10/30/24, 6:39 PM Epidemiology, pathogenesis, microbiology, and diagnosis of hospital-acquired and ventilator-associated pneumonia in adults - UpToDate

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Epidemiology, pathogenesis, microbiology, and diagnosis

of hospital-acquired and ventilator-associated
pneumonia in adults
AUTHOR: Michael Klompas, MD, MPH
SECTION EDITOR: Thomas M File, Jr, MD
DEPUTY EDITOR: Milana Bogorodskaya, MD

All topics are updated as new evidence becomes available and our peer review process is complete.

Literature review current through: Sep 2024.

This topic last updated: Mar 14, 2023.

INTRODUCTION

Hospital-acquired (or nosocomial) pneumonia (HAP) and ventilator-associated pneumonia (VAP)

remain important causes of morbidity and mortality despite improvements in prevention,
antimicrobial therapy, and supportive care.

The epidemiology, pathogenesis, and microbiology of HAP and VAP will be reviewed here. The
risk factors, prevention, and treatment of HAP and VAP are discussed separately. (See "Clinical
presentation and diagnostic evaluation of ventilator-associated pneumonia" and "Risk factors
and prevention of hospital-acquired and ventilator-associated pneumonia in adults" and
"Treatment of hospital-acquired and ventilator-associated pneumonia in adults".)

DEFINITIONS

Pneumonia types — Pneumonia is frequently categorized based on site of acquisition

( table 1).

● Hospital-acquired (or nosocomial) pneumonia (HAP) is pneumonia that occurs 48 hours

or more after admission to the hospital and did not appear to be incubating at the time of
admission.

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● Ventilator-associated pneumonia (VAP) is a type of HAP that develops in intubated

patients on mechanical ventilation for more than 48 hours. VAP also includes HAP that
occurs within 48 hours of extubation.

● Non-ventilator-associated HAP (NV-HAP) refers to HAP that develops in hospitalized

patients who are not on mechanical ventilation nor underwent extubation within 48 hours
before pneumonia developed. NV-HAP can be divided into patients that ultimately require
mechanical ventilation (VHAP) due to the pneumonia versus those that do not. VHAP is
associated with particularly poor clinical outcomes.

The category of health care-associated pneumonia (HCAP) is no longer recognized as a separate

category of pneumonia and was purposefully not included in the 2016 and 2019 American
Thoracic Society (ATS)/Infectious Diseases Society of America (IDSA) HAP [1] and community-
acquired pneumonia (CAP) [2] guidelines or the combined 2017 European and Latin American
HAP guidelines [3]. Historically, HCAP referred to pneumonia acquired in health care facilities
such as nursing homes, hemodialysis centers, outpatient clinics, or pneumonia acquired within
three months following a hospitalization [4]. This category was used to identify patients at risk
for infection with multidrug-resistant (MDR) pathogens. However, this categorization may have
been overly sensitive and may have led to increased, inappropriate broad antibiotic use.
Although patients with recent contact with health care facilities are at increased risk for
infection with MDR pathogens, this risk is small for most patients and the overall incidence of
MDR pathogens in this population is low [5-11].

We manage patients who would have been previously classified as having HCAP in a similar way
to those with CAP, deciding whether to include therapy targeting MDR pathogens on a case-by-
case basis depending upon each patient's specific risk factors and severity of illness [2]. Specific
risk factors for resistance that should be assessed include known colonization with MDR
pathogens, recent receipt of antimicrobials, comorbidities, functional status, and severity of
illness [12,13]. (See "Treatment of community-acquired pneumonia in adults in the outpatient
setting" and "Treatment of community-acquired pneumonia in adults who require
hospitalization".)

Antimicrobial resistance — The United States Centers for Disease Control and Prevention
(CDC) and the European Centre for Disease Prevention and Control (ECDC) have developed
standard terminology for antimicrobial-resistant gram-negative bacilli, which are important
causes of HAP and VAP [14]:

● MDR refers to acquired nonsusceptibility to at least one agent in three different

antimicrobial classes.

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● Extensively drug-resistant (XDR) refers to nonsusceptibility to at least one agent in all but
two antimicrobial classes.

