Infectious Diseases: Syndromes and Etiologies

The primary goal of Sherris Medical Microbiology is to help students of medical sciences understand how microbes pathogenic to humans cause infectious disease. The approach is a classic biologic one connecting basic science (structure, metabolism, genetics) to disease science (epidemiology, pathogenesis, immunity) for each microbe category (viruses, bacteria, fungi, parasites) and eventually, the individual pathogens. For each of the major pathogens, we also present clinical science (manifestations, diagnosis, treatment, prevention) both to illuminate disease understanding and as preparation for clinical application. Everyone knows that clinically, infectious diseases do not present as microbes but as patients with complaints, lesions, and laboratory findings. The challenge of their effective management involves a deductive process that begins with the clinical (fever, cough, age, season) and proceeds to the etiologic (Influenza A, Staphylococcus aureus, Candida albicans, Plasmodium falciparum). This supplement includes listings of the most common infectious syndromes accompanied by tables that present which infectious agents most commonly produce disease in those circumstances. In a few instances where laboratory findings are crucial to the decision process, they are included as well.

Folliculitis

Folliculitis is a minor infection of the hair follicles (Table S–1). It is often associated with areas of friction and of sweat gland activity and is thus seen most frequently on the neck, face, axillae, and buttocks. Blockage of ducts with inspissated sebum, as in acne vulgaris, predisposes to the condition. Acne vulgaris also involves inflammation of hair follicles and associated sebaceous glands.

Furuncles

The furuncle is a small abscess that develops in the region of a hair follicle. Furuncles may be solitary or multiple and may constitute a troublesome recurrent disease. Spread of infection to the dermis and subcutaneous tissues can result in a more extensive multiloculated abscess, the carbuncle.

Impetigo

Pyoderma, also termed impetigo, is a common, sometimes epidemic, skin lesion. The initial lesion is often a small vesicle that develops at the site of invasion and ruptures with superficial spread characterized by skin erosion and a serous exudate, which dries to produce a honey-colored crust.

Erysipelas

Erysipelas is a rapidly spreading infection of the deeper layers of the dermis. It is associated with edema of the skin, marked erythema, pain, and systemic manifestations of infection including fever and lymphadenopathy.

Cellulitis

Cellulitis is not a skin infection as such, but it can develop by extension from skin or wound infections. It usually manifests as an acute inflammation of subcutaneous connective tissue with swelling and pain and often with marked constitutional signs and symptoms.

Wound Infections

Wounds subject to infection can be surgical, traumatic, or physiologic. The latter include the endometrial surface, after separation of the placenta, and the umbilical stump in the neonate. Traumatic wounds comprise such diverse damage as deep cuts, compound fractures, frostbite necrosis, and thermal burns. Sources of infection include: (1) the patient’s own microbiota; (2) material from infected individuals or carriers that may reach the wound on fomites, hands, or through the air; and (3) pathogens from the environment that can contaminate the wound through soil, clothing, and other foreign material.

Osteomyelitis

The onset of acute hematogenous osteomyelitis is usually abrupt, but can sometimes be insidious. It is classically characterized by localized pain, fever, and tenderness to palpation over the affected site. More than one bone or joint may be involved as a result of hematogenous spread to multiple sites. With progression, the classic signs of heat, redness, and swelling may develop. Osteomyelitis caused by a contiguous focus of infection is usually associated with the presence of local findings of soft tissue infection, such as skin abscesses and infected wounds (Table S–2).

Septic Arthritis

The usual clinical features of septic arthritis include onset of pain, which is often abrupt and accompanied by fever. Single or multiple joints may be involved. Tenderness and swelling of the affected joints and frequently other signs of local inflammation are present. Attempts to move the joints, either actively or passively, result in severe pain (Tables S–3 and S–4).

Eye Infections

Blepharitis is an acute or chronic inflammatory disease of the eyelid margin (Table S–5). It can take the form of a localized inflammation in the external margin (hordeolum or stye) or a granulomatous reaction to infection and plugging of a sebaceous gland of the eyelid (chalazion).

Dacryocystitis is an inflammation of the lacrimal sac. It usually results from partial or complete obstruction within the sac or nasolacrimal duct, where bacteria may be trapped and initiate either an acute or a chronic infection.

