50TH ANNIVERSARY ARTICLES

Nosocomial Infection
OBJECTIVE: The first 70 years of critical care can be considered a pe- Marin H. Kollef, MD1
riod of “industrial revolution-like” advancement in terms of progressing the Antoni Torres, MD, PhD2
understanding and care of critical illness. Unfortunately, like the industrial Andrew F. Shorr, MD, MPH, MBA3
revolution’s impact on the environment, advancing ICU care of increas- Ignacio Martin-Loeches, MD, PhD4
ingly elderly, immunosuppressed, and debilitated individuals has resulted
Scott T. Micek, PharmD5
in a greater overall burden and complexity of nosocomial infections within
modern ICUs. Given the rapid evolution of nosocomial infections, the
Downloaded from http://journals.lww.com/ccmjournal by BhDMf5ePHKav1zEoum1tQfN4a+kJLhEZgbsIHo4XMi0hCywCX1AWnYQp/IlQrHD3i3D0OdRyi7TvSFl4Cf3VC1y0abggQZXdgGj2MwlZLeI= on 02/14/2021

authors provide an updated review.

DATA SOURCES AND STUDY SELECTION: We searched PubMed
and OVID for peer-reviewed literature dealing with nosocomial infections
in the critically ill, as well as the websites of government agencies involved
with the reporting and prevention of nosocomial infections. Search terms
included nosocomial infection, antibiotic resistance, microbiome, antibiot-
ics, and intensive care.
DATA EXTRACTION AND DATA SYNTHESIS: Nosocomial infections
in the ICU setting are evolving in multiple domains including etiologic
pathogens plus novel or emerging pathogens, prevalence, host risk fac-
tors, antimicrobial resistance, interactions of the host microbiome with
nosocomial infection occurrence, and understanding of pathogenesis and
prevention strategies. Increasing virulence and antimicrobial resistance of
nosocomial infections mandate increasing efforts toward their prevention.
CONCLUSIONS: Nosocomial infections are an important determinant of
outcome for patients in the ICU setting. Systematic research aimed at improv-
ing the prevention and treatment of nosocomial infections is still needed.
KEY WORDS: antibiotic resistance; intensive care unit; nosocomial
infection; outcomes

N
osocomial infections (NIs) are major threats to hospitalized patients.
NIs are common within ICUs and associated with prolonged hospi-
talization, development of multiple organ dysfunction, and increased
hospital mortality (1). NIs can be considered an inevitable consequence of crit-
ical care due to the utilization of invasive life prolonging procedures including
venous and arterial catheterizations, tracheal intubation, urinary catheteriza-
tion, invasive intracranial pressure monitoring, and placement of sterile site
drainage catheters. From the advent of critical care, coinciding with the polio
outbreak from the 1950s when early ICUs focused on the use of hand ventila-
tion, oxygen therapy, IV fluids, and ventilation with the iron lung to the present
modern ICUs, NIs have been steadily increasing. Coinciding with the escalat-
ing technology of critical care, there has been a change in the types of patients Copyright © 2021 by the Society of
admitted to ICUs who are older, with greater disease severity and multiple Critical Care Medicine and Wolters
organ derangements. Increasingly, critically ill patients also have significant Kluwer Health, Inc. All Rights
immune suppression due to either their underlying disease or organ dysfunc- Reserved.
tion and the administration of immunosuppressive therapies (2). DOI: 10.1097/CCM.0000000000004783

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Kollef et al
NIs are estimated to increase total annual health-
care costs in the United States by almost 10 billion
dollars (3). The clinical impact and costs associated
with NIs have resulted in concerted efforts aimed at
their prevention. NIs within ICUs are relatively com-
mon compared with non-ICU patient areas, especially
nosocomial pneumonia and Clostridium difficile infec-
tions as reported by the Centers for Disease Control
and Prevention (CDC) and other groups (4, 5). In
addition, as critical care advances, with the use of in-
vasive devices especially within immunocompromised
patients, novel pathogens and types of NIs are be-
coming ever more recognized (6, 7). The first 70 years
of critical care can be considered a period of “indus-
trial revolution-like” advancement. Unfortunately, like
the industrial revolution’s impact on the environment,
advancing ICU care of increasingly elderly, immuno-
suppressed, and debilitated individuals has resulted in
a greater overall burden and complexity of NIs within
modern ICUs.
DATA SOURCES AND STUDY
SELECTION
We searched PubMed and OVID for peer-reviewed
literature dealing with NIs in the critically ill, as well
as the websites of government agencies involved with
the reporting and prevention of NIs. Search terms in-
cluded NI, antibiotic resistance, microbiome, antibiot-
ics, and intensive care.
MAJOR NI AND UNDIAGNOSED
INFECTION
During the first decades of critical care from the 1950s
through the 1970s, nosocomial bacterial infections
were more common among surgical patients than
medical patients (8). Wound infections, pneumonia,
urinary tract infections, and bacteremia predominated
and the most common causes of bacteremia in the
hospital were Streptococcus pneumoniae followed by
Escherichia coli, Klebsiella species, and Staphylococcus
aureus (9). Although these infections were generally
antibiotic susceptible, compared with todays’ patho-
gens, outbreaks of penicillin-resistant S. aureus infec-
tions especially in nurseries led to public concern
regarding NIs for the first time (10). Throughout the
1980s and 1990s, NIs became increasingly associated
with antibiotic-resistant bacteria.
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Currently, the most common NIs in the ICU setting
are those related to the use of specific invasive proce-
dures and prior parenteral antibiotic exposure (11).
Urinary tract infections, lower respiratory tract infec-
tions (ventilator-associated tracheobronchitis [VAT],
ventilator-associated pneumonia [VAP], and hospital-
acquired pneumonia), central line-associated blood
stream infections, skin and skin structure infections in-
cluding wound infections, and C. difficile-associated in-
fection make up the most common NIs seen in the ICU
setting. Table 1 provides an overview of the relation-
ship between life-supporting technologies employed in
the ICU with the major NIs and pathogens associated
with those interventions. It is very likely that future
technologic advances in critical care will be associated
with their own specific types of NIs. Indeed, one of the
necessary elements in the development of such new
technologies is the need to minimize or eliminate the
occurrence of NIs. Advances in materials engineering,
device coatings, and device-patient connectivity should
help in preventing many future NIs (12).
In 1995, Vincent et al (13) published the first European
Prevalence of Infection in Intensive Care (EPIC) study.
Out of 10,038 patients, in their 1-day point prevalence
study, 2,064 (20.6%) had ICU-acquired infection with
pneumonia (46.9%) being most frequent followed by
other lower respiratory tract infection (17.8%), urinary
tract infection (17.6%), and bloodstream infection
(12%). The identified risk factors for ICU-acquired in-
fection included increasing length of ICU stay, mechan-
ical ventilation, trauma, central venous, pulmonary
artery, urinary catheterization, stress ulcer prophylaxis.
ICU-acquired pneumonia, clinical sepsis, and blood-
stream infection were associated with increased risk of
ICU death. Vincent et al (14) published EPIC II in 2009
encompassing a more global distribution of ICUs and
reported that 7,087 of 13,796 ICU patients (51%) were
infected. However, 9,084 patients (71%) were receiving
antibiotics in the ICU. The lungs were the most com-
mon site of infection (64%), followed by the abdomen
(20%), the bloodstream (15%), and the renal tract/
genitourinary system (14%). Patients who had longer
ICU stays prior to the study day had higher rates of in-
fection, especially infections due to resistant bacterial
species and fungi. Most recently, EPIC III conducted in
2017 showed similar distribution of NIs (Fig. 1) (15).
Furthermore, EPIC III found that antibiotic-resistant
microorganisms increasingly accounted for NIs.
 50th Anniversary Articles

TABLE 1.
ICU Technologies and Corresponding Nosocomial Infections
Technology Nosocomial Infection Major Pathogens

Intracranial pressure monitor Ventriculostomy-associated •  Coagulase negative Staphyloocci

• Intraventricular Infections •  Staphylococcus aureus
• Intraparenchymal • Ventriculitis • Diphtheroids
• Subarachnoid • Meningitis • Streptococci
• Epidural •  Brain abscess • GNB
• Anaerobes
• Fungi
• Mycobacteria
Vascular catheters Catheter-related bloodstream •  Coagulase negative Staphyloocci
•  Central vein catheter infection •  S. aureus
•  Arterial catheter • Enterococci
•  Pulmonary artery catheter •  Candida species
• GNB
Implantable pacemakers and •  Pocket infection •  S. aureus
cardioverter-defibrillators •  Endocarditis (lead or valve •  Coagulase negative Staphyloocci
vegetation) • Cutibacterium
• Bacteremia •  Candida species
• Mediastinitis •  Alpha-hemolytic streptococci
• Pericarditis •  Beta-hemolytic streptococci
• Enterococci
Cardiopulmonary assist devices •  Pump or cannula infection •  See Implantable pacemakers and
•  Intraaortic balloon pump •  Pocket infection cardioverter-defibrillators
•  Ventricular assist devices •  Percutaneous driveline infection • GNB
•  Extracorporeal membrane • Mediastinitis
oxygenation •  Sternal wound infection
• Bacteremia
• Cellulitis
Urinary catheter •  Symptomatic bacteriuria •  Escherichia coli
• Urethral •  Asymptomatic bacteriuria •  Candida species
• Supracubic • Pyelonephritis •  Enterococcus species
•  Percutaneous nephrostomy •  Pseudomonas aeruginosa
•  Klebsiella species
Ventilatory support •  Ventilator-associated pneumonia •  S. aureus
•  Endotracheal tube • Ventilator-associated • GNB
• Tracheostomy tracheobronchitis   –  P. aeruginosa
•  Mechanical ventilation   – Acinetobacter species
  –  E. coli
  –  Enterobacter species
  –  Klebsiella species
• Viruses
Nutrition support • Sinusitis •  S. aureus
•  Enteral via nasogastric tube, • Bacteremia • GNB
orogastric tube, or gastrostomy- • Cellulitis •  Candida species
tube/gastrojejunostomy tube  Peritonitis
•  Parenteral via central vein catheter
GNB = Gram-negative bacteria.

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Kollef et al
Figure 1. Bar graph indicating the prevalence of nosocomial infections from European Prevalence of Infection in Intensive Care III (see
Vincent et al [15]). GU = genitourinary.
The EPIC studies are important in demonstrating
that NIs are increasingly prevalent, associated with
worse outcomes and more commonly associated with
infection due to antibiotic-resistant pathogens. These
findings are similar to those reported by the CDC
and the European Centre for Disease Control and
Prevention (ECDC). In 2012, the ECDC described the
results of a point-prevalence study conducted in 2010
with 19,888 surveyed patients, of whom 7.1% had an
NI and 34.6% were receiving at least one antimicrobial
agent (16). NI-prevalence results were highest in ICUs
(28.1%) and 61.4% of ICU patients were being treated
with antimicrobials. Pneumonia and other lower respi-
ratory tract infections represented the most common
type of NI. The ECDC also reported similar NI prev-
alence rates for pediatric and neonatal ICUs (17). In
the United States, the CDC has described comparable
distributions of NIs, although NI rates appeared to be
dropping for several important infections due in large
part to state-sponsored prevention programs (4, 18).
The increasing prevalence of antibiotic resistance
among NIs is also an increasing threat to human health
(19). Carriers of multidrug-resistant microorganisms
(MDROs) are at greater risk for developing infections
that are difficult to treat and associated with greater mor-
tality due to initial empiric therapy with antimicrobial
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Copyright © 2021 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.
regimens that fail to treat the resistant pathogens (20, 21).
In addition to prior antibiotic exposure, risk factors
for antibiotic-resistant NIs include age, underlying ill-
ness, international travel, and use of acid-suppression
therapy, especially in the ICU setting (22). We should
view the prevention of NIs in parallel with the preven-
tion of antibiotic resistance given their close relation-
ship. This will require reexamining common practices
performed in the ICU environment such as the use of
prophylactic antibiotics and acid-suppression therapies.
One of the main challenges for ICU clinicians, in
addition to preventing NIs, is identifying the presence
of an NI and selecting an appropriate empiric antibi-
otic regimen based on the likely source of infection, the
prevailing local antibiotic susceptibility patterns, and
individual patient risk profiles for antibiotic resistance.
Traditional laboratory methods for pathogen identifica-
tion and antibiotic susceptibility typically require 48–72
hours (23). Unfortunately, such historically acceptable
diagnostic delays can result in inadequate initial treat-
ment regimens or unnecessary use of broad-spectrum
antimicrobials. In addition, these traditional micro-
biology methods predating the first ICUs are insensi-
tive for the identification of many atypical pathogens
including viruses and fungi. Use of novel diagnostics
including real-time molecular methods like multiplex
 50th Anniversary Articles

