Hospital Acquired Pneumonia

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:
Sheila Bond, MD
Contributor Disclosures
All topics are updated as new evidence becomes available and our peer review process is
complete.
Literature review current through: Jun 2019. | This topic last updated: Nov 01, 2018.
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
diagnosis, 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 — The 2016 Infectious Diseases Society of
America (IDSA)/American Thoracic Society (ATS) guidelines on the management of adults with
HAP and VAP used the following definitions [1] (see 'Society guideline links' below):
●HAP (or nosocomial pneumonia) is pneumonia that occurs 48 hours or more after
admission and did not appear to be incubating at the time of admission.
●VAP is a type of pneumonia that develops ≥48 hours after endotracheal intubation.
The category of health care-associated pneumonia (HCAP) was included in the

2005 ATS/IDSA guidelines and referred to pneumonia acquired in health care facilities such as
nursing homes, hemodialysis centers, outpatient clinics, or during a hospitalization within the
past three months [2]. 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, inappropriately 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 is low [3-9]. Thus, the
category of HCAP was purposefully not included in the 2016 IDSA/ATS guidelines. For similar
reasons, the combined 2017 European and Latin American guidelines on the management of
HAP and VAP did not categorize HCAP as a distinct type of pneumonia [10].
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 [11]:
●Multidrug resistant (MDR) refers to acquired nonsusceptibility to at least one agent in
three different antimicrobial classes.
●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.
EPIDEMIOLOGY HAP is one of the most common hospital-acquired infections [12].
Most cases of HAP occur in nonventilated patients [12]. However, the highest risk for HAP is in
patients on mechanical ventilation (ie, VAP), in whom the entity has been best studied.
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 [13,14]. 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 [15].
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) [16]. 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 [17].
VAP is 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 [18,19].
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 HAP (or nosocomial pneumonia) and 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 lesser extent, the gastrointestinal tract) [20]. Approximately 45
percent of healthy subjects aspirate during sleep and an even higher proportion of severely ill
patients aspirate routinely [21,22]. Although frequently regarded as partially protective, the
presence of an endotracheal tube facilitates aspiration of oropharyngeal material or bacteria of
gastrointestinal origin into the lungs [22]. Depending upon the number and virulence of
organisms reaching the lung 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
[20,21,23]. An additional mechanism of inoculation in mechanically ventilated patients is direct
contact with environmental reservoirs, including respiratory devices and contaminated water
reservoirs [24,25]. 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 [26]. Less frequently, pneumonia results from inhalation of infectious aerosols or
from bacteremia originating in a distant focus. (See "Risk factors and prevention of hospital-
acquired and ventilator-associated pneumonia in adults", section on 'Role of gastric pH'.)
MICROBIOLOGY HAP (or nosocomial pneumonia) and VAP may be caused by a wide
variety of pathogens and can be polymicrobial. Common pathogens include aerobic gram-
negative bacilli (eg, Escherichia coli, Klebsiella pneumoniae, Enterobacter spp, Pseudomonas
aeruginosa, Acinetobacter spp) and gram-positive cocci (eg, Staphylococcus aureus, including
methicillin-resistant S. aureus [MRSA], Streptococcus spp) [27,28]. 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 [29,30].
Among 8474 cases of VAP reported to the United States Centers for Disease Control and
Prevention from 2009 to 2010, the distribution of pathogens associated was S. aureus (24.1
percent), P. aeruginosa (16.6 percent), Klebsiellaspecies (10.1 percent), Enterobacter species
(8.6 percent), Acinetobacter baumannii (6.6 percent), and E. coli (5.9 percent) [31]. Similar
findings have been observed in other surveillance studies [27].
There is a paucity of data regarding whether and how the pathogens that cause HAP in
nonventilated patients differ from those that cause VAP. One prospective observational study
evaluated 158,519 patients admitted to the University of North Carolina Hospital over a four-
year period [32]. 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 nonventilated patients with 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 meta-analysis of 24 studies performed
during the development of the 2016 Infectious Diseases Society of America/American Thoracic
Society HAP/VAP guidelines to determine the prevalence of micro-organisms causing HAP [1].
In this analysis, the prevalence of S. aureus infections were 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 [33]. This finding and the history of success treating
VAP using regimens that do not include anaerobic coverage suggests that including anaerobic
coverage in most VAP regimens is unnecessary.
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 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 for appropriate empiric antimicrobial therapy.
Risk factors for MDR VAP are summarized in the following table (table 1). Risk factors for
MDR HAP (as well as risk factors for increased mortality) are summarized in the following table
(table 2).
DIAGNOSIS The clinical diagnosis of HAP and VAP is difficult in part because the
clinical findings are nonspecific. The 2016 Infectious Diseases Society

of America/American Thoracic Society 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 [34]. As an example, the presence of a new or progressive
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) [34].
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 [35-37]. Although there are
limitations regarding the specificity of these tests (eg, colonization or true pathogen), they offer
the potential for more rapid identification of pathogens and resistance patterns (eg, methicillin
resistance for S. aureus, carbapenemase presence for Enterobacteriaceae), 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 [38]. Future studies to assess the
utility of these tests will ideally evaluate whether and how they affect patient outcomes.
(See "Treatment of hospital-acquired and ventilator-associated pneumonia in adults", section on
'Tailoring therapy'.)
Of note, the 2016 guidelines do not include the entities of ventilator-associated conditions and
infection-related ventilator-associated complications introduced by the United States Centers for
Disease Control and Prevention as criteria for clinical diagnosis or indications for initiation of
antimicrobial therapy [1,39]. These definitions were designed for the purposes of surveillance
and quality improvement at the population level and not to aid in diagnosis and treatment
decisions for individual patients.
The diagnostic approach to VAP is also discussed in more detail separately. (See "Clinical
presentation and diagnostic evaluation of ventilator-associated pneumonia".)
isk factors and prevention of hospital-acquired and ventilator-associated pneumonia in
adults
Author:
Section Editor:
Deputy Editor:
Sheila Bond, MD
complete.
Literature review current through: Jun 2019. | This topic last updated: Mar 07, 2019.
associated pneumonia (VAP) are important causes of morbidity and mortality despite improved
antimicrobial therapy, supportive care, and prevention. The risk factors and prevention of HAP
and VAP will be reviewed here.
The clinical presentation, diagnosis, epidemiology, pathogenesis, microbiology, and treatment of

HAP and VAP are discussed separately. (See "Clinical presentation and diagnostic evaluation of
ventilator-associated pneumonia" and "Epidemiology, pathogenesis, microbiology, and diagnosis
of hospital-acquired and ventilator-associated pneumonia in adults" and "Treatment of hospital-
acquired and ventilator-associated pneumonia in adults".)
DEFINITIONS

America (IDSA)/American Thoracic Society (ATS) guidelines distinguish the following types of
pneumonia [1] (see "Treatment of hospital-acquired and ventilator-associated pneumonia in
adults", section on 'Society guideline links'):
●Hospital-acquired (or nosocomial) pneumonia (HAP) is pneumonia that occurs 48
hours or more after admission and did not appear to be incubating at the time of admission.
●Ventilator-associated pneumonia (VAP) is a type of HAP that develops ≥48 hours after
endotracheal intubation.

sensitive and led to increased, inappropriate broad-spectrum antibiotic use. Although patients
pathogens, this risk is small for most patients and the overall incidence is low [3-9]. Thus, the
category of HCAP was purposefully not included in the 2016 ATS/IDSA guidelines. For similar
reasons, the combined 2017 European and Latin American guidelines on the management of
HAP and VAP did not categorize HCAP as a distinct type of pneumonia [10].
●MDR refers to acquired nonsusceptibility to at least one agent in three different
antimicrobial classes.
used for treatment.
RISK FACTORS The most significant risk factor for hospital-acquired pneumonia
(HAP) is mechanical ventilation. Other risk factors, which have emerged from multivariate
analyses, include [12-22]:
●Older age [18,23]
●Chronic lung disease [15]
●Depressed consciousness [24]
●Aspiration [15]
●Chest or upper abdominal surgery [15,22,24]
●The presence of an intracranial pressure monitor [12]
●Agents that increase gastric pH (H2 blockers, antacids, proton pump inhibitors [PPIs])
(see 'Role of gastric pH'below)
●Previous antibiotic exposure, especially broad spectrum [25,26]
●Reintubation or prolonged intubation [16,17,22,25,27,28]
●Mechanical ventilation for acute respiratory distress syndrome [20,29]
●Frequent ventilator circuit changes (see "The ventilator circuit")
●Total opioid exposure [30]
●Multiple trauma [25,27]
●Paralysis [27]
●Number of central venous catheter placements and surgeries [28]
●Use of muscle relaxants or glucocorticoids [28]
●Malnutrition, chronic renal failure, anemia, Charlson Comorbidity Index, previous
hospitalization [24]
Role of gastric pH — Several studies have noted an increased incidence of HAP when the
gastric pH is increased with the use of H2 blockers, antacids, or PPIs [13,31-36]. We avoid
agents that raise gastric pH in patients who are not at high risk of developing a stress ulcer or
stress gastritis.
A randomized trial conducted >20 years ago compared three strategies of stress ulcer
prophylaxis (ranitidine, aluminum hydroxide-magnesium hydroxide antacid, and sucralfate) [32].
The incidence of late-onset pneumonia (more than four days after intubation) was significantly
lower with sucralfate compared with pH-altering drugs (5 versus 16 percent with antacids and 21
percent with ranitidine). Patients who received sucralfate had a lower median gastric pH and less
frequent gastric colonization compared with the other groups. Nevertheless, when patients with
pH >4 were evaluated separately, the patients receiving sucralfate still exhibited lower rates of
gastric colonization, suggesting that sucralfate may possess intrinsic antibacterial activity. There
was a trend toward an increased incidence of gastric bleeding in patients taking sucralfate
compared with antacids and ranitidine (10, 4, and 6 percent, respectively), but this difference was
not statistically significant.
Subsequent meta-analyses have also found decreased rates of pneumonia in critically ill patients
using sucralfate for stress ulcer prophylaxis compared with H2 blockers and PPIs [37,38]. In a
meta-analysis of 21 randomized trials, the incidence of pneumonia was decreased in critically ill
patients receiving sucralfate compared with those receiving H2blockers (relative risk [RR] 0.84,
95% CI 0.72-0.98) [37]. No difference in bleeding risk was detected. Similar findings were
observed in a network meta-analysis of 57 trials evaluating 7293 critically ill patients receiving
stress ulcer prophylaxis [38]. Both H2 blockers and PPIs were associated with an increased risk
of pneumonia when compared with sucralfate (odds ratio [OR] 1.30, 95% CI 1.08-1.58, and OR
1.65, 95% CI 1.20-2.27, respectively).
A large randomized trial, however, reached a different conclusion [39]. In this study, 3298
intensive care unit patients were randomized to daily pantoprazole versus placebo. There was no
difference between groups in 90-day mortality nor in the composite outcome of gastrointestinal
bleeding, pneumonia, Clostridioides (formerly Clostridium) difficileinfection, or myocardial
ischemia. Specifically, pneumonia rates were identical between groups.
Additional large randomized controlled trials on the impact of stress ulcer prophylaxis on
bleeding, pneumonia, and other outcomes are underway [40].
PREVENTION In 2014, the Society for Healthcare Epidemiology of America (SHEA)
and the Infectious Diseases Society of America (IDSA) issued updated practice

