP caused by Acinetobacter species or B cepacia may be associated with outbreaks.

Streptococcus pneumoniae and Haemophilus influenzae are recovered only in early-onset HAP.
Less-common pathogens associated with hospital-acquired pneumonia
The

following

are

less-common

pathogens

implicated

in

nosocomial

pneumonia

clusters/outbreaks:

Legionella species

Influenza A virus

Respiratory syncytial virus (RSV)

Human parainfluenza virus 3 (HPIV-3)

Human metapneumovirus (hMPV)

Nosocomial Legionella pneumonia occurs often in outbreaks or clusters.

Influenza A, RSV, hMPV, or HPIV-3 may cause hospital-acquired pneumonia (HAP) from
person-to-person spread.
Organisms associated with ventilator-associated pneumonia
Organisms associated with ventilator-associated pneumonia (VAP) include the following:

P aeruginosa

S Aureus, including MSSA and MRSA

S maltophilia

Acinetobacter species

Enterobacteriaceae are less commonly seen in VAP than in hospital-acquired pneumonia

(HAP)

These organisms are commonly recovered from respiratory secretions in patients with
VAP. [8] The recovery of a respiratory pathogen from respiratory secretions does not establish it as
the cause of nosocomial pneumonia. MSSA/MRSA frequently colonize respiratory secretions in
intubated patients but rarely, if ever, cause nosocomial pneumonia/VAP. In contrast,
MSSA/MRSA may cause community-acquired pneumonia (CAP) in those with influenza.
Anaerobic organisms are not important pathogens in nosocomial pneumonia. (See Differentials
in Nosocomial Pneumonia.)

Risk factors
The stomach appears to be an important reservoir of gram-negative bacilli that can ascend and
colonize the respiratory tract. A prospective observational study found that patients who used
acid-suppressive medications were more likely to develop hospital-acquired pneumonia (HAP)
than were patients who did not (5% vs 2%).
Further evaluation by drug class showed that the risk for pneumonia was significantly increased
with proton pump inhibitors, but not with histamine 2blocking agents. [5]

Epidemiology of Nosocomial Pneumonia

Incidence in the United States
The combination of hospital-acquired pneumonia (HAP) and ventilator-associated pneumonia
(VAP) constitutes the most common cause of death among all hospital-acquired infections, with
mortality rates of up to 33%.
International incidence
The international incidence and prevalence of nosocomial pneumonia is similar to that in the
United States, with comparable rates of responsible microorganisms.
Racial and sexual predilections
Nosocomial pneumonia has no racial or sexual predilection.
Age predilection
Nosocomial pneumonia is most common in elderly patients; however, patients of any age may be
affected.
Morbidity and mortality in hospital-acquired pneumonia and ventilator-associated
pneumonia
Intubation and ventilatory support bypass the normal host defense mechanisms, predisposing
patients with ventilator-associated pneumonia (VAP) to infection.
In addition, hospital-acquired pneumonia (HAP)/VAP that develops in ICU patients is associated
with high morbidity and mortality rates, because these patients are already critically ill.

Compromised cardiac and lung function may further decrease their cardiopulmonary reserve.
Ventilator-associated barotrauma often decreases already compromised lung function. In
addition, it may alter chest radiographic appearances.
As mentioned above, early-onset HAP/VAP pneumonia (ie, hospital onset of CAP) expectedly
has a better prognosis than late-onset nosocomial pneumonia because the latter tends to be
associated with multidrug-resistant (MDR) organisms. [9, 10, 11, 12, 13]

Patient Prognosis
The prognosis in patients with hospital-acquired pneumonia (HAP) depends primarily on
preexisting underlying cardiopulmonary function and host defenses.
In

HAP/ventilator-associated

pneumonia

(VAP),

outcomes

usually

depend

on

risk

factors/comorbidities rather than on the initial empiric therapy. [14, 15, 16]

Differential Diagnoses of Nosocomial Pneumonia

All patients with presumed nosocomial pneumonia should undergo testing to rule out conditions
that mimic nosocomial pneumonia. The diagnosis of nosocomial pneumonia is difficult because
it may present in a very nonspecific fashion. A summary of management strategies is available
through a recently released practice guideline provided by the Infectious Diseases Society of
America (IDSA) and American Thoracic Society (ATS). [3]
The wide list of differential diagnoses presents a major challenge in diagnosing nosocomial
pneumonia. Many conditions other than nosocomial pneumonia mimic pulmonary infiltrates (eg,
fluid, atelectasis) on chest radiographs.
Any disorder that results in leukocytosis with variable degrees of left shift may be included in the
differential diagnoses. Noninfectious inflammation may produce fever.
Consider all of these differential diagnoses carefully before settling on a diagnosis and
embarking on a course of antimicrobial therapy.
The most common causes of infiltrates in ventilated patients with fever and/or leukocytosis
include the following conditions:

Congestive heart failure

Pulmonary embolus or infarction

Acute respiratory distress syndrome ( ARDS)

Pulmonary drug reactions

Collagen vascular diseases

Lung hemorrhage

Bronchiolitis obliterans-organizing pneumonia (BOOP)

Collagen-vascular diseases (eg, systemic lupus erythematosus [SLE])

Interstitial lung disease

Bronchogenic carcinomas

Metastatic carcinomas

ARDS is usually readily diagnosable based on the appearance of small lung volumes due to
microatelectatic changes on the chest radiograph and the progressive and severe hypoxemia.
Little or no fever accompanies ARDS, unless it is due to acute pancreatitis.
Electrocardiography (ECG) and ventilation-perfusion scans help to exclude pneumonia mimics.
ECGs, cardiac enzymes, and Swan-Ganz readings may rule out left ventricular failure caused by
exacerbation of heart failure or new myocardial infarction.

Obtain other tests that are related to the possible underlying causes of the pulmonary
infiltrates; for example, if lupus pneumonitis is suspected, ask the patient about a
history of systemic lupus erythematosus (SLE) pneumonitis. Afterward, serologic
tests should be performed to assess for SLE.

Treatment Considerations
Guidelines on management of adults with hospital-acquired pneumonia (HAP) and ventilatorassociated pneumonia (VAP) by the Infectious Diseases Society of America and the American
Thoracic Society are as follows: [3]

Recommend that each hospital generate antibiograms to guide healthcare professionals

with respect to the optimal choice of antibiotics.

In an effort to minimize patient harm and exposure to unnecessary antibiotics and reduce
the development of antibiotic resistance, the guidelines recommend that the antibiogram data
be used to decrease the unnecessary use of dual gram-negative and empiric methicillinresistantStaphylococcus aureus (MRSA) antibiotic treatment.

Short-course antibiotic therapy is recommended for most patients with HAP or VAP
regardless of microbial etiology, as well as antibiotic de-escalation.

Suggest noninvasive sampling with semiquantitative cultures to diagnose VAP, rather

than invasive sampling with quantitative cultures or noninvasive sampling with quantitative
cultures.

However, the panel recognizes that invasive quantitative cultures will occasionally be
performed by some clinicians. For patients with suspected VAP whose invasive quantitative
culture results are below the diagnostic threshold for VAP, the guidelines suggest that
antibiotics be withheld rather than continued.

Suggest that patients with suspected HAP (non-VAP) be treated according to the results
of microbiologic studies performed on respiratory samples obtained noninvasively, rather than
being treated empirically.

For patients with suspected HAP/VAP, the guidelines recommend using clinical criteria
alone, rather than using serum procalcitonin (PCT) plus clinical criteria, bronchoalveolar
lavage fluid (BALF) sTREM-1 plus clinical criteria, or C-reactive protein (CRP) plus clinical
criteria to decide whether to initiate antibiotic therapy.

In patients with suspected VAP, include coverage for S aureus, Pseudomonas

aeruginosa, and other gram-negative bacilli in all empiric regimens.

If empiric coverage for MRSA is indicated, either vancomycin or linezolid is

recommended.

When empiric treatment that includes coverage for MSSA (and not MRSA) is indicated,
the guidelines suggest a regimen including piperacillin-tazobactam, cefepime, levofloxacin,
imipenem, or meropenem. Oxacillin, nafcillin, and cefazolin are preferred agents for
treatment of proven MSSA, but are not necessary for the empiric treatment of VAP if one of
the above agents is used.

For patients being treated empirically for HAP, prescribe an antibiotic with activity
against S aureus.

For patients with HAP who require empiric coverage for MRSA, vancomycin or linezolid
is recommended.

For patients with HAP/VAP due to P aeruginosa, the guidelines recommend that the
choice of an antibiotic for definitive (not empiric) therapy be based on the results of
antimicrobial susceptibility testing.

For patients with VAP or HAP, a 7-day course of antimicrobial therapy is recommended.

Antimicrobial therapy
Traditionally, nosocomial pneumonias have been treated for 7-14 days. However, ventilatorassociated pneumonia (VAP) (except due to nonfermenting gram-negative rods [eg, P
aeruginosa]) can be successfully treated in 7 days). If the patient receives appropriate
antimicrobial therapy for 2 weeks and does not respond (ie, improved infiltrates findings on
chest radiograph), initiate a diagnostic workup to detect nonbacterial infections (eg, herpesvirus
type 1 [HSV-1] pneumonitis) or noninfectious disease mimics (eg, bronchogenic carcinomas).
The specific pathogen that causes a given case of nosocomial pneumonia is usually unknown.
Therefore, empiric antimicrobial therapy is the only practical approach. These regimens should
be based on the local profile of organisms associated with hospital-acquired pneumonia (HAP)
and their antibiotic sensitivities.
Initial and definitive treatment of hospital-acquired pneumonia
MSSA should be covered unless the patient has risk factors for MRSA, including intravenous
antibiotic use within the preceding 90 days, exposure to a hospital unit where more than 20%
of S aureus isolates are MRSA, or a high risk of death (eg, need for ventilatory support due to
septic shock). Vancomycin or linezolid should be used to empirically cover MRSA.
For empiric coverage of MSSA, piperacillin-tazobactam cefepime, levofloxacin, imipenem, or
meropenem is preferred. In cases of proven MSSA infection, oxacillin, nafcillin, or cefazolin is
favored.
Double coverage against P aeruginosa should be provided in the empiric treatment of individuals
with HAP who are likely to have Pseudomonas and other gram-negative infections or who are at
a high risk of mortality (need for ventilatory support and/or septic shock). For all other cases,
single coverage of P aeruginosa is indicated. [9]

Initial and definitive treatment of ventilator-associated pneumonia

Empiric treatment of VAP should include coverage of S aureus, P aeruginosa, and other gramnegative bacilli.
MRSA should be covered empirically in patients with any of the following risk factors for
antibiotic resistance:

Patients located in units were more than 10%-20% of S aureus isolates are MRSA

Patients in units where the prevalence of MRSA is unknown

The preferred antibiotics for treatment of MRSA infections include vancomycin and linezolid.
The recommended antibiotics for the treatment of suspected MSSA infections include
piperacillin-tazobactam, cefepime, levofloxacin, imipenem, and meropenem. When the pathogen
is confirmed as MSSA, the patient should be switched to oxacillin, nafcillin, or cefazolin.
The preferred antibiotics for treatment of MRSA VAP include vancomycin and linezolid.
A single antibiotic with activity against P aeruginosa should be administered, except in patients
with risk factors for multidrug-resistant (MDR) organisms, including the following:

Intravenous antibiotic use within the preceding 90 days

Septic shock or ARDS preceding VAP

Five or more days of hospitalization prior to VAP onset

Acute renal replacement therapy prior to the onset of VAP

The patient is located where more than 10% of gram-negative isolates are resistant

Patients in ICUs where antibiotic sensitivity rates are not available

In general, aminoglycosides should be avoided in the treatment of VAP. This also holds true for
colistin. This recommendation is most likely based on poor penetration of these agents in the
lung tissue, in addition to the potential nephrotoxicity of aminoglycosides and the challenge in
achieving therapeutic blood levels in patients with fluctuating renal function.
In cases of HAP and VAP, antibiotics should be administered by either extended or continuous
infusion. Dosing needs to be based on an antibiotic blood levels and should also be weightbased, when applicable.
The use of inhaled antibiotic therapy should be generally limited to cases of VAP produced by
gram-negative bacilli that are sensitive only to aminoglycosides, colistin, or polymyxin B. These
antibiotics should also be administered systemically.

Double-drug coverage of P aeruginosa should combine agents with a high degree of

antipseudomonal

activity

and

low

resistance

potential.

Optimal

combinations

include meropenem or doripenem plus either levofloxacin oraztreonam or amikacin.

A carbapenem or ampicillin/sulbactam should be used in treatingAcinetobacter HAP/VAP. If
there is resistance to these agents, inhaled and intravenous colistin should be substituted. The
guidelines recommend against the use of tigecycline in the treatment of Acinetobacter VAP.
Caveats
An important caveat is to differentiate P aeruginosa colonization from actual lung infection. P
aeruginosa pneumonia is characterized by fever, cyanosis, hypotension, and rapid cavitation
(<72 hours) on chest radiography. Sputum recovered from these cases is typically greenish due to
the pyocyanin pigment that is produced by the organism when it invades tissue. This is usually
accompanied by an almond odor.
Enterobacter species do not typically cause hospital-acquired pneumonia (HAP)/ventilatorassociated pneumonia (VAP). S maltophilia and B cepaciaare common colonizers of respiratory
secretions, but they rarely, if ever, cause nosocomial pneumonia in otherwise healthy hosts.
However, they are colonizers/potential pathogens in patients with bronchiectasis or cystic
fibrosis.
When the final culture and sensitivity results are available, the empiric broad-spectrum regimen
should be converted to more narrow and specific coverage.
S aureus (MSSA/MRSA) commonly colonizes respiratory secretions (30%-50%) but rarely, if
ever, causes necrotizing cavity nosocomial pneumonia. Oropharyngeal anaerobes are
unimportant from a therapeutic standpoint.
Duration of therapy
In general, for both hospital-acquired pneumonia (HAP) and VAP, 7 days of treatment with
appropriate antibiotics/antibiotics is recommended. This duration may be shortened or
lengthened depending on the clinical response of the individual. Normalization of PCT levels
may provide useful corroboration of clinical judgment in deciding to stop antibiotic therapy.

Complications in Nosocomial Pneumonia

Failure to successfully wean the patient from the respirator (possibly because of a lack of
cardiopulmonary function or a superimposed process [eg, HSV-1 pneumonitis]) is a common
problem following intubation for nosocomial pneumonia.
HSV-1 pneumonitis develops in intubated patients who have unchanging or persistent pulmonary
infiltrates after 2 weeks of antimicrobial therapy. These patients usually have low-grade fevers
with variable degrees of leukocytosis. Demonstrating HSV-1 in samples of respiratory secretions
may establish the diagnosis.
Start treatment with acyclovir in patients diagnosed with HSV-1 infection; acyclovir decreases
hypoxemia and subsequently permits weaning of the patient from the respirator.

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