TABLE 2.
Clinical Isolates From U.S. Hospitals as Reported by the National Nosocomial Infections
Surveillance
1990–1997
1970–1979 1986–1989 1990–1992
(Unknown, (76,798 (70,411 Blood Pneumonia
Organism Not Reported) Isolates) Isolates) (2,971 Isolates) (4,389 Isolates)

Escherichia coli 19 16 12 3 4
Staphylococcus aureus 9 10 12 13 20
Coagulase-negative staphylococci — 9 11 36 1
Enterococcus species 10 12 10 16 2
Pseudomonas aeruginosa 9 11 9 3 21
Candida albicans 5 5 5 3 1
Klebsiella species 8 5 5 4 8
Numbers are shown as percentages.
See Allen et al (32), Schaberg et al (33), Emori and Gaynes (34), and Richards et al (35). Blanks reflect missing data or inability to cal-
culate accurately percentage.

polymerase chain reaction and advanced microscopy
should enhance microbiologic diagnostics leading to
improved outcomes (23–25). In the future, metage-
nomic next-generation sequencing should allow earlier
and more targeted treatments for NIs, identify emerg-
ing infections causing NI outbreaks, and accelerate the
workup and treatment for noninfectious causes of di-
sease promoting antimicrobial stewardship (AMS) (26).
The importance of early identification of novel NI
outbreaks for purposes of epidemiologic surveillance,
curtailing NI spread, and providing early treatment is
illustrated by nosocomial outbreaks of Candida auris,
middle eastern respiratory syndrome coronavirus,
novel coronavirus disease 2019 (COVID-19, Wuhan,
China), and pan-resistant E. coli (6, 27–30).
COMMON CAUSES OF NI
The causative pathogens responsible for NIs within
ICUs have dramatically changed over the last 70 years
predominantly in terms of their antimicrobial resist-
ance. In the 1960s, wound infections constituted the
predominant postoperative ICU infection replaced by
urinary tract infection in the 1970s and 1980s and closely
followed by bloodstream infections (31). In the 1990s,
nosocomial pneumonia became the most common
NI within ICUs. Gram-positive organisms especially
methicillin-resistant S. aureus (MRSA) increased in
predominance from the 1960s to the 1980s. This was
followed by a period of escalating prevalence of antibi-
otic-resistant Gram-negative bacteria (32, 33). Table 2
provides an overview of the predominant bacterial
isolates from U.S. hospitals, including ICUs, from
the 1980s and 1990s as reported from the National
Nosocomial Infections Surveillance system, which is
conducted by the CDC (32–35). As these surveys show,
the 1980s introduced the predominance of potentially
antibiotic-resistant Gram-negative bacteria especially
Pseudomonas aeruginosa.
The EPIC studies for the first time provided a global
perspective on the changing landscape of NIs within
ICUs. The first EPIC point-prevalence study in 1992
found that 4,501 ICU patients (44.8%) had one or
more infections with more than 35% being NIs (13).
The most frequent isolates were Enterobacterales
(34.4%) (E. coli, Klebsiella species, and Enterobacter
species), S. aureus (30.1%), P. aeruginosa (28.7%),
coagulase-negative staphylococci (19.1%), and fungi
(17.1%). Interestingly, only 0.2% of patients had iden-
tified viral infections. In terms of antibiotic resistance,
59.6% of S. aureus infections were methicillin-resis-
tant, whereas 65.1% of Pseudomonas species and 75%

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Kollef et al

of coagulase-negative staphylococci were resistant to
one or more antibiotics.
Forty percent of the positive cultures revealed
Gram-positive bacteria, 62% had Gram-negative bac-
teria, 19% revealed fungi, and no viruses were reported
in EPIC II (14). The most common Gram-positive bac-
terium was S. aureus, and the most frequent Gram-
negative bacteria were P. aeruginosa and E. coli. Patients
with longer ICU stays prior to the study day had higher
rates of infection, especially infections due to resistant
staphylococci, Acinetobacter species, Pseudomonas
species, and Candida species. Unfortunately, the EPIC
II study did not differentiate between nosocomial
and community-acquired infections. However, when
comparing the two first EPIC studies, the infections
attributed to MRSA decreased and infections caused
by Gram-negative bacteria increased as a proportion
of all infections (Table 3).
A total of 1,150 centers from 88 countries partici-
pated in EPIC III and 8,135 patients (54%) had at least
one suspected or proven infection on the day of the
study (15). Community-acquired infections occurred
in 44% of patients with hospital- or healthcare-acquired
infections in 35% and ICU-acquired infections in 22%
(Fig. 1). As in the previous EPIC studies, the lung was
the most frequent source of infection (60%) followed
by the abdomen (18%) and the bloodstream (15%).
Sixty-five percent of patients had at least one posi-
tive microbiological culture with 67% of isolates being
Gram-negative bacteria, 37% Gram-positive bac-
teria, and 16% fungal. Gram-negative bacteria were
more frequently isolated in hospital-acquired than in
community-acquired infections (71% vs 51%). The
most common Gram-negative bacteria isolated were
Enterobacterales (26%), Pseudomonas species (16%),
and Acinetobacter species (11%). Gram-positive bac-
teria including MRSA were more frequently isolated
in North America. Viruses represented 3.7% of the
microbiologic isolates. Among antibiotic-resistant
microorganisms, infections with vancomycin-resistant
Enterococcus (VRE), beta-lactam-resistant Klebsiella,
and carbapenem-resistant Acinetobacter species were
independently associated with increased risk of death.
The EPIC studies provide an overview of changes
in infections in the ICU setting over a 25-year period.
The EPIC studies are consistent in demonstrating the
lungs as the main source of ICU infections, followed by
the abdomen and the bloodstream. The EPIC studies

