Observational descriptive studies establish the case definition of an infectious disease event by obtaining data for analysis from available primary (eg, medical records) or secondary (eg, infection control surveillance) sources. These data enable the characteristics of the population that has acquired the infection to be delineated according to (1) “person” (age, sex, race, marital status, personal habits, occupation, socioeconomic status, medical or surgical procedure or therapy, device use, underlying disease, or other exposures or events), (2) “place” (geographic occurrence of the health event or outbreak, medical or surgical service, place of acquisition of infection, or travel), and (3) “time” (preepidemic and postepidemic periods, seasonal variation, secular trends, or duration of stay in hospital). The information from descriptive studies might provide important clues regarding the risk factors associated with infection, and in each case, it is hoped that an analysis of the collected data might be used to generate hypotheses regarding the occurrence and distribution of disease or infection in the population(s) being studied.

Observational analytic studies are designed to test hypotheses raised by the findings in descriptive investigations. The objectives of these studies are (1) to establish the cause and effects of infection in a population and (2) to determine why a population acquired a particular infection in the first place. The three most common types of observational analytic studies are cohort studies, case-control studies, and prevalence or cross-sectional studies.

Cohort Studies In cohort studies, hypotheses that have been generated from previous (descriptive) studies are tested in a new population. A population of individuals (a cohort) that is free of the infection or disease of interest is recruited for study. The presence or absence of the suspected (hypothesized) risk factors for the disease is recorded at the beginning of the study and throughout the observational period. All members of the cohort population (eg, all premature infants admitted to a neonatal intensive care unit [ICU] during a defined time period) are followed over time for evidence or appearance of the infection or disease and classified accordingly as exposed or unexposed to specific risk factors. If the observation period begins at the present time and continues into the future or until the appearance of disease, the study is called a prospective cohort study. If the population studied is one that in the past was apparently free of the markers of disease on examination of records or banked laboratory specimens, it may be chosen for study if data on exposure to the suspected risk factors for disease are also available. The population may be followed to the present or until the appearance of disease. This type of study, common in occupational epidemiology, is called a historical or retrospective cohort study.

A key requirement of a cohort study is that participants be reliably categorized into exposed and unexposed groups. Relative risk, that is, the ratio of the incidence of the outcome in the exposed group to the incidence in the unexposed group, is used to measure the strength of an association between exposures or risk factors and disease. Cohort studies have the advantage of enabling identification and direct measurement of risk factors associated with disease, determination of the incidence of infection and disease, and ascertainment of the temporal relationship between exposure and disease. In cohort studies, observational bias may be less of a limitation on the validity or results, since the information on the presence of risk factors is recorded before the outcome of disease is established. To ensure sufficient numbers for analysis, cohort studies require continual follow-up of large populations for long periods unless the disease under investigation is one of high incidence. Cohort studies are, in general, more expensive and time-consuming to conduct and are not suitable for the investigation of uncommon infections or conditions. However, they render the most convincing nonexperimental approach for establishing causation.

Case-Control Studies In a case-control study, individuals (cases) who are already infected, ill, or meet a given case definition are compared with a group of individuals (controls) who do not have the infection, disease, or other outcome of medical interest. In contrast to cohort studies, participants in a case-control study are selected by manifestation of symptoms and signs, laboratory parameters, or a specific condition, disease, or outcome. Thus, the search for exposure of case and control subjects to potential risk factors remains a retrospective one. For case-control studies, the measure of association between exposures or risk factors and health outcomes are expressed as an odds ratio, that is, the ratio of the odds of an exposure, event, or outcome occurring in a population to the odds in a control group, where the odds of an event is the ratio of the probability of it occurring to the probability of it not occurring.

The presence of significant differences in the exposure to risk factors among cases vs control subjects suggests an etiologic (causal) association between those factors and the infection or disease defined by cases. Case-control methods are useful for studying infections, events, or outcomes likely associated with multiple risk factors or low incidence rates; for investigating situations in which there is a long lag-time between exposure and outcome of interest; and for establishing etiologic associates or causation of a disease, infection, or other outcome when there is no existing information about the cause or source. In an attempt to reduce bias, control subjects might be selected from individuals matched with cases for selected characteristics, such as age, gender, socioeconomic status, or other variables not suspected or under investigation as risk factors. Compared with cohort studies, case-control studies may be conducted in relatively shorter time, are
relatively less expensive, or may require a smaller samples size to execute. Limitations of case-control studies include selection bias in choosing cases and control subjects; recall bias in which study subjects might have difficulty in remembering possible exposures; incomplete information on specific exposures; or risk factor data may be difficult to find (or remember). Case-control studies are not used to measure incidence or prevalence rates and, generally, are not capable of establishing temporal relationships between an exposure and outcome.

