Understanding the mechanisms of infectious organisms can aid hospital staff in preventing and treating nosocomial infections.

One of the biggest challenges for hospitals has always been preventing the spread of disease within a confined setting. A century ago, infectious-disease patients were segregated in separate hospitals, with individuals having similar diseases clustered on the same floor. In 1910, a cubicle system of isolation, in which patients were placed in multiple-bed wards was introduced. Aseptic nursing procedures were aimed at preventing the transmission of disease to other patients and personnel. These careful procedures were so successful that general hospitals were able to incorporate infectious-disease patients, ultimately resulting in the closure of many infectious-disease hospitals in the 1950s.

Patients are admitted to the hospital for a variety of reasons. Among the most serious are potentially life-threatening bacterial infections. Examples include pneumonia, sepsis, intra-abdominal infection, endocarditis, and staphylococcal skin infection, as well as a number of infections caused by multidrug-resistant pathogens. These microorganisms can cause serious clinical conditions, particularly in the immunocompromised patient.

The routes of transmission of bacterial pathogens, whether direct or indirect, should be considered, and the health care practitioner must be aware of any physical contact with the patient that might lead to nosocomial infection, a major source of morbidity and mortality in critically ill hospitalized patients.

Although the ability to care for critically ill patients has improved greatly over the past several decades, the widespread application of techniques such as tracheal intubation and mechanical ventilation in increasingly ill patients has resulted in nosocomial hazards such as ventilator-associated pneumonia. Pneumonia is associated with the greatest mortality rate among nosocomial infections,^1,2 and also with substantial costs of care.^3,4 Although respiratory organisms are a serious concern, pathogens that enter through a variety of other routes cannot be ignored.

Transmission of Pathogens
Bacteria reside in a variety of environments, including soil, food, water, and many areas in and on human and animal bodies. In order for invasion to occur, bacteria must be transported to areas within the body where conditions will be conducive to their growth and replication.

Direct transmission occurs when bacteria are transported to the host through actual contact with the skin or mucous membranes of an infected individual. Direct transmission can occur during sexual intercourse or any other form of close physical contact. Indirect transmission occurs when bacteria reside for a period of time in some intermediate environment before reaching the human host. The bacteria are transferred when the host comes into contact with that intermediate environment. Indirect transmission can occur in a variety of ways. For example, it can occur when a host comes into contact with inanimate objects (fomites) such as clothing, tabletops, doorknobs, and drinking glasses contaminated by an infected individual.

It is also possible for bacteria to be transported indirectly through fine droplets of secretions coughed or sneezed into the air by an infected individual. Pathogens can, in addition, be transported into the body through contaminated blood, drugs, food, or water. Indirect transmission can occur when an intermediate animal or insect carries a pathogen from an infected individual to a new host.

The body has several natural openings that allow the passage of pathogens into its tissues. The mouth, nose, and urinary tract are common points of entry. Bacteria can also pass into the body through areas in which there has been a disruption in the normal defense mechanisms. When there is a weakening of the body’s defenses, an individual is more vulnerable to bacterial infection. For example, the skin and mucous membranes normally form effective protective barriers against infection. When there is a break in these barriers, such as a cut, burn, wound, or surgical incision, bacteria are allowed to enter, often leading to infection.

Once bacteria have entered the body, they must find an environment that will allow them to grow and multiply. When such a body site has been found, the second stage of the infectious process, incubation, can occur. During this phase, bacteria will overcome host defenses to the extent that they are able to reproduce effectively. In time, these bacteria may spread to other areas of the body and/or may proliferate to such an extent that they cause harm. Throughout the periods of bacterial invasion and incubation, no symptoms of disease are apparent.

Symptom Production
Once pathogenic bacteria have gained entry into the body, they may begin to reproduce rapidly and proliferate until they overwhelm body tissue. As this happens, the disease process enters the prodrome stage, and symptoms of infectious disease become manifest. Symptoms are produced through three different mechanisms: colonization of body tissues, secretion of bacterial toxins, and reaction of host defenses.

Colonization is one means through which bacteria can cause cellular damage in the host by overpopulating areas of tissue in the body. This overpopulation can prevent the tissues from obtaining necessary oxygen and nutrients, causing local damage to the area of bacterial colonization.

More frequently, the signs and symptoms of infection result from the effects of bacterial toxins. Exotoxins are proteins produced and secreted by certain bacterial cells. They can produce profound effects in the host, altering cell membranes, inhibiting cellular protein synthesis, and disrupting nervous-system function. Exotoxins are usually produced by gram-positive bacteria. While, in some cases, exotoxins may be distributed throughout the body by the blood, for the most part, exotoxins produce local effects on body tissues. Clostridium species are the most frequent producers of exotoxins.^5,6

Endotoxins are components of the cell walls of gram-negative bacteria. They are generally liberated when a gram-negative bacterium dies or is destroyed. Endotoxins enter the bloodstream and produce generalized signs and symptoms such as malaise, fever, and chills. Regardless of the bacterium releasing the endotoxin, the effects produced are essentially the same.

Infection may spread in the body and cause disease when the bacterial ability to invade tissues is greater than the host’s ability to defend against that invasion. In some cases, pathogens that have a high level of virulence or resistance may persist, despite a strong defensive host response. More frequently, compromised host defenses increase susceptibility to infection and allow bacterial pathogens to invade and multiply. An infection that is caused by a pathogen that does not ordinarily cause infection or disease unless it is presented with an opportunity to do so (by weakened host defenses) is called an opportunistic infection.

Any break in the body’s external barriers allows bacteria greater access into areas where they are not normally found. For example, surgery opens the skin, bypassing one important natural barrier to infection. Introduction of catheters, bypass tubes, and prosthetic devices into the body’s interior may also be accompanied by infection due to the penetration of the body’s external defenses and the introduction of bacteria. Any condition that weakens an individual can diminish host defenses. Advanced age, nutritional deficiencies, smoking, stress, psychological trauma, and lack of sleep all may weaken defensive responses and increase susceptibility to infection. Preexisting heart and circulatory disorders, as well as acute and chronic illnesses, are common in patients with weakened defensive responses.

Certain therapies can increase the risk of infection. For example, cancer patients may be treated with chemotherapeutic agents that kill rapidly dividing cells. These drugs may kill dividing immunologic cells as well as dividing cancer cells; hence, they leave the patient more susceptible to infection. Similarly, antibiotic therapy can, in some cases, destroy the protective normal flora and leave the patient susceptible to superinfection.

Host Defense Mechanisms
The body reacts to the invasion and proliferation of bacteria with a variety of defensive responses. While the main effects of these responses are to restrict the spread of bacteria and kill bacterial cells, they can also be the cause of many clinically important signs and symptoms. Inflammation is one example of the body’s defensive response. Fever (pyrexia) is another.

The four cardinal signs of inflammation are pain, swelling, redness, and heat. A fifth cardinal sign, functio laesa (dysfunction),⁷ is sometimes described. These signs result primarily from two mechanisms: dilation of blood vessels and increased permeability of blood-vessel walls.

When blood vessels dilate, they carry increased amounts of blood, protective cells, and plasma proteins to injury sites. Redness and heat result from the accelerated flow of blood that accompanies these dilatory changes. The increased permeability of blood-vessel walls results in the escape of blood proteins and blood cells into the tissues, which causes swelling. This permeability allows increased concentrations of immune-system cells and chemicals into the injured tissue, facilitating the elimination of foreign substances.

Fever is another symptom that can result from the body’s defensive responses. Body temperature is regulated by the hypothalamus. Pyrogens cause fever by resetting the hypothalamic thermostat at a warmer level, forcing the body to reach and maintain this higher temperature. Some pyrogens are secreted by pathogenic invaders; others are manufactured in the body and released by damaged tissues during inflammatory reactions. In addition, nonpathogenic invaders, such as some drugs, may be pyrogenic. Exogenous pyrogens may act directly to reset the hypothalamic thermostat or may act indirectly by causing the release of potent endogenous pyrogens.

While prolonged, high fever eventually leads to tissue destruction, limited fever is believed to have some beneficial effects. A rising temperature may augment host defenses by stimulating the proliferation and activity of immune-system cells. In addition, a higher body temperature may be less favorable for the growth and multiplication of bacteria.

Types of Infection
Clinicians commonly distinguish among several types of infection. A primary infection is the initial infection that the patient suffers. It may or may not be the patient’s primary medical condition. Secondary infection occurs when a bacterial infection follows or complicates a preexisting condition. Mixed infections are caused by two or more pathogens; they can cause two or more distinct clinical problems. This may make it difficult to isolate and identify the causative pathogens. In addition, treatment may be difficult because the two or more organisms may not be susceptible to the same antibiotic. Mixed infections sometimes require two or more antibiotics given at the same time.

Acute infections are characterized by their sudden onset. The course of acute infections is usually relatively short and is sometimes marked by very severe symptoms. Chronic infections, on the other hand, have a prolonged course. Most chronic infections show little change over their slow progression.

A recurrent infection is a repetition of an infection previously experienced by a patient. It is a distinct episode in which the pathogen(s) involved may be the same as, or different from, those responsible for the initial infection. A recurrent infection is not a relapse, the recurrence of an infection after its apparent cessation. In a relapse, the same pathogen is responsible for the initial infection and the recurrent infection.

A community-acquired infection is transmitted through normal contact with the general community, as opposed to acquired in a unique environment such as a hospital or nursing home, where the presence of infected individuals is known to contribute to the development of infections. A nosocomial infection is acquired during hospitalization. This may occur as a result either of exposure to an increased number of pathogenic bacteria or of weakened host defenses due to the primary illness.

It is estimated that, in the United States alone, between 5% and 10% of people entering a hospital will acquire a nosocomial infection,^8-12 adding more than $4 billion to the annual cost of health care.¹³ As a result, hospitals are now required to establish infection-control committees responsible for establishing guidelines and protocols designed to minimize the transmission of pathogenic bacteria.

Nosocomial infections are so common that, according to one estimate,¹⁴ they make up at least half of all cases of disease treated in the hospital where they were contracted. Four groups of bacteria are most commonly implicated in nosocomial infections.

• Enterococcus species are part of the normal intestinal flora. Some strains are resistant to all conventional antimicrobial drugs. Enterococci are a common cause of nosocomial urinary-tract infections, as well as wound and blood infections.
• Escherichia coli and other enterobacteria are part of the normal intestinal flora. E. coli is the most common cause of nosocomial urinary-tract infections.
• Pseudomonas species grow in many moist, nutrient-poor environments, such as the water in the humidifier of a mechanical ventilator. Pseudomonas species are resistant to many disinfectants and antibiotics. They are a common cause of hospital-acquired pneumonia, urinary-tract infections, and burn infections.
• Staphylococcus species are normal skin organisms that can colonize the tips of intravenous catheters, resulting in the formation of biofilms. These biofilms continuously seed organisms into the bloodstream and increase the likelihood of systemic infection. Staphylococcus aureus is a common cause of nosocomial pneumonia and surgical-site infections. Hospital strains are often resistant to a variety of antibiotics

Multidrug-Resistant Pathogens
Bacteria can resist the effects of antimicrobial drugs through a variety of mechanisms. In some cases, antimicrobial resistance occurs naturally due to a spontaneous mutation that alters existing genes. In other cases, antimicrobial resistance may be acquired through the transfer of plasmids containing resistance genes. Resistance plasmids (R-plasmids) frequently carry several different resistance genes, each one conferring resistance to a specific antimicrobial drug. R-plasmid transfer can spread drug resistance to different strains, species, and even genera.