TABLE 3.
Distribution (%) of Microorganisms From All Sites—European Prevalence of Infection in
Intensive Care (I, II, and III)
Pathogen Type EPIC I EPIC II EPIC III

Year 1992 2007 2017

Number of infected patients 4,501 7,087 8,135
Gram-negative bacteria — 62.2% 67.1%
  Enterobacterales (Escherichia coli, Klebsiella species, 34.4% 35.7% 25.5%
and Enterobacter species)
  Pseudomonas aeruginosa 28.7% 19.9% 16.2%
  Acinetobacter — 8.8% 11.4%
Gram-positive bacteria
  Staphylococcus aureus 30.1% 20.5% 9.6%
 Methicillin-resistant S. aureus — 10.2% 4.6 %
Fungi 17.1% 19.4% 16.4%
Viruses 0.2% — 3.7%
EPIC = European Prevalence of Infection in Intensive Care.
Blanks reflect missing data or inability to calculate accurately percentage.

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demonstrate a discernable decrease in S. aureus infec-
tions but an increase in Gram-negative bacterial infec-
tions including MDROs, more fungal infections (mainly
Candida and Aspergillus species), and more reported
viral infections. Approximately half of all infections
identified in ICUs are now hospital- or healthcare-
acquired NIs. Fungal infections have become more
common presumably due in large part to the greater
numbers of immunosuppressed patients admitted to
the ICU and the increasing presence of long-term cen-
tral vein catheters. Additionally, the increasing emer-
gence of antimicrobial resistance in fungi has become a
reality with the emergence of C. auris infections as the
most recent example of this trend (6, 30).
The increasing presence of immunosuppressed
patients within ICUs also reflects a major change in
the microbial etiologies (36). Solid and liquid organ-
transplant patients and patients undergoing chemo-
therapy, corticosteroid administration, and biological
treatments frequently present with infections that may
require ICU admission, with these infections being ei-
ther community- or hospital-acquired. It is expected
that other novel pathogens, or reemergence of older
pathogens with greater antibiotic resistance or viru-
lence, will likely arise as important causes of NIs in the
future as host factors continue to evolve (37).
HOST-MICROBIOME INTERACTION
Microbiota are the set of microorganisms that coexist
symbiotically with our own body (38, 39). The delicate
Figure 2. Homeostasis within the intestinal microbiome contrasted to subsequent dysbiosis along with the resulting adverse
consequences to the host.
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50th Anniversary Articles
interrelationships between the microbiota and disease
have only begun to emerge in the last 2 decades, limiting
any historical perspective, especially within critically ill
patients. Microbiota are detectable in health possess-
ing their own genetic code, termed the microbiome,
and closely interact with host cells to maintain overall
body homeostasis. A common hypothesis related to the
microbiome and its impact on host disease activity is that
changes in microbiota gene activity and metabolic pro-
cesses can directly impact host tissues and result in ab-
normal host immune responses (Fig. 2) (40).
VAP and sepsis caused by MDROs are two of the
conditions best understood, whereby alterations in the
host microbiome contribute to the development and
progression of disease activity (41). It is increasingly
apparent that dysbiosis or microbial imbalances or
maladaptations within the body such as an impaired
intestinal microbiome represent an important patho-
genic mechanism for the development of nosocomial
lung infections. Animal studies indicate that dys-
biosis results in a proinflammatory environment that
can lead to alteration of microbial molecules termed
pathogen-associated molecular patterns (PAMPs)
(42). Subsequent translocation of bacteria and their by-
products including PAMPs is associated with immune
pathology such as systemic immune activation, tissue
damage, and sepsis with organ dysfunction (42).
Kelly et al (43) demonstrated that critically ill sub-
jects had lower initial diversity of their microbiota in
both the upper and lower respiratory tracts compared
with healthy controls. Presence of endotracheal tubes
Kollef et al
and antibiotic administration can promote pathogenic
bacterial colonization in the airways contributing to
both lower microbiota diversity and the development of
an intermediate respiratory infection termed VAT (44).
VAT represents a compartmentalized host response as-
sociated with a better overall prognosis than VAP (45).
If the aforementioned response is not compartmental-
ized, progression to VAP is likely and potentially other
organ failure to include the acute respiratory distress
syndrome (ARDS) may occur (46). An observational
study performed in European ICUs attempted to eluci-
date the role of the microbiome in the development of
VAP (47). Dysbiosis of microbial communities in the
respiratory tract was most profound in patients who
developed VAP. However, mechanical ventilation it-
self, but not antibiotic administration, was associated
with more pronounced changes in the respiratory
microbiome. These findings provide alternative po-
tential mechanisms by which ventilator-induced lung
injury influences local changes at the airway level pro-
moting the occurrence of NIs.
Dickson et al (48) examined the lungs of critically
ill patients and found a correlation between lung-spe-
cific microbiota and clinical outcomes. Patients with
increased lung bacterial burden had fewer ventilator-
free days. In addition, these investigators found that
the community composition of lung bacteria, driven
primarily by gut-associated bacteria, was also predic-
tive of ventilator-free days and the presence of ARDS.
Thus, bacterial burden and community composition
of the microbiota both influence disease presenta-
tion and clinical outcomes. Other investigators have
also demonstrated the importance of the microbiota
in the gastrointestinal tract as a contributor to critical
illness (49). The gut functioning as a “complex organ”
regulates many aspects of the interaction between mi-
crobiota and the immune system of the host. Recently,
the development of enteropathy and growth stunting
in undernourished children has been linked to mi-
crobiota changes (50). These findings have important
implications for further understanding the role of the
microbiota on disease progression and outcomes of
critical illness.
Antimicrobial preventative therapies such as selec-
tive digestive decontamination have shown the ability
to avert NIs in the short term but result in the disrup-
tion of the microbiota, leading to future antibiotic-
resistant infections (51–53). Probiotics are live bacteria
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and yeast introduced into the intestine in order to sup-
port and enhance the integrity of the gut microbiome.
Regrettably, there is not conclusive evidence yet to
support the routine use of probiotics in the critically
ill population (54, 55). Another novel therapeutic
approach termed “postbiotic therapy” has emerged,
which focuses on molecules or metabolites that are
secreted, modulated, or degraded by the microbiota
subsequently exerting their effects directly onto host
cells (56). Metabolite-based therapeutics could po-
tentially target downstream signaling pathways of the
microbiota, mitigating the negative effects of an ex-
cess, scarcity, or dysregulation of metabolites involved
in these pathways (57). Finally, fecal transplantation
to restore the normal microbiome activity is another
therapeutic approach in critically ill patients being ac-
tively investigated (58).
Host-pathogen interactions represent one of the most
exciting areas of future research, as it relates to the de-
velopment of NIs and outcomes in the critically ill. The
first 70 years of critical care have undoubtedly resulted
in alterations of the microbiome from ICU therapies in-
cluding mechanical ventilation and antibiotics. Better
understanding of the continuum between local colo-
nization with pathogenic microorganisms altering the
microbiome to NI development and organ failure will
benefit from new investigative techniques potentially
leading to future novel treatment strategies (50, 59).
CURES OF INFECTION: ANTIBIOTICS
AND OTHER THERAPIES
The first 70 years of critical care have demonstrated
that prompt administration of antimicrobial therapy
is the foundation upon which all other therapies are
based on the treatment of infections in ICU patients.
As such, clinical practice guidelines, most notably the
Surviving Sepsis Campaign, have endorsed the admin-
istration of broad-spectrum antibiotics within 1 hour
of sepsis and septic shock recognition (60). This strong
recommendation is based on multiple observational
studies of large patient cohorts spanning the last 15–20
years (61–63). During this same time period, equal im-
portance has been placed on the administration of ap-
propriate initial antimicrobial therapy, therapy active
against the offending pathogens, stemming from asso-
ciations of significant reductions in all-cause mortality
and a number needed to treat as low as 10 patients
to prevent one fatal outcome (64). Unfortunately,
 50th Anniversary Articles