Prevalence or Cross-sectional Studies In prevalence studies, the presence of putative risk factors and the disease under investigation is recorded in a survey of a study population at a specific point in time or within a (short) time period. The rates of disease among those with and without the suspected risk factors are compared. Thus, cross-sectional studies can establish association but not causation for suspected risk factors. Prevalence studies are relatively inexpensive and can be carried out rapidly if well planned. However, they do not allow the ascertainment of risk factors at the beginning of disease nor do they enable one to establish a temporal sequence of risk factors preceding the infection or other outcome of interest. Point prevalence, period prevalence, and seroprevalence surveys are examples of cross-sectional studies.

In experimental studies, the investigator compares an exposure of individuals in a population to a suspected causal factor, a prevention measure, a therapeutic regimen, or some other specific intervention. These exposure modalities are randomly allocated to comparable groups, thereby minimizing confounding factors. Both the exposed and unexposed groups are monitored thereafter for specific outcomes (eg, appearance of infection or disease, evidence of effective prevention or control of the disease, or cure). Experimental studies often are used to evaluate antimicrobial or vaccine treatment regimens and are generally more expensive to conduct than observational studies. Within healthcare settings, studies that examine restriction of certain antimicrobials or promotion of use of alternative antimicrobials for the control of antimicrobial resistance could be considered under the category of experimental. For ethical reasons, it is rarely possible to expose human populations to potential pathogens or to withhold a preventive measure that could potentially be beneficial to patients. Unfortunately, many animal hosts are not naturally susceptible to many agents of human disease. Thus, one has to be careful when extrapolating epidemiologic findings in animal experimental studies to the control of infections in human subjects.

Quasi-experimental studies: This type of study shares the design characteristics of experimental studies but lacks random assignments of study subjects. Quasi-experimental studies are useful where randomization is impossible, impractical, or unethical. The main drawbacks of quasi-experimental studies are their inability to eliminate confounding bias or establish causal relationships. The most common quasi-experimental design is the beforeafter study in which there is a baseline measurement of the outcome (prospectively or retrospectively) followed by an intervention with measurement of the outcome and an assessment whether the intervention altered the outcome.

The agents causing healthcare-associated infectious diseases are diverse microorganism ranging in size and
complexity from viruses and bacteria to protozoa and helminths. Bacteria, fungi, and certain viruses have been the most recognized and studied causes of HAIs.²² For transmission to take place, microorganisms must remain viable in the environment until contact with the host has been sufficient to allow infection. Reservoirs that allow the agent to survive or multiply may be animate, as exemplified by HCP carriage of S aureus in the anterior nares or throat,²³ or inanimate as occurs in the environment, as demonstrated by Pseudomonas spp. colonization of sink areas, Legionella in hot and cold water supply systems,²⁴ C difficile spores on computer keyboards,²⁵ or Serratia marcescens growing in contaminated soap or hand lotion preparations.²⁶

Certain intrinsic and genetically determined properties of microorganisms are important for their survival in the environment. Intrinsic and genetic properties that enhance survival include the ability to resist the effects of heat, drying, ultraviolet light, or chemical agents, especially antimicrobials, and the ability to independently multiply in the environment or to develop and multiply within another host or vector. Intrinsic infectious agent factors important to the production of disease include infectivity; pathogenicity; virulence; the infecting dose; the infectious agent’s ability to produce toxins; its immunogenicity and ability to resist or overcome the human immune defense system; its ability to replicate only in certain types of cells, tissues, or hosts (vectors); its ability to persist or cause chronic infection; and its interaction with other host mechanisms, including the ability to cause immunosuppression (eg, HIV).

