**3. Prevalence of MDROs and risk factors in the critically ill**

The CDC in 2013 published *Antibiotic Resistance Threats in the United States*. Regarding the level of concern, CDC has, for the first time, prioritized bacteria in this report into one of three categories: urgent, serious, and concerning (**Table 1**).

The CDC has placed carbapenem-resistant *Enterobacteriaceae* (CRE) as an urgent threat level. CRE confers resistance to last-line antibiotics such as carbapenems, by producing a β-lactamase enzyme called KPC (*K. pneumoniae* carbapenemase-producing). The CDC reports their laboratories have confirmed CRE in 44 states within healthcare facilities across the United States. CRE causes more than 9000 healthcare-associated infections (HAI) annually, among these the two most common types are carbapenem-resistant *Klebsiella* and carbapenem-resistant *E. coli*. The percentages of the United States CRE healthcare-associated infections for *Klebsiella* spp. and carbapenem-resistant *Escherichia coli* are 11 and 2%, respectively. These serious infections contribute to roughly 600 deaths each year [5].


2013 [5].

key for survival in the critically ill. We will emphasize on the importance of robust antimicrobial stewardship programs, which are in accordance with Centers for Disease Control and Prevention (CDC) core elements. New regulatory mandates from the Joint Commission (TJC) on antimicrobial stewardship programs will require hospitals to be compliant for accreditation. Finally, we will end the chapter with an outlook on future antibiotics in Phase III development to aid in the

The preantibiotic era is a reality for many parts around the world, especially among the developed countries, driven in part by antibiotic overuse and misuse. Increasing antibiotic resistance is a global threat to patients worldwide and an economic burden. According to the U.S. Centers for Disease Control and Prevention (CDC), each year in the United States, drug-resistant bacteria cause approximately 2 million cases of illnesses and contribute to 23,000 deaths. A key driver has been the inappropriate use of antibiotics, which as an avoidable cost and burden to healthcare dollars, ranges from \$27 billion to 42 billion annually [1, 2]. The Infectious Diseases Society of America (IDSA) white paper entitled "Bad Bugs, No Drugs" commented on the declining research investments in antimicrobial development, as did an update on this article from clinical infectious disease (CID) in 2009 [3]. These papers identified certain Gram-negative bacteria that are particularly problematic pathogens, which tend to "escape" the activity of many antibiotics. These problematic pathogens are known as, the "ESKAPE" pathogens, which include: *Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, Enterobacter species* and can *Clostridium difficile* is also include to the list. In addition to the "ESKAPE" pathogens, the prevalence of *C. difficile* infection (CDI) has risen dramatically in just the last 2 decades. Since 2001, surveillance data has shown a dramatic increase. The number of CDI cases (any diagnosis) per 10,000 hospital discharges increased from 25.0 to 40.0, a 60% increase. However, over the next 4 years (2001–2005), a 92% increase was observed (from 40.0 to 76.9) [3–5]. The CDC has placed these resistant pathogens into three categories: urgent, serious, and concerning threat levels. Several recent efforts have attempted to raise awareness and focus attention on antibiotic overuse in healthcare including: the World Health Organization, the CDC, and White House. The White House issued executive order 13,676: combating antibiotic-resistant bacteria, which is a roadmap to guide the nation that was issued by President Obama on September 18, 2014. This executive order will implement the *National Action Plan for Combating Antibiotic-Resistant Bacteria*, a plan that intends to have major reductions in the occurrence of urgent and serious threating pathogens, including methicillin-resistant *S. aureus* (MRSA), carbapenemresistant *Enterobacteriaceae* (CRE), and *C. difficile* [6]. Recent studies have demonstrated that critically ill patients colonized with multidrug-resistant pathogens also have a high prevalence of being infected with that particular organism. In such, antimicrobial resistance (AMR) as an independent risk factor also increases morbidity and mortality [7, 8].

combat against multidrug-resistant (MDR) organisms.