Figure 3. Pharmacokinetic and pharmacodynamic alterations in critically ill patients. AUC = area under the concentration/time curve,
CL = drug clearance, Cmax = maximum serum concentration, fu = fraction of unbound drug, t½ = serum concentration half-life, Vd = volume
of distribution.

broad-spectrum antimicrobials prescribed with the
intention of improving patient outcomes can lead to
unintended collateral damage by selecting for resistant
pathogens (65). This likely explains the temporal trend
of increasing antimicrobial resistance, necessitating the
development of newer and more powerful antibiotics.
The cause and effect relationship of antibiotic use-
spurring antibiotic resistance has been a constant since
the introduction of penicillin, but this is often height-
ened in critically ill patients because of altered phar-
macokinetic parameters that lead to subinhibitory
and subtherapeutic antibiotic concentrations (Fig. 3).
This in turn can stimulate resistant gene expression
and transfer as well as mutagenesis (66). Alterations
in pharmacokinetic observed in critically ill patients
include variability in absorption of oral medications
in patients with mesenteric hypoperfusion or delayed
gastric emptying. This can result in reduced max-
imum serum concentrations (Cmax), total serum con-
centrations as described by the area under the curve,
and changes in drug half-life. Likewise, critically ill
patients often display variability in drug distribution
stemming from fluid shifts or changes in plasma pro-
tein concentrations such as albumin. This can result
in increased volumes of distribution, particularly for
hydrophilic antibiotics like beta-lactams, and lead to
decreased serum concentrations (67). Reduced serum
concentrations generally result in lower concentra-
tions at the site of infection, which may be responsible
for several failed VAP clinical studies of contemporary
antibiotics (68, 69). Taken together, antibiotics along
with their ineffective delivery in increasingly complex
patients promote the development of NIs and, more
importantly, antibiotic resistance (70, 71).
Therapeutic drug monitoring (TDM) for amino-
glycosides has been available since the advent of crit-
ical care (72). Although initially limited in scope and
applicability for critically ill patients, TDM has more
recently been advocated as a tool to optimize serum
antibiotic concentrations in the face of altered phar-
macokinetic in critically ill patients. Studies performed
in the last decade evaluating the first dose of antibiot-
ics including beta-lactams and aminoglycosides con-
sistently demonstrate that target concentrations are
seldom-achieved despite the use of recommended
maximal doses (73–75). Continuous or prolonged
infusions of beta-lactams have been vigorously studied
as a method to meet target concentrations, commonly
defined as the percentage of time the free beta-lactam
concentration is above the minimum inhibitory con-
centration (%fT > minimum inhibitory concentra-
tion). Although application of this approach does
improve the frequency at which targeted serum con-
centrations are met, there has been minimal evidence
that associates improved clinical outcomes within het-
erogeneous populations of critically ill patients when
evaluating individual trials. However, when meta-ana-
lytic techniques are applied to randomized, controlled