recommendations to reduce the risk of VAP (table 1) [41]. Basic practices that are recommended
by SHEA/IDSA for preventing VAP in all acute care hospitals include avoiding intubation when
possible (eg, noninvasive ventilation), minimizing transport while ventilated (when feasible),
implementation of weaning protocols, minimizing sedation, maintaining and improving physical
conditioning, minimizing pooling of secretions above the endotracheal tube cuff, elevating the
head of the bed, and maintaining ventilator circuits. We agree with the recommendations
included in these guidelines. Although evidence supporting the use of bundles is mixed,
combining a core set of prevention measures into a bundle can be a practical way to enhance care
[41-48]. (See 'Prevention bundles' below.)
The following discussion will review some of the modalities that have been evaluated for
preventing VAP. The approach to mechanical ventilation, noninvasive ventilation, maintenance
of the ventilator circuit, and sedation are discussed separately. (See "Overview of mechanical
ventilation" and "Complications of the endotracheal tube following initial placement: Prevention
and management in adult intensive care unit patients", section on 'Suctioning and oral
care' and "The ventilator circuit" and "Sedative-analgesic medications in critically ill adults:
Selection, initiation, maintenance, and withdrawal".)
General issues related to prevention of infections in the intensive care unit (ICU) and infection
control are discussed separately. (See "Infections and antimicrobial resistance in the intensive
care unit: Epidemiology and prevention" and "Infection prevention: Precautions for preventing
transmission of infection".)
Preventing aspiration — Aspiration is a major predisposing mechanism for both HAP and

VAP. Appropriate patient positioning and subglottic drainage in ventilated patients are two
modalities proposed for the prevention of aspiration. Other factors that may reduce aspiration
include maintaining endotracheal tube airway cuff pressure (20 to 30 cm H 2O) and application of
positive end-expiratory pressure [49,50]. (See "Complications of the endotracheal tube following
initial placement: Prevention and management in adult intensive care unit patients", section on
'Maintain optimal cuff pressure' and "Positive end-expiratory pressure (PEEP)".)
Patient positioning — Supine positioning appears to predispose to aspiration and the

development of HAP, particularly in patients receiving enteral nutrition [48]. The head of the bed
should therefore be elevated to 30 to 45° [41]. In a meta-analysis of eight randomized trials
evaluating over 750 mechanically ventilated adults, semirecumbent positioning (≥30 to 60°)
appeared to reduce rates of clinically suspected VAP when compared with supine positioning
[51]. One randomized trial evaluated the impact of placing patients in the lateral Trendelenburg
position in order to preferentially drain oral secretions away from the lungs [52]. Although rates
of VAP were lower in patients placed in lateral Trendelenburg compared with the
semirecumbent position (relative risk 0.13, 95% CI 0.02-1.03), this trial was stopped early due to
increased adverse events (eg, transient oxygen desaturation and hemodynamic instability) among
patients placed in lateral Trendelenburg. While no effect of positioning on duration of
mechanical ventilation or mortality has been demonstrated, it seems prudent to preferentially
place intubated patients in the semirecumbent position unless contraindicated [46,53].
Subglottic drainage — Drainage of subglottic secretions that pool above the endotracheal tube
cuff may lessen the risk of aspiration of secretions around the cuff and thereby decrease the
incidence of VAP. Specially designed endotracheal tubes have been developed to provide
continuous or intermittent aspiration of subglottic secretions (figure 1) [54-56]. However, these
devices cost more than standard endotracheal tubes and are not widely available. When
available, they should be used for patients expected to require >48 or 72 hours of mechanical
ventilation [41]. In a 2016 meta-analysis of 17 randomized trials evaluating 3369 patients,
subglottic secretion drainage reduced the risk of VAP from 21 to 13 percent (risk ratio 0.58, 95%
CI 0.51-0.67) [57]. No significant differences in mortality, length of ICU stay, duration of
mechanical ventilation, or antibiotic use were found.
Gastric volume monitoring — It has long been standard clinical practice to monitor the
patient's gastric residual volume at regular intervals and/or prior to increasing the infusion rate of
gastric tube feeding, with the hope of minimizing the risk of unrecognized gastric fluid
accumulation and vomiting resulting in pneumonia. However, several studies have shown that
measurement of gastric residuals correlates poorly with aspiration risk and is associated with a
decrease in calorie delivery [58-60]. Furthermore, a randomized trial has shown that the rate of
VAP was not higher in patients who did not undergo monitoring of gastric residuals [61]. Based
on these findings, we do not routinely check gastric residual volumes in asymptomatic patients
receiving tube feedings. This is discussed in greater detail separately. (See "Nutrition support in
critically ill patients: Enteral nutrition", section on 'Monitoring'.)
Decontamination of the digestive tract — Decontamination of the digestive tract may reduce

the incidence of pneumonia in critically ill patients by decreasing colonization of the upper
respiratory tract. The methods used include antiseptics (eg, chlorhexidine) in the oropharynx,
selective decontamination of the oropharyngeal tract (SOD) with nonabsorbable antibiotics
applied in the oropharynx, and selective decontamination of the digestive tract (SDD) with
nonabsorbable antibiotics applied to the oropharynx and administered orally, with or without
intravenous antibiotics.
Chlorhexidine — Chlorhexidine use is controversial because of its uncertain efficacy and

possible association with increased mortality [46,62-66].
Several meta-analyses of randomized trials have reported an association

between chlorhexidine and lower VAP rates [62-66]. As an example, in one meta-analysis of 16
trials evaluating 3630 critically ill patients, a trend toward decreased VAP rates was detected but
did not reach statistical significance among open label trials (relative risk 0.61, 95% CI 0.35-
1.04) or blinded trials (relative risk 0.88, 95% CI 0.66-1.16) [66]. These analyses should be
interpreted with caution, however, because diagnostic criteria for VAP are subjective and
nonspecific. None of the meta-analyses have found differences between chlorhexidine versus
placebo in duration of mechanical ventilation, ICU length of stay, or hospital length of stay.
An increase in mortality with chlorhexidine use was detected in a single meta-analysis of 11

trials evaluating 2618 ICU patients when compared with placebo (28.5 versus 24.5 percent; odds
ratio [OR] 1.25, 95% CI 1.05-1.50) [64]. In a subsequent retrospective review of 5539
mechanically ventilated patients, chlorhexidine was associated with an increased risk for
ventilator mortality (hazard ratio [HR], 1.63, 95% CI 1.15-2.31) [46]. Due to the possible
increase in mortality, the combined European and Latin American guidelines chose not to issue a
recommendation on chlorhexidine use for VAP prevention until further efficacy data are
available [10]. The mechanism by which chlorhexidine might increase mortality is unclear. One
hypothesis is that aspiration of chlorhexidine may precipitate acute respiratory distress syndrome
in a small fraction of patients.
Selective decontamination of the digestive tract — SDD refers to use of nonabsorbable
antibiotics applied to the oropharynx and administered orally, with or without intravenous
antibiotics.
Meta-analyses have shown that SDD reduces the risk of VAP and HAP [67-69]. Both SOD and
SDD have shown mortality benefits in trials of ICU patients performed mainly in regions with
low baseline antimicrobial resistance rates [70,71]. The applicability of the studies showing
benefit to other settings has been questioned since very low rates of antibiotic resistance were
present at the institutions included in the key trials [72,73].
In a multicenter randomized trial performed in ICUs with high baseline antimicrobial resistance
rates, no difference in 28-day mortality was detected with SOD, SDD, or 1% chlorhexidine oral
care when compared with standard practice [74]. Because standard practice included oral care
with 0.12 or 0.20% in most centers, the effect of chlorhexidine alone on mortality cannot be
determined. The effect of these interventions on VAP was not reported.
Additional detail on SDD is discussed separately. (See "Infections and antimicrobial resistance in

the intensive care unit: Epidemiology and prevention", section on 'Digestive and oropharyngeal
decontamination'.)
Because of the potential for promoting antimicrobial resistance with widespread SDD use, the
practice has not been routinely adopted in North America [2,41,73,75,76]; the 2014 Society for
Healthcare Epidemiology of America guidelines and 2017 combined European and Latin
American HAP and VAP guidelines recommend against SDD [10,41].
Probiotics — Probiotics are defined as live microorganisms of human origin that are able to
tolerate the hostile gastrointestinal environment such that they persist in the lower alimentary
tract to confer a health benefit to the host [77,78]. Available results do not provide sufficient
evidence to draw conclusions regarding the efficacy or safety of probiotics for the prevention of
VAP. We therefore do not use probiotics for the prevention of VAP.
A 2014 meta-analysis evaluated eight randomized trials with 1083 participants that compared a
probiotic (eg, Lactobacillus spp) with a control (placebo, glutamine, fermentable fiber,
peptide, chlorhexidine) for the prevention of VAP [79]. The use of probiotics decreased the
incidence of VAP from 29 to 21 percent (OR 0.70, 95% CI 0.52-0.95). No significant differences
in mortality, length of ICU stay, or duration of mechanical ventilation were detected. Adverse
effects were not estimable in this analysis. Similar findings were observed in a 2017 meta-
analysis [80]; however, the quality of the evidence in each meta-analysis was low.
Silver-coated endotracheal tube — We do not use silver-coated endotracheal tubes (ETTs).

Silver-coated ETTs reduce the incidence of VAP but not of other important outcomes [81,82].
This was illustrated in a randomized single-blinded trial (NASCENT) in which a silver-coated
ETT was compared with an uncoated ETT in 2003 patients requiring mechanical ventilation
[81]. Among patients intubated for more than 24 hours, the rate of microbiologically confirmed
VAP was significantly lower with the silver-coated ETT (4.8 versus 7.5 percent). The silver-
coated ETT was also associated with a significant delay in the occurrence of VAP. There were
no differences between groups, however, in the duration of intubation, ICU stay, or hospital stay;
mortality; or the frequency or severity of adverse events.
Glucocorticoids — Stress-dose glucocorticoids have been proposed as a possible method for

preventing HAP in critically ill patients. Hydrocortisone (200 mg/day for five days followed by
100 mg on day 6 and 50 mg on day 7) was compared with placebo in a multicenter trial that
included 150 intubated patients with severe trauma requiring intensive care [83]. The treatment
was stopped in patients who had an appropriate adrenal response within the first 48 hours
following inclusion. In the modified intention-to-treat analysis, patients who received
hydrocortisone had a lower risk of HAP at 28 days compared with patients who received placebo
(HR 0.47, 95% CI 0.25-0.86). Hydrocortisone use was also associated with a shorter duration of
mechanical ventilation and a reduced risk of hyponatremia, but there was no difference in
mortality compared with placebo.
An accompanying editorial noted that this trial was not adequately powered to assess the effect
of glucocorticoids on mortality and that earlier trials have shown an increase in mortality in
patients with traumatic brain injury (TBI) or persistent acute respiratory distress syndrome
(ARDS) and mixed results regarding the effect on HAP [84-86]. In patients with TBI,
administration of glucocorticoids was not associated with a reduced rate of HAP [85], whereas in
patients with ARDS, administration of glucocorticoids was associated with lower rates of
suspected or probable HAP [86]. Further studies are necessary to more clearly define the
potential benefits and safety of glucocorticoid use in these populations [84].
The use of glucocorticoids in patients with septic shock and ARDS is discussed in detail
separately. (See "Glucocorticoid therapy in septic shock" and "Acute respiratory distress
syndrome: Supportive care and oxygenation in adults", section on 'Glucocorticoids'.)
Prevention bundles — VAP prevention bundles involve the implementation of various