● Pandrug-resistant (PDR) refers to nonsusceptibility to all antimicrobial agents that can be

used for treatment.

Awareness of local resistance patterns is critical for decisions regarding empiric therapy for HAP
and VAP [1,15]. All hospitals should regularly create and disseminate a local antibiogram, ideally
one that is specific to the different units in the hospital (although small numbers of cases per
unit may preclude this) [1].

EPIDEMIOLOGY

Hospital-acquired (or nosocomial) pneumonia (HAP) is one of the most common and morbid
hospital-acquired infections [16]. The risk for HAP is greatest in patients on mechanical
ventilation but most cases of HAP occur in nonventilated patients (NV-HAP) by virtue of their
greater numbers [16,17]. The risk of HAP is about 10-fold higher in ventilated versus non-
ventilated patients.

According to the United States Center for Disease Control and Prevention's National Healthcare
Safety Network (NHSN), there has been a steady decline in reported VAP rates in the United
States; between 2006 and 2012, in medical intensive care units (ICUs), the reported incidence of
VAP per 1000 ventilator-days decreased from 3.1 to 0.9 and, in surgical ICUs, the reported
incidence decreased from 5.2 to 2.0 [18,19]. Because the NHSN definition of VAP includes
qualitative criteria (eg, increased secretions or worsening oxygenation), it is unclear whether
the reported decrease in VAP incidence represents a true decline or reflects stricter application
of these subjective criteria [20,21].

Notwithstanding the drop in cases reported to NHSN, independent audits of data from the
Medicare Patient Safety Monitoring System (limited to patients ≥65 years of age) suggest that
the rate of VAP remained stable among ventilated patients between 2005 and 2013 (10.8
percent during 2005 to 2006 versus 9.7 percent during 2012 to 2013) [22]. A follow-up study
using the same methodology found that VAP rates have continued to remain stable through
2019 [23]. The differences between the rates reported to NHSN and this independent audit
reflect the lack of definitive criteria for VAP and the subjectivity of surveillance [21,24].

Crude mortality rates for VAP and NV-HAP are similar and range between 15 to 30 percent
[25,26]. Determining the fraction of these deaths attributable to pneumonia versus patients'
underlying conditions is complicated but most estimates are relatively low [27,28].
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VAP and NV-HAP are also associated with long hospital stays and significant costs [1]. Two
studies estimated that VAP prolongs the length of mechanical ventilation by 7.6 to 11.5 days and
prolongs hospitalization by 11.5 to 13.1 days compared with similar patients without VAP; the
excess cost associated with VAP has been estimated at approximately USD $40,000 per patient
[25,29-31].

The prognosis of HAP and VAP is discussed separately. (See "Treatment of hospital-acquired and
ventilator-associated pneumonia in adults" and "Treatment of hospital-acquired and ventilator-
associated pneumonia in adults", section on 'Prognosis'.)

PATHOGENESIS

The pathogenesis of hospital-acquired (or nosocomial) pneumonia (HAP) and ventilator-

associated pneumonia (VAP) is related to the number and virulence of micro-organisms
entering the lower respiratory tract and the response of the host (eg, mechanical, humoral, and
cellular host defenses). The primary route of infection of the lungs is through microaspiration of
organisms that have colonized the oropharyngeal tract (or, to a lesser extent, the
gastrointestinal tract) [32]. Approximately 45 percent of healthy subjects aspirate during sleep
and an even higher proportion of severely ill patients aspirate routinely. Although frequently
regarded as partially protective, the presence of an endotracheal tube facilitates aspiration of
oropharyngeal secretions and bacteria into the lungs [33]. Depending upon the number and
virulence of organisms reaching the lungs and the host response, pneumonia may ensue.

Hospitalized patients often become colonized with microorganisms acquired from the hospital
environment, and as many as 75 percent of severely ill patients will be colonized within 48 hours
[32,34]. An additional mechanism of inoculation in mechanically ventilated patients is direct
contact with environmental reservoirs, including respiratory devices and contaminated water
reservoirs [35,36]. Disposable tubing used in respiratory circuits or tracheostomy or
endotracheal tubes may become contaminated in the process of routine nursing care or via the
(contaminated) hands of hospital personnel. Such contamination can occur despite rigorous
cleaning of ventilator equipment.