78 Contemporary Topics of Pneumonia

**2. Global resistance and global economic impact**

**Table 1.** CDC antibiotic resistance threats in the United States, 2013.

The first case of *K. pneumoniae* carbapenemase-producing CRE was reported in North Carolina in 2001. Since then, cases have been reported in almost every state. Carbapenemase-producing CRE carries antimicrobial resistance genes on mobile plasmids that can move between organisms, thus potentially facilitating a wider and more rapid spread. A clone known as *K. pneumoniae* sequence type 258 was responsible for this global dissemination, particularly in the United States. Knowing the genotype level aids in tracking the epidemiology worldwide [9]. Guh et al. conducted a 2-year surveillance period, which included 599 incident CRE cases that were reported across 7 Emerging Infections Program (EIP) sites (Georgia, Minnesota, Oregon, Colorado, Maryland, New Mexico, and New York). They concluded that the overall crude incidence CRE was 2.93 per 100,000 populations [10]. The overall CRE incidence may be underreported as many hospital laboratories may not preform confirmatory testing [11].

increased from ~5% to an approaching 40%, an increase that has been observed across most of U.S. states [15]. *Acinetobacter* is uniquely able to survive in hospital environments and to develop resistance to antibiotics. When combined these attributes result in both a high potential for endemicity and epidemicity, resulting in both hospital outbreaks and persistent colonization [16]. Studies have indicated that key sources of *Acinetobacter* transmission within hospital units include the following: hands of hospital personnel, contamination of environmental surfaces and medical equipment, environmental shedding by colonized patients, procedures that result in a spray of contaminated fluids, and airborne particles are

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In critically ill patients, *A. baumannii* can invade through breaches in skin integrity or airway protection. This pathogen is associated with high mortality [18]. Debilitated patients in ICUs

a) Severe underlying illness or comorbidities such as diabetes mellitus and chronic lung

b) Circumstances of hospitalization, such as length of stay, high workload, and admission to

c) Infection or colonization of specific sites, respiratory, urinary, gastrointestinal tracts,

d) Exposure to prolonged antimicrobial therapy with broad-spectrum antibiotics, which include carbapenems, fluoroquinolones, aminoglycosides, third generation cephalosporins.

e) Administration of blood product transfusions, enteral feeding and contaminated parenteral

Common sites of infection include respiratory, bloodstream, skin and soft tissue and urine. Mortality associated with *A. baumannii* infections ranges from 7.8 to 23% in general hospital patients and from 10 to 43% in ICU patients. Bacteremia has the highest mortality, and in hematopoietic stem cell transplantation (HSCT) recipients, mortality rates associated with

Extended spectrum β-lactamase (ESBLs) producing *Enterobacteriaceae* produce a hydrolytic β-lactamase enzyme that confers resistance to various penicillins, which also include extended spectrum cephalosporins. Given the resistance, clinicians' remaining treatment option is a carbapenem antibiotic. Carbapenems are last-line antibiotics, and their use in ESBL infections has also contributing to additional resistance [20, 21]. In the United States, the CDC reports an estimated 140,000 healthcare-associated *Enterobacteriaceae* infections occur each year. The CDC also reports that approximately 26,000 of these infections are caused by ESBL-containing *Enterobacteriaceae* bloodstream infections, which contribute to 1700 deaths. The total excess hospital charges per episode of ESBL-bacteraemia are roughly \$40,000 per occurrence. ESBL-producing *Klebsiella* spp. and ESBL-producing *E. coli* are the most common and percentage resistant to extended spectrum cephalosporins are 23 and

are especially prone to *Acinetobacter* infections [15]. High-risk patients include:

units in the acute care center with high a density of infected.

believed to play a role in transmission [17].

burns, or surgical wounds.

*Acinetobacter* bacteremia may reach up to 70% [19].

disease.

solutions.

14%, respectively [5].

CRE is encountered in patients with extensive healthcare exposure. Patients can be hospitalized in an acute short stay hospital, residents of LTCFs (long-term care facilities), LTACHs (long-term acute care hospitals), or outpatients with recent healthcare exposure. These patients also frequently have multiple comorbidities, poor functional status, recent intravenous antibiotic exposure (within 90 days), and indwelling devices (urinary catheter, mechanical ventilation, indwelling lines). Patients that recover from their acute hospitalization are frequently discharged to LTCFs or LTACHs, thus contributing to a viscous cycle [10, 12]. LTACHs play an important role in the regional epidemiology of CRE. In a recent study, 30% of LTACH residents were colonized with *K. pneumoniae* carbapenemase-producing CRE. This represented a ninefold higher prevalence in LTACHs compared to intensive care unit (ICU) patients in acute short-stay hospitals in the same area. Various efforts to reduce the burden of CRE in LTACHs have had only a slight impact [13].

Common sites of infection include respiratory, bloodstream, -wounds, and urinary tract. Urine is the most common site for infection and colonization. Outcomes associated with CRE infections are poor with high mortality rates as high as 50% in some studies. Outcomes vary by the site of infection with blood stream infections carrying the highest mortality and urinary tract infection the lowest [10, 13].