Conjunctivitis is a term used to describe inflammation of the conjunctiva; it may extend to involve the eyelids, cornea (keratitis), or sclera (episcleritis). Extensive disease involving the conjunctiva and cornea is often called keratoconjunctivitis. Progressive keratitis can lead to ulceration, scarring, and blindness. Ophthalmia neonatorum is an acute, sometimes severe, conjunctivitis or keratoconjunctivitis of newborn infants.

Endophthalmitis is rare, but often leads to blindness even when treated aggressively. The term refers to infection of the aqueous or vitreous humor, usually by bacteria or fungi.

Uveitis consists of inflammation of the uveal tract—iris, ciliary body, and choroid. Although most inflammations of the iris and ciliary body (iridocyclitis) are not of infectious origin, some agents have been implicated. The acute disease may be associated with severe eye pain, redness, and photophobia; other cases may progress silently, with decreased visual acuity as the only symptom in the late stages.

Chorioretinitis The most common infective involvement of the uveal tract is chorioretinitis, in which inflammatory infiltrates are seen in the retina; this infection can lead to destruction of the choroid and inflammation of the optic nerve (optic neuritis) and may extend into the vitreous humor to cause endophthalmitis.

Ear Infections

Otitis externa is characterized by inflammation of the ear canal, with purulent ear drainage (Table S–6). It can be quite painful, and cellulitis can extend into adjacent soft tissues. A common form is associated with swimming in water that may be contaminated with aerobic gram-negative organisms such as Pseudomonas species.

Otitis media is arbitrarily classified as acute, chronic, or serous (secretory). Acute otitis media, nearly always caused by bacteria, is often a complication of acute viral upper respiratory illness. Fever, irritability, and acute pain are common, and otoscopic examination reveals bulging of the tympanic membrane, poor mobility, and obscuration of normal anatomic landmarks by fluid and inflammatory cells under pressure. In some cases, the tympanic membrane is also acutely inflamed, with blisters (bullae) on its external surface (myringitis).

The eustachian tube, which vents the middle ear to the nasopharynx, appears to play a major role in predisposing patients to otitis media. The tube performs three functions: ventilation, protection, and clearance via mucociliary transport. Viral upper respiratory infections or allergic conditions can cause inflammation and edema in the eustachian tube or at its orifice. These developments disturb its functions, of which ventilation may be the most important.

Chronic otitis media is usually a result of acute infection that has not resolved adequately, either because of inadequate treatment in the acute phase or because of host factors that perpetuate the inflammatory process (eg, continued eustachian tube dysfunction, caused by allergic or anatomic factors or immunodeficiency).

Sinus Infections

The paranasal sinuses (ethmoid, frontal, sphenoid, and maxillary) all communicate with the nasal cavity (Table S–7). In healthy persons, these sinuses are air-filled cavities lined with ciliated epithelium and are normally sterile. The pathogenesis of sinus infection can involve several factors, most of which act by producing obstruction or edema of the sinus opening, impeding normal drainage. Consequently, bacterial infection and inflammation of the mucosal lining tissues develop.

Upper Respiratory Tract Infection

Rhinitis is the most common manifestation of the common cold (Table S–8). It is characterized by variable fever, inflammatory edema of the nasal mucosa, and an increase in mucous secretions. The net result is varying degrees of nasal obstruction; the nasal discharge may be clear and watery at the onset of illness, becoming thick and sometimes purulent as the infection progresses over 5 to 10 days.

Pharyngitis and tonsillitis are associated with pharyngeal pain (sore throat) and the clinical appearance of erythema and swelling of the affected tissues. There may be exudates, consisting of inflammatory cells overlying the mucous membrane, and petechial hemorrhages; the latter may be seen in viral infections but tend to be more prominent in bacterial infections. Viral infections, particularly herpes simplex, may also lead to the formation of vesicles in the mucosa, which quickly rupture to leave ulcers.

Peritonsillar or retrotonsillar abscesses are usually a complication of tonsillitis. They are manifested by local pain, and examination of the pharynx reveals tonsillar asymmetry with one tonsil usually displaced medially by the abscess. This infection is most common in children older than 5 years and in young adults.

Retropharyngeal or lateral pharyngeal abscesses occur most frequently in infants and children under 5 years of age. They can result from pharyngitis or from accidental perforation of the pharyngeal wall by a foreign body. The infection is characterized by pain, inability or unwillingness to swallow, and, if the pharyngeal wall is displaced anteriorly near the palate, a change in phonation (nasal speech).

Middle Respiratory Tract Infection

Epiglottitis is often characterized by the abrupt onset of throat and neck pain, fever, and inspiratory stridor (difficulty in moving adequate amounts of air through the larynx) (Table S–9). Because of the inflammation and edema in the epiglottis and other soft tissues above the vocal cords (supraglottic area), phonation becomes difficult (muffled phonation or aphonia), and the associated pain leads to difficulty in swallowing.

Laryngitis or its more severe form, croup, may have an abrupt onset (spasmodic croup) or may develop more slowly over hours or a few days as a result of spread of infection from the upper respiratory tract. The illness is characterized by variable fever, inspiratory stridor, hoarse phonation, and a harsh, barking cough. In contrast to epiglottitis, the inflammation is localized to the subglottic laryngeal structures, including the vocal cords. It sometimes extends to the trachea (laryngotracheitis) and bronchi (laryngotracheobronchitis), where it is associated with a deeper, more severe cough that may provoke chest pain and variable degrees of sputum production.

Bronchitis or tracheobronchitis may be a primary manifestation of infection or a result of spread from upper respiratory tissues. It is characterized by cough, variable fever, and sputum production, which is often clear at the onset but may become purulent as the illness persists. Auscultation of the chest with the stethoscope often reveals coarse bubbling rhonchi, which are a result of inflammation and increased fluid production in the larger airways.

Chronic bronchitis is a result of longstanding damage to the bronchial epithelium. A common cause is cigarette smoking, but a variety of environmental pollutants, chronic infections (eg, tuberculosis), and defects that hinder normal clearance of tracheobronchial secretions and bacteria (eg, cystic fibrosis) can be responsible. Because of the lack of functional integrity of their large airways, such patients are susceptible to chronic infection with members of the oropharyngeal microbiota and to recurrent, acute flare-ups of symptoms when they become colonized and infected by viruses and bacteria.

Lower Respiratory Tract Infection

Acute pneumonia is an infection of the lung parenchyma that develops over hours to days and, if untreated, runs a natural course lasting days to weeks (Table S–10). The onset may be gradual, with malaise and slowly increasing fever, or sudden, as with the bed-shaking chill associated with the onset of pneumococcal pneumonia. The only early symptom referable to the lung may be cough, which is caused by bronchial irritation. In adults, the cough becomes productive of sputum, which is purulent material generated in the alveoli and small air passages. In some cases, the sputum may be blood-streaked, rusty in color, or foul smelling.

Chronic pneumonia has a slow insidious onset that develops over weeks to months and may last for weeks or even years. The initial symptoms are the same as those of acute pneumonia (fever, chills, and malaise), but they develop more slowly. Cough can develop early or late in the illness. As the disease progresses, appetite and weight loss, insomnia, and night sweats are common. Cough and sputum production may be the first indication of a vague constitutional illness referable to the lung. Bloody sputum (hemoptysis), dyspnea, and chest pain appear as the disease progresses. There may be parenchymal destruction and the formation of abscesses or cavities communicating with the bronchial tree.

Pleural effusion is the transudation of fluid into the pleural space in response to an inflammatory process in adjacent lung parenchyma. It may result from a wide variety of causes, both infectious and noninfectious.

Empyema is a purulent infection of the pleural space that develops when the infectious agent gains access by contiguous spread from an infected lung through a bronchopleural fistula or, less often, by extension of an abdominal infection through the diaphragm. Symptoms are usually insidious and related to the primary infection until enough exudate is formed to produce symptoms referable to the chest wall or to compromise the function of the lung.

Lung abscess is usually a complication of acute or chronic pneumonia caused by organisms that can cause localized destruction of lung parenchyma. It may occur as part of a chronic process or as an extension of an acute, destructive pneumonia, often after aspiration of oral or gastric contents. The symptoms of lung abscess, which are usually not specific, resemble those of chronic pneumonia or an acute pneumonia that has failed to resolve. Persistent fever, cough, and the production of foul-smelling sputum are typical.

Sputum

The examination of expectorated sputum has been the primary means of diagnosing the causes of bacterial pneumonia, but this approach has several advantages and disadvantages. The advantages are ease of collection and absence of risk to the patient. The primary disadvantage is the confusion that results from contamination of the sputum with oropharyngeal microbiota in the process of expectoration and excessive contamination with saliva. Microscopic examination before culture of direct Gram smears of specimens alleged to be sputum has proved useful. Polymorphonuclear leukocytes (PMNs) and large numbers of a single morphologic type of organism are typical findings in sputum from patients with bacterial pneumonia. Squamous epithelial cells from the oropharynx and a mixed bacterial population are characteristic of saliva. Another approach is to attempt a more direct collection from the lung using methods that bypass the oropharyngeal flora. This approach may be used in patients who are not producing sputum or in cases where analysis of expectorated sputum has been inconclusive. The major techniques include transtracheal aspiration, bronchoalveolar lavage (BAL), direct aspiration, and open lung biopsy.

Diarrhea Syndromes

(Table S–11)

Watery Diarrhea

The most common form of gastrointestinal infection is the rapid development of frequent intestinal evacuations of a more or less fluid character known as diarrhea. Nausea, vomiting, fever, and abdominal pain may also be present, but the dominant feature is intestinal fluid loss. Diarrhea is produced by pathogenic mechanisms that attack the proximal small intestine, the portion of the bowel in which more than 90% of physiologic net fluid absorption occurs.

Dysentery

Dysentery begins with the rapid onset of frequent intestinal evacuations, but the stools are of smaller volume than in watery diarrhea and contain blood and pus. If watery diarrhea is the “runs,” dysentery is the “squirts.” Fever, abdominal pain, cramps, and tenesmus are common complaints. Vomiting occurs less often. The focus of pathology is the colon. Organisms causing dysentery can produce inflammatory and/or destructive changes in the colonic mucosa either by direct invasion or by production of cytotoxins. This damage produces the pus and blood seen in the stools, but does not result in substantial fluid loss because the absorptive and secretory capacity of the colon is much less than that of the small bowel.

Enteric Fever

Enteric fever is a systemic infection, the origin and focus of which are the gastrointestinal tract. The most prominent features are fever and abdominal pain, which develop gradually over a few days in contrast to the abrupt onset of the other syndromes. Diarrhea is usually present but may be mild and not appear until later in the course of the illness. The pathogenesis of enteric fever is more complex than that of watery diarrhea or dysentery. It generally involves penetration by the organism of the cells of the distal small bowel with subsequent spread outside the bowel to the biliary tract, liver, mesentery, or reticuloendothelial organs. Bacteremia is common, occasionally causing metastatic infection in other organs.

Epidemiologic Setting

(Table S–12)

Endemic Infections

By definition, endemic diarrheas are those that occur sporadically in the usual living circumstances of the patient. Some organisms are endemic worldwide, whereas others are geographically limited. There are also seasonal variations and age-related attack rates within the endemic foci.

Epidemic Infections

Under certain epidemiologic conditions, some of the organisms responsible for endemic infections can spread beyond the family unit to cause epidemics involving regional, national, and even international populations. The diarrheal diseases most frequently associated with epidemics are typhoid fever, cholera, and shigellosis. All three epidemics are related to the failure of basic public health sanitary measures.

Traveler’s Diarrhea

From 20% to 50% of travelers from developed countries who go to less developed countries experience a diarrheal illness in the first week that is usually brief but can be serious. The common names applied to this syndrome, such as “Delhi belly” and “Montezuma revenge,” reflect geographic associations and the cumulative frustration of those forced to spend part of their vacation next to the toilet rather than the swimming pool.

Food Poisoning

Many gastrointestinal infections involve food as a vehicle of transmission. The term “food poisoning,” however, is usually reserved for instances in which a single meal can be incriminated as the source. This situation typically arises when multiple cases of the same gastrointestinal syndrome develop at the same time among persons whose only common experience is a meal shared at a social event or a restaurant. The probable etiologic agent can usually be assessed from knowledge of the incubation period, the food vehicle, and the clinical findings. Changes in the importation, processing, and distribution of foods have increased the complexity and potential for foodborne transmission of enteric pathogens. Outbreaks in the past might have been limited, but may now be widely distributed by fast-food chains or airline catering services.

Urinary Tract Infections

Cystitis

The symptoms of cystitis are dysuria (painful urination), frequency (frequent voiding), and urgency (an imperative “call to toilet”). These findings are similar to those of urethritis caused by sexually transmitted agents. The cystitis complex is, in fact, produced by irritation of the mucosal surface of the urethra as well as the bladder. It is clinically distinguished from pure urethritis by a more acute onset, more severe symptoms, the presence of bacteriuria, and in approximately 50% of cases—hematuria. The urine is often cloudy and malodorous and occasionally frankly bloody. Cystitis patients also experience pain and tenderness in the suprapubic area. Fever and systemic manifestations of illness are usually absent unless the infection spreads to involve the kidney.

Pyelonephritis

The typical presentation of upper urinary infection consists of flank pain and fever that exceeds 38.3°C. These findings may be preceded or accompanied by manifestations of cystitis. Rigors, vomiting, diarrhea, and tachycardia are present in more severely ill patients. Physical examination reveals tenderness over the costovertebral areas of the back and, occasionally, evidence of septic shock.

Prostatitis

Infection of the prostate is typically manifested as pain in the lower back, perirectal area, and testicles. The same bacteria that cause cystitis and pyelonephritis are involved. In acute infection, the pain may be severe and accompanied by high fever, chills, and the signs and symptoms of cystitis. Inflammatory swelling can lead to obstruction of the neighboring urethra and urinary retention. On rectal palpation, the prostate is boggy and exquisitely tender.

Etiologic Agents

Over 95% of urinary tract infections (UTIs) are caused by gram-negative rods, and 90% of these are Escherichia coli. Other Enterobacteriaceae, Pseudomonas, and gram-positive bacteria become increasingly common with chronic, complicated, and hospitalized patients. Of the gram-positive bacteria, enterococci are the most important. Staphylococcus saprophyticus, a coagulase-negative staphylococcus, is now recognized as the cause in a significant minority of symptomatic infections in young, sexually active women. Yeasts, particularly species of Candida, may be isolated from catheterized patients receiving antibacterial therapy and from diabetic individuals, but they seldom produce symptomatic disease.

Urine Culture

The diagnosis of UTI is based on examination of the normally sterile urine for evidence of bacteria or an accompanying inflammatory reaction. Critical to this examination is the use of appropriate techniques for specimen collection. Unfortunately, voided urine is invariably contaminated with urethral flora and, in female patients, perineal and vaginal flora, which can confound interpretation of culture results. Contaminants may be diminished by carefully cleansing the periurethrum before voiding and allowing the initial part of the stream to flush the urethra before collecting a specimen for examination. This clean-voided midstream urine collection procedure is preferred to catheterization for routine purposes because it prevents the introduction of organisms into the bladder. Because the number of bacteria in infected urine is typically large, quantitative bacteriology has been the gold diagnostic standard for UTI. The results of quantitative urine cultures (bacteria/mL) for various specimens and clinical situations are illustrated in Figure S–1.

Genital Ulcers

Single or multiple ulcerative lesions on the genitalia constitute one of the most common manifestations of sexually transmitted diseases (STDs) (Table S–13). Infection may begin as a papule or pustule and evolve into an ulcer. The nature of the ulcer and whether it is painful are significant differential features.

Genital Warts

Genital warts may be caused by either bacteria or viruses. Those caused by certain types of human papillomavirus are highly associated with cervical cancer, but are less common causes of warts. Condylomata lata are painless mucosal warty erosions that develop in warm, moist sites such as the genitals and perineum in about one-third of cases of secondary syphilis.

Urethritis

Urethritis usually manifests as dysuria, urethral discharge, or both. The discharge may be prominent enough to be the chief complaint or may have to be milked from the urethra. Infection with more than one organism is common, particularly dual gonococcal and chlamydial infection.

Epididymitis

Unilateral swelling of the epididymis is a common clinical illness seen in sexually active men. It is usually painful, with fever and acute unilateral swelling of the testicle that is sometimes confused with testicular torsion.

Cervicitis

The major clinical manifestation of cervicitis is a mucopurulent vaginal discharge. The cervix is friable and inflamed, and PMNs are present in the exudate.

Vaginitis

Symptomatic vaginal discharge may occur alone or accompany salpingitis, endometritis, or cervicitis. Pelvic examination is valuable in determining whether uterine, adnexal, or cervical tenderness is present and whether the source of the discharge is the cervix or the vagina.

Pelvic Inflammatory Disease

Clinical manifestations of pelvic inflammatory disease (PID) vary but generally include lower abdominal pain elicited by movement of the cervix or palpation of the adnexal or endometrial areas. The incidence of PID is five to ten times higher in women with intrauterine devices than in those not using this form of contraception.

Lymphadenitis

Inguinal lymphadenitis may be seen with several sexually transmitted diseases, especially primary herpes simplex infection and lymphogranuloma venereum. The latter is caused by specific strains of C trachomatis. It may begin as a small genital ulcer, which is frequently unnoticed.

Most central nervous system (CNS) infections appear to result from bloodborne spread; for example, bacteremia or viremia resulting from infection of tissue at a site remote from the CNS may result in penetration of the blood–brain barrier (Tables S–14, S–15, S–16, S–17). Occasionally, the route of infection is from a focus close to or contiguous with the CNS. These possible sources include middle ear infection (otitis media), mastoiditis, sinusitis, or pyogenic infections of the skin or bone. Infection may extend directly into the CNS, indirectly via venous pathways, or in the sheaths of cranial and spinal nerves.

In some cases, a contiguous or distant infectious focus may not be necessary to produce CNS infection. If an anatomic defect exists in the structures encasing the CNS, infectious agents may readily gain access to the vulnerable site and establish themselves. Such defects may be traumatically or surgically induced or result from congenital malformations. Abscesses of the CNS may be within the tissues of the CNS (eg, brain abscess) or localized in the subdural or epidural spaces. They sometimes develop as a complication of pyogenic meningitis or from embolization of bacteria or fungi from a distant focus.

Purulent meningitis refers to infections of the meninges associated with a marked, acute inflammatory exudate and is usually caused by a bacterial infection. Such infections frequently involve the underlying CNS tissue to a variable degree, and often the ventricular system is also involved (ventriculitis). Most cases of purulent meningitis are acute in onset and progression and are characterized by fever, stiff neck, irritability, and varying degrees of neurologic dysfunction, which, if untreated, usually progress to a fatal outcome. Large numbers of PMNs are present in the cerebrospinal fluid (CSF) of established cases.

Chronic meningitis has a more insidious onset, with progression of signs and symptoms over a period of weeks. This is usually caused by mycobacteria or fungi that produce granulomatous inflammatory changes, but occasionally protozoal agents are responsible. The cellular response in the CSF reflects the chronic inflammatory nature of the disease.

Aseptic meningitis is a term used to describe a syndrome of meningeal inflammation associated mostly with an increase of cells (pleocytosis), primarily lymphocytes and other mononuclear cells in the CSF, and absence of readily cultivable bacteria or fungi. It is associated most commonly with viral infections and is often self-limiting. The primary site of inflammation is in the meninges without clinical evidence of involvement of the neural tissue. Such patients may have fever, headache, a stiff neck or back, nausea, and vomiting.

Encephalitis also implies a primary viral etiology; however, acute or chronic demyelinating diseases with or without inflammation must also be considered. The latter group includes the postinfectious or allergic encephalomyelitis syndromes, in which the cause and pathogenesis are not always clearly defined. Clinically, the diagnosis of encephalitis is applied to patients who may or may not show signs and CSF findings compatible with aseptic meningitis, but also show objective evidence of CNS dysfunction (eg, seizures, paralysis, and disordered mentation).

Meningoencephalitis is a term used to describe conditions of patients with both meningeal and encephalitic manifestations.

Intravascular Infection

Infective Endocarditis

The term infective endocarditis is preferable to the commonly used term bacterial endocarditis, simply because not all infections of the endocardial surface of the heart are caused by bacteria. Most infections occur on natural or prosthetic cardiac valves, but can also develop on septal defects, shunts (eg, patent ductus arteriosus), or the mural endocardium. Infections involving coarctation of the aorta are also classified as infective endocarditis because the clinical manifestations and complications are similar (Tables S–18 and S–19).

Acute endocarditis is generally fulminant with high fever and toxicity, and death may occur in a few days or weeks. Subacute endocarditis progresses to death over weeks to months with low-grade fever, night sweats, weight loss, and vague constitutional complaints. The clinical course is substantially related to the virulence of the infecting organism; S aureus, for example, usually produces acute disease, whereas infections by the less virulent viridans streptococci are subacute. Before the advent of antimicrobial therapy, death was considered inevitable in all cases of infective endocarditis. Physical findings often include a new or changing heart murmur, splenomegaly, various skin lesions (petechiae, splinter hemorrhages, Osler nodes, and Janeway lesions), and retinal lesions.

Suppurative Thrombophlebitis

Suppurative (or septic) thrombophlebitis is an inflammation of a vein wall frequently associated with thrombosis and bacteremia. There are four basic forms: superficial, pelvic, intracranial venous sinus, and portal vein infection (pylephlebitis). With the steadily increasing use of intravenous catheters, the incidence of superficial thrombophlebitis has risen and represents a major complication in hospitalized patients. The pathogenesis involves thrombus formation, which may result from trauma to the vein, extrinsic inflammation, hypercoagulable states, stasis of blood flow, or combinations of these factors. The thrombosed site is then seeded with organisms, and a focus of infection is established (Table S-20).

In superficial thrombophlebitis, an intravenous cannula or catheter may cause local venous wall trauma, as well as serve as a foreign body nidus for thrombus formation. Infection develops if bacteria are introduced by intravenous fluid, local wound contamination, or bacteremic seeding from a remote infected site. Thrombophlebitis of pelvic, portal, or intracranial venous systems most often occurs as a result of direct extension of an infectious process from adjacent structures or from venous and lymphatic pathways near sites of infection.

Intravenous Catheter Bacteremia

A variant of intravascular infection develops when a medical device such as an intravenous catheter or any of several types of monitoring devices placed in the bloodstream becomes colonized with microorganisms. The event itself does not have immediate clinical significance but, unlike transient bacteremia from manipulation of sites containing the resident microbiota, the bacteremia continues. This persistence greatly increases the chances of secondary complications such as infective endocarditis and metastatic infection, depending on any underlying disease and the virulence of the organism involved.

Extravascular Infection

Although bacteremia is an integral feature of intravascular infection, most cases of clinically significant bacteremia are the result of overflow from an extravascular infection. In these cases, the organisms drained by the lymphatics, or otherwise escaping from the infected focus, reach the capillary and venous circulation through the lymphatic vessels. Depending on the magnitude of the infection and the degree of local control, these organisms may be filtered in the reticuloendothelial system or circulate more widely, producing bacteremia or fungemia. The process is dependent on the timing and interaction of multiple events and is thus much less predictable than intravascular infection. The causative organisms and the frequencies with which they usually produce bacteremia are listed in Table S–21. There is considerable overlap, and the probability of bacteremia is dependent on the site as well as the organism.

Blood Culture

The primary means of establishing a diagnosis of sepsis is by blood culture. The microbiologic principles involved are the same as with any culture. A sample of the patient’s blood is obtained by aseptic venipuncture and cultured in an enriched broth or, after special processing, on plates. Growth is detected, and the organisms are isolated, identified, and tested for antimicrobial susceptibility.

Blood Culture Sampling

Before venipuncture, the skin over the vein must be carefully disinfected to reduce the probability of contamination of the blood sample with skin bacteria. Although it is not possible to “sterilize” the skin, quantitative counts can be markedly reduced with a combination of 70% alcohol and an iodine-based antiseptic.

Volume of Blood

The number of organisms present in blood is often low (less than 1 organism/mL) and cannot be predicted in advance. Thus, small samples yield fewer positive cultures than larger ones. Samples of at least 10 mL should be collected from adult patients. The same principles apply with infants and young children, but the sample size must be reduced to take account of the smaller total blood volume of a child.

Number of Cultures

If the volume is adequate, it is rarely necessary to collect more than two or three blood cultures to achieve a positive result. In intravascular infections (eg, infective endocarditis), a single blood culture is positive in more than 95% of cases. Studies of sequential blood cultures from bacteremic patients without endocarditis have yielded 80% to 90% positive results on the first culture and 99% in at least one of a series of three cultures.

Timing of Cultures

Figure S–2 illustrates some typical bacteremic patterns that can be related to the probability of obtaining positive blood cultures. Transient bacteremia is usually not detected because organisms are cleared before the appearance of any clinical findings suggesting sepsis. The continuous bacteremia of infective endocarditis is usually readily detected, and timing is not critical. Intermittent bacteremia presents the greatest challenge because fever spikes generally occur after, rather than during, the bacteremia. Closely spaced samples are less likely to detect the organism than those spaced an hour or more apart (Table S–21).