Spontaneous mutation, or the acquisition of R-plasmids, generally allows the microorganism to become resistant to an antimicrobial drug; the drug-resistant microorganism may produce enzymes that chemically modify a specific antimicrobial agent so that the drug is no longer effective. Minor structural changes to the target site in a microorganism can also prevent the drug from binding. Cell-wall proteins in a microorganism may be altered, thereby changing the permeability of the cell and preventing certain drugs from entering. Increased expression of proteins involved in exporting compounds out of the cell can increase the overall capacity of an organism to eliminate a drug, thus enabling the organism to resist greater concentrations of that antimicrobial agent.

Some strains of pathogenic bacteria are resistant to essentially all antimicrobial drugs, while others remain susceptible to only one. The lack of new drug classes is a consequence of many factors, including the difficulty of discovering new compounds. Between 1968 and 2000, the US Food and Drug Administration (FDA) approved no novel class of antibacterial drug for use. Indeed, most of the new drugs approved since 1968 have been chemical modifications of existing drugs. Since 2000, however, two new drug classes—the oxazolidinones (linezolid) and the lipopeptides (daptomycin)—have been approved by the FDA.

Linezolid disrupts bacterial growth by inhibiting the initiation process of protein synthesis, a mechanism of action that is unique to the oxazolidinone class of drugs.¹⁵ Daptomycin is a natural product derived from Streptomyces roseosporus.¹⁶ It works by disrupting the bacterial membrane through the formation of transmembrane channels.¹⁶ These channels cause leakage of intracellular ions, leading to depolarization of the cellular membrane and inhibition of macromolecular synthesis. Already, reports of daptomycin-resistant pathogens have emerged, illustrating the need for ongoing research and development.^17,18

According to the National Nosocomial Infections Surveillance (NNIS) System,^19,20 multidrug-resistant pathogens have become an increasing problem in recent years, particularly in the critical care setting. Vancomycin-resistant enterococci (VRE), highly resistant strains of Enterococcus faecalis and/or Enterococcus faecium, were first reported in Europe in 1988,²¹ and are becoming an increasing concern worldwide. Vancomycin is an extremely potent intravenous antibiotic. When bacteria become resistant to vancomycin, it means that the infection has become difficult to treat. VRE are likely to be resistant to antibiotics other than vancomycin, particularly penicillins. VRE are a recognized cause of intra-abdominal infections, as well as endocarditis, urinary-tract infections, wound infections, and bacterial sepsis.

Methicillin-resistant S. aureus (MRSA) was first described in the early 1960s,²² shortly after the introduction of penicillinase-resistant b-lactam antibiotics into clinical practice. Since then, hospitals worldwide have reported varying proportions of MRSA among S. aureus isolates. Over time, several MRSA isolates have acquired resistance to other antibiotics; thus, MRSA has become a real clinical and therapeutic problem. Today, MRSA is a major nosocomial pathogen found in an increasing number of hospitals worldwide. According to data from the NNIS,^23,24 the percentage of MRSA among all S. aureus isolates is rising significantly. Many MRSA isolates are also becoming clindamycin resistant.²⁵

S. aureus is one of the most common causes of both nosocomial and community-acquired infections worldwide, and vancomycin has been used to treat many S. aureus infections (particularly those caused by MRSA). Although S. aureus remains susceptible to vancomycin, the emergence of strains with only intermediate susceptibility to the antibiotic is raising fears of the emergence of a fully resistant strain.

Organisms are deemed susceptible to vancomycin if the minimum inhibitory concentration is 4 or fewer mg/mL, intermediately susceptible at 8 to 16 mg/mL, and resistant at 32 or more mg/mL.^26,27

The first report of an infection with a strain of S. aureus that had only intermediate susceptibility to vancomycin came from Japan in June 1996.²⁶ This report raised concern among infectious disease experts and led the US Centers for Disease Control and Prevention (CDC) to issue interim recommendations for controlling vancomycin-intermediate S. aureus (VISA) infections.²⁷ More recently, several reports of VISA infections outside Japan suggest that this pathogen is becoming more prevalent.^28-30

Most cases of VISA infections have one feature in common: The organism was initially sensitive to the antibiotic, but a moderately resistant strain was subsequently isolated after prolonged vancomycin use. The mechanism through which staphylococci become resistant to vancomycin is not clearly understood. Investigators have isolated a vancomycin-resistant S. aureus mutant in vitro that appeared to have structural cell-wall alterations that increased its ability to bind vancomycin.³¹ The researchers theorized that this alteration may prevent vancomycin from reaching crucial sites of cell-wall synthesis, thus impeding its bactericidal effect.

The CDC recommends that all clinical isolates of S. aureus be tested for susceptibility to vancomycin.^32,33 Laboratory personnel should notify the laboratory director if vancomycin-resistant or vancomycin-sensitive S. aureus is discovered. Many isolates of S. aureus presumed to have been vancomycin-resistant have been found to be mixed with other organisms in cultures; therefore, vancomycin resistance should be confirmed by restreaking the colony to certify that the culture is pure. The hospital epidemiology program should be notified so that it can institute appropriate isolation procedures. The public health department, other hospitals in the vicinity, and the CDC should also be notified.

Preventing Nosocomial Infection
The most important steps in preventing nosocomial infections are to recognize their occurrence and then establish policies to prevent their development.^34-38

• Hands must be washed with soap and water after touching blood, body fluids, secretions, excretions, or contaminated items, whether or not gloves are worn. Hand hygiene with alcohol-based hand rubs has been shown to decrease the transmission of resistant organisms. A campaign initiated in 2005 by the World Health Organization is promoting this practice throughout the world.³⁹
• Early screening and isolation of patients carrying resistant organisms appears to decrease the spread of resistant microorganisms and may be more widely implemented.
• Clean, disposable gloves are to be worn whenever there is possible contact with blood, body fluids, secretions, excretions, mucous membranes, skin wounds, or contaminated items. Gloves must be changed between procedures on the same patient after contact with material that may contain high concentrations of microbes. Gloves are to be removed immediately after use and hands are to be washed thoroughly. Gloves should always be removed in a reverse manner so that the contaminated surface is not touched.
• When performing a procedure that is likely to generate splashes or sprays of blood, body fluids, secretions, or excretions, clinicians must wear a mask and eye protection or a face shield to protect the mucous membranes of the eyes, nose, and mouth; a clean gown must be worn. The soiled gown must be removed as soon as possible and hands must be washed.
• Used patient-care equipment soiled with blood, body fluids, secretions, or excretions must be handled in a manner that prevents skin and mucous-membrane exposure, as well as contamination and transfer to other patients and environments. Reusable equipment must be cleaned and processed appropriately. Single-use items must be disposed of properly.
• Adequate procedures must be employed for the routine care, cleaning, and disinfection of environmental surfaces, bed rails, and other frequently touched surfaces.
• Soiled, reusable linens are to be placed in protective bags to prevent leaking and contamination.
• All needles and sharp objects are to be discarded in rigid, puncture-proof containers; the clinician must not touch the objects or replace needle caps.
• Private rooms are to be used for any patient who contaminates the environment or might soil other people and their surroundings.

Conclusion
It is important for the health care worker in a hospital to understand how infection occurs, the modes of bacterial transmission, and the prevalent microorganisms involved in causing disease. Focused efforts aimed at treating existing infection and preventing the occurrence of nosocomial infection can dramatically improve the care and recovery of hospitalized patients.

Phyllis C. Braun, PhD, is professor, Department of Biology, Fairfield University, Fairfield, Conn. John D. Zoidis, MD, is a contributing writer for RT.

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