According to the CDC, *Acinetobacter* in the United States causes approximately 12,000 healthcare-associated infections annually. Approximately 7000 of these infections are considered to be multidrug-resistant *Acinetobacter* at a staggering 63%, meaning at least three different classes of antibiotics no longer cures these infections, which contributes to 500 deaths per year. The CDC 2013 publication does not estimate long-term care hospitals or long-term care facilities in the prevalence statistics [10]. Others [14] have estimated that there may be as many as approximately 46,000 cases of *Acinetobacter*-related infections per year in the U.S. and approximately 1 million cases per year globally. In the United States, a 2006–2007 report of 463 hospitals participating in the National Healthcare Safety Network (NHSN) indicated that infections due to *Acinetobacter baumannii* accounted for 3% of all healthcare-associated infections (HAI). Focusing on the ICU, approximately 7% of all HAIs were associated with critically ill patients on mechanical ventilation in the United States, which were caused by *Acinetobacter* [11].

A further concern is that the prevalence of resistance among *Acinetobacter* infections is increasing. Between 2000 and 2009, the percentage of imipenem-resistant *A. baumannii*

increased from ~5% to an approaching 40%, an increase that has been observed across most of U.S. states [15]. *Acinetobacter* is uniquely able to survive in hospital environments and to develop resistance to antibiotics. When combined these attributes result in both a high potential for endemicity and epidemicity, resulting in both hospital outbreaks and persistent colonization [16]. Studies have indicated that key sources of *Acinetobacter* transmission within hospital units include the following: hands of hospital personnel, contamination of environmental surfaces and medical equipment, environmental shedding by colonized patients, procedures that result in a spray of contaminated fluids, and airborne particles are believed to play a role in transmission [17].

The first case of *K. pneumoniae* carbapenemase-producing CRE was reported in North Carolina in 2001. Since then, cases have been reported in almost every state. Carbapenemase-producing CRE carries antimicrobial resistance genes on mobile plasmids that can move between organisms, thus potentially facilitating a wider and more rapid spread. A clone known as *K. pneumoniae* sequence type 258 was responsible for this global dissemination, particularly in the United States. Knowing the genotype level aids in tracking the epidemiology worldwide [9]. Guh et al. conducted a 2-year surveillance period, which included 599 incident CRE cases that were reported across 7 Emerging Infections Program (EIP) sites (Georgia, Minnesota, Oregon, Colorado, Maryland, New Mexico, and New York). They concluded that the overall crude incidence CRE was 2.93 per 100,000 populations [10]. The overall CRE incidence may be underreported as many hospital laboratories may not preform confirmatory testing [11]. CRE is encountered in patients with extensive healthcare exposure. Patients can be hospitalized in an acute short stay hospital, residents of LTCFs (long-term care facilities), LTACHs (long-term acute care hospitals), or outpatients with recent healthcare exposure. These patients also frequently have multiple comorbidities, poor functional status, recent intravenous antibiotic exposure (within 90 days), and indwelling devices (urinary catheter, mechanical ventilation, indwelling lines). Patients that recover from their acute hospitalization are frequently discharged to LTCFs or LTACHs, thus contributing to a viscous cycle [10, 12]. LTACHs play an important role in the regional epidemiology of CRE. In a recent study, 30% of LTACH residents were colonized with *K. pneumoniae* carbapenemase-producing CRE. This represented a ninefold higher prevalence in LTACHs compared to intensive care unit (ICU) patients in acute short-stay hospitals in the same area. Various efforts to reduce the burden of

Common sites of infection include respiratory, bloodstream, -wounds, and urinary tract. Urine is the most common site for infection and colonization. Outcomes associated with CRE infections are poor with high mortality rates as high as 50% in some studies. Outcomes vary by the site of infection with blood stream infections carrying the highest mortality and urinary

According to the CDC, *Acinetobacter* in the United States causes approximately 12,000 healthcare-associated infections annually. Approximately 7000 of these infections are considered to be multidrug-resistant *Acinetobacter* at a staggering 63%, meaning at least three different classes of antibiotics no longer cures these infections, which contributes to 500 deaths per year. The CDC 2013 publication does not estimate long-term care hospitals or long-term care facilities in the prevalence statistics [10]. Others [14] have estimated that there may be as many as approximately 46,000 cases of *Acinetobacter*-related infections per year in the U.S. and approximately 1 million cases per year globally. In the United States, a 2006–2007 report of 463 hospitals participating in the National Healthcare Safety Network (NHSN) indicated that infections due to *Acinetobacter baumannii* accounted for 3% of all healthcare-associated infections (HAI). Focusing on the ICU, approximately 7% of all HAIs were associated with critically ill patients on mechan-

A further concern is that the prevalence of resistance among *Acinetobacter* infections is increasing. Between 2000 and 2009, the percentage of imipenem-resistant *A. baumannii*

ical ventilation in the United States, which were caused by *Acinetobacter* [11].