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Kollef et al
trials of patients with sepsis or severe sepsis, prolonged
infusions appear to offer a significant survival benefit
compared with short-term infusions (76, 77). Beta-
lactam infusion group (BLING) III, an ongoing multi-
center, open, phase 3 trial will recruit 7,000 critically ill
patients to compare 90-day mortality rates in patients
randomized to continuous infusions of meropenem or
piperacillin/tazobactam or intermittent infusions of
the same antibiotics (78). In addition to the primary
outcome evaluation, this study will provide a more de-
finitive look into the relationship between beta-lactam
target attainment and patient outcomes.
One specific population that is of particular in-
terest when considering adequate doses of antibiotics
are patients presenting with or developing augmented
renal clearance (ARC). It is quite clear that traditional
dosing approaches of beta-lactams are inadequate for
achieving targeted serum concentrations in the pres-
ence of ARC (79, 80). Due to the concerns associated
with inadequate antibiotic concentrations at the sites
of infection in the critically ill, especially individuals
with ARC, TDM has been recommended as standard
practice in this group of patients when available (81).
In addition to optimizing how antibiotics are
administered and monitored, the addition of new
agents with novel pharmacology to the therapeutic ar-
mamentarium is a much needed approach to combat-
ing antibiotic resistance. Since 2014, the United States
Food and Drug Administration has approved 10 new
antibiotics. Each new approval targets difficult to treat,
drug-resistant pathogens including carbapenem-resis-
tant Enterobacterales (CRE), multidrug-resistant P.
aeruginosa, and MRSA (Table 4).
Other novel approaches to circumventing bacterial
drug resistance have been in development for several
years. One such approach is via inhibition of viru-
lence factor (VF) production or activity. An example
of this that is available for clinical use is bezlotoxumab,
a human monoclonal antibody (mAb) that binds to C.
difficile toxin B indicated in patients who are receiving
antibacterial therapy and are at high risk for infection
recurrence (82). Other VFs that are mAb targets are S.
aureus α-toxin and protein A, and Type III secretion
systems embedded in many Gram-negative bacteria
including P. aeruginosa. The field of phage research has
been rekindled in response to the epidemic of MDROs.
Phage therapy is attractive because of the specificity to
single bacterial species and, in particular, strains that
178      www.ccmjournal.org February 2021 • Volume 49 • Number 2
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harbor resistance mechanisms that are difficult to treat
with traditional antibiotics and the potential to serve
as nanodelivery vehicles that carry agents that exert
antibacterial activity beyond the current drug phar-
macology. However, with any of the nontraditional
approaches mentioned, it is unlikely that any innova-
tion will replace the use of antibiotics in the near term
and instead will be used as part of combinations of
therapy with currently approved antibiotics.
ANTIMICROBIAL RESISTANCE
No review of the historical trends of NIs in critically ill
patients would be complete without addressing antimi-
crobial resistance. Antimicrobial resistance represents
one of the most important challenges in all types of
NIs since the beginning of critical care in both Gram-
positive and Gram-negative bacteria. Antimicrobial re-
sistance has also been progressively observed in fungal
and viral pathogens over the past 70 years. Concurrent
with the evolution of critical care as a distinct subspe-
cialty, we have witnessed an alarming increase in anti-
microbial resistance. The World Health Organization
now considers antimicrobial resistance a major threat
to human health, whereas others suggest that nearly
300 million individuals will die over the next 3 decades
as a direct result of antimicrobial resistance (83, 84).
The economic costs, both direct and indirect, associ-
ated with antimicrobial resistance are staggering (85).
Antimicrobial resistance denotes a particular
problem in ICUs. The burden and prevalence of anti-
microbial resistance in the ICU reflect a combination
of both patient and organizational pressures that mu-
tually reinforce each other. In terms of patient-related
factors, those cared for in the ICU have often been
exposed to antibiotic therapy prior to ICU admission,
routinely are treated with broad-spectrum antibiotics
while in the ICU, and may be colonized with antibi-
otic-resistant pathogens (85, 86). Organizationally and
historically, patients in the ICU are cohorted in a small
geographic area such that failures in infection control
can have a significant and rapid impact across the ICU
(87, 88). Similarly, many ICUs face nursing shortages,
made more acute by the recent COVID-19 pandemic,
which result in nurses having to care for multiple
patients.
Epidemiologically, few analyses have specifically fo-
cused on antimicrobial resistance in ICU populations.

Rather, prevalence studies generally describe the pro-
portion of resistant organisms seen throughout the hos-
pital or throughout a country and/or region (87, 88).
Reports that explore risk factors for infection with anti-
microbial-resistant organisms and indirectly describe
epidemiology, though, generally indicate that requir-
ing ICU care serves as an independent risk factor for
such processes (89, 90). In addition, one should recog-
nize that the prevalence of specific resistant pathogens
varies from ICU to ICU based on local epidemiology
and multiple other variables such as the frequency of
resistance in the community- and antibiotic-prescrib-
ing patterns outside the ICU. Currently, the major con-
cerns surrounding antimicrobial resistance center on
Gram-negative organisms. Specific pathogens that lead
to trepidation include both extended-spectrum beta
lactamase producing Enterobacterales, CREs, multi-
drug resistant (MDR) P. aeruginosa, and carbapenem-
resistant Acinetobacter baumannii. In earlier decades,
more emphasis was placed on resistant Gram-positive
bacteria such as MRSA and VRE. For both MRSA and
VRE, however, rates of infection with these pathogens
have either plateaued (as in the United States) or fallen
(as in parts of Europe) (91). Additionally, and in con-
trast to the scenario with resistant Gram-negative bac-
terial infections, multiple agents presently exist to treat
both MRSA and VRE.
Historically, it is important to realize that resistance
has arisen to every antibiotic ever developed for use in
the ICU setting. Initial reports of resistance often fol-
low soon after a new molecule’s introduction into the
anti-infective armamentarium (Fig. 4). The key issue,
though, revolves around when resistance becomes suf-
ficiently common such that traditional anti-infective
regimens are no longer reliable choices for therapy. In
that vein, many epidemiologic reports employ a vo-
cabulary that categorizes resistant pathogens as either
MDR (e.g., resistance to one or more agents in three
or more classes of antibiotics), extensively drug-resis-
tant (e.g., resistance to at least one agent in all but two
classes of antibiotics), or pandrug-resistant (e.g., re-
sistant to all currently available agents) (92). Although
this approach to classification facilitates case finding
and reporting, it is of little value to clinicians. For ex-
ample, MDR P. aeruginosa is now fairly common across
the globe. However, in many cases, MDR P. aeruginosa
may remain in vitro susceptible to routinely used anti-
biotics such as cefepime and piperacillin-tazobactam.
Critical Care Medicine www.ccmjournal.org      179
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50th Anniversary Articles
Hence, the key issue related to antimicrobial resist-
ance and its impact centers on how resistance affects
initial antibiotic prescribing. The higher mortality
rates and greater resource use associated with antimi-
crobial-resistant NIs do not, per se, relate to the pres-
ence of resistance. Resistance, in other words, does not
make a specific pathogen more virulent. Rather, the
presence of resistance complicates the clinician’s an-
tibiotic selection process and, in turn, decreases the
probability that the patient will receive initially ap-
propriate antimicrobial therapy (IAAT). For nearly
all infections, the timeliness and appropriateness of
antibiotic treatment are the central modifiable deter-
minant of outcomes. Multiple analyses document that
failure to administer promptly an agent to which the
culprit pathogen is in vitro susceptible independently
increases a patient’s risk for death (61, 93–96). One re-
cent report suggests that the number needed to treat
to save one life with appropriate antibiotic therapy is
as low as five (96). Strikingly, the number needed to
treat is lowest for antibiotic-resistant infections. The
significant impact of IAAT has also been noted in the
cases of infections due to both molds and yeast, two
nonbacterial pathogens routinely encountered in ICU
patients. Why do some patients fail to receive IAAT?
Often it is either because of a failure to recognize that
an infection is present or, more often, because the pa-
tient harbors a resistant organism that the prescriber
failed to consider. In short, antimicrobial resistance
presents two specific challenges in the care of NIs: 1)
correct identification and treatment of NIs caused by
antibiotic-resistant pathogens and 2) the prevention
and spread of further antimicrobial resistance.
With respect to the concerns associated with antibi-
otic-resistant NIs, AMS represents a key undertaking.
Several position statements describe the central com-
ponents of AMS (90, 91). Put simply, AMS as it relates
to the ICU “involves a multifaceted and multidiscipli-
nary approach to … combating antimicrobial resist-
ance, improving clinical outcomes, and controlling
costs by improving [anti-infective] use” (90). Important
components of any AMS initiative address proper pa-
tient identification, dosing optimization, anti-infective
deescalation, and shortening the duration of therapy.
Furthermore, any AMS project should include a
mechanism for prospective audit and feedback so that
members of the AMS team and bedside physicians can
assess the impact of their efforts. Although a complete
Kollef et al