Once transferred to a host surface, infectious agents may multiply and colonize without invading or evoking a measurable host immune response.²⁷ The presence of an infectious agent at surface sites in the host does not define the presence of an infection. Nonetheless, colonized patients may act as the reservoir and/or source of transmission to other patients or HCP.²⁸

If infection takes place, a measurable immune response will develop in most hosts even if the infection is subclinical. The likelihood of infectious agents causing infections is increased in nonimmune hosts, and infections are most likely to occur in nonimmune, immunocompromised hosts. A microorganism’s ability to infect another host vector (eg, yellow fever virus in mosquitoes) or another nonhuman reservoir (eg, yellow fever virus in monkeys) is important in the epidemiology of certain infectious diseases globally but plays little role in the epidemiology of HAIs where vector-borne infectious diseases are uncommon and where hospital settings have sealed windows/doors and controlled heating, ventilation, and air conditioning (HVAC) systems in the United States.

Infection depends on exposure of a susceptible host to an infecting agent. Exposure of the susceptible host to such agents is influenced by age, behavior, family associations, occupation, socioeconomic level, travel, avocation, access to preventive healthcare, vaccination status, or hospitalization. Whether or not disease takes place in the infected host and the severity of disease when it occurs depends not only on the intrinsic virulence factors of the infectious agent but also more importantly on the pathogenicity of the infectious agent and host pathogen interactions. The host immune defenses exist to prevent infection. Thus, any reduction in host defenses may allow infection to take place with a smaller dose of microorganisms or at a body site that is not usually susceptible to infection. A combination of reductions in host defense characteristics and the requirements for an agent to cause infection are typical of the interactions that allow acquisition of opportunistic infections in immunocompromised patients.^29,30

Host factors important to the development and severity of infection or disease may be categorized as intrinsic or extrinsic. Intrinsic factors include the person’s age at infection; birth weight; sex; race; nutritional status³¹; comorbid conditions (including anatomic anomalies) and diseases; genetically determined immune function; immunosuppression associated with other infections, diseases, or therapy; vaccination or immunization status; previous exposure or infection with an infectious agent or similar agents; and the psychological state of the host.^32,33 Colonization of the upper and lower respiratory tracts is more likely when the severity of illness increases in critically ill patients. This, along with other host impairments (eg, reduced mucociliary clearance or changes in systemic (pH), allows colonization to progress to invasive infection. Moreover, other clinical conditions may lead to an alteration in epithelial cell surface susceptibility to binding by bacteria, leading to enhanced colonization.²⁷ Extrinsic factors include invasive medical or surgical procedures, the presence of medical devices, such as intravenous catheters or mechanical ventilators, specific behaviors such as sexual practices and contraception, duration of antimicrobial therapy and hospitalization, and exposure to hospital personnel.

The environment serves as the background on which infectious agent-host interactions take place. Environmental factors can positively or negatively influence the spread of infection. Environmental factors that influence the spread of infection include (1) physical factors such as climate conditions of heat, cold, humidity, seasons, and the built environment (eg, ICUs, outpatient clinics, long-term care [LTC] facilities, or water reservoirs); (2) biologic factors (eg, the presence or absence of intermediary hosts such as insect or snail vectors, presence of biofilms in sinks or devices); and (3) social factors (eg, socioeconomic status, types of food and methods of preparation, and availability of adequate housing, potable water, adequate waste disposal, and healthcare amenities).³⁴ These environmental factors influence both the survival and the multiplication of infectious disease agents in their reservoirs and the behavior of the host in housing, occupation, and recreation that relate to exposure to pathogens. Food- and waterborne diseases flourish in warmer months due to better incubation temperatures for microorganism multiplication and the recreational exposures of the host, whereas respiratory agents appear to benefit from increased opportunities for airborne and droplet transmission in the reduced humidity and closer living environments during the winter. In U.S. hospitals, the frequency of hospital-acquired Acinetobacter spp. infections is increasing in ICUs. The seasonal variation in the incidence of Acinetobacter spp. infections is thought to be due to changes in climate since the number of Acinetobacter spp. infections identified increases in the summer months.³⁵