CRE in LTACHs have had only a slight impact [13].

tract infection the lowest [10, 13].

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In critically ill patients, *A. baumannii* can invade through breaches in skin integrity or airway protection. This pathogen is associated with high mortality [18]. Debilitated patients in ICUs are especially prone to *Acinetobacter* infections [15]. High-risk patients include:


Common sites of infection include respiratory, bloodstream, skin and soft tissue and urine. Mortality associated with *A. baumannii* infections ranges from 7.8 to 23% in general hospital patients and from 10 to 43% in ICU patients. Bacteremia has the highest mortality, and in hematopoietic stem cell transplantation (HSCT) recipients, mortality rates associated with *Acinetobacter* bacteremia may reach up to 70% [19].

Extended spectrum β-lactamase (ESBLs) producing *Enterobacteriaceae* produce a hydrolytic β-lactamase enzyme that confers resistance to various penicillins, which also include extended spectrum cephalosporins. Given the resistance, clinicians' remaining treatment option is a carbapenem antibiotic. Carbapenems are last-line antibiotics, and their use in ESBL infections has also contributing to additional resistance [20, 21]. In the United States, the CDC reports an estimated 140,000 healthcare-associated *Enterobacteriaceae* infections occur each year. The CDC also reports that approximately 26,000 of these infections are caused by ESBL-containing *Enterobacteriaceae* bloodstream infections, which contribute to 1700 deaths. The total excess hospital charges per episode of ESBL-bacteraemia are roughly \$40,000 per occurrence. ESBL-producing *Klebsiella* spp. and ESBL-producing *E. coli* are the most common and percentage resistant to extended spectrum cephalosporins are 23 and 14%, respectively [5].

Sequence type 131 (ST131) is a pathogenic clone of *E. coli* and it also frequently expresses a hydrolytic β-lactamase enzyme called CTX-M-type and has rapidly disseminated worldwide. *E. coli* expressing CTX-M-type enzymes containing ESBLs have been increasingly seen in the community [12, 22–26]. Residency of a long-term care facility has been recognized as a prominent risk factor for acquisition of ESBL infections in the community. Various studies have also identified ESBL bacteremia as an independent risk factor from exposure to fluoroquinolones, first-generation cephalosporins, and finally, a previously known colonization history with an ESBL [25, 27]. Patients are 57% more likely to die from bloodstream infections associated with ESBL-producing *Enterobacteriaceae* than those with bloodstream infections caused by a non ESBL-producing strain [26].

in three or more classes. Extensively drug-resistant (XDR), resistance to all FDA-approved, systemically active agents except for those known to be substantially more toxic than or inferior in efficacy to alternative agents when used to treat susceptible organisms [30]. Finally, PDR, defined, is resistant to all commercially available antibiotics in all classes. MDR *P. aeruginosa* should not be synonymous with carbapenem resistance, as multiple mechanisms of can contribute to resistance. Risk factors for multidrug-resistant (MDR) infections include the following: length of hospital stay, prior use of IV antibiotics, history of *P. aeruginosa* infection, or colonization within the previous year, bedridden in the intensive care unit, mechanical ventilation, history of chronic obstructive pulmonary disease, and malignant disease. Nseir et al. concluded that a new patient admission into a previously occupied ICU room with a patient that had either MDR *P. aeruginosa* or *A. baumannii* was at an independent risk factor for acquisition of those pathogenic organisms. Many studies have examined multidrug-resistant infections as an independent risk factor for mortality, especially when combined with inappropriate antimicrobial

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Environmental reservoirs may be unrecognized as the culprit for outbreaks or ongoing sporadic transmission. Recent studies suggest that the risk of acquiring multidrug-resistant pathogens such as *Acinetobacter* spp., *Pseudomonas* spp., vancomycin-resistant Enterococcus (VRE), MRSA, or *C. difficile* is increased if a new patient admission is placed in a room previously occupied by a colonized or infected patient with one of the above pathogens [33–38]. "Terminal cleans" have been utilized for multidrug-resistant Gram-negative organisms and may be integrated with infection control measures, along with surveillance to limit the hori-

Environmental surfaces are routinely disinfected in hospitals based on infection control policies and procedures. Several factors dictate the type and frequency for these cleanings such as surface characteristics, intensity of people traffic, clinical risk, and patient turnover. Following a patient discharge that was known to be colonized or infected with a multidrugresistant pathogen, a terminal or deep cleaning may be performed. The cleaning regimen

therapy [31, 32].

**4. Infection control**

zontal transmission of multidrug-resistant organisms.

Environmental survival times of infectious pathogens [39]:

a) MRSA survival time ranges from 7 days to >7 months

c) *C. difficile* survival is >5 months

e) *E. coli* from 2 h to 16 months

f) *Klebsiella* from 2 h to >30 months.

b) *Acinetobacter* survival time ranges from 3 days to >5 months

d) *Vancomycin-resistant Enterococcus* ranges from 5 days to >4 months

In a study by Ha et al. [28], they concluded that significant risk factors associated with ESBLproducing *E. coli* bacteremia were prior treatment with fluoroquinolones and cephalosporins, as previous studies have also demonstrated. Moreover, recent surgery, liver disease, and immunosuppressant use were also deemed as significant risk factors. The study resulted in an overall 30-day mortality rate of 14.9%. As described previously, the mortality rate was higher in patients with ESBL-producing *E. coli* than in those without ESBL bacteremia (22.1 vs. 12.2%; *P* = 0.02). A multivariate analysis in this study demonstrated an independent risk factor for mortality (odds ratio = 3.01, 95% confidence interval 1.45–6.28; *P* = 0.003) for ESBL bacteremia [26, 28].

*P. aeruginosa* is a common cause of healthcare-associated infections including pneumonia, bloodstream infections, urinary tract infections, and surgical site infections. *P. aeruginosa* can easily adapt to the environment it inhabits, this ability can lead to colonization, and ultimately invade the human host defenses and cause serious infections. According to the CDC, approximately 7.1% of all healthcare-associated infections in the United States are caused by *P. aeruginosa*. This organism was the second most common cause of pneumonia in the hospital setting, and the third most common cause of Gram-negative bloodstream infections [5]. Kollef et al. recently conducted a global prospective epidemiological study on the prevalence of *P. aeruginosa* causing Ventilator-associated pneumonia (VAP). They concluded that global incidence was 4.1%, and did not differ among countries significantly [29].

In 2013, the CDC's National Healthcare Safety Network (NSHN) reported that 8% of all healthcare-associated infections are caused by *P. aeruginosa*. Among these 8% reported to the NSHN, approximately 13% were considered severe healthcare-associated infections caused by MDR *P. aeruginosa*. By definition, MDR is resistance to at least three different antibiotics classes (mainly antipseudomonal penicillins, aminoglycosides, cephalosporins, and carbapenems). Each year, approximately 51,000 healthcare-associated *P. aeruginosa* infections occur in the United States (according to the CDC). Of these infections, more than 13% are classified as multidrug-resistant (MDR) *P. aeruginosa* and contribute roughly to 400 deaths per year [5].

The true prevalence of multidrug-resistant *P. aeruginosa* is not well established, mainly because there are considerable different definitions used in the literature. Upon reviewing many studies, they tend to report on both MDR and "pan-drug resistant" *P. aeruginosa* infections. In 2011, a new standardized definition was proposed, which classified *Pseudomonas* as MDR, XDR, or pan drug-resistant (PDR) bacteria. MDR as described above is resistant to at least one antibiotic in three or more classes. Extensively drug-resistant (XDR), resistance to all FDA-approved, systemically active agents except for those known to be substantially more toxic than or inferior in efficacy to alternative agents when used to treat susceptible organisms [30]. Finally, PDR, defined, is resistant to all commercially available antibiotics in all classes. MDR *P. aeruginosa* should not be synonymous with carbapenem resistance, as multiple mechanisms of can contribute to resistance. Risk factors for multidrug-resistant (MDR) infections include the following: length of hospital stay, prior use of IV antibiotics, history of *P. aeruginosa* infection, or colonization within the previous year, bedridden in the intensive care unit, mechanical ventilation, history of chronic obstructive pulmonary disease, and malignant disease. Nseir et al. concluded that a new patient admission into a previously occupied ICU room with a patient that had either MDR *P. aeruginosa* or *A. baumannii* was at an independent risk factor for acquisition of those pathogenic organisms. Many studies have examined multidrug-resistant infections as an independent risk factor for mortality, especially when combined with inappropriate antimicrobial therapy [31, 32].