measures in an attempt to reduce the incidence of VAP among patients at risk. Such measures
often include educational programs, technical measures, surveillance, and feedback [87].
Developing VAP prevention bundles is a practical way to enhance care. However, there is no
consensus about which care processes to include, definitions of VAP vary, baseline VAP rates
differ among institutions, there is substantial heterogeneity in different hospitals' bundles, and
bundle adherence is generally incomplete [41,88].
Accurately assessing the impact of VAP bundles is challenging because of the subjectivity and
lack of specificity of VAP diagnostic criteria. For example, it is difficult to determine whether
observed decreases in VAP incidence represent a true decline or stricter application of subjective
criteria. This is of particular concern because hospitals and surveyors often have an interest in
being able to report lower VAP rates, and bundle implementations by nature are implemented in
an open-label fashion.
Examples of studies that evaluated VAP prevention bundles include the following:
●In a prospective surveillance study conducted in 181 Spanish ICUs (the Pneumonia Zero
project), VAP incidence declined from 9.8 to 4.3 episodes per 1000 ventilator days with
institution of a prevention bundle that included seven mandatory measures including
education and training in airway management, strict hand hygiene before airway
management, control and maintenance of cuff pressure, oral care with chlorhexidine,
semirecumbent positioning, protocols for minimizing sedation, and avoiding elective
changes of ventilator circuits, humidifiers, and endotracheal tubes [89].
●In another cohort study, VAP incidence declined from 23 to 13 episodes per 1000
ventilator days with the institution of a bundle that contained hand hygiene, glove and gown
compliance, elevation of the head of the bed, oral care with chlorhexidine, maintaining an
endotracheal tube cuff pressure >20 cm H20, orogastric rather than nasogastric feeding
tubes, avoiding gastric overdistention, and eliminating nonessential tracheal suctioning [87].
●In a multicenter cohort study, VAP incidence declined from 5.5 to 0 cases per 1000
ventilator days across 110 ICUs with institution of a bundle that included semirecumbent
positioning, minimization of sedation, daily assessments for extubation, stress ulcer
prophylaxis, and deep vein thrombosis prophylaxis [90].
A single retrospective cohort study has sought to determine which components of VAP
prevention bundles are efficacious [46]. In evaluation of 5539 mechanically ventilated patients,
the following interventions were found to be beneficial: semirecumbent positioning, sedation
interruptions, spontaneous breathing trials, and deep vein thrombosis prophylaxis. By contrast,
stress ulcer prophylaxis was associated with an increased risk of VAP (HR 7.69, 95% CI 1.44-
41.1), and oral chlorhexidine was associated with increased mortality (HR 1.63, 95% CI 1.15-
2.31). While the latter association is concerning, whether chlorhexidine is a causal factor is not
clear. (See 'Decontamination of the digestive tract' above.)
Although a meta-analysis of 13 observational studies evaluating the effect of VAP bundles on

mortality reported a 10 percent decrease in mortality following bundle implementation (OR 0.90,
95% CI 0.84-0.97) [91], these results should be interpreted with caution due to the observational
nature of included studies, variations in bundle components, and lack of correlation between
bundle adherence rates and mortality.
Treatment of hospital-acquired and ventilator-associated pneumonia in adults
Author:
Section Editor:
Deputy Editor:
Sheila Bond, MD
complete.
Literature review current through: Jun 2019. | This topic last updated: Jul 10, 2019.
associated pneumonia (VAP) are important causes of morbidity and mortality despite improved
prevention, antimicrobial therapy, and supportive care [1].
The treatment of HAP and VAP will be reviewed here. The diagnosis, epidemiology,
pathogenesis, microbiology, risk factors, and prevention of HAP and VAP are discussed
separately. (See "Clinical presentation and diagnostic evaluation of ventilator-associated
pneumonia" and "Epidemiology, pathogenesis, microbiology, and diagnosis of hospital-acquired
and ventilator-associated pneumonia in adults" and "Risk factors and prevention of hospital-
acquired and ventilator-associated pneumonia in adults".)
DEFINITIONS

America (IDSA)/American Thoracic Society (ATS) guidelines distinguish the following types of
pneumonia [1] (see 'Society guideline links' below):
●Hospital-acquired (or nosocomial) pneumonia (HAP) is pneumonia that occurs 48
hours or more after admission and did not appear to be incubating at the time of admission.
●Ventilator-associated pneumonia (VAP) is a type of HAP that develops more than 48
hours after endotracheal intubation.

sensitive and may have led to increased, inappropriately broad antibiotic use. Although patients
pathogens, this risk is small for most patients and the overall incidence of MDR pathogens in this
population is low [3-9]. Thus, the category of HCAP was purposefully not included in the
2016 ATS/IDSA guidelines. For similar reasons, the combined 2017 European and Latin
American guidelines on the management of HAP and VAP did not categorize HCAP as a distinct
type of pneumonia [10].
We thus manage patients who would have been previously classified as having HCAP in a
similar way to those with community-acquired pneumonia (CAP), deciding whether to include
therapy targeting MDR pathogens on a case-by-case basis. Specific risk factors for resistance
that should be assessed include recent receipt of antimicrobials, comorbidities, functional status,
and severity of illness [11,12]. (See "Treatment of community-acquired pneumonia in adults in
the outpatient setting" and "Treatment of community-acquired pneumonia in adults who require
hospitalization".)
●MDR refers to acquired nonsusceptibility to at least one agent in three different
antimicrobial classes.
used for treatment.
Awareness of local resistance patterns is critical for decisions regarding empiric therapy for HAP
and VAP [14]. All hospitals should regularly create and disseminate a local antibiogram, ideally
one that is specific to their hospital units [1].
Risk factors for multidrug resistance are discussed separately. (See "Epidemiology, pathogenesis,
microbiology, and diagnosis of hospital-acquired and ventilator-associated pneumonia in adults",
section on 'MDR risk factors'.)
EMPIRIC THERAPY Empiric therapy for HAP and VAP should include agents with
activity against Staphylococcus aureus, Pseudomonas aeruginosa, and other gram-negative

bacilli. The choice of a specific regimen for empiric therapy should be based upon knowledge of
the prevailing pathogens and susceptibility patterns within the health care setting as well as the
individual patient's risk factors for multidrug resistance and prior microbiology data. A good
quality Gram stain can also be useful for guiding the choice of initial therapy.
The recommendations below are generally in keeping with the 2016 Infectious Diseases Society
of America (IDSA)/American Thoracic Society (ATS) guidelines on the management of HAP
and VAP [1] (see 'Society guideline links' below). Modifications to these recommendations may
be needed based on the local prevalence of pathogens and local and hospital antimicrobial
resistance patterns. The 2017 combined European and Latin American guidelines differ
somewhat in their approach to initial antibiotic selection, opting to reserve empiric treatment
for Pseudomonas species for those who are critically ill or have specific risk factors in an effort
to reduce antimicrobial resistance [10].
Approach to therapy — Once HAP or VAP is suspected clinically, diagnostic specimens

should be obtained as soon as possible and antimicrobial therapy started as soon as possible,
particularly in patients with signs of septic shock or rapidly progressive organ dysfunction [1].
(See "Evaluation and management of suspected sepsis and septic shock in adults", section on
'Empiric antibiotic therapy (first hour)'.)
Delaying treatment and failing to give a regimen with activity against the causative pathogens
are both associated with higher mortality rates in patients with VAP [15-18]. However, broader
regimens and longer treatment courses increase the risks of adverse drug
effects, Clostridioides (formerly Clostridium) difficile infections, and antimicrobial resistance.
An appropriate compromise is to pair early and aggressive treatment with early and aggressive
de-escalation. Establishing the diagnosis of HAP and VAP can be difficult, especially for
hospitalized patients in whom clinical, radiologic, and microbiologic findings can be due to
numerous etiologies besides pneumonia. The difficulty in diagnosis may lead to overtreatment
and its attendant risks of superinfection and antibiotic toxicity. (See "Epidemiology,
pathogenesis, microbiology, and diagnosis of hospital-acquired and ventilator-associated
pneumonia in adults" and "Clinical presentation and diagnostic evaluation of ventilator-
associated pneumonia".)
Empiric treatment choices should be informed by the local distribution of pathogens causing
HAP and VAP and their antimicrobial susceptibility patterns [14]. As noted above, all hospitals
should regularly create and disseminate a local antibiogram, ideally ones that are specific to their
different units. In addition to awareness of local pathogen distribution, antimicrobial selection
should also be based upon risk factors for multidrug-resistant (MDR) pathogens [1,19], including
recent antibiotic therapy (if any), the presence of underlying diseases, and both current and
historic culture data (interpreted with care). For patients with risk factors for MDR pathogens,
empiric broad-spectrum multidrug therapy is recommended (table 1 and table 2).
Additional considerations include potential toxicities, potential drug interactions, cost,

availability, and clinician familiarity with the medications. Once microbiologic results are
available, therapy should be narrowed based upon the susceptibility pattern of the pathogens
identified and the potential toxicities of the regimens. (See 'Antimicrobial resistance' above
and 'Specific antimicrobial considerations' below and 'Potential toxicities' below and 'Tailoring
therapy'below.)
The choice of which of the following agents to select should be based in part upon knowledge of
local pathogen susceptibility patterns and whether or not the agent is likely to be active against
suspected pathogens. Because patients experience worse outcomes if initial antimicrobial therapy
is ineffective against the causative pathogen, the 2016 HAP and VAP guidelines have chosen a
goal of trying to assure that ≥95 percent of patients with VAP receive empiric therapy with
activity against the most likely pathogens [1].
If patients have recently received antibiotics, empiric therapy should generally be with a drug
from a different class since earlier treatment may have selected for pathogens resistant to the
initial class. For patients with highly resistant or pan-resistant gram-negative bacilli, consultation
with a specialist with expertise in antimicrobial management of such infections is recommended.
Risk factors for MDR VAP have been addressed in several studies. In a meta-analysis that
included 15 studies, factors associated with an increased risk of MDR VAP were use of
intravenous (IV) antibiotics in the past 90 days (odds ratio [OR] 12.3, 95% CI 6.48-23.35), ≥5
days of hospitalization prior to the occurrence of VAP, septic shock at the time of VAP (OR
2.01, 95% CI 1.12-3.61), acute respiratory distress syndrome before VAP (OR 3.1, 95% CI 1.88-
5.1), and renal replacement therapy prior to VAP (OR 2.5, 95% CI 1.14-5.49) [1]. Coma present
at the time of intensive care unit (ICU) admission was associated with lower risk of MDR VAP
(OR 0.21, 95% CI 0.08-0.52). In a meta-analysis of observational studies of patients with VAP
and bacteremia, inappropriate therapy significantly increased patients' odds of mortality (OR
3.03, 95% CI 1.12-8.19) [15].
Reassessing a patient's status 48 to 72 hours after the initiation of therapy with consideration of
discontinuing antibiotics or narrowing the regimen (de-escalating therapy) based upon
appropriate culture results may reduce the selective pressure for antimicrobial resistance.
(See 'Tailoring therapy' below.)
Antimicrobial stewardship programs have been shown to reduce rates of nosocomial infections
(ie, C. difficile, methicillin-resistant S. aureus [MRSA], vancomycin-resistant enterococcal
infections, and MDR gram-negative infections) and antimicrobial expenditures without
increasing mortality or extending length of hospital stay [20-24]. (See "Antimicrobial
stewardship in hospital settings".)
Ventilator-associated pneumonia — Empiric regimens for VAP are outlined in the following
algorithm (algorithm 1).
Determining coverage based on risk of resistance — The selection of an empiric regimen

depends upon risk factors for MDR pathogens, local antimicrobial resistance rates, and the
individual patient's prior microbiology data (table 1) [1].
Risk factors for MDR pathogens (including Pseudomonas, other gram-negative bacilli, and
MRSA) in patients with VAP include:
●IV antibiotic use within the previous 90 days

●Septic shock at the time of VAP
●Acute respiratory distress syndrome (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 include:
●Treatment in an ICU in which >10 percent of gram-negative bacilli are resistant to an

agent being considered for monotherapy
●Treatment in an ICU in which local antimicrobial susceptibility rates among gram-
negative bacilli are not known
●Colonization with OR prior isolation of MDR Pseudomonas or other gram-negative bacilli
Risk factors for MRSA include:
●Treatment in a unit in which >10 to 20 percent of S. aureus isolates are methicillin

resistant
●Treatment in a unit in which the prevalence of MRSA is not known
●Colonization with OR prior isolation of MRSA
Our approach to selecting a regimen based upon these risk factors:
●Patients with VAP who have no known risk factors for MDR pathogens and who are in a
unit in which ≤10 percent of gram-negative isolates are resistant to an agent being
considered for monotherapy and ≤20 percent of S. aureus is resistant to methicillin should
receive one agent that has activity against Pseudomonas, other gram-negative bacilli, and
methicillin-susceptible S. aureus (MSSA).
●Patients with VAP who have any of the following risk factors for MDR VAP should
receive two agents with activity against P. aeruginosa and other gram-negative bacilli
and one agent with activity against 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
●Any patient being treated in a unit in which >10 percent of gram-negative bacilli are
resistant to an agent being considered for monotherapy or in which the prevalence of
resistance among gram-negative bacilli is unknown should receive two agents with activity
against gram-negative bacilli. If this is the patient's only risk factor for MDR pathogens and
local MRSA resistance rates are low (ie, <20 percent), then empiric treatment for MRSA is
not needed.
●Any patient being treated in a unit in which MRSA prevalence is >20 percent or unknown
should receive one agent with activity against MRSA. If this is the patient's only risk factor
for MDR pathogens and local resistance rates among gram-negative bacilli are low (ie, <10
percent), a single agent with activity against P. aeruginosa and other gram-negative bacilli
can be given in addition to the agent active against MRSA.
Ideally, local resistance rates should be determined for each hospital unit and derived from
pulmonary culture results from patients with VAP [25]. The resistance rate calculation
should account for both the frequency of pathogens causing VAP and their resistance rates,
resulting in a blended estimate of the probability that any given antibiotic will be active
[1,26]. Because most hospitals do not have sufficient numbers of VAP isolates and data
management support to generate such estimates, unit-wide MRSA and P.
aeruginosa resistance rates are acceptable, albeit conservative, proxies.
Specific regimens are presented in the following section.

Regimens — As noted above, the choice of regimen depends upon risk factors for MDR
pathogens, including local pathogen susceptibility patterns and the individual patient's prior
microbiology data. (See 'Determining coverage based on risk of resistance' above.)
The dosing provided below is intended for patient with normal renal function; dosing will need
to be adjusted in those with renal dysfunction.
The traditional intermittent dosing of each agent for VAP is described in the following
discussion, but we generally favor prolonged infusions of certain (eg, antipseudomonal) beta-
lactams to optimize pharmacodynamics, especially in critically ill patients with infections caused
by gram-negative bacilli and for patients with infections caused by gram-negative bacilli that
have elevated but susceptible minimum inhibitory concentrations (MICs) to the chosen agent
(table 3). (See 'Prolonged infusions' below.)
No MDR risk factors — For patients with VAP who have no known risk factors for multidrug-
resistant pathogens and who are in a unit in which ≤10 percent of gram-negative isolates are
resistant to an agent being considered for monotherapy and ≤20 percent of S. aureus is resistant
to methicillin (table 1), we suggest one of the following intravenous empiric antibiotic regimens:
●Piperacillin-tazobactam 4.5 g IV every 6 hours

●Cefepime 2 g IV every 8 hours
●Levofloxacin 750 mg IV daily – When the patient is clinically improved and able to take
oral medications, levofloxacin may be administered orally at the same dose as that used for
IV administration
Among these agents, we generally prefer piperacillin-tazobactam or cefepime because they are

more likely to have activity against gram-negative bacilli than the fluoroquinolones.
The IDSA/ATS guidelines also include imipenem and meropenem as options, but we generally
reserve these agents for patients with a high likelihood of infection with an extended-spectrum
beta-lactamase (ESBL)-producing gram-negative bacillus or for patients in units where local
antibiograms favor these agents over other broad-spectrum beta-lactams. (See 'Gram-negative
pathogens' below.)
MDR risk factors — Patients with VAP who have any of the following risk factors for
multidrug-resistant VAP should receive two agents with activity against P. aeruginosa and other
gram-negative bacilli and one agent with activity against MRSA:
●IV antibiotic use within the previous 90 days

●Septic shock at the time of VAP
●ARDS preceding VAP
●≥5 days hospitalization prior to the occurrence of VAP
●Acute renal replacement therapy prior to VAP onset
Such patients should receive (algorithm 1):
ONE of the following:
●Piperacillin-tazobactam 4.5 g IV every six hours

●Cefepime 2 g IV every eight hours
●Ceftazidime 2 g IV every eight hours
●Imipenem 500 mg IV every six hours
●Meropenem 1 g IV every eight hours
●Aztreonam 2 g IV every eight hours – We use aztreonam infrequently since rates of
resistance among gram-negative bacilli are typically higher than to the other beta-lactams
options
PLUS one of the following:
●An aminoglycoside – Once-daily dosing is only appropriate for patients with normal renal
function. A single serum concentration should be obtained 6 to 14 hours after the first dose,
and the dose should be adjusted as needed based upon the following nomogram (figure 1)
(see "Dosing and administration of parenteral aminoglycosides"):
•Amikacin 15 to 20 mg/kg IV daily
•Gentamicin 5 to 7 mg/kg IV daily
•Tobramycin 5 to 7 mg/kg IV daily
Because the aminoglycosides have poor lung penetration, increased risk of nephrotoxicity
and ototoxicity, and poorer clinical response rates compared with other antibiotic classes,
aminoglycosides are not recommended as monotherapy for gram-negative infections. If
they are used as part of combination therapy and subsequent culture results indicate that the
isolate is susceptible to one of the beta-lactams, the aminoglycoside should be discontinued.
We typically discontinue the aminoglycoside after one or two days, especially in patients
who have improved clinically and in whom the pathogen (if identified) is susceptible to the
beta-lactam. There are data suggesting that even very brief courses of aminoglycosides
increase the risk of nephrotoxicity [27]. (See 'Potential toxicities' below.)
●An antipseudomonal fluoroquinolone such as ciprofloxacin (400 mg IV every eight hours)
or levofloxacin (750 mg IV daily) is preferred if Legionella is likely. These agents may be
administered orally when the patient is able to take oral medications. The dose of
levofloxacin is the same when given intravenously and orally, while the dose of
ciprofloxacin is 750 mg orally twice daily. In many institutions, addition of a
fluoroquinolone confers minimal additional in vitro activity against local pathogens.
The IDSA/ATS guidelines recommend either an antipseudomonal fluoroquinolone or an
aminoglycoside for the second agent for gram-negative bacilli and they also state that
aminoglycosides should be avoided if alternative agents with adequate activity against
gram-negative bacilli are available [1]. However, we generally prefer an aminoglycoside
over a fluoroquinolone for patients with severe disease if there is not concern
for Legionella, as aminoglycosides are more likely to have in vitro activity against gram-
negative bacilli in those with risk factors for resistance. When possible, clinicians should
consult their local antibiogram to help determine whether similar resistance patterns exist at
their institutions.
●A polymyxin – Addition of an alternative agent, such as IV colistin or polymyxin B, may
be appropriate if highly resistant Pseudomonas spp, Acinetobacter spp, Enterobacteriaceae
(including Klebsiella pneumoniae) is suspected or established [28]. Polymyxins are used
rarely given their significant nephrotoxicity and should be avoided if alternative agents with
adequate activity against gram-negative bacilli are available [1]. When they are required, an
infectious disease physician and/or pharmacist with expertise using these agents should be
consulted. Dosing recommendations are provided separately. (See "Polymyxins: An
overview", section on 'Intravenous administration' and 'Potential toxicities' below
and "Principles of antimicrobial therapy of Pseudomonas aeruginosa infections", section on
'Alternative antibiotics for multidrug-resistant infections' and "Acinetobacter infection:
Treatment and prevention", section on 'Pneumonia' and "Clinical features, diagnosis, and
treatment of Klebsiella pneumoniae infection", section on 'Treatment' and "Overview of
carbapenemase-producing gram-negative bacilli", section on 'Treatment'.)
In some cases of VAP with highly resistant organisms, inhaled colistin may be appropriate
adjunctive therapy in combination with systemic antimicrobials, as discussed below.
(See 'Aerosolized antibiotics' below.)
●Aztreonam 2 g IV every eight hours – Although the use of two beta-lactams is generally
avoided, in the absence of other options, it is acceptable to use aztreonam as a second agent
for gram-negative bacteria with another beta-lactam because it has different targets within
the bacterial cell wall [1].
●Linezolid 600 mg IV every 12 hours, which may be administered orally when the patient
is able to take oral medications. (See 'Methicillin-resistant Staphylococcus aureus' below.)
●Vancomycin 15 mg/kg (based on actual body weight) IV (maximum 2 g per dose initially)
every 8 to 12 hours for patients with normal renal function, with a target serum trough
concentration of 15 to 20 mcg/mL. In seriously ill patients, a loading dose of 25 to
30 mg/kg (maximum 3 g) can be used to facilitate rapid attainment of the target trough
concentration. (See 'Methicillin-resistant Staphylococcus aureus' below and "Vancomycin:
Parenteral dosing, monitoring, and adverse effects in adults".)
●Telavancin 10 mg/kg IV every 24 hours is an alternative agent when
neither linezolid nor vancomycin can be used, but there are several boxed warnings that
must be considered before choosing it. (See 'Telavancin' below.)
Because clinical outcomes appear to be similar for linezolid and vancomycin [29-31], we select