TABLE 4.
New Antibacterial Agents—Activity Versus Difficult-to-Treat Pathogens and Major Toxicities
Β-Lactamase

New Delhi Metallo-

Extended- Klebsiella Beta-Lactamase/
AmpC Spectrum pneumoniae OXA Verona Integron- Methicillin-
Beta- Beta carba- Beta- Encoded Metallo- Resistant
Antibacterial Lactamase Lactamase penemase Lactamase Beta-Lactamase Staphylococcus
Agent (Ambler C) (Ambler A) (Ambler A) (Ambler D) (Ambler B) Acinetobacter Pseudomonas aureus
Cephalosporin
 Ceftaroline +

  Ceftolozane and ± + +
tazobactam

  Ceftazidime and + + + ± +
avibactam

 Cefiderocola + + + + + + +

Carbapenem
  Meropenem and + + + ± +
vaborbactam
 Imipenem/ + + + ± +
cilastatin and
relebactam

Tetracycline
 Omadacycline + + + ± ± + +

 Eravacycline + + + ± ± + +

Aminoglycoside
 Plazomicin + + + + ± ± ±

Fluoroquinolone
 Delafloxacin + ± + +

Lipoglycopeptide
 Dalbavancin +

 Oritavancin +

Oxazolidinone
 Tedizolid +

Virulence factor inhibitor (human monocolonal antibody)

 Bezlotoxumab

+ = active, ± = potentially active, cIAI = complicated intra-abdominal infection.

Functions as a siderophore and binds to extracellular free ferric iron.
a

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 50th Anniversary Articles

Vancomycin-
Intermediate Vancomycin-
Staphylococcus Resistant Clostridium
aureus Enterococcus difficile Toxicities

+ Diarrhea, nausea, and rash

Direct Coombs’ test seroconversion
Decreased efficacy in cIAI patients with a baseline CrCl of 30–50 mL/min
Nausea, diarrhea, headache, pyrexia, elevations in liver tests, and renal impairment/renal
failure
Decreased efficacy in cIAI patients with a baseline CrCl of 30–50 mL/min
CNS reactions, especially in renal impairment
Diarrhea, nausea, and vomiting
An increase in all-cause mortality with cefiderocol compared with the best available therapy in
patients with carbapenem-resistant Gram-negative infections, primarily due to Acinetobacter,
Stenotrophomonas, and Pseudomonas.
Diarrhea, constipation, nausea, vomiting, infusion-site reactions, elevations in liver tests,
hypokalemia, and cough

Coadministration with valproic acid or divalproex sodium may increase the risk of breakthrough seizures
Headache, infusion-site reactions, and diarrhea
Seizures and CNS reactions, and coadministration with valproic acid or divalproex sodium
may increase the risk of breakthrough seizures
Diarrhea, nausea, vomiting, infusion-site reactions, elevations in liver tests, pyrexia,
hypertension, and headache

+ + Mortality imbalance (> moxifloxacin) in community-acquired bacterial pneumonia trial

Tooth discoloration and enamel hypoplasia
Diarrhea, constipation, nausea, vomiting, infusion-site reactions, elevations in liver tests, and insomnia
+ + Tooth discoloration and enamel hypoplasia
Infusion-site reactions, nausea, and vomiting

Nephrotoxicity, ototoxicity, neuromuscular blockade, and fetal harm

Diarrhea

Tendinitis and tendon rupture, peripheral neuropathy and CNS effect, and exacerbation of
myasthenia gravis
Diarrhea, nausea, vomiting, elevations in liver tests, and headache

+ Elevations in alanine aminotransferase

+ +
Diarrhea, nausea, and headache
Coagulation test interference (activated partial thromboplastin time, prothrombin time/
international normalized ratio, and activated clotting time) and infusion-related reactions
(slow infusion over 3 hr recommended)
Avoid use in osteomyelitis
Diarrhea, nausea, vomiting, limb and subcutaneous abscesses, and headache

+ + Safety and efficacy have not been established in patients with neutropenia
Diarrhea, nausea, vomiting, infusion-related reactions, dizziness, and headache

+ Heart failure exacerbations commonly reported in patients with a history of congestive heart failure
Nausea, headache, and pyrexia

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Kollef et al

For example, if the prev-

alence of antimicrobial
resistance is low in a par-
ticular ICU, regular use of
these newer technologies
may result in more false-
positive than true-positive
results. As such, one may
need to employ rapid diag-
nostics based on a risk-
stratification scheme so
as to optimize their utility.
Likewise, machine learn-
ing and artificial intelli-
gence models may either
augment or perhaps sup-
plant novel rapid diagnos-
Figure 4. The year of introduction of several commonly used antimicrobials along with some
recently approved agents specifically designed to address antibiotic resistance. The bar for each
tics (99). With sufficient
antibiotic begins with the year of introduction and ends with the year that in vitro resistance to data, one might be able to
that agent was initially reported for the pathogen the agent targeted. For example, for levofloxacin, create trainable models to
the end of the bar indicates the report of Streptococcus pneumoniae resistance to levofloxacin, predict resistance and se-
whereas the end of the bar for ceftazadime-avibactam reveals the year of reports of resistance lect the most appropriate
for this agent in Enterobacterales. Source: compiled from information contained in the Centers for
anti-infective for a patient
Disease Control and Prevention: Report on Antibiotic Resistance, 2019. Available at: https://www.
cdc.gov/drugresistance/pdf/threats-report/2019-ar-threats-report-508.pdf. Accessed Jan 1, 2020.
with a specific NI. In sum,
antimicrobial resistance
discussion of AMS is beyond the scope of this review, will continue to represent a challenge in the treatment
readers should note that one area where the evidence of NIs. However, with recognition of the problem, an
is relatively clear relates to antibiotic treatment dura- emphasis on IAAT and, by implementing AMS, those
tion, particularly in critically ill subjects. Essentially who practice in the ICU can help to limit the impact of
every randomized trial comparing longer durations antimicrobial resistance.
of therapy to shorter ones has demonstrated that the
shorter duration is associated with similar if not bet- PREVENTION OF NI
ter outcomes for the patients (97). Shorter durations Despite the technological and medical advances that
of treatment also decrease the selection pressure that have occurred in the care of critically ill patients over
promotes further antimicrobial resistance and reduces the past 70 years, NIs continue to be a present and
the risk for C. difficile-associated diarrhea. seemingly more difficult problem for the modern
Future approaches to combating antimicrobial re- intensivist. It is very likely that NIs will continue to be
sistance will certainly include the incorporation of a vexing problem for future generations of intensivists
newer rapid diagnostic tests. These tools hold the to come. The use of standardized infection-prevention
promise of being able to narrow therapy more quickly practices appears to reduce the occurrence of NIs but
while shifting patients treated inappropriately to bet- may be limited in the prevention of the more difficult
ter anti-infective options sooner (23). It remains un- infections such as VAP and C. difficile, as well as the
clear how to best employ these newer diagnostics as prevention of antibiotic resistance emergence (4). The
some remain cumbersome to use while others either contributions of Ignaz Philipp Semmelweis in terms
are only validated on selected types of samples (e.g., of hand cleansing, approaches to antiseptic surgery
blood) or are costly to purchase. Similarly, these tests by Joseph Lister, and development of modern nurs-
cannot be interpreted without consideration of the un- ing by Florence Nightingale still serve as the pillars
derlying prevalence of antimicrobial resistance (98). upon which our current infection control practices are

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 50th Anniversary Articles

TABLE 5.
Emerging and Future Approaches for the Prevention of Nosocomial Infections in the ICU
Pathogen-focused approaches
  Vaccines to prevent common nosocomial infections (Clostridium difficile, Staphylococcus aureus, Pseudom-
onas aeruginosa, Candida species, and respiratory syncytial virus)
  Biologic prevention strategies (pathogen and virulence factor-directed monoclonal and polyclonal antibodies)
  Bacteriophage therapy
  Quorum-sensing inhibitor molecules
Host-focused strategies
  Microbiome preservation (prebiotics, probiotics, and fecal microbiota transplantation)
  Immune enhancement therapies (antiprogrammed cell death protein 1, antiprogrammed cell death protein 1
ligand, and anticytotoxic T lymphocyte-associated protein 4)
  Topical disinfectants with longer term persistence
  Gene and stem-cell therapies
Environment-focused approaches
  Self-disinfecting surfaces in hospital rooms and on medical devices/endoscopes
  Continuous room disinfection (ultraviolet light, dilute hydrogen peroxide aerosolization, antimicrobial peptides,
photoactivated surfaces)
  Heavy-metal coatings (silver and copper)
  Antiadhesive surfaces

based (100). Disappointingly, the increasing com- CONCLUSIONS

plexity of the patients cared for in modern and future
ICUs along with the intensifying threat of antimicro-
bial resistant pathogens serves as a warning that novel
approaches to NI prevention are needed.
Table 5 presents potential new approaches for the
prevention of future NIs in the ICU population. These
potential new approaches include therapies focusing on
specific pathogens to prevent NIs including vaccines,
mAbs, bacteriophage, and molecules aimed at disrupt-
ing quorum sensing. Host-directed strategies targeting
microbiome preservation, enhancement of the host
immune response, and improved persistent topical dis-
infectants may also play a role in the future prevention
of NIs. Improvements in environmental and equipment
disinfection employing novel surfaces and disinfection
techniques could also be employed in the future espe-
cially within high risk environments such as ICUs. One
key challenge will be to develop such approaches in a
cost-effective manner given the economic constraints
already placed on most hospitals around the world.
NIs continue to be and will be for the foreseeable
future an important detrimental influence on pa-
tient outcomes in the ICU setting (101). Further re-
search focusing on the prevention and treatment
of NIs is needed going forward to improve the out-
comes and to reduce healthcare costs for critically ill
patients.
1 Division of Pulmonary and Critical Care Medicine,
Department of Internal Medicine, Washington University
School of Medicine, St. Louis, MO.
2 Pulmonology and Respiratory Intensive Care Department,
Hospital Clinic of Barcelona, University of Barcelona,
Barcelona, Spain.
3 Section of Pulmonary, Critical Care, and Respiratory Services,
MedStar Washington Hospital Center, Washington, DC.
4 Department of Clinical Medicine, Multidisciplinary Intensive
Care Research Organization (MICRO), St James’s Hospital,
Trinity Centre for Health Sciences, Dublin, Ireland.

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Kollef et al
5 Department of Pharmacy Practice, St. Louis College of
Pharmacy, St. Louis, MO.
Dr. Kollef’s efforts are supported by the Barnes-Jewish Hospital
Foundation. The remaining authors have disclosed that they do
not have any potential conflicts of interest.
For information regarding this article, E-mail: kollefm@wustl.edu
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