Current Diagnosis & Treatment in Infectious Diseases

Section V - Bacterial Infections

60. Brucella, Francisella, Pasteurella, Yersinia, & HACEK

Elie F. Berbari MD

Walter R. Wilson MD


Essentials of Diagnosis

  • Suspected in patients with chronic fever of unknown etiology who have a history of occupational exposure or come from a high prevalence area.
  • Leukopenia.
  • Blood culture or bone marrow cultures on appropriate media.
  • Serum antibody titer ≥ 1:160.
  • Polymerase chain reaction.

General Considerations

Brucellosis (also called undulant fever, Mediterranean fever, Malta fever) is an infection that causes abortion in domestic animals. It is caused by one of six species of Brucella coccobacilli. It may occasionally be transmitted to humans, in whom the disease could be acute or chronic with ongoing fever and constitutional symptoms without localized findings.

  1. Epidemiology.Brucellosis is transmitted to humans by either direct contact with infected cattle, goat, or sheep (eg, through milk, urine, and products of pregnancy) or indirectly by ingesting contaminated animal products (eg, unpasteurized dairy products). Human-to-human transmission does not occur. The natural reservoir of brucellosis in the United States is domestic animals, especially cattle, bison, sheep, goats, and swine.

The disease exists worldwide, mainly in the Mediterranean basin, the Arabian peninsula, the Indian subcontinent, Mexico, and Central and South America. In the United States, the incidence of brucellosis fell from 4.5 cases/100,000 population annually in the late 1940s to < 0.5 cases/100,000 by the 1990s. Most reported cases in the United States are due to ingestion of unpasteurized goat milk product imported from Mexico or to occupational exposure involving meat-packing plant employees, veterinarians, laboratory personnel, farmers, and ranchers. Recently, bison herds in the Rocky Mountain plains of the United States have become infected with brucellae and could potentially infect domestic cattle in the United States.

  1. Microbiology.Sir David Bruce, a British microbiologist, isolated the microorganisms responsible for brucellosis in 1886. Brucellae are nonspore-forming, noncapsulated, small gram-negative coccobacilli. They grow best aerobically in high-peptone media at 37°C and at pH 6.7. Incubation time could take ≤ 30 days for visible growth on solid media. Colonies are small, smooth, translucent, and amber colored. Of the six known Brucellaspecies, only four are reported to cause human disease: B abortus (cattle), B melitensis (goats), B suis (pigs), and B canis (dogs). Brucellae may be distinguished from each other by their requirements for carbon monoxide atmosphere for growth, growth in the presence of dyes, production of hydrogen sulfide and urease, and specific agglutination in antisera.
  2. Pathogenesis.Routes of infection include ingestion of the contaminated food or dairy products by way of the gastrointestinal tract, direct inoculation through skin cuts or mucus membrane contact, or inhalation of the organisms via the respiratory tract. Subsequently, the microorganisms enter the lymphatics and replicate intracellularly in the regional lymph nodes and from there disseminate hematogenously and localize in the reticuloendothelial system (ie, spleen, liver, other lymph nodes, and bone marrow). The bacilli multiply intracellularly within the phagocytic cell where they may be killed rapidly, or the organisms may replicate and destroy the phagocytic cell. This results in proliferation within the reticuloendothelial system and the formation of noncaseating granulomas in affected tissue. In most instances, the granulomas undergo a process of healing, with fibrosis, death of the organisms, and frequently calcification.

Clinical Findings

  1. Signs and Symptoms.After a 2- to 8-week incubation period, affected patients present with a spectrum of disease that varies from an asymptomatic form to a severe illness with bacteremia (Box 60-1). Affected patients typically present with fever, sweats, headaches, malaise, and weight loss. If undiagnosed, these symptoms may persist for months to a year. When symptoms last for more than 12 months without any localization, the disease is classified as chronic. Physical examination, though normal in most cases, may reveal bilateral diffuse lymphadenopathy, splenomegaly, and hepatomegaly in 20%–30% of patients.

In the localized form, the infection may affect virtually any organ system. The osteoarticular, gastrointestinal, genitourinary, and cardiovascular are among the more common affected systems. These forms have signs and symptoms related to the affected organ system. An infectious discitis with adjacent vertebral bony osteomyelitis typically in the lumbar area, is the most common manifestation of localized osteoarticular disease. Sacroilitis is also characteristic of the musculoskeletal form of the infection. Infective endocarditis occurs in < 2% of brucellosis cases.

Patients with chronic brucellosis may have long periods of no symptoms followed by the intermittent recurrence of fever, chills, myalgias, and nonspecific symptoms. This form of relapsing brucellosis may persist for decades and is often refractory to antimicrobial therapy and is frequently associated with multiple or large calcific lesions in the liver and spleen. Many other common illnesses can mimic the most common clinical presentation of brucellosis.

  1. Laboratory Findings.Patients typically have a mild anemia, neutropenia, and rarely thrombocytopenia. The diagnosis of brucellosis is made with certainty when Brucellaspp. are recovered from cultures of the blood, bone marrow, or other site. Bone marrow cultures are more often positive than are blood cultures. Blood cultures are often negative in chronic or localized forms. The standard Brucella serum agglutination test is the most widely used serologic test for the diagnosis of Brucella. The antibodies measured are directed against the lipopolysaccharide. A titer of at least 1:160 is representative of a past or present infection. A fourfold increase or decrease over a 2- to 4-week period represents acute infection.

The current serum agglutination test does not detect antibodies directed against Brucella canis, and diagnosis requires a special serologic test or a positive culture. After successful therapy, the antibody titer may become negative in approximately a year but may remain positive in low titer throughout the patient's life. Persistence of an elevated titer indicates ongoing infection. The prozone phenomena could lead to a false negative test.

Polymerase chain reaction may be used for diagnosis. Primers are directed at different sites of the genomic bacterial DNA. The specificity and sensitivity of this technique may provide a valuable tool for the diagnosis of brucellosis; however, the test is not widely available.

BOX 60-1 Brucellosis in Adults and Children




Chronic 1

Relapsing Brucellosis

More Common

· Malaise, fever, chills, lethargy, weakness, weight loss, anorexia

· Headaches, myalgias, back pain

· Lymphadenopathy, splenomegaly, hepatomegaly

· Bone and joint (spondylitis, arthralgias)

· Gastrointestinal (spleen abscess, splenic calcifications)

· Infective endocarditis

· Respiratory (hilar adenopathy, perihilar infiltrates)

· Weakness, fatigue, mental depression, vague pains, intermittent fever

· Splenomegaly

· Calcification in liver and spleen, including “bulls-eye”

Long periods of no symptoms with intermittent fever and chills

· Genitourinary (perinephric abscess, epididymitis)


Less Common

Monoarticular arthralgias

Fever, chills, malaise, weight loss


1Defined as chronic when duration of symptoms is >12 m.

Differential Diagnosis

The differential diagnosis is one of a fever of unknown origin and includes typhoid fever, infectious mononucleosis, Q-fever, hepatitis, and a host of noninfectious syndromes including lymphoma and systemic lupus erythematosus. Infection with Vibrio cholerae, Francisella tularensis, or Yersinia enterocolitica may give a falsely elevated serum agglutination test since antigen of these microorganisms can cross-react with antigen of Brucella spp.


Several antimