Bloodstream Infections

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Bloodstream Infections

Objectives

1. Identify and describe some of the medical consequences that occur when the bloodstream is infected by microorganisms.

2. Name the most common causes of bacterial bloodstream infection, and explain the route of transmission and source of infection.

3. Define the following bloodstream infections: bacteremia, fungemia, and septicemia.

4. List the most common fungi associated with bloodstream infections and the population of patients most often affected by this type of infection.

5. Explain what causes mortality in most cases of parasitic blood-borne infections.

6. Differentiate between intravascular and extravascular bloodstream infections.

7. Define continuous bacteremia, and provide an example.

8. Describe the development of infective endocarditis, including the contributing factors and the microorganisms that are the primary cause for the condition.

9. Define mycotic aneurysms and suppurative thrombophlebitis, and describe the causes for these conditions.

10. Explain the pathogenic features of S. epidermidis that make it uniquely suited for causing catheter-related infections.

11. Explain the importance of collection parameters associated with blood cultures for suspected cases of bloodstream infections, including collection time, the number of cultures, and the volume of blood required.

12. List and briefly describe some of the blood culture systems available to the microbiologist, including the self-contained systems, the lysis centrifugation systems, and instrument-based systems.

13. List some of the most common causes of bloodstream infection associated with the blood cultures from HIV-infected patients.

14. Define the acronym AACEK, and describe the type of blood-borne infections these organisms are most often associated with.

15. Outline the guidelines used to determine if agents isolated from blood cultures are true pathogens or probable contaminants.

Invasion of the bloodstream by microorganisms constitutes one of the most serious situations in infectious disease. Microorganisms present in the circulating blood—whether continuously, intermittently, or transiently—are a threat to every organ in the body. The suffix emia is derived from the Greek word meaning “blood” and refers to the presence of a substance in the blood; bacteremia refers to the presence of bacteria in the blood, fungemia refers to the presence of fungi in the bloodstream, and septicemia indicates bacteria are present in the blood, producing an infection and reproducing within the bloodstream. Microbial invasion of the bloodstream resulting from any organism can have serious immediate consequences, including shock, multiple organ failure, disseminated intravascular coagulation (DIC), and death. Approximately 200,000 cases of bacteremia and fungemia occur annually, with mortality rates ranging from 20% to 50%. Timely detection and identification of blood-borne pathogens are two of the most important functions of the microbiology laboratory. Pathogens of all four major groups of microbes—bacteria, fungi, viruses, and parasites—may be found circulating in blood during the course of many diseases. Positive blood cultures may help provide a clinical diagnosis, as well as a specific etiologic diagnosis.

General Considerations

The successful recovery of microorganisms from blood by the laboratory depends on many, often complex, factors: the type of bacteremia, the specimen collection method, the blood volume, the number and timing of blood cultures, the interpretation of results, and the type of patient population being served by the laboratory. All of these parameters must be considered in the development of the blood culture protocol within the laboratory in order to maximize the detection and recovery of microorganisms and ensure quality patient care.

Etiology

As previously mentioned, all major groups of microbes can be present in the bloodstream during the course of many diseases.

Bacteria

The organisms most commonly isolated from blood are gram-positive cocci, including coagulase-negative staphylococci, Staphylococcus aureus, and Enterococcus spp., and other organisms likely to be inhabitants of the hospital environment that colonize the skin, oropharynx, and gastrointestinal tract of patients. Some of the most common, clinically significant bacteria isolated from blood cultures are listed in Box 68-1. In general, the number of fungi and coagulase-negative staphylococci has increased, whereas the number of clinically significant anaerobic isolates has decreased since the early 2000s.

Of importance, the laboratory isolation of certain bacterial species from blood can indicate the presence of an underlying, occult, or undiagnosed neoplasm. Alterations in local conditions at the site of the neoplasm allowing bacteria to proliferate and seed the bloodstream have been suggested as a potential mechanism for the association between bacteremia and cancer. Another possible mechanism is reduced killing of bacterial cells by the host phagocytes. Organisms associated with neoplastic disease include Clostridium septicum and other uncommonly isolated clostridial species, Streptococcus galldyticus, Aeromonas hydrophila, Plesiomonas shigelloides, and Campylobacter spp. Finally, if Streptococcus anginosis group bacteria are isolated from blood, the possibility of an abscess should be considered.

Fungi

Fungemia (the presence of fungi in blood) is usually a serious condition, occurring primarily in immunosuppressed patients and in those with serious or terminal illness. Candida albicans is by far the most common species, but Malassezia furfur can often be isolated in patients, particularly neonates, receiving lipid-supplemented parenteral nutrition. Candida spp. account for approximately 8% to 10% of all nosocomial bloodstream infections.

Except for Histoplasma, which multiply in leukocytes (white blood cells), fungi do not invade blood cells, but their presence in the blood usually indicates a focus of infection elsewhere in the body. Fungi in the bloodstream can disseminate (be carried) to all organs of the host, where they may grow, invade normal tissue, and produce toxic products. Fungi gain entrance to the circulatory system via loss of integrity of the gastrointestinal or other mucosa; through damaged skin; from primary sites of infection, such as the lung or other organs; or by means of intravascular catheters.

Systemic fungal infections begin as pneumonia and may disseminate from the lungs, which serve as the portal of entry. Arthroconidia of Coccidioides immitis and microconidia of Histoplasma capsulatum and Blastomyces dermatitidis are ingested by alveolar macrophages in the lung. These macrophages carry the fungi to nearby lymph nodes, usually the hilar nodes. The fungi multiply within the node tissue and ultimately are released into the circulating blood, from which they are capable of seeding other organs or are destroyed by the body’s defenses. Molds are particularly insensitive to host defenses such as antibody and phagocytic cells because of their large size and their sterol containing cell wall structure.

Parasites

Eukaryotic parasites may be found transiently in the bloodstream as they migrate to other tissues or organs. Their presence, however, cannot be considered consistent with a state of good health. For example, tachyzoites of the parasite Toxoplasma gondii may be found in circulating blood. They invade cells within lymph nodes and other organs, including the lungs, liver, heart, brain, and eyes. The resulting cellular destruction accounts for the manifestations of toxoplasmosis. Also, microfilariae are seen in peripheral blood during infection with Dipetalonema, Mansonella, Loa loa, Wuchereria, or Brugia.

Malarial parasites invade host erythrocytes and hepatic parenchymal cells. The significant anemia and subsequent tissue hypoxia (reduction in oxygen levels) may result from destruction of red blood cells by the parasite. Vascular trapping of normal erythrocytes by the infected red blood cells, which are less flexible and tend to clog small capillaries, is a major cause of morbidity. The host’s immunologic response is to remove the parasites and damaged red blood cells; the immune response may also have deleterious effects.

Parasites in the bloodstream are usually detected by direct visualization. Those parasites for which traditional diagnosis is dependent on observation of the organism in peripheral blood smears include Plasmodium, Trypanosoma, and Babesia. Patients with malaria or filariasis may display a periodicity in their episodes of fever that allows the physician to time the collection of blood for microscopic examination intended for optimal detection. Rapid serological methods and molecular methods are currently used to detect malaria, babesiosis, and trypanosomiasis. These tests are described in Chapter 49.

Viruses

Although many viruses do circulate in the peripheral blood at some stage of disease, the primary pathology relates to infection of the target organ or cells. Those viruses that preferentially infect blood cells are Epstein-Barr virus (invades lymphocytes), cytomegalovirus (invades monocytes, polymorphonuclear cells, and lymphocytes), and human immunodeficiency virus (HIV) (involves only certain T lymphocytes and perhaps macrophages) and other human retroviruses that attack lymphocytes. The pathogenesis of viral diseases of the blood is the same as that for viral diseases of any organ; by diverting the cellular machinery to create new viral components or by other means, the virus may prevent the host cell from performing its normal function. The cell may be destroyed or damaged by viral replication, and immunologic responses of the host may also contribute to the pathogenesis.

Although many viral diseases have a viremic stage, recovery of virus particles or detection of circulating viruses is used in the diagnosis of only a few diseases. Chapter 66 discusses the recovery of viruses from blood in greater detail.

Types of Bacteremia

Bacteremia may be transient, continuous, or intermittent. Most people have experienced transient bacteremia; teething infants and people having dental procedures have had oral flora gain entry to the bloodstream through breaks in the gums. Other conditions in which bacteria are only transiently present in the bloodstream include manipulation of infected tissues, devices or instrumentation inserted through contaminated mucosal surfaces, and surgery involving nonsterile sites. These circumstances may also lead to significant septicemia, although normally the bacteria are cleared from the blood by scavenging leukocytes, resulting in no infection. Septicemia can occur when the bacteria multiply more rapidly than the immune system is capable of killing and removing the organism.

In septic shock, bacterial endocarditis, and other endovascular infections, organisms are released into the bloodstream at a fairly constant rate (continuous bacteremia). Also, during the early stages of specific infections, including typhoid fever, brucellosis, and leptospirosis, bacteria are continuously present in the bloodstream.

In most other infections, such as in patients with undrained abscesses, bacteria can be found intermittently in the bloodstream. Of note, the causative agents of meningitis, pneumonia, pyogenic arthritis, and osteomyelitis are often recovered from blood during the early course of these diseases. In the case of transient seeding of the blood from a sequestered focus of infection, such as an abscess, bacteria are released into the blood approximately 45 minutes before a febrile episode.

The symptoms of septicemia are fever, chills, and malaise; these are caused by the presence of the invading microorganism and the toxins produced by these microorganisms. The older the patient is, the greater the risk and the rate of mortality as a result of septicemia.

Types of Bloodstream Infections

The two major categories of bloodstream infections are intravascular (those that originate within the cardiovascular system) and extravascular (those that result from bacteria entering the blood circulation through the lymphatic system from another site of infection). Of note, other organisms, such as fungi, may also cause intravascular or extravascular infections. However, because bacteria account for the majority of significant vascular infections, these types of bloodstream infections are discussed in more detail. Factors contributing to the initiation of bloodstream infections are immunosuppressive agents, widespread use of broad-spectrum antibiotics that suppress the normal flora and allow the emergence of resistant strains of bacteria, invasive procedures allowing bacteria access to the interior of the host, more extensive surgical procedures, and prolonged survival of debilitated and seriously ill patients.

Intravascular Infections

Intravascular infections include infective endocarditis, mycotic aneurysm, suppurative thrombophlebitis, and intravenous (IV), catheter-associated bacteremia. Because these infections are within the vascular system, organisms are present in the bloodstream at a fairly constant rate (i.e., a continuous bacteremia). These infections in the cardiovascular system are extremely serious and considered life threatening.

Infective Endocarditis.

The development of infective endocarditis (infection of the endocardium most commonly caused by bacteria) is believed to involve several independent events. Cardiac abnormalities, such as congenital valvular diseases that lead to turbulence in blood flow or direct trauma from IV catheters, can damage cardiac endothelium. This damage to the endothelial surface results in the deposition of platelets and fibrin. If bacteria transiently gain access to the bloodstream (this can occur after an innocuous procedure such as brushing the teeth) after alteration of the capillary endothelial cells, the organisms may stick to and then colonize the damaged cardiac endothelial cell surface. After colonization, the surface will rapidly be covered with a protective layer of fibrin and platelets. This protective environment is favorable to further bacterial multiplication. This web of platelets, fibrin, inflammatory cells, and entrapped organisms is called a vegetation (Figure 68-1). The resulting vegetations ultimately seed bacteria into the blood at a slow but constant rate.

The primary causes of infective endocarditis are the viridans streptococci, comprising several species (Box 68-2). These organisms are normal inhabitants of the oral cavity, often gaining entrance to the bloodstream as a result of gingivitis, periodontitis, or dental manipulation. Heart valves, especially those previously damaged, present convenient surfaces for attachment of these bacteria. Streptococcus sanguis and Streptococcus mutans are frequently isolated in streptococcal endocarditis. Gram-negative bacilli, known as the AACEK group, Aggregatibacter aphrophilus, Actinobacillus actinomycetemcomitans, Cardiobacterium hominis, Eikenella corrodens, and Kingella kingae, can also be associated with endocarditis.

With the ever-increasing use of IV catheters, arterial lines, and vascular prostheses, organisms considered normal or hospital-acquired inhabitants of the human skin are able to gain access to the bloodstream and attach to various surfaces, including heart valves and vascular endothelium. It has been estimated that more than 200,000 nosocomial infections (bloodstream) occur annually in the United States in adults and children. The majority of these infections are caused by the use of intravascular catheters. Staphylococcus epidermidis and other coagulase-negative staphylococci have been increasingly implicated as the cause of infection associated with intravascular catheters. S. epidermidis is the most common etiologic agent identified in prosthetic valve endocarditis, with S. aureus being the second most common. S. aureus is an important cause of septicemia without endocarditis and is found in association with other foci, such as abscesses, wound infections, and pneumonia, as well as sepsis related to indwelling intravascular catheters.

Mycotic Aneurysm and Suppurative Thrombophlebitis.

Two other intravascular infections, mycotic aneurysms and suppurative thrombophlebitis, result from damage to the endothelial cells lining blood vessels. With respect to mycotic aneurysm, an infection causes inflammatory damage and weakening of an arterial wall; this weakening causes a bulging of the arterial wall (i.e., aneurysm) that can eventually rupture. The etiologic agents are similar to those that cause endocarditis.

Suppurative thrombophlebitis is an inflammation of a vein wall. The pathogenesis of this intravascular infection involves an alteration in the vein’s endothelial lining followed by clot formation. The site is then seeded with organisms, thereby establishing a primary site of infection. Suppurative thrombophlebitis represents a frequent complication of hospitalized patients caused by the increasing use of IV catheters.

Intravenous Catheter–Associated Bacteremia.

IV catheters are an integral part of the care for many hospitalized patients. More than 3 million central venous catheters are used annually in the United States. For example, central venous catheters are used to administer fluids, blood products, medications, antibiotics, and nutrition, and for hemodynamic monitoring. A short-term, triple-lumen (channel opening within a tube) central venous catheter is shown in Figure 68-2. Unfortunately, a major consequence of these medical devices is colonization of the catheter by either bacteria or fungi, which can lead to catheter infection and serious bloodstream infection. This consequence is a major nosocomial source of illness and even death.

IV catheter–associated bacteremia (or fungemia) is believed to occur primarily by two routes (Figure 68-3). The first route involves the movement of organisms from the catheter entry site through the patient’s skin and down the external surface of the catheter to the catheter tip within the bloodstream. After arriving at the tip, the organisms multiply and may cause a bacteremia. The second way that IV catheter–associated bacteremia may occur is by migration of organisms along the inside of the catheter (the lumen) to the catheter tip. The catheter’s hub, where tubing connects into the IV catheter, is considered the site at which organisms gain access to the patient’s bloodstream through the catheter lumen. The most common etiologic agents for IV catheter–associated bloodstream infections, regardless of the route of infection, are organisms found on the skin (Box 68-3). Certain strains of S. epidermidis appear to be uniquely suited for causing catheter-related infections because of their ability to produce a biofilm or “slime” that consists of complex sugars (polysaccharides) believed to help the organism adhere to the catheter’s surface. The initial attachment of S. epidermidis to the catheter’s polystyrene surface is related to a cell surface protein. Once attached, the organism proliferates, subsequently forming a biofilm. Uncommon routes of IV catheter–tip infection include contaminated fluids or blood-borne seeding from another infection site.

Extravascular Infections

Except for intravascular infections, bacteria usually enter the circulation through the lymphatic system. Most cases of clinically significant bacteremia are a result of extravascular infection. When organisms multiply at a local site of infection such as the lung, they are drained by the lymphatics and reach the bloodstream. In most individuals, organisms in the bloodstream are effectively and rapidly removed by the reticuloendothelial system in the liver, spleen, and bone marrow and by circulating phagocytic cells. Depending on the extent of immunologic control of the infection, the organism may be circulated more widely, thereby causing a bacteremia or fungemia.

The most common portals of entry for bacteremia are the genitourinary tract (25%), respiratory tract (20%), abscesses (10%), surgical wound infections (5%), biliary tract (5%), miscellaneous sites (10%), and uncertain sites (25%). For the most part, the probability of bacteremia occurring from an extravascular site depends on the site of infection, its severity, and the organism. For example, any organism producing meningitis is likely to produce bacteremia at the same time. Of importance, certain organisms causing extravascular infections commonly invade the bloodstream; some of these organisms are listed in Table 68-1. In addition to these organisms, a large number of other bacteria and fungi that cause extravascular infections are also capable of invading the bloodstream. Whether these organisms invade the bloodstream depends on the host’s ability to control the infection and the organism’s pathogenic potential. Some of the organisms associated with potential bloodstream infections from a localized site include members of the family Enterobacteriaceae, Streptococcus pneumoniae, Staphylococcus aureus, Neisseria gonorrhoeae, anaerobic cocci, Bacteroides, Clostridium, beta-hemolytic streptococci, and Pseudomonas. These are only some of the organisms frequently isolated from blood. Almost every known bacterial species and many fungal species have been implicated in extravascular bloodstream infections.

TABLE 68-1

Organisms Commonly Associated with Bloodstream Invasion from Extravascular Sites of Infection

Organism Extravascular Site of Infection
Anaerobic organisms Wound, soft tissue
Brucella spp. Reticuloendothelial system
Candida albicans Genitourinary tract
Chlamydia pneumoniae Respiratory
Clostridium spp. Wound, soft tissue
Coagulase negative staphylococci Wound, soft tissue
Enterobacteriaceae (E.coli, Klebsiella spp., Enterobacter spp., Proteus spp., Enterococcus spp.) Genitourinary tract infections, central nervous system
Haemophilus influenzae Meninges (CNS), epiglotitis, periorbital region, respiratory
Legionella spp. Respiratory
Listeria monocytogenes Meninges (CNS)
Neisseria meningitidis Meninges (CNS)
Pseudomonas aeruginosa Wound, soft tissue, central nervous system
Salmonella enterica typhi Small intestine, regional lymph nodes of the intestine, reticuloendothelial system
Streptococcus penumoniae Meninges (CNS), respiratory
Streptococcus pyogenes Wound, soft tissue
Staphylococcus aureus Wound, soft tissue, meninges (CNS)

Clinical Manifestations

As previously discussed, bacteremia may indicate the presence of a focus of disease, such as intravascular infection, pneumonia, or liver abscess, or it may represent transient release of bacteria into the bloodstream. Septicemia or sepsis indicates a condition in which bacteria or their products (toxins) are causing harm to the host. Unfortunately, clinicians often use the terms bacteremia and septicemia interchangeably. Signs and symptoms of septicemia may include fever or hypothermia (low body temperature), chills, hyperventilation (abnormally increased breathing leading to excess loss of carbon dioxide from the body) and subsequent respiratory alkalosis (a condition caused by the loss of acid leading to an increase in pH), skin lesions, change in mental status, and diarrhea. More serious manifestations include hypotension or shock, DIC, and major organ system failure. The syndrome known as septic shock, characterized by fever, acute respiratory distress, shock, renal failure, intravascular coagulation, and tissue destruction, can be initiated by either exotoxins or endotoxins. Septic shock is mediated by the production of cytokines from activated mononuclear cells, such as tumor necrosis factor and interleukins.

Shock is the gravest complication of septicemia. In septic shock, the presence of bacterial products and the host’s response act to shut down major host physiologic systems. Clinical manifestations include a drop in blood pressure, increase in heart rate, functional impairment in vital organs (brain, kidney, liver, and lungs), acid-base alterations, and bleeding problems. Gram-negative bacteria contain a substance in their cell walls, called endotoxin, which has a strong effect on several physiologic functions. This substance, a lipopolysaccharide (LPS) comprising part of the cell wall structure (see Chapter 2), may be released during the normal growth cycles of bacteria or after the destruction of bacteria by host defenses. Endotoxin (or the core of the LPS, lipid A) has been shown to mediate numerous systemic reactions, including a febrile response, and the activation of complement and certain blood-clotting factors. Although gram-positive bacteria do not contain the lipid A endotoxin, many produce exotoxins, and the effects of their presence in the bloodstream may be equally devastating to the patient.

Disseminated intravascular coagulation (DIC) is a disastrous complication of sepsis. DIC is characterized by numerous small blood vessels becoming clogged with blood clots and bleeding as a result of the depletion of coagulation factors. DIC can occur with septicemia involving any circulating pathogen, including parasites, viruses, and fungi, although it is most often a consequence of gram-negative bacterial sepsis.

Immunocompromised Patients

One of the greatest challenges facing microbiologists is the handling of blood cultures from immunocompromised patients. The number of immunocompromised patients has steadily increased in recent years in large part as the result of advances in medicine. People undergoing organ transplantation, elderly persons, individuals with malignant disease (e.g., malignancies and cancer), and those receiving therapy for the malignancy are examples of immunosuppressed patients. Acquired immunodeficiency syndrome (AIDS) has also contributed to the increase in the number of immunocompromised individuals. The marked immunosuppression brought about by infection with the human immunodeficiency virus (HIV) in patients with AIDS is a result of this virus’ profound impairment of cellular immunity. Patients with AIDS have the greatest diversity of pathogens recovered from blood, including mycobacterial species, Bartonella henselae, Corynebacterium jeikeium, Shigella flexneri, unusual Salmonella species, Histoplasma capsulatum, Cryptococcus neoformans, and cytomegalovirus.

As is typically observed in other hospitalized patients, organisms such as gram-positive aerobic bacteria (e.g., Staphylococcus aureus, Enterococcus) and gram-negative aerobic bacteria (e.g., Enterobacteriaceae, Pseudomonas aeruginosa) are common causes of bloodstream infections in immunocompromised patients. In addition, bloodstream infections in immunocompromised patients are frequently caused by either unusual pathogens whose recovery from blood requires special techniques or by organisms normally considered contaminants when isolated from blood cultures. Therefore, microbiologists must be aware of the potential pathogenicity of organisms in immunosuppressed patients that are typically considered as probable blood culture contaminants. Without this knowledge, aerobic gram-positive rods isolated from blood cultures may be dismissed as contaminating diphtheroids, when, in fact, the organism is C. jeikeium, known to cause bacteremia in immunosuppressed patients. Microbiologists must be familiar with the unusual pathogens isolated from blood cultures obtained from immunocompromised patients and organisms that require special techniques for isolation (some of the special considerations are covered later in this chapter).