between these agents based on other factors such as renal function, monitoring convenience,
potential drug interactions, blood cell counts, and quality of intravenous access. (See 'Linezolid
and vancomycin' below.)
The combination of vancomycin and piperacillin-tazobactam has been associated with acute

kidney injury [32]. In patients who require an anti-MRSA agent and an antipseudomonal beta-
lactam, options include using a beta-lactam other than piperacillin-tazobactam
(eg, cefepime or ceftazidime) or, if piperacillin-tazobactam is favored, using linezolidinstead of
vancomycin. (See "Vancomycin: Parenteral dosing, monitoring, and adverse effects in adults",
section on 'Nephrotoxicity'.)
High local prevalence of resistant gram-negatives — If the patient is being treated in an ICU
in which >10 percent of gram-negative bacilli are resistant to an agent being considered for
monotherapy or in which the prevalence of resistant gram-negative bacilli is unknown,
then two agents should be used for gram-negative coverage. Specific regimens are summarized
in the following algorithm (algorithm 1). Appropriate regimens are outlined in the previous
section. (See 'MDR risk factors' above.)
High local prevalence of MRSA — If none of the risk factors for MDR VAP are present and
the patient is in an ICU in which ≤10 percent of gram-negative isolates are resistant to an agent
being considered for monotherapy (table 1), but >20 percent of S. aureus isolates in the unit are
methicillin resistant or the local MRSA prevalence is unknown, the patient should
receive one agent with activity against P. aeruginosa and one agent with activity against MRSA
(algorithm 1).
Adding an agent with MRSA activity to the treatment regimen allows for more flexibility in the
choice of gram-negative agents since the gram-negative agent does not need to include activity
against S. aureus. Potential regimens are summarized below.

●Levofloxacin 750 mg IV daily – When the patient is clinically improved and able to take
oral medications, levofloxacin may be administered orally at the same dose as that used for
IV administration
●Ciprofloxacin 400 mg IV every eight hours – When the patient is clinically improved and
able to take oral medication, ciprofloxacin may be administered orally at 750 mg twice
daily
●Aztreonam 2 g IV every eight hours
Among these agents, we generally prefer piperacillin-tazobactam, cefepime,
or ceftazidime because they are more likely to have activity against gram-negative bacilli
than the fluoroquinolones or aztreonam. The IDSA/ATSguidelines also
include imipenem and meropenem as options, but we generally reserve these agents for
situations in which they are required, such as in patients with a high likelihood of infection
with an ESBL-producing gram-negative bacillus. (See 'Gram-negative pathogens' below.)
Because clinical outcomes appear to be similar for linezolid and vancomycin [29-31], we select


Hospital-acquired pneumonia — The appropriate regimen for HAP depends upon the presence
or absence of risk factors for MDR pathogens, knowledge of the predominant pathogens (and
susceptibility patterns) within the health care setting, and the individual patient's prior
microbiology data. In general, HAP patients who are not in the ICU tend to be less severely ill
than VAP patients, and, therefore, the negative consequences of initial inappropriate antibiotic
therapy are likely less pronounced with HAP than with VAP. In addition, MDR pathogens tend
to be less common in patients who develop HAP outside of the intensive care unit, particularly
early in the hospitalization course. (See "Epidemiology, pathogenesis, microbiology, and
diagnosis of hospital-acquired and ventilator-associated pneumonia in adults", section on
'Microbiology'.)
For this reason, the 2016 HAP and VAP guidelines suggest that a smaller subset of patients with
HAP as compared with VAP require empiric treatment for MRSA and MDR gram-negative
organisms [1]. A single agent active against both MSSA and P. aeruginosa is often sufficient.
Description of risk factors — Risk factors for MDR pathogens and/or mortality in patients with

HAP include the following (table 2):
●Risk factors for increased mortality:

•Ventilatory support for HAP
•Septic shock
●Risk factor for MDR Pseudomonas, other gram-negative bacilli, and MRSA:
•IV antibiotics within the past 90 days
●Risk factors for MDR Pseudomonas and other gram-negative bacilli:
•Structural lung disease (bronchiectasis or cystic fibrosis)
•A respiratory specimen Gram stain with numerous and predominant gram-negative
bacilli
•Colonization with OR prior isolation of MDR Pseudomonas or other gram-negative
bacilli
●Risk factors for MRSA:
•Treatment in a unit in which >20 percent of S. aureus isolates are methicillin resistant
•Treatment in a unit in which the prevalence of MRSA is not known
•Colonization with OR prior isolation of MRSA
Regimens — Empiric regimens for HAP are outlined in the following algorithm (algorithm 2).
As noted above, the appropriate regimen depends upon the presence or absence of risk factors for
MDR pathogens, including local pathogen susceptibility patterns and the individual patient's
prior microbiology data.
The dosing described below is intended for patients with normal renal function and represents
traditional intermittent dosing; dosing will need to be adjusted in those with renal dysfunction.
As an alternative to the traditional dosing regimens described below, prolonged infusions of

certain beta-lactams may be given to optimize pharmacodynamics; we favor prolonged infusions
in critically ill patients with infections caused by gram-negative bacilli and in patients with
infections caused by gram-negative bacilli that have elevated but susceptible minimum inhibitory
concentrations to the chosen agent (table 3). (See 'Prolonged infusions' below.)
No MDR risk factors or increased risk of mortality — If there are no risk factors for
increased mortality, for multidrug-resistant Pseudomonas and other gram-negative bacilli, or for
MRSA, the patient should receive one agent that has activity against Pseudomonas and MSSA.
Risk factors for increased mortality and for MDR pathogens are outlined above.
(See 'Description of risk factors' above.)
Choices include:

●Levofloxacin 750 mg IV daily. When the patient is clinically improved and able to take
oral medications, it may be administered orally at the same dose as that used for IV
administration.
Among these agents, we generally prefer piperacillin-tazobactam or cefepime because they are
more likely to have activity against hospital-acquired gram-negative bacilli than the
fluoroquinolones.
The IDSA/ATS guidelines also include imipenem and meropenem as options, but we generally

reserve these agents for patients with a high likelihood of infection with an ESBL-producing
gram-negative bacillus. (See 'Gram-negative pathogens' below.)
Risk factors for MDR gram-negative bacilli and MRSA or for increased mortality — If
there are risk factors either for increased mortality (need for ventilatory support due to HAP or
septic shock) or for both multidrug-resistant Pseudomonas and other MDR gram-negative
bacilli and methicillin-resistant S. aureus (table 2), the patient should receive two agents with
activity against P. aeruginosa and other gram-negative bacilli and one agent with activity against
MRSA. Such patients should receive:

●Aztreonam 2 g IV every eight hours – We use aztreonam infrequently since rates of
resistance among gram-negative bacilli are typically higher than to the other beta-lactams
options
and the dose should be adjusted as needed based upon the following nomogram (figure 1).
(See "Dosing and administration of parenteral aminoglycosides".)
increase the risk of nephrotoxicity [27].
fluoroquinolone adds minimal additional in vitro activity against other local pathogens.
aminoglycoside as a second agent for gram-negative bacilli and they also state that
gram-negative bacilli are available. However, we generally prefer an aminoglycoside over a
fluoroquinolone for patients with severe disease if there is not concern for Legionella as
aminoglycosides are more likely to have in vitro activity against gram-negative bacilli in
those with risk factors for resistance. When possible, clinicians should consult their local
antibiogram to help determine whether similar resistance patterns exist at their institutions.

Because clinical outcomes appear to be similar for linezolid and vancomycin [29,30], we select


Risk factors for MDR gram-negative bacilli only — If there are risk factors for methicillin-
resistant Pseudomonas and other gram-negative bacilli but not MRSA (table 2), the patient
should receive two agents with activity against P. aeruginosa; the regimen should also have
activity against MSSA. Such patients should receive (algorithm 2):

and the dose should be adjusted as needed based upon the following nomogram (figure 1)
(see "Dosing and administration of parenteral aminoglycosides"):
increase the risk of nephrotoxicity [27].
fluoroquinolone adds minimal additional in vitro activity against other local pathogens.
aminoglycoside as a second agent for gram-negative bacilli and they also state that
gram-negative bacilli are available. However, we generally prefer an aminoglycoside over a
fluoroquinolone for patients with severe disease if there is not concern for Legionella, as
aminoglycosides are more likely to have in vitro activity against gram-negative bacilli in
those with risk factors for resistance. When possible, clinicians should consult their local
antibiogram to help determine whether similar resistance patterns exist at their institutions.
MRSA risk factors only — If there are risk factors for methicillin-resistant S. aureus but not
MDR Pseudomonasand other gram-negative bacilli (table 2), the patient should receive one
agent with activity against P. aeruginosa and other gram-negative bacilli and one agent with
activity against MRSA. Adding an agent with MRSA activity to the treatment regimen allows for
more flexibility in the choice of gram-negative agent because the selected gram-negative agent
does not need to include activity against S. aureus.
Patients with risk factors for MRSA only should receive:

●Levofloxacin 750 mg IV daily. When the patient is clinically improved and able to take
oral medications, it may be administered orally at the same dose as that used for IV
administration.
●Ciprofloxacin 400 mg IV every eight hours. When the patient is clinically improved and
able to take oral medication, ciprofloxacin may be administered orally at 750 mg twice
daily.
Among these agents, we generally prefer piperacillin-tazobactam, cefepime,
or ceftazidime because they are more likely to have activity against gram-negative bacilli
than the fluoroquinolones or aztreonam. The IDSA/ATSguidelines also
include imipenem and meropenem as options, but we generally reserve these agents for
patients with a high likelihood of infection with an ESBL-producing gram-negative bacillus.
Optimally, local antibiograms should indicate that ≤10 percent of gram-negative isolates are
resistant to an agent being considered for monotherapy. (See 'Gram-negative
pathogens' below.)
Because clinical outcomes appear to be similar for linezolid and vancomycin [29,30], we select