In addition, the near sterility of the stomach and upper gastrointestinal tract may be disrupted
by alterations in gastric pH due to illness, medications, or enteric feedings. For this reason,
much attention has been paid to the possible adverse effect of ulcer prophylaxis regimens that
raise the gastric pH [37,38]. Less frequently, pneumonia results from inhalation of infectious
aerosols or from bacteremia originating in a distant focus. (See "Risk factors and prevention of

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hospital-acquired and ventilator-associated pneumonia in adults", section on 'Role of gastric

pH'.)

MICROBIOLOGY

Ventilator-associated pneumonia (VAP) and non-ventilator-associated pneumonia (NV-HAP) may

be caused by a wide variety of pathogens and can be polymicrobial. The most common
organisms are Staphylococcus aureus (including methicillin-resistant S. aureus) and Pseudomonas
aeruginosa. Other common causes include other aerobic gram-negative bacilli (eg, Escherichia
coli, Klebsiella pneumoniae, Enterobacter spp, Acinetobacter spp) and gram-positive cocci (eg,
Streptococcus spp) [39,40]. There is increasing recognition that a substantial fraction of
nosocomial pneumonias may be due to viruses in general medical and surgical patients and
both viruses and fungi in immunocompromised patients [41-43].

Among 9266 cases of VAP reported to the United States Centers for Disease Control and
Prevention (CDC) from 2015 to 2017, the distribution of pathogens associated was S. aureus
(28.8 percent), P. aeruginosa (12.9 percent), Klebsiella species (10.1 percent), Enterobacter species
(8.4 percent), Haemophilus influenzae (5.9 percent), Streptococcus (5.7 percent), E. coli (5.6
percent), and Acinetobacter baumannii (3.2 percent) [44]. Similar findings have been observed in
other surveillance studies [45].

The pathogens that cause NV-HAP are generally similar to those that cause VAP. As an example,
one prospective observational study evaluated 158,519 patients admitted to the University of
North Carolina Hospital over a four-year period [46]. A total of 327 episodes of VAP and 261
episodes of HAP in nonventilated patients were identified:

● The infecting flora in patients with VAP included methicillin-susceptible S. aureus (MSSA; 9
percent), MRSA (18 percent), P. aeruginosa (18 percent), Stenotrophomonas maltophilia (7
percent), Acinetobacter spp (8 percent), and other species (9 percent).

● The infecting flora in NV-HAP was similar, except non-Enterobacteriaceae gram-negative

bacilli (P. aeruginosa, Acinetobacter, and S. maltophilia) were less likely. Specifically, it
included MSSA (13 percent), MRSA (20 percent), P. aeruginosa (9 percent), S. maltophilia (1
percent), Acinetobacter spp (3 percent), and other species (18 percent).

These findings are largely similar to those observed in a retrospective analysis of 17,819
patients with culture-confirmed HAP [45] and a meta-analysis of 24 studies performed during
the development of the 2016 Infectious Diseases Society of America/American Thoracic Society
(IDSA/ATS) HAP/VAP guidelines [1]. In this analysis, the prevalence of S. aureus infections were
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lower, with MRSA accounting for 10 percent of isolates and MSSA for 6 percent; Pseudomonas
species accounted for 13 percent, enteric gram-negative bacilli for 16 percent, and Acinetobacter
species for 4 percent.

A frequent criticism of such studies is that they may underestimate the prevalence of certain
pathogens (eg, anaerobes) because special culturing techniques are required to identify them.
However, a study that performed anaerobic cultures using protective brush specimens and
bronchoalveolar lavage fluid from 185 patients with possible VAP identified only one anaerobic
organism, nonpathogenic Veillonella spp [47]. This finding and the history of success treating
VAP using regimens that do not include anaerobic coverage suggests that anaerobes may play a
relatively minor role in the pathogenesis of VAP.

Differences in host factors and in the hospital flora of an institution also influence the patterns
of pathogens seen.