Within healthcare settings, the components of the agent, host, and environment triad interact in a variety of ways to produce HAIs. For example, ICUs are now considered the areas with the highest risk for the transmission of healthcare-associated pathogens in U.S. hospitals.^36,37 Moreover, methicillin-resistant S aureus (MRSA), VRE, extended spectrum β-lactamase (ESBL) producing E coli and Klebsiella, and β-lactam-resistant Pseudomonas aeruginosa are endemic in many ICUs in these hospitals.^36,37 The emergence of vancomycin-resistant S aureus (VRSA) in U.S. institutions in 2002 highlighted the unwelcome but inevitable reality that VRSA may become endemic in acute care settings.^38,39 A complex interaction of contributory factors, such as inadequate hand hygiene and suboptimal infection control practices among HCP, fluctuating staffing levels, an unexpected increase in patient census relative to staffing levels in the ICU, or an unprecedented increase in the number of severely ill patients with multiple invasive devices, could all contribute to the acquisition of hospital or long-term care facility infections caused by one of these endemic microorganisms.^{40,41,42,43,44} Adding to the complexity of the process would be the unquantifiable mechanism of transmission of the agent from the host to HCP, HCPto-HCP, and host-to-environment. Thus, acceptable measures for the prevention and control of HAIs dictate that healthcare epidemiologists study and analyze the interrelationships among all components of the triad of agent, host, and environment.^36,37

It is well known that the social environment is important in influencing personal behavior that affects the direct transmission of agents, such as HIV transmission to infants from nursing mothers via breast milk in regions of high HIV endemicity, Gram-negative microorganisms transmitted via artificial nails worn by HCP in U.S. ICUs,^43,45 and increased risk of sexually transmitted infections among vulnerable populations who cannot always use condoms or other barrier protection or do not have access to preexposure prophylaxis. What must be understood to be equally relevant is the impact of other factors in the social environment, such as the distribution of and access to medical resources; the use of preventive services^{46,47,48,49,50}; the enforcement of codes in food preparation, infection prevention practices, or occupational health practices; the extent of acceptance of breast-feeding for children^51,52,53; and the acceptance of advice on the appropriate use of antimicrobials.^{54,55,56,57,58} Also, there must be an appreciation by patients, relatives, and healthcare providers alike that at-risk patients (eg, those born very prematurely, the very elderly, or those with premorbid end-stage cardiac or pulmonary disease) who have numerous indwelling catheters or invasive devices, or who have undergone multiple invasive or surgical procedures will be particularly susceptible to HAIs that are likely nonpreventable.

Microenvironments, including military barracks, dormitories, day care centers, LTC settings, ambulatory surgery and dialysis centers, and acute care hospitals, provide special venues for infectious agent-host interactions. Historically, epidemics in these institutional environments provided the experience that drove the development and acceptance of infection control and prevention measures, guidelines, and the need for formal infection control resources and infrastructure. Acute care hospitals, especially those offering regional, secondary, and tertiary care, remain the dominant examples of high-risk environments. Changing patterns of outpatient practice, home healthcare, and technical advances in medicine have resulted in increasingly severely diseased and injured populations being managed in acute care facilities. Data from the CDC demonstrate that the changing healthcare environments in the United States are resulting in increasing numbers of ICU patients, while there has been a general decrease in the number of general medical beds.²²

Special units for intensive medical or surgical care for extensive burns, trauma, transplantation, and cancer chemotherapy frequently care for patients with increased susceptibility to infection.⁵⁹ In these susceptible patients, reduced inocula of pathogens or commensals are required to cause infection, infection may take place at unusual sites, and usually nonpathogenic agents may cause serious disease and death. Frequent opportunistic infections in these patients often require repeated, broad-spectrum, and extended therapy with multiple antimicrobials, leading to increasingly resistant resident microbial populations.^22,57,58 The emergence in ICU settings of pathogens resistant to all available antimicrobials is becoming more common.³⁶ For example, P aeruginosa has the capability to acquire new resistance mechanisms through horizontal transfer or chromosome mutations. This can occur while the patient is actively being treated and result in antibiotic failure and lead to mortality.⁶⁰ Additionally, VRE colonization and contamination in the ICU has been associated with transmission to other patients.⁶¹

Outpatient parenteral antimicrobial therapy (OPAT) was originally developed in the 1970s to treat cystic fibrosis patients. OPAT gives patients the opportunity to have central venous catheters (CVC) placed and kept in situ for intravenous home infusion therapy to avoid prolonged hospital stays. The Infectious Diseases Society of America (IDSA) has published guidelines listing requirements for teamwork, communication, monitoring, and outcome measurements in order to establish an effective and safe OPAT program.^62,63 The benefit of OPAT is reduced exposure to hospital environments and decreased costs to patients, hospitals, and payers. OPAT also offers significant benefits to patients. It reduces their hospital stays and allows them to be in the familiar setting of their own home. Patients also learn to become advocates for their own health and ensure that appropriate and complete treatment is provided. On the other hand, a patient with a CVC in the home environment may potentially be at risk of CLABSI due to contamination of lines, dressings, and infusates in a care environment where infection control practices are not as well understood, practiced, or regulated. Some studies have reported readmission rates above 20% in patients participating in OPAT because of worsening infection, adverse drug reactions, and catheter-related complications. Recent studies have suggested that early infectious disease follow-up was associated with a lower 30-day hospital readmission rate.⁶⁴

For infection to take place, microorganisms must be transferred from a reservoir to an acceptable entry site on a susceptible host in sufficient numbers (the infecting dose) for multiplication to occur. The infecting dose of a microorganism may depend in varying degrees on infectivity, pathogenicity, or virulence of the microorganism itself. The entire transmission process constitutes the chain of infection. Within the healthcare setting, the reservoir of an agent may include patients themselves, HCP (eg, nares or fingernails), potable water, soap dispensers, hand lotions, mechanical ventilators, intravascular devices, infusates, multi-dose vials, or various other seemingly innocuous elements in the environment.

Direct transmission from another host (healthy or ill) or from an environmental reservoir or surface by direct contact or direct large-droplet spread of infectious secretions is the simplest route of agent spread. Examples of direct contact transmission routes include kissing (infectious mononucleosis), shaking hands (common cold [rhinovirus]), or other skin contact (eg, contamination of a wound with Staphylococcus spp. or Enterococcus spp. during trauma, surgical procedures, or dressing changes). Transmission of Neisseria meningitidis, group A Streptococcus, or the respiratory syncytial virus (an important cause of respiratory infection in young children worldwide) by large respiratory droplets that travel only a few feet is regarded as a special case of direct contact transmission.

Vertical transmission of infection from mother to fetus is another form of direct contact transmission that may occur through the placenta during pregnancy (eg, HIV, rubella virus, hepatitis B virus, or parvovirus) by direct contact of the infant with the birth canal during childbirth (group B streptococci) or via breast milk (HIV).

Indirect contact transmission may occur via the hands of people, contaminated inanimate objects (fomites), various work surfaces, food, biological fluids (eg, respiratory, salivary, gastrointestinal, or genital secretions, blood, urine, and stool), invasive or shared medical devices, or through arthropod or animal vectors. Indirect contact transmission is the most common mechanism of transfer of the microorganisms that cause HAIs and commonly occurs via the hands of HCPs, their clothing, or instruments like stethoscopes or thermometers. Rapid dissemination of agents, such as respiratory syncytial virus or the influenza virus may occur in day care centers through salivary contamination of shared toys and games. C difficile is an important cause of infectious diarrhea transmitted from patient to patient in acute care hospitals. Its transmission is abetted by its spore-forming ability to survive in the environment, and its selection and promotion in patients by the repeated and prolonged use of antimicrobials.^83,84,85 Medical devices contaminated with bloodborne pathogens, including hepatitis B and C viruses and HIV, are sources of infection for both patients and HCPs in healthcare institutions. Some viruses can remain viable for extended periods under suitable conditions. For example, hepatitis B virus is relatively stable in the environment and remains viable in dried form for at least 7 days to 2 weeks on normal working surfaces
at room temperature. This property has led to hepatitis B virus transmission among dialysis patients through indirect contact via dialysis personnel or work surfaces in the dialysis unit.^{86,87,88,89,90,91} Examples of other sources of HAIs that occur through indirect contact include bacterial or viral contamination of musculoskeletal allograft tissues, intrinsic contamination of infusates or injectable medications, liquid soap dispensers, or contaminated medications prepared in the hospital pharmacy.^{92,93,94,95,96,97} The continuing presence of Pseudomonas spp. and other Gram-negative rods in potable water supplies acts as an important reservoir for these agents and a readily available source for hand transmission to patients, especially the severely ill.^{98,99,100,101,102}

Airborne transmission is another mechanism of indirect transfer of pathogens. Microorganisms transmitted by this method include droplet nuclei (1-10 µm) that remain suspended in air for long periods, spores, and shed microorganisms. The airborne transfer of droplet nuclei is the principal route of transmission of M tuberculosis, varicella, and measles. The transmission of Legionella spp. through the air in droplet nuclei from cooling tower emissions, and from environmental water sites, such as air conditioning systems, central humidifiers, and respiratory humidification devices, is another important example of this type of spread.^{103,104,105,106,107,108} More recently, outbreaks of Mycobacterium chimaera were found to be secondary to contamination of exhaust air from heater-cooler devices used during cardiac surgery.^109,110 The emergence of extensively drug-resistant (XDR) strains of M tuberculosis (ie, strains resistant to practically all second-line agents) has again highlighted the importance of airborne transmission and the fact that the underlying reason for XDR emergence stems from poor general tuberculosis control measures and the subsequent development of multidrug-resistant (MDR) tuberculosis.^111,112,113

CDI, the most common cause of healthcare-associated diarrhea in the United States, can be acquired through the transmission of spores via hospital work surfaces and the hands of HCP.^85,114,115 Fungal spores can be an important cause of HAIs. Spores of invasive fungi, such as Aspergillus spp., may be carried over long distances in hospitals to cause severe infections in immunosuppressed patients. The risk of spore contamination was highlighted by an outbreak of Curvularia lunata (a black fungus) among silicone breast implant recipients, who had undergone the breast augmentation procedures in an operating room that was erroneously maintained at negative pressure resulting in high spore counts in the operating room environment (operating rooms are supposed to be maintained at net positive pressures relative to adjacent areas).¹¹⁶ The surgeons had not implemented a closed system for inflating the breast prostheses with saline; instead, they had inflated the silicone prostheses using syringes filled with saline drawn up from a sterile bowl exposed to the ambient operating room environment. The end result was contamination of sterile saline in the open bowl with C lunata spores, which were then injected inadvertently into the breast prostheses.¹¹⁷ In some settings (eg, burn units), staphylococci have been thought to spread on skin squamous cells that have been shed from patients or HCP. The importance of this mode of transmission, however, is not thought to be of great significance in other care settings. More recent data suggest that S aureus is a common isolate in oropharyngeal cultures.^118,119 Although the epidemiologic implications of this finding remain uncharacterized, the ramification for infection control in healthcare facilities would be enormous if indeed the chain of infection for S aureus includes oropharyngeal secretions or droplet nuclei.

Vector-borne transmission by arthropods or other insects is a form of indirect transmission and may be mechanical or biologic. In mechanical vector-borne transmission, the agent does not multiply or undergo physiologic changes in the vector; in biologic vector-borne transmission, the agent is modified within the host before being transmitted. Although the potential for microorganism carriage by arthropods or other insect vectors has been described,^120,121 this type of transmission has not played any substantial role in the transmission of HAIs in the United States. In tropical countries with endemic dengue, yellow fever, or malaria, vector-borne transmission of infectious diseases is more important, requiring screening of patients or other interventions, and preventive measures not ordinarily required for patients in colder climates.

Humans are the primary reservoir for Neisseria gonorrhoeae, Salmonella enterica serotype Typhi, HIV, hepatitis B and C viruses, and Shigella spp. Animals (zoonoses) harbor rabies virus, Yersinia pestis, Leptospira spp., nontyphi Salmonella, and Brucella spp. Environmental reservoirs include the soil (Histoplasma capsulatum, Clostridium tetani, and Bacillus anthracis) and water (Legionella spp., P aeruginosa, Serratia spp., and Acinetobacter spp). For some infections, the interaction between host, agent, and environment might include an extrinsic life cycle of the agent outside of the human host. The interplay of such factors can add significant layers of epidemiological complexity to properly understand the cause of an outbreak or in characterizing the chain of infection.

Interventions chosen to modify a reservoir depend on whether the reservoir is animate or inanimate. Quarantine, the restriction of movement of individuals who have been exposed to a potentially transmissible agent for the entire incubation period of the infection, is rarely used to control human disease in healthcare settings and has been replaced, largely, by active surveillance of exposed individuals in acute care hospitals and LTC facilities. Animate reservoirs (ie, carriers) include HCP who are colonized with potential pathogens in their nares or hands, relatives (or pets) who visit patients in the hospital, and patients known to be colonized or infected with a particular healthcare pathogen and are moved from one unit to another within a given institution or are transferred from one hospital to another. Since disease is often subclinical, it may be difficult to recognize and separate silent carriers from susceptible persons.