TAILORING THERAPY All patients with HAP or VAP should be evaluated for
clinical response and results of microbiologic studies after initial empiric antimicrobial therapy.
●For patients in whom a pathogen has been identified, the empiric regimen should be
tailored to the pathogen's susceptibility pattern [1,33,34]. Tailoring antibiotic therapy has
not been associated with increased mortality [35-37], recurrent pneumonia [36], or longer
intensive care unit admission [37]. (See 'Specific antimicrobial considerations'below.)
●For patients who are clinically improving who do not have an identified pathogen, empiric
treatment for S. aureus or multidrug-resistant gram-negative bacilli can be discontinued if
these organisms have not grown in culture from a high-quality sputum specimen within 48
to 72 hours.
●Patients who have not improved within 72 hours of starting empiric antibiotics should be
evaluated for complications, other sites of infection, and alternate diagnoses. If the
diagnosis of pneumonia appears certain, there is no evidence of a pyogenic complication
that requires drainage (eg, empyema, lung abscess), and the patient has risk factors for drug-
resistant pathogens (eg, prolonged hospitalization, recent exposure to multiple antibiotics),
additional diagnostic pulmonary cultures should be obtained and the empiric regimen
should be expanded to cover additional resistant organisms.
DURATION We treat most patients with HAP or VAP for seven days, in agreement with
the 2016 Infectious Diseases Society of America (IDSA)/American Thoracic Society (ATS)

guidelines and the combined 2017 European and Latin American guidelines on HAP and VAP
[1,10]. Seven days appears to be as effective as longer durations in most circumstances and may
reduce the emergence of resistant organisms [1,3].
For selected patients with severe illness, bacteremia, metastatic infection, slow response to
therapy, immunocompromise, and pyogenic complications such as empyema or lung abscess, the
duration of therapy is often individualized and courses longer than seven days may be warranted.
(See "Clinical approach to Staphylococcus aureus bacteremia in adults", section on 'Duration of
therapy' and "Pseudomonas aeruginosa pneumonia", section on 'Directed antimicrobial therapy'.)
Monitoring serial procalcitonin levels can help guide the decision to discontinue antibiotics.
While the optimal approach to using procalcitonin in patients with HAP or VAP has not been
determined, a low or declining procalcitonin level (eg, <0.25 ng/mL or ≥80 percent decrease
from peak) in a patient who has clinically responded to antibiotics provides additional
reassurance that antibiotics can be safely stopped [38-45]. (See "Procalcitonin use in lower
respiratory tract infections", section on 'Ventilator-associated pneumonia'.)
A seven-day course of antimicrobial therapy is supported by two meta-analyses of six

randomized trials evaluating over 1000 patients with HAP or VAP, in which short courses (7 to 8
days) of therapy were as effective as longer courses (10 to 15 days) [1,46]. In subgroup analysis
of one of the meta-analyses [46], a higher rate of recurrent pneumonia was observed in patients
with pneumonia caused by nonfermenting gram-negative rods, such as P. aeruginosa, who
received shorter courses of therapy. This finding was primarily driven by a single large trial that
used a microbiological definition of pneumonia [47]. No differences in ventilator-free days,
organ failure-free days, length of stay, or mortality were detected in patients with nonfermenting
gram-negative bacillus infections randomized to short versus long courses [1,46,48].
Although a retrospective cohort study suggested that patients with suspected VAP who have
stable and minimal ventilator settings (positive-end expiratory pressure <5 cm H 2O and FiO2 ≤40
percent) have similar outcomes whether they are treated with ≤3 days or >3 days of antibiotics
[49], these observations must be confirmed in a randomized trial before this strategy can be
broadly applied.
CONVERSION TO ORAL ANTIBIOTICS Generally, patients can be switched to oral
therapy when they are hemodynamically stable, clinically improving, and able to tolerate oral
medications. If a pathogen has been identified, the choice of antibiotic for oral therapy should be
based on the organism's susceptibility pattern. If a pathogen has not been identified, the oral
antibiotic selected should be the same (or in the same drug class) as the intravenous agent and
should have good lung penetration.
SPECIFIC ANTIMICROBIAL CONSIDERATIONS In critically ill patients with
rapidly progressive HAP despite broad-spectrum antibiotic use, other potential hospital-acquired
infections such as respiratory viral infections or Legionella should be considered. During
outbreaks of highly drug-resistant organisms, such as Acinetobacter species
or Stenotrophomonas species, including an antibiotic that targets these organisms in the empiric
treatment regimen may be warranted. In immunocompromised patients, the differential diagnosis
should be broad and include fungal, viral, parasitic, and less common bacterial pathogens.
(See "Pulmonary infections in immunocompromised patients".)
Allergy to penicillins or cephalosporins — For patients who are allergic to penicillin, the type
and severity of reaction should be assessed. The great majority of patients who are allergic to
penicillin by skin testing can still receive cephalosporins (especially third-generation
cephalosporins) or carbapenems. If there is a history of a mild reaction to penicillin (not an
immunoglobulin [Ig]E-mediated reaction, Stevens-Johnson syndrome, or toxic epidermal
necrolysis), it is reasonable to administer a cephalosporin or an antipseudomonal carbapenem
using a simple graded challenge (1/10dose followed by a one-hour period of observation; if no
symptoms, give the full dose followed by another hour of observation). Skin testing is indicated
in some situations. If a skin test is positive or if there is significant concern to warrant avoidance
of a cephalosporin or carbapenem, aztreonam (2 g intravenously [IV] every eight hours) is
recommended. Indications and strategies for skin testing are reviewed elsewhere. (See "Allergy
evaluation for immediate penicillin allergy: Skin test-based diagnostic strategies and cross-
reactivity with other beta-lactam antibiotics".)
Patients with a history of allergic reactions to cephalosporins may also be treated

with aztreonam, with the possible exception of those allergic to ceftazidime. Ceftazidime and
aztreonam have similar side chain groups, and cross-reactivity between the two drugs is possible.
The prevalence of cross-sensitivity has been estimated at <5 percent of patients, based upon
limited data. Patients with past reactions to ceftazidime that were life-threatening or suggestive
of anaphylaxis (involving urticaria, bronchospasm, and/or hypotension) should not be given
aztreonam unless evaluated by an allergy specialist. In contrast, in patients with mild past
reactions to ceftazidime (eg, uncomplicated maculopapular rash), it is reasonable to inform the
patient of the low risk of cross-reactivity if the patient is agreeable, administer aztreonam with a
simple graded challenge (1/10 dose followed by a one-hour period of observation; if no
symptoms, give the full dose followed by another hour of observation). (See "Cephalosporin-
allergic patients: Subsequent use of cephalosporins and related antibiotics" and "An approach to
the patient with drug allergy", section on 'Graded challenge'.)
It is important to note that aztreonam does not provide activity against gram-positive bacteria

like S. aureus. Also, ceftazidime has less activity against methicillin-susceptible S.
aureus (MSSA) than the other beta-lactams suggested above for HAP and VAP. When one of
these agents is used for empiric therapy, an additional agent with activity against S.
aureus (eg, linezolid or vancomycin) should also be used.
Potential toxicities — Clinicians should consider the potential toxicities of the antimicrobial

choices when selecting a regimen. All antibiotics increase the risk of C. difficile infection; among
the agents used for HAP and VAP, the fluoroquinolones and broad-spectrum cephalosporins are
most commonly implicated. (See "Clostridioides (formerly Clostridium) difficile infection in
adults: Epidemiology, microbiology, and pathophysiology", section on 'Antibiotic use'.)
Other potential toxicities of antibiotics used for HAP and VAP include the following:
●Aminoglycosides are nephrotoxic and ototoxic. However, rates of susceptibility among

gram-negative bacilli are high, so we sometimes use them as part of the initial empiric
regimen in patients with septic shock or rapidly progressive disease. Given the potential
toxicity, we typically discontinue the aminoglycoside after one or two days, especially in
patients who have improved clinically and in whom the pathogen (if identified) is
susceptible to the beta-lactam. There are data suggesting that even very brief courses of
aminoglycosides increase the risk of nephrotoxicity [27]. (See "Aminoglycosides", section
on 'Toxicity'.)
●Polymyxins (polymyxin B and colistin) are very nephrotoxic. Polymyxins are therefore
used rarely and should be avoided if alternative agents with adequate activity against gram-
negative bacilli are available [1]. When they are required, an infectious disease
physician and/or pharmacist with expertise using these agents should be consulted.
(See "Polymyxins: An overview", section on 'Nephrotoxicity'.)
●The combination of vancomycin and piperacillin-tazobactam has been associated with
acute kidney injury [32]. In patients who require an anti-methicillin-resistant S.
aureus (MRSA) agent and an antipseudomonal beta-lactam, options include using a beta-
lactam other than piperacillin-tazobactam (eg, cefepime or ceftazidime) or, if piperacillin-
tazobactam is favored, using linezolid instead of vancomycin. (See "Vancomycin:
Parenteral dosing, monitoring, and adverse effects in adults", section on 'Nephrotoxicity'.)
●In patients with renal insufficiency, imipenem and cefepime have been associated with
seizures. Alternative beta-lactams should be used in patients at risk. (See "Beta-lactam
antibiotics: Mechanisms of action and resistance and adverse effects", section on
'Neurologic reactions'.)
●The fluoroquinolones have multiple potential toxicities, including QT interval
prolongation, tendinitis and tendon rupture, and neurotoxicity. (See "Fluoroquinolones",
section on 'Adverse effects'.)
Methicillin-resistant Staphylococcus aureus — If MRSA is a frequent nosocomial pathogen in

the institution (ie, >20 percent local prevalence), linezolid or vancomycin should be included as
part of the initial regimen to provide antistaphylococcal coverage [1,50,51] but should be
discontinued if MRSA is not isolated. Because clinical outcomes appear to be similar for
linezolid and vancomycin [29-31], we select between these agents based on other factors such as
renal function, monitoring convenience, potential drug interactions, blood cell counts, and
quality of intravenous access. As examples, when all other factors are equal, we prefer linezolid
to vancomycin in patients with limited intravenous access or difficulty achieving therapeutic
serum concentrations of vancomycin. We prefer vancomycin to linezolid in patients receiving
selective serotonin-reuptake inhibitors and for patients with cytopenias.
Telavancin and ceftaroline are alternatives when neither linezolid nor vancomycin can be used.

However, ceftaroline is not US Food and Drug Administration (FDA) approved for the treatment
of HAP or VAP. There are several boxed warnings that must be considered before choosing
telavancin (see 'Telavancin' below). Clindamycin (600 mg IV or orally three times daily) is an
additional alternative for patients with susceptible MRSA isolates; however, data supporting
clindamycin use for HAP and VAP are limited [51].
Our approach to the treatment of HAP or VAP caused by MRSA is largely similar to the 2016
Infectious Diseases Society of America (IDSA)/American Thoracic Society (ATS) guidelines on
HAP and VAP and the 2011 IDSA guidelines for the treatment of MRSA infections, which
recommend either linezolid or vancomycin for infections suspected or proven to be due to
MRSA [1,51].
Linezolid and vancomycin — The dosing of linezolid and vancomycin is presented above.