MDR risk factors — The etiology of HAP and VAP depends in large part upon whether the
patient has risk factors for multidrug-resistant (MDR) pathogens [1]. The frequency of specific
MDR pathogens varies among hospitals, within hospitals, and between different patient
populations. Prolonged hospitalization and recent exposure to antibiotics are two of the most
important risk factors for MDR pathogens [1]. An awareness of the susceptibility patterns of the
nosocomial pathogens within a given health care setting is important to inform the selection of
appropriate empiric antimicrobial therapy.

Risk factors for MDR VAP are summarized in the following table ( table 2). Risk factors for MDR
HAP (as well as risk factors for increased mortality) are summarized in the following table
( table 3).

DIAGNOSIS

The clinical diagnosis of hospital-acquired (or nosocomial) pneumonia (HAP) and ventilator-
associated pneumonia (VAP) is difficult in part because the clinical findings are nonspecific. The
2016 Infectious Diseases Society of America/American Thoracic Society (IDSA/ATS) guidelines for
the management of HAP and VAP recommend a clinical diagnosis based upon a new lung
infiltrate plus clinical evidence that the infiltrate is of infectious origin, which includes the new
onset of fever, purulent sputum, leukocytosis, and decline in oxygenation [1].

While the clinical features described above support the diagnosis of HAP or VAP, no individual
sign or symptoms nor any combination of signs and symptoms have been found to be highly
sensitive or specific for diagnosis [24,48]. As an example, the presence of a new or progressive
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radiographic infiltrate plus at least two of three clinical features (fever >38ºC, leukocytosis or
leukopenia, and purulent secretions) has a 69 percent sensitivity and 75 percent specificity for
VAP, corresponding to a positive likelihood ratio of 2.5 (95% CI 1.3-4.8) and negative likelihood
ratio of 0.06 (95% CI 0-0.87) [48].

Cultures of pulmonary secretions (sputum, endotracheal aspirates, bronchoalveolar lavage) are

also prone to false positives and false negatives. When compared with histology, quantitative
endotracheal aspirate cultures had a pooled sensitivity of 48 percent (95% CI 38-57 percent) and
positive predictive value of 81 percent (95% CI 67-91 percent); quantitative bronchoalveolar
lavage cultures had a sensitivity of 75 percent (95% CI 58-88 percent) and positive predictive
value of 77 percent (95% CI 66-85 percent) [1].

Molecular diagnostic tests for detection of respiratory pathogens are being developed and offer
promise for more rapid identification of the causes of HAP or VAP [49-51]. Although there are
limitations regarding the sensitivity and specificity of these tests (eg, colonization or true
pathogen) [51,52], they offer the potential for more rapid identification of pathogens and
resistance patterns (eg, methicillin resistance for S. aureus [53], carbapenemase presence for
Enterobacteriaceae, and influenza and other respiratory viruses), which may result in better
selection of active empiric regimens and more rapid tailoring of directed antibiotic regimens. As
an example, a multiplex polymerase chain reaction assay, which detects an array of respiratory
bacterial pathogens including Streptococcus pneumoniae and several antibiotic-resistance genes,
is approved for the diagnosis of pneumonia using bronchoalveolar lavage specimens in the
United States but is not yet widely available [54]. Future studies to assess the utility of these
tests will ideally evaluate whether and how they affect antibiotic utilization and patient
outcomes. (See "Treatment of hospital-acquired and ventilator-associated pneumonia in adults",
section on 'Tailoring therapy'.)

The diagnostic approach to VAP is also discussed in more detail separately. (See "Clinical
presentation and diagnostic evaluation of ventilator-associated pneumonia".)

SOCIETY GUIDELINE LINKS

Links to society and government-sponsored guidelines from selected countries and regions
around the world are provided separately. (See "Society guideline links: Hospital-acquired
pneumonia and ventilator-associated pneumonia in adults".)

INFORMATION FOR PATIENTS

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UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics."
The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading
level, and they answer the four or five key questions a patient might have about a given
condition. These articles are best for patients who want a general overview and who prefer
short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more
sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading
level and are best for patients who want in-depth information and are comfortable with some
medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print
or email these topics to your patients. (You can also locate patient education articles on a variety
of subjects by searching on "patient info" and the keyword(s) of interest.)

● Basics topic (see "Patient education: Hospital-acquired pneumonia (The Basics)")

SUMMARY

● Definitions – Pneumonia is frequently categorized based on site of acquisition ( table 1).

(See 'Definitions' above.)

• Hospital-acquired (or nosocomial) pneumonia (HAP) is pneumonia that occurs 48

hours or more after admission to the hospital and did not appear to be incubating at
the time of admission.

• Ventilator-associated pneumonia (VAP) is a type of HAP that develops in intubated

patients on mechanical ventilation for more than 48 hours. VAP also includes HAP that
occurs within 48 hours of extubation.

• Non-ventilator-associated HAP (NV-HAP) refers to HAP that develops in hospitalized

patients who are not on mechanical ventilation nor underwent extubation within 48
hours before pneumonia developed. NV-HAP can be divided into patients that
ultimately require mechanical ventilation (VHAP) due to the pneumonia versus those
that do not. VHAP is associated with particularly poor clinical outcomes.

● Epidemiology – HAP is among the most common and morbid hospital-acquired infections.
(See 'Epidemiology' above.)

● Pathogenesis – The pathogenesis of HAP and VAP is related to the numbers and virulence
of micro-organisms entering the lower respiratory tract and the response of the host. The
primary route of infection of the lungs is through microaspiration of organisms that have
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colonized the oropharyngeal tract (or to a lesser extent the gastrointestinal tract). (See
'Pathogenesis' above.)

● Microbiology – HAP and VAP may be caused by a wide variety of pathogens, can be
polymicrobial, and may be due to multidrug-resistant (MDR) pathogens. (See
'Microbiology' above.) Staphylococcus aureus and Pseudomonas aeruginosa are the most
common pathogens.

● MDR risk factors – MDR bacteria are most common in patients who have been
hospitalized for prolonged periods (≥5 days) and/or who have received antibiotics within
the preceding 90 days. (See 'MDR risk factors' above.)

● Diagnosis – The diagnosis of HAP and VAP should be suspected in patients with new onset
of fever, purulent sputum, leukocytosis, and decline in oxygenation. (See 'Diagnosis'
above.)

ACKNOWLEDGMENT

UpToDate gratefully acknowledges John G Bartlett, MD (deceased), who contributed on earlier

versions of this topic and was a founding Editor-in-Chief for UpToDate in Infectious Diseases.

Use of UpToDate is subject to the Terms of Use.

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GRAPHICS

Pneumonia terminology

Term Definition

Classification by site of acquisition

Community-acquired An acute infection of the pulmonary parenchyma acquired outside of

pneumonia (CAP) health care settings

Nosocomial pneumonia An acute infection of the pulmonary parenchyma acquired in hospital

settings, which encompasses hospital-acquired pneumonia and
ventilator-associated pneumonia

Hospital-acquired Pneumonia acquired ≥48 hours after hospital admission; includes both
pneumonia (HAP) HAP and VAP

Ventilator-associated Pneumonia acquired ≥48 hours after endotracheal intubation

pneumonia (VAP)

Health care-associated Retired term, which referred to pneumonia acquired in health care
pneumonia (HCAP) facilities (eg, nursing homes, hemodialysis centers) or after recent
hospitalization *

Classification by etiology

Atypical pneumonia Pneumonia caused by "atypical" ¶ bacterial pathogens including Legionella

spp, Mycoplasma pneumoniae, Chlamydia pneumoniae, Chlamydia psittaci,
and Coxiella burnetii

Aspiration pneumonia Pneumonia resulting from entry of gastric or oropharyngeal fluid, which
may contain bacteria and/or exogenous substances (eg, ingested food
particles or liquids, mineral oil, salt or fresh water) or be of low pH, into
the lower airways

Chemical pneumonitis Aspiration of substances (eg, acidic gastric fluid) that cause an
inflammatory reaction in the lower airways, independent of bacterial
infection

Bacterial aspiration An active infection caused by inoculation of large amounts of bacteria into
pneumonia the lungs via orogastric contents

* The term HCAP was used to identify patients at risk for infection with multidrug-resistant pathogens.
This categorization may have been overly sensitive, leading to increased, inappropriately broad antibiotic
use.

¶ The origin of the term "atypical" is a matter of debate. The term may refer to the fact that these
organisms are not "typical" bacteria, which cannot be identified by standard microbiologic techniques.