Treatment of humans to eradicate carriage of transmissible pathogens that are typically found in healthcare settings has had variable success. For example, treatment to eradicate VRE often yields mixed results,^131,132,133 whereas there has been some success in the eradication of MRSA among hospital inpatients^134,135,136 and in the community.¹³⁷ There are no compelling data that show an association between eradication of Gram-negative carriage among patients or HCP and reduced rates of transmission. Thus, removal of an individual HCP, known to be a reservoir for a potentially transmissible pathogen, from a healthcare setting (eg, bone marrow unit or surgical ICU) with susceptible patients might be the only control or preventive option. However, removal of a colonized healthcare provider should generally only be undertaken if the provider has been linked by epidemiology and molecular diagnostics to the patient infections (eg, MRSA, carbapenem-resistant Enterobacteriaceae [CRE], C difficile). Human carriers of transmissible pathogens may be isolated from susceptible individuals, who are not colonized or infected, for the duration of their stay at the institution or for as long as they harbor the microorganism.¹³⁸ Finally, ethical issues arise when the decision is made to expose asymptomatic carriers or colonized but well persons to medical therapy that might have serious side effects, or render them susceptible to adverse events, such as HAIs, disease, or undue morbidity.

In healthcare settings, reservoirs of a transmissible pathogen might be limited solely to the inanimate environment. Thus, appropriate control measures might include removing contaminated fruit, flowers, intravenous infusates, hand lotions, toys, white coats, stethoscopes, or other objects deemed to be potential reservoirs; appropriate handling of sewage and medical waste per published guidelines; ensuring that scrupulous aseptic techniques are maintained during invasive procedures or catheter insertion; or eliminating the agent from the environmental niche (eg, work surfaces in an ICU, medicine preparation areas, or moisture reservoirs in mechanical ventilators) by chemical or physical means. In some healthcare settings, microorganisms such as VRE or C difficile, may remain endemic or persistent despite identification and appropriate treatment or elimination of reservoirs. Persistence of resistant microorganisms may require periodic enhanced environmental disinfection of the concerned unit to curtail the endemicity of the pathogen (eg, use of a UV-C device for terminal disinfection).¹³⁹ The importance of modifying environmental reservoirs for the prevention and control of infectious disease is sustained by the fact that much of the reduction in disease and death from infectious diseases in the industrialized world during the 20th century has been attributed to purification of potable water by filtration and chlorination; improvements in the cooking, processing, and inspection of food; and advancements in housing, nutrition, and sanitary disposal of human waste.¹⁴⁰

Many of the features of interventions necessary to interrupt the transmission of infection are identical to those included in the interventions necessary for modifying inanimate environmental reservoirs discussed above. The most important addition to the measures to eliminate environmental reservoirs described above has been in interventions to improve the behavioral changes necessary to ensure appropriate hand hygiene between tasks in the preparation of food, caring for children, and caring for the sick. In the control of HAIs, the use of appropriate barriers, including the use of gloves, gowns, and eye protection, has been emphasized to prevent the transmission of bloodborne pathogens (eg, HIV and hepatitis B) between
patients and HCPs, as has the use of high-filtration masks for protection from respiratory transmission of influenza or tuberculosis.^141,142,143 Although one of the key measures for the prevention and control of HAIs remains consistent use of hand hygiene before, between, and after patient contacts in healthcare settings, compliance or adherence to hand washing protocols among healthcare professions—a behavioral attribute—remains less than ideal. This is not surprising since as far back as 1996, Goldmann et al. found that National Guidelines are not well studied by physicians, and, if they are read, they rarely are incorporated into everyday practice.¹⁴⁴ Compounding the problem is the growing body of evidence that hand hygiene is but one factor in the complex interplay of host, agent, and the environment that facilitates disease transmission. For a microorganism like VRE, transmission is enabled by one or more of the following factors: (1) the degree of hand hygiene among HCP; (2) the inherent properties of the microorganism that enable it to remain viable for days to weeks on dry, inert environmental surfaces, coats, or ties; (3) the proportion of patients in the unit of concern who are colonized with VRE; (4) the proportion of patients who are inherently susceptible to infection; (5) the selective pressure of vancomycin use in the unit; and (6) adherence to prevention efforts among HCP. Given the above, it follows that complete adherence to a strict hand hygiene policy alone will not necessarily preclude intrahospital transmission of VRE. One method commonly used to interrupt transmission of pathogens in healthcare settings is the isolation of patients known to be colonized or infected with a particular pathogen in a separate area, so as to reduce the probability of transmission of infection to other patients. These methods may include the use of private rooms, isolation precautions, dedicated patient equipment, and the allocation patients to specific HCP to avoid transmission of the pathogen by the HCPs themselves.

The risk of acquisition and transmission of infectious diseases among patient populations in healthcare settings is better characterized if the patients’ immune status or immune response is known. Immunization is the most effective method of individual and community protection against epidemic diseases and can be active or passive. Through active immunization, smallpox, one of the major global communicable diseases, was eradicated.^145,146 Although polio has been eliminated from large areas, including all of the Americas, and indigenous transmission of wild poliovirus types 1 and 3 infection has been interrupted in all but three countries worldwide (Afghanistan, Nigeria, and Pakistan), there were 33 reported cases in 2018.^{124,147,148,149,150,151,152,153} The occurrences of other childhood diseases have been substantially reduced, including diphtheria, pertussis, tetanus, measles, mumps, rubella, and infections of H influenzae type B.^154,155,156 Despite the reduction in these vaccine preventable diseases, recent outbreaks of measles, mumps, and pertussis have been reported in unvaccinated and under vaccinated children and adults in several geographic areas including the United States. This raises concern about the potential resurgence of these diseases and the potential for outbreaks in HCP and healthcare settings.

Since one of the main goals of epidemiology is to identify subgroups in the patient population that are at high risk for infection and disease, a knowledge of the vaccination status of patients is essential for the prevention of infection or disease. Institutional immunization programs have been recommended as part of the occupational health services of healthcare facilities for some time, but compliance for all HCP has only recently come under mandate. Evaluation of patients for immunization during hospital admission is another program widely recommended but incompletely implemented. The residual endemic problems and periodic outbreaks of these vaccine-preventable diseases in both populations at large and in healthcare institutions have been multifactorial, including the failure of the delivery programs for the vaccines and vaccine hesitancy. Failures in vaccine delivery programs have been due to poor funding, poor prioritization of the programs, the lack of political infrastructure, and the lack of organization of the vaccine effort. Vaccine hesitancy stems from lack of trust in public health agencies, coincidental temporal relationships to adverse health outcomes, and unfamiliarity with preventable diseases. This has led to outbreaks of measles, pertussis, Haemophilus influenzae type B, and pneumococcal disease causing unnecessary use of public resources and morbidity.^157,158

Passive immunization with hyperimmune or standard immunoglobulins is a valuable intervention in a small group of diseases, including certain genetic and acquired immunodeficiency diseases, primary antibody deficiency disorders, hypogammaglobulinemia in chronic lymphocytic leukemia, measles, hepatitis A, varicella-zoster virus exposure, hepatitis B, and HIV infections in children.¹⁵⁹ Hyperimmune globulin preparations are obtained from blood plasma donor pools preselected for high antibody content against a specific antigen (eg, hepatitis B immune globulin, varicella-zoster immune globulin, cytomegalovirus immune globulin, and respiratory syncytial virus immune globulin). Although active searches have been carried out for other kinds of immunomodulating agents (eg, interferons and cytokines) and biologics that heighten host immune function and protect the host from infection or disease, there are no data that indicate such treatment modalities play any significant role in the prevention and control of HAIs.

Administering antimicrobials to ensure the presence of an anti-infective agent at the site of a potential infection is a more recent addition to the control programs protecting the host. The use of a single dose or short course of preoperative antimicrobials to reduce the probability of a surgical site infection with agents commonly seen following certain procedures has become a standard part of surgical practice.¹⁶⁰ Profound cellular and humoral immunosuppression may ensue in patients following chemotherapy or radiotherapy of certain malignancies or may be a consequence of the primary disease process. Therapyrelated immunosuppression occurs during or following bone marrow transplantation or may be a sequela of therapeutic regimens used to prevent rejection of transplanted organs. The use of local and systemic anti-infectives in these patients has either prevented infection or mitigated the duration and severity of infection, leading to reduced morbidity and mortality, and improved outcomes.^{161,162,163,164}
The use of preprocedural (eg, surgery or dental) antimicrobial prophylaxis in individuals with a history of rheumatic heart disease is also a standard recommendation to prevent bacterial endocarditis.^165,166 Unfortunately, one of the side effects of repeated short courses of antimicrobials has been the appearance of significant antimicrobial resistance to these agents among pathogens associated with HAIs.¹⁶⁷ This problem has been aggravated by overprescribing of antimicrobials for nonbacterial infections by some practitioners, over-the-counter sale of antimicrobials in many parts of the world, and the use of subtherapeutic doses of antimicrobials as growth promoters in animal husbandry in the United States and other countries.^{168,169,170,171}