(See 'Ventilator-associated pneumonia' above and 'Hospital-acquired pneumonia' above.)
Several trials have compared linezolid and vancomycin for the treatment of HAP and VAP;

clinical outcomes appear to be similar when comparing these two agents [29-31]. As an example,
in a meta-analysis of nine randomized trials that compared linezolid to vancomycin for HAP, no
differences in mortality, clinical response, microbiologic eradication, or MRSA eradication were
detected [31]. Linezolid was associated with a higher rate of gastrointestinal adverse effects, but
there were no differences in rates of acute kidney injury, thrombocytopenia, or drug
discontinuation due to adverse effects.
Several trials included in this meta-analysis used lower doses for vancomycin than those
recommended by the ATS and IDSA [1,51-53], which may have resulted in lower efficacy rates
for this agent. In one trial that did use optimal vancomycin dosing, clinical success rates were
lower for vancomycin when compared with linezolid in the per-protocol analysis (47 versus 58
percent, p<0.05) [54]. However, higher rates of mechanical ventilation, renal dysfunction, and
bacteremia in the vancomycin per-protocol group may account for this difference. No differences
in all-cause 60-day mortality or overall adverse events were detected in this trial, although
nephrotoxicity did occur more frequently with vancomycin than linezolid (18 versus 8 percent, p
value not reported).
Vancomycin failure might also be related to vancomycin minimum inhibitory concentrations

(MICs). Pharmacokinetic and pharmacodynamic analyses suggest that lung vancomycin area
under time-concentration curve to minimum inhibitory concentration ratio (AUC:MIC) >400
may be difficult to achieve (particularly for isolates with MIC >1) [55-57]. Cohort studies have
also reported worse outcomes in patients with HAP due to MRSA with higher MICs. In one
prospective cohort of 95 patients, patients with MRSA isolates with MICs ≥2 mcg/mL had
higher mortality rates than those with lower MICs (24 percent versus 10 percent) [58]. Another
study of 158 intensive care patients reported a stepwise increase in mortality as the vancomycin
MIC increased from 0.75 to 3 mcg/mL and was present even for strains within the susceptible
range [59]. These findings are controversial, however, because studies of MSSA bacteremia have
also correlated higher vancomycin MICs with higher mortality rates even though all patients
were treated with beta-lactams [60,61]. These studies suggest that worse outcomes in patients
with higher MICs may be due to clinical factors other than vancomycin failure alone. In addition,
there are no data as of yet demonstrating better outcomes with linezolid or other alternatives
compared to vancomycin in patients infected with MRSA with high vancomycin MICs. Some
clinicians nonetheless favor using an alternative to vancomycin for treatment of pneumonia
caused by MRSA strains with vancomycin MICs ≥2 mcg/mL.
Telavancin — Telavancin is an antibiotic with activity against MRSA [62]. In 2013, telavancin

was approved by the FDA for the treatment of HAP and VAP caused by S. aureus but not for
other bacterial causes of HAP or VAP; it is recommended only when alternative agents cannot
be used and should ideally be reserved for patients with normal renal function [63]. In patients
with normal renal function, the dose of telavancin is 10 mg/kg IV every 24 hours.
The FDA has included the following boxed warnings for telavancin [64]:
●Patients with pre-existing moderate or severe renal impairment (creatinine clearance

[CrCl] ≤50 mL/minute) who were treated with telavancin for HAP or VAP had increased
mortality compared with vancomycin. Use of telavancin in patients with pre-existing
moderate or severe renal impairment (CrCl ≤50 mL/minute) should therefore be considered
only when the potential benefit to the patient outweighs the potential risk.
●New-onset or worsening renal impairment has occurred in patients receiving telavancin.
Renal function should be monitored in all patients receiving telavancin.
●Adverse developmental outcomes were observed in three animal species at clinically
relevant doses. These findings raise concerns about potential adverse developmental
outcomes in humans. Women of childbearing potential should have a serum pregnancy test
prior to administration of telavancin, and its use should be avoided during pregnancy unless
the potential benefit to the patient outweighs the potential risk to the fetus.
The data on the performance of telavancin for HAP and VAP come from two randomized trials
(the ATTAIN trials) comparing telavancin versus vancomycin for hospitalized patients with
HAP or VAP (29 percent had VAP) caused by gram-positive pathogens, particularly S. aureus.
Pooled results from these two studies revealed no differences in overall cure rates or mortality in
the vancomycin versus telavancin groups [65]. However, in a subgroup analysis of patients with
renal impairment (CrCl <50 mL/minute), cure rates were lower in patients who received
telavancin when compared with vancomycin (47 versus 55 percent; 8 percent difference, 95% CI
-17.5 to 1.9) [66].
Other agents — There has been interest in using other agents for the treatment of MRSA
pneumonia, but none of the following agents can be recommended:
●Daptomycin cannot be used to treat pneumonia because it is inactivated by surfactant and

does not achieve adequate concentrations in the respiratory tract.
●Ceftaroline is a broad-spectrum cephalosporin with activity against MRSA. It has been
approved by the FDA for community-acquired pneumonia (CAP) but not for CAP caused
by MRSA, nor for HAP or VAP. Clinical success with ceftaroline use for the treatment of
MRSA pneumonia has been reported in cases series but comparative studies are lacking
[67-69]
●Tigecycline is a broad-spectrum antibiotic with activity against MRSA. It has been
approved by the FDA for skin and skin structure infections and intra-abdominal infections
caused by MRSA. It has also been approved for CAP but not for CAP caused by MRSA or
for HAP or VAP. In 2010, the FDA issued a safety announcement regarding an increased
mortality risk associated with the use of tigecycline compared with other drugs observed in
a pooled analysis of 13 trials [70]. The increased risk was seen most clearly in patients
treated for HAP, particularly VAP. In 2013, the FDA added a boxed warning in reaction to
an additional analysis showing an increased risk of death associated with tigecycline use
[71]. The boxed warning states that tigecycline should be reserved for use in situations
when alternative agents are not suitable. In an analysis of 10 trials conducted for FDA-
approved uses (CAP, complicated skin and skin structure infections, complicated intra-
abdominal infections), tigecycline was associated with increased mortality compared with
other antibacterial agents (2.5 versus 1.8 percent, adjusted risk difference 0.6 percent, 95%
CI 0.0-1.2 percent). Most deaths resulted from worsening infections, complications of
infection, or underlying comorbidities. Randomized trials of patients with HAP have
reported similar results [72,73].
●Ceftobiprole is a broad-spectrum cephalosporin with activity against a broad range of
gram-positive bacteria including MRSA and penicillin- and ceftriaxone-resistant
pneumococci, as well as gram-negative bacteria. It has not been approved by the FDA, but
it has been approved in Europe and Canada for treatment of HAP and CAP but not VAP. In
a trial of patients with HAP, 781 patients with HAP (including 210 with VAP) were
randomly assigned to receive either ceftobiprole or linezolid plus ceftazidime [74]. In the
intention-to-treat population, overall cure rates for ceftobiprole versus linezolid plus
ceftazidime were similar (50 versus 53 percent). Cure rates in HAP (excluding VAP)
patients were also similar (60 versus 59 percent). However, cure rates in VAP patients were
substantially lower in those who received ceftobiprole (23 versus 37 percent).
Microbiologic eradication rates in HAP (excluding VAP) patients were 63 versus 68 percent
(microbiologically evaluable [ME], 95% CI -16.7 to 7.6) and in VAP patients were 30
versus 50 percent (ME, 95% CI -38.8 to -0.4) [75].
Methicillin-susceptible Staphylococcus aureus — If a sputum culture reveals MSSA, empiric

therapy for MRSA should be replaced with nafcillin (2 g IV every four hours), oxacillin (2 g IV
every four hours), or cefazolin (2 g IV every eight hours) [1].
Gram-negative pathogens — Although combination antimicrobial therapy for HAP and VAP

due to gram-negative bacilli (especially Pseudomonas) is commonly administered, evidence to
support this practice is limited. The most appropriate use of combination therapy is during the
empiric treatment phase before the infecting pathogen(s) has been identified and susceptibilities
reported. During this phase, the goal of combination therapy is to ensure that at least one active
agent is administered as soon as possible in patients at risk for multidrug-resistant (MDR)
pathogens (eg, if the infecting pathogen is resistant to one agent, it may be susceptible to the
other). Other commonly cited reasons for combination therapy include the potential for
synergistic efficacy as well as the potential to reduce the emergence of resistance.
The IDSA/ATS 2016 guidelines include a meta-analysis of seven randomized controlled trials of

combination gram-negative versus monotherapy for VAP [1]. There were no differences in
mortality, clinical response, adverse effects, or acquired resistance with combination therapy
versus monotherapy. However, many of the trials in the analysis excluded patients at high risk
for MDR pathogens. Thus, this analysis does not adequately address whether providing empiric
combination therapy to patients at risk for MDR pathogens improves outcomes, but it does
suggest that continuing combination therapy once the susceptibilities of an infecting pathogen
are known is unlikely to provide benefit.
Our recommendations for empiric therapy (ie, before the causative pathogen has been
identified and/or antimicrobial susceptibility results are available) are presented above.
(See 'Ventilator-associated pneumonia' above and 'Hospital-acquired pneumonia' above.)
The approach to therapy for specific gram-negative pathogens is summarized briefly below and
discussed in greater detail separately:
●Extended-spectrum beta-lactamase (ESBL)-producing Enterobacteriaceae – In

settings in which ESBL–producing Enterobacteriaceae are found, cephalosporins should be
used selectively depending on the prevalence of resistance to ceftazidime and cefepime. If
local cefepime resistance rates are high (ie, >10 percent), we generally select a carbapenem
(ie, imipenem, ertapenem, or meropenem) as part of our empiric antibiotic regimen [76].
(See "Extended-spectrum beta-lactamases".)
Among carbapenems, doripenem should not be used for treatment of VAP when other
carbapenems are available. Doripenem is not approved by the FDA for the treatment of
VAP, and a warning about increased mortality with doripenem use in patients with VAP
was added to its label in 2014 [77]. The warning is based on a randomized trial which
compared doripenem administered as 1 g via a four-hour infusion every eight hours for
seven days with imipenem administered as a 1 g infusion over one hour every eight hours
for 10 days [78]. In the intention-to-treat analysis, 28-day all-cause mortality was
numerically higher among patients receiving doripenem when compared with imipenem (22
versus 15 percent, 95% CI -5.0 to 18.5). It is unclear whether the difference was due to the
differing duration of therapy, the lack of a loading dose with doripenem, doripenem
inferiority, or other factors.
●Carbapenemase-producing gram-negative bacilli – The optimal treatment of infection
due to carbapenemase-producing organisms is uncertain, and antibiotic options are limited.
Management of patients with infections due to carbapenemase-producing organisms should
be done in consultation with an expert in the treatment of multidrug-resistant bacteria. A
combination regimen is often given, often including a polymyxin (colistin or polymyxin B).
For those with an isolate that is susceptible only to a polymyxin (colistin or polymyxin B),
one of these agents should be given intravenously together with inhaled colistin. The
combination of inhaled and IV colistin is used because IV colistin does not achieve high
concentrations in the lung [1]. (See 'MDR risk factors' above and "Overview of
carbapenemase-producing gram-negative bacilli".)
●Acinetobacter baumannii – For patients with HAP or VAP caused by A. baumannii, a
carbapenem or ampicillin-sulbactam should be used if the isolate is susceptible [1]. If the
isolate is susceptible only to polymyxins (colistin or polymyxin B), one of these agents
should be given intravenously together with inhaled colistin since intravenous colistin
yields low lung concentrations. (See "Acinetobacter infection: Treatment and prevention",
section on 'Pneumonia'.)
The cephalosporin-beta-lactamase inhibitor combination ceftazidime-avibactam was approved

by the FDA for treatment of nosocomial pneumonia. The approval was based on the REPROVE
trial, a multicenter, international randomized trial evaluating 879 patients with HAP or VAP
[79]. Clinical cure and mortality rates were similar when comparing 2 g ceftazidime and 500 mg
avibactam by intravenous two-hour infusion every eight hours versus meropenem 1 g by
intravenous 30-minute infusion every eight hours for 7 to 14 days. However, the rate of serious
adverse events was higher in patients treated with ceftazidime-avibactam (19 percent versus 13
percent, p value not reported). Approximately one-third of gram-negative pathogens in this study
were resistant to ceftazidime but susceptible to ceftazidime-avibactam, affirming ceftazidime-
avibactam's capacity to provide broader coverage compared with ceftazidime alone. We
generally reserve use of ceftazidime-avibactam for patients with HAP or VAP caused by an
MDR gram-negative pathogen that is known to be susceptible to this agent but not other
cephalosporins or as part of an empiric treatment regimen for patients who are known to be
colonized by a MDR gram-negative pathogen that is susceptible to this agent.
Ceftolozane-tazobactam, a second cephalosporin-beta-lactamase inhibitor combination, has also

been approved for treatment of HAP and VAP [80].
Meropenem-vaborbactam has been approved for the treatment of urinary tract infections and not
pneumonia [81]. Further study is necessary to determine the role of this agent in the treatment of
HAP and VAP. (See "Combination beta-lactamase inhibitors, carbapenems, and monobactams",
section on 'Ceftolozane-tazobactam' and "Combination beta-lactamase inhibitors, carbapenems,
and monobactams", section on 'Ceftazidime-avibactam'.)
Prolonged infusions — Because of increasing resistance of pathogens associated with VAP and

HAP, one potential strategy to enhance the antimicrobial potential of a given agent is to optimize
the pharmacodynamic effect. As an alternative to traditional intermittent dosing (eg,
administered over 30 minutes), prolonged infusions of certain beta-lactam antibiotics may be
given in critically ill patients when MDR pathogens are suspected.
We favor prolonged infusions of beta-lactams for empiric and targeted therapy of gram-negative
bacilli in critically ill patients with VAP or HAP as well as for patients with VAP or HAP caused
by gram-negative bacilli that have elevated but susceptible MICs to the chosen agent (table 3).
Suitable agents for prolonged infusions include piperacillin-tazobactam, meropenem, imipenem,
and cefepime. The decision to use this dosing strategy should also take into account logistical
issues such as staffing or intravenous access availability.
Beta-lactam antibiotics demonstrate a time-dependent effect on bacterial eradication. Prolonged

infusions achieve pharmacodynamic efficacy targets defined for beta-lactam antibiotics more
effectively than short infusions. A prolonged infusion may therefore improve microbiologic and
clinical cure, especially for pathogens with high MICs. Prolonged infusion for intravenous beta-
lactams may include either a continuous infusion (over the entire dosing interval) or an extended
infusion (over three to four hours).
Pharmacologic and clinical data indicate that patients who have an elevated risk of drug-resistant
pathogens or who are critically ill in the setting of a severe infection are most likely to benefit
from prolonged infusions. In a patient-level meta-analysis of 22 randomized trials comparing
prolonged versus rapid infusions of antipseudomonal beta-lactams in patients with sepsis,
mortality was 30 percent lower in patients receiving prolonged infusions (risk ratio [RR] 0.70,
95% CI 0.56-0.87) [82]. Further discussion of prolonged infusions of beta-lactams is provided
separately. (See "Prolonged infusions of beta-lactam antibiotics".)
Aerosolized antibiotics — Aerosolized colistin, polymyxin, or aminoglycosides can be used as

adjunctive therapy (in combination with IV antibiotics) in patients with VAP or HAP caused by
MDR gram-negative bacilli, such as A. baumannii or P. aeruginosa [1,83-89].
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 [90]. However, the evidence supporting use of aerosolized antibiotics is not strong [91-
93] and administration can be associated with adverse effects, particularly in hypoxemic patients
[91,92]. Overall, knowledge on the most appropriate use of aerosolized antibiotics is evolving.
As examples, in a meta-analysis of six observational and six randomized trials, adding

aerosolized antibiotics to intravenous antibiotics was associated with higher rates of clinical cure
in observational studies but not in randomized trials [93]. There were no differences in
microbiologic cure rates, duration of mechanical ventilation, or mortality among patients who
did and did not receive aerosolized antibiotics. The meta-analysis included 812 patients,
underscoring the lack of robust data. In a second meta-analysis, which included adverse event
data, 9 percent of patients in four randomized trials who received aerosolized antibiotics
developed cardiorespiratory complications [91]. These included worsening hypoxemia as well as
cardiac arrest due to obstruction of the ventilator circuit expiratory filter.
A further meta-analysis analyzed the potential impact of adding aerosolized colistin to

intravenous colistin in particular [94]. The meta-analysis included seven observational studies
and one randomized trial. The investigators reported better clinical outcomes and microbiologic
eradication rates associated with aerosolized colistin. There was a nonsignificant trend toward
lower mortality rates with aerosolized colistin (odds ratio 0.74, 95% CI 0.54-1.01, p = 0.06) but
no difference in nephrotoxicity rates. The overall quality of evidence was deemed low.
A randomized trial published after these meta-analyses compared
aerosolized amikacin and fosfomycin with placebo as adjunctive therapy for VAP among 143
patients with VAP due to gram-negative bacilli; aerosolized therapy was given twice daily for 10
days (or to extubation if it occurred at <10 days) [95]. There were no differences between the
groups in clinical cure, mortality, or ventilator-free days.
Legionella — Patients who have compromised immune systems, diabetes mellitus, renal disease,
structural lung disease, or have been recently treated with glucocorticoids may require coverage
for Legionella spp (eg, with azithromycin or a fluoroquinolone). Nosocomial cases of HAP and
VAP due to Legionella spp attributable to contamination of the hospital water supply have been
reported. (See "Microbiology, epidemiology, and pathogenesis of Legionella
infection" and "Treatment and prevention of Legionella infection".)
Anaerobes — Patients who have aspirated or had recent abdominal surgery may warrant
coverage for anaerobes (clindamycin, beta-lactam-beta-lactamase inhibitor, or a carbapenem). In
general, however, anaerobes are rarely implicated in VAP, and some retrospective analyses
suggest little difference in outcomes in patients with aspiration pneumonitis treated with and
without anaerobic coverage [96]. (See "Aspiration pneumonia in adults" and "Anaerobic
bacterial infections", section on 'Pleuropulmonary infections'.)
PROGNOSIS Despite high absolute mortality rates in hospital-acquired (or nosocomial)
pneumonia patients, the mortality attributable to the infection is difficult to gauge. Many studies
have found that HAP is associated with significant increased risk of death. However, many of
these critically ill patients die from their underlying disease and not from pneumonia. While all-
cause mortality associated with VAP has ranged from 20 to 50 percent in different studies [1], a
meta-analysis of randomized trials of VAP prevention estimated the attributable mortality at 13
percent [97].
Variables associated with increased mortality include [1,98-107]:

●Serious illness at the time of diagnosis (eg, high Acute Physiology and Chronic Health
Evaluation [APACHE] score, shock, coma, respiratory failure, acute respiratory distress
syndrome [ARDS])
●Bacteremia
●Severe underlying comorbid disease
●Infection caused by an organism associated with multidrug resistance (eg, P.
aeruginosa, Acinetobacter spp, and Enterobacteriaceae, including K. pneumoniae)
●Multilobar, cavitating, or rapidly progressive infiltrates on lung imaging
●Delay in the institution of effective antimicrobial therapy
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 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.)

Hospital Acquired Pneumonia

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Hospital Acquired Pneumonia

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Epidemiology, pathogenesis, microbiology, and diagnosis of hospital-acquired and

ventilator-associated pneumonia in adults

INTRODUCTION Hospital-acquired (or nosocomial) pneumonia (HAP) and ventilator-

The category of health care-associated pneumonia (HCAP) was included in the

The prognosis of HAP and VAP is discussed separately. (See "Treatment of hospital-acquired

PATHOGENESIS The pathogenesis of HAP (or nosocomial pneumonia) and VAP is

●The infecting flora in patients with VAP included methicillin-susceptible S.

clinical findings are nonspecific. The 2016 Infectious Diseases Society

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

INTRODUCTION Hospital-acquired (or nosocomial) pneumonia (HAP) and ventilator-

The clinical presentation, diagnosis, epidemiology, pathogenesis, microbiology, and treatment of

Pneumonia types — The 2016 Infectious Diseases Society of

The category of health care-associated pneumonia (HCAP) was included in the

PREVENTION In 2014, the Society for Healthcare Epidemiology of America (SHEA)

and the Infectious Diseases Society of America (IDSA) issued updated practice

Preventing aspiration — Aspiration is a major predisposing mechanism for both HAP and

Patient positioning — Supine positioning appears to predispose to aspiration and the

Decontamination of the digestive tract — Decontamination of the digestive tract may reduce

Chlorhexidine — Chlorhexidine use is controversial because of its uncertain efficacy and

Several meta-analyses of randomized trials have reported an association

An increase in mortality with chlorhexidine use was detected in a single meta-analysis of 11

Additional detail on SDD is discussed separately. (See "Infections and antimicrobial resistance in

Silver-coated endotracheal tube — We do not use silver-coated endotracheal tubes (ETTs).

Glucocorticoids — Stress-dose glucocorticoids have been proposed as a possible method for

Prevention bundles — VAP prevention bundles involve the implementation of various

Although a meta-analysis of 13 observational studies evaluating the effect of VAP bundles on

INTRODUCTION Hospital-acquired (or nosocomial) pneumonia (HAP) and ventilator-

Pneumonia types — The 2016 Infectious Diseases Society of

The category of health care-associated pneumonia (HCAP) was included in the

activity against Staphylococcus aureus, Pseudomonas aeruginosa, and other gram-negative

Approach to therapy — Once HAP or VAP is suspected clinically, diagnostic specimens

Additional considerations include potential toxicities, potential drug interactions, cost,

Determining coverage based on risk of resistance — The selection of an empiric regimen

●IV antibiotic use within the previous 90 days

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

●Treatment in an ICU in which >10 percent of gram-negative bacilli are resistant to an

Risk factors for MRSA include:

●Treatment in a unit in which >10 to 20 percent of S. aureus isolates are methicillin

Our approach to selecting a regimen based upon these risk factors:

Specific regimens are presented in the following section.

●Piperacillin-tazobactam 4.5 g IV every 6 hours

Among these agents, we generally prefer piperacillin-tazobactam or cefepime because they are

●IV antibiotic use within the previous 90 days

Such patients should receive (algorithm 1):

ONE of the following:

●Piperacillin-tazobactam 4.5 g IV every six hours

PLUS one of the following:

PLUS one of the following:

Because clinical outcomes appear to be similar for linezolid and vancomycin [29-31], we select

The combination of vancomycin and piperacillin-tazobactam has been associated with acute

ONE of the following:

●Piperacillin-tazobactam 4.5 g IV every six hours

Because clinical outcomes appear to be similar for linezolid and vancomycin [29-31], we select

The combination of vancomycin and piperacillin-tazobactam has been associated with acute

Description of risk factors — Risk factors for MDR pathogens and/or mortality in patients with

●Risk factors for increased mortality:

As an alternative to the traditional dosing regimens described below, prolonged infusions of

●Piperacillin-tazobactam 4.5 g IV every six hours

The IDSA/ATS guidelines also include imipenem and meropenem as options, but we generally

ONE of the following:

●Piperacillin-tazobactam 4.5 g IV every six hours

PLUS one of the following:

PLUS one of the following: