By its mechanism of action, an antimicrobial can either kill susceptible microbes (i.e., microbicidal) or inhibit their growth (i.e., microbiostatic). Antimicrobial drugs have been developed against the whole range of microbial pathogens, including viruses, bacteria, fungi, and many parasites. With respect to bacterial pathogens, examples of bacteriostatic antibiotics are the tetracyclines, macrolides, sulfonamides, and chloramphenicol. Bactericidal drugs include the beta-lactams, carbapenems, vancomycin, and aminoglycosides [13].

Mechanisms by which antimicrobials act on susceptible organisms include [13]:

When the infecting organism and its susceptibility are known, it is unnecessary to use a broad-spectrum antimicrobial. Broad-spectrum antimicrobials may disrupt the patient's normal flora and cause colonization by resistant strains, super infection, or pseudomembranous colitis. For specific therapy, the safest narrow-spectrum antibiotic should be selected, or, in some situations, a combination of drugs should be used.

Chromosomal and extrachromosomal changes can lead either to drug destruction (e.g., beta-lactamases destroy penicillin and cephalosporin derivatives) or to an alteration of drug-receptor/target sites (e.g., methicillin resistance in S. aureus). Although it occurs infrequently, chromosomal resistance results from spontaneous mutation in the gene locus that controls susceptibility to a drug and is usually expressed as a change in the drug-receptor/target site.

Extrachromosomal drug resistance achieved by plasmid exchange is potentially more serious and enables micro-organisms to distribute genetic material more rapidly. Chromosomal change is spread mainly to daughter cells from generation to generation. Extrachromosomal resistance involving plasmids can spread between organisms to different strains and even to different species of bacteria. Chromosomal changes usually mediate resistance to a single antimicrobial, while plasmids usually code for resistance to several antimicrobials [20].

According to 2015–2017 data, 15 pathogen groups accounted for about 86% of reported healthcare-associated infections, the most common being Escherichia coli (17.5%), S. aureus (11.8%), Klebsiella spp. (8.8%), and Pseudomonas aeruginosa (8%) [167]. Nearly 20% of cases were associated with drug-resistant phenotypes. This is important to note because, in the last several decades, there has been an increase in the ability of these common bacteria to resist standard antibiotics. Examples of this antibiotic resistance include [13]:

Although some organisms remain sensitive to antibiotics for many years, this is not usually the case. From a historical perspective, the major antibiotic resistance events include [14,22,54,136,166]:

As discussed, resistance to antibiotics is an emerging problem in medicine, and its effects are being noted on an ever-increasing scale. Multidrug-resistant organisms are diminishing the ability to control the spread of infectious diseases. The rate at which resistant organisms develop is not solely a function of the use of antimicrobials in humans. It is also influenced by the use of these agents in veterinary medicine, animal husbandry, agriculture, and aquaculture, as has been emphasized in a report on bacterial resistance issued by the U.S. Office of Technology Assessment [24].

The growth of resistant organisms in healthcare settings has had a significant effect on healthcare costs. Although it is difficult to calculate, researchers estimate that resistant organisms are responsible for up to $20 billion in direct healthcare costs each year, with an additional $35 billion in indirect costs (e.g., lost productivity) [54].

In the early 1940s, when penicillin first became available, S. aureus isolates were highly susceptible. By the early 1950s, 65% to 80% of nosocomial isolates were reported to be resistant to penicillin. Now, more than 90% of community- and hospital-acquired S. aureus isolates are penicillin-resistant [13].

The prevalent community-acquired strain in the United States appears to have evolved from the methicillin-susceptible S. aureus (MSSA) strain known as ST8. The resistant strains have been designated by the CDC as USA300 and USA400, with USA300 being more common [36,37]. Both strains are characterized by the Panton-Valentine leukocidin (PVL) gene and the SCCmec IV element, which are responsible for the resistance to beta-lactam antibiotics and rarely identified in healthcare-associated MRSA isolates [38]. The USA400 strains (designated ST1) were first seen in the Midwest in 1966 and appear to have more S. aureus toxins than the USA300 strains. The epidemic is predominately caused by the USA300 strain.

Healthy children and adults commonly carry S. aureus in the anterior nares. In most individuals, this carriage state is transient, lasting a matter of weeks. At any given time, an estimated 30% of the U.S. population has S. aureus nasal carriage [38,40]. About 2% of the general population carries MRSA in the nose, a rate that increases to 5% among hospitalized patients [39]. As with sensitive strains of S. aureus, nasal carriage of MRSA is transient, and carriers are at low risk for developing a serious MRSA infection. Healthcare workers have a 50% to 90% higher S. aureus nasal carriage rate than the general population. S. aureus can be easily transferred from the anterior nares to the skin and other body areas (e.g., pharynx, axilla, rectum, perineum); consequently, when given a portal of entry, it can cause a significant infection [13,38]. MRSA infections most commonly present as skin and soft tissue inflammatory lesions (e.g., cellulitis, furuncles) and have been reported as an emerging cause of recurrent skin and soft tissue disease among otherwise healthy persons outside the healthcare setting [38,41]. In 2005, an estimated 14 million outpatient healthcare visits were related to infections of the skin and soft tissue [42].

As noted, MRSA is thought to be transmitted within institutions from patient to patient primarily via hand carriage of healthcare workers who have been contaminated by contact with colonized or infected patients or with devices, items, or environmental surfaces that have been contaminated with body fluids containing MRSA. Colonized or infected healthcare workers may also be reservoirs [43]. The role of the environment seems to be less important, except in burn units, ICUs, and other special facilities where prevention and control measures should be tailored to the area's unique needs and population [11]. Other risk factors for acquiring MRSA during hospitalization vary and depend on the population studied and specific circumstances. Important risk factors include prolonged hospitalization, the length of the period preceding antimicrobial therapy, stay in an ICU or burn unit, or exposure to a colonized or infected patient [13,43].

Vancomycin has been the preferred treatment for both community-acquired and healthcare-associated MRSA. However, concerns have been raised about its efficacy, particularly over its slow bactericidal activity, emergence of resistant strains, and possible "MIC creep" among susceptible strains [82]. Strains of MRSA with reduced susceptibility to vancomycin were first discovered in Japan in 1996. Resistant strains are called VISA and VRSA. Several documented cases of VRSA infection have occurred worldwide, with most occurring in the United States, but as of 2014, these instances are exceedingly rare and are able to be treated with other FDA-approved antimicrobials [83,124]. In January 2011, the American Society of Health-System Pharmacists, the Infectious Diseases Society of America (IDSA), and the Society of Infectious Diseases Pharmacists published consensus-based recommendations for vancomycin dosing and monitoring [82].

Several risk factors have been identified for VRE, including age older than 60 years, prior hospitalization, placement in the ICU, major underlying disease, surgery, immunosuppression, exposure to invasive devices, and long-term antibiotic therapy [125]. The reservoirs most often identified in outbreaks of VRE include infected or colonized patients, healthcare workers' hands, and contaminated inanimate objects. Risk of transmission is greatly increased in patients receiving care at multiple facilities and in patients who are transported between acute care, ambulatory and/or chronic care, and long-term care environments [9,11,72].

Penicillin resistance occurs in a number of different pneumococcal serotypes, but it appears to be much more prevalent among those types that most frequently cause disease in children. This is consistent with the hypothesis that many of these organisms originate in children and spread to adults. This concept is supported by the occurrence of outbreaks of resistant pneumococci in childcare facilities.

Crowded conditions, such as those found in day care centers, and prior beta-lactam antibiotic therapy are the principal predisposing factors to colonization and disease. Populations at greatest risk include the elderly, children younger than 2 years of age, African Americans, American Indians, Alaska Natives, and persons with underlying medical conditions, including human immunodeficiency virus (HIV) infection and sickle-cell disease [99]. Acute otitis media and meningitis are the two conditions caused by resistant pneumococci that are the most difficult to treat [102]. Treating meningitis is especially challenging when caused by a strain of S. pneumoniae that is highly resistant to penicillin and third-generation cephalosporins [101]. The concentration of beta-lactams in cerebrospinal fluid and middle ear fluid are frequently inadequate to allow prompt elimination of some intermediate and highly resistant pneumococcal strains.

In the 1950s, streptomycin was found to effectively treat TB; however, resistance soon developed, not only to streptomycin but also to several other antibiotics, including rifampin, isoniazid, pyrazinamide, and ethambutol, all of which had previously shown reasonable effectiveness against TB. MDR-TB was subsequently defined by the CDC as M. tuberculosis bacilli that are resistant to at least the two most effective antituberculosis drugs, isoniazid and rifampicin. The emergence of MDR-TB has become a serious threat to elimination of the disease [114]. XDR-TB has been defined as M. tuberculosis bacilli that are resistant to isoniazid and rifampin, plus resistant to any fluoroquinolone, and at least one of three injectable second-line drugs (i.e., amikacin, kanamycin, or capreomycin) [119,120]. Because of its resistance to both first- and second-line drugs, treatment of patients with XDR-TB often is ineffective. XDR-TB is of particular concern in patients with HIV or other immunodeficiency [119].

Many infections in hospitalized or institutionalized patients are the direct result of indwelling urinary catheters, central venous catheters, and intubation. These invasive medical devices should be avoided unless they are clearly indicated. In addition, proper vaccination of medical staff and patients to prevent infection is an effective method to prevent the spread of S. pneumoniae, Haemophilus influenzae, and Neisseria meningitides [10,11].

Another step is to prevent transmission of resistant bacteria between patients. A simple, effective method of infection containment is hand washing [11]. Participation in hospital infection control programs also is necessary [20]. A coordinated effort to contain pathogens according to hospital infection control guidelines makes it easier to prevent the spread of multidrug-resistant bacteria.

Education in basic infection control practices, such as Contact Precautions, should not be confined only to direct clinical caregivers. Any person entering a patient's room, from physicians to maintenance personnel, increases the possibility of the organism progressing from that room to another patient's room or other hospital areas. All persons in contact with a patient infected with a resistant organism should be diligent about necessary precautions.

Cohorting patients who have resistant organisms is an accepted practice to control transmission and involves placing patients with similar infections together in rooms. This is effective unless an immunocompromised patient who has been treated successfully is placed in the same room with a patient who is still infectious. In these cases, transmission is possible. Cross-contamination also is a constant danger in the hospital setting. Resistant infections can be particularly dangerous in acute-care facilities that involve treatment of immunocompromised patients, such as oncology wards. All long-term care facilities, including acute or subacute facilities or skilled nursing facilities, face the same length of stay, cohorting, and discharge difficulties, as do short-term acute-care facilities.