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Others suggest that atypical refers to the mild nature of the pneumonia caused by some of these
organisms compared with pneumonia caused by Streptococcus pneumoniae.

Graphic 130821 Version 4.0

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Ventilator-associated pneumonia: Risk factors for multidrug-resistance in

adults

Risk factors for MDR pathogens (including Pseudomonas aeruginosa, other gram-
negative bacilli, and MRSA):

IV antibiotic use within the previous 90 days

Septic shock at the time of VAP
ARDS preceding VAP
≥5 days of hospitalization prior to the occurrence of VAP
Acute renal replacement therapy prior to VAP onset

Risk factors for MDR Pseudomonas and other gram-negative bacilli:

Treatment in an ICU in which >10% of gram-negative isolates are resistant to an agent being
considered for monotherapy
Treatment in an ICU in which local antimicrobial susceptibility rates are not known
Colonization with or prior isolation of MDR Pseudomonas or other gram-negative bacilli on culture
from any body site

Risk factors for MRSA:

Treatment in an ICU in which >10 to 20% of Staphylococcus aureus isolates are methicillin resistant
Treatment in an ICU in which the prevalence of MRSA is not known
Colonization with or prior isolation of MRSA on culture from any body site

MDR: multidrug resistant; IV: intravenous; VAP: ventilator-associated pneumonia; ARDS: acute respiratory
distress syndrome; ICU: intensive care unit; MRSA: methicillin-resistant S. aureus; ICU: intensive care unit.

Adapted from: Kalil AC, Metersky ML, Klompas M, et al. Management of adults with hospital-acquired and ventilator-associated
pneumonia: 2016 clinical practice guidelines by the Infectious Diseases Society of America and the American Thoracic Society. Clin
Infect Dis 2016; 63:e61.

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Non-ventilator hospital-acquired pneumonia: Risk factors for MDR pathogens

and/or increased mortality in adults

Risk factors for increased mortality:

Ventilatory support for HAP

Septic shock

Risk factor for MDR Pseudomonas aeruginosa, other gram-negative bacilli, and MRSA:

IV antibiotics within the past 90 days

Risk factors for MDR Pseudomonas aeruginosa and other gram-negative bacilli:

Colonization with or prior isolation of MDR Pseudomonas or other gram-negative bacilli

Risk factors for MRSA:

Treatment in an ICU in which >20% of Staphylococcus aureus isolates are methicillin resistant
Treatment in an ICU in which the prevalence of MRSA is not known
Colonization with or prior isolation of MRSA

ICU: intensive care unit; IV: intravenous; HAP: hospital-acquired pneumonia; MDR: multidrug resistant;
MRSA: methicillin-resistant S. aureus.

Adapted from: Kalil AC, Metersky ML, Klompas M, et al. Management of adults with hospital-acquired and ventilator-associated
pneumonia: 2016 clinical practice guidelines by the Infectious Diseases Society of America and the American Thoracic Society. Clin
Infect Dis 2016; 63:e61.

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Contributor Disclosures
Michael Klompas, MD, MPH No relevant financial relationship(s) with ineligible companies to
disclose. Thomas M File, Jr, MD Consultant/Advisory Boards: Eagle Pharmaceuticals [Severe community-
acquired pneumonia]; Merck [Pneumococcal vaccine]; MicroGenDX [Next generation sequencing
diagnostics]; Nabriva Therapeutics [Community-acquired pneumonia]; Shionogi [Cefiderocol];
ThermoFisher [Biomarker for infection]. Other Financial Interest: Board of Directors of Infectious Diseases
Society of America (2017-2022) [Infections diseases]; HealthTrackRX [Travel expenses]; Wolters Kluwer-
Editor-in-Chief, Infectious Diseases in Clinical Practice [Infections diseases]. All of the relevant financial
relationships listed have been mitigated. Milana Bogorodskaya, MD No relevant financial relationship(s)
with ineligible companies to disclose.

Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are
addressed by vetting through a multi-level review process, and through requirements for references to be
provided to support the content. Appropriately referenced content is required of all authors and must
conform to UpToDate standards of evidence.

Conflict of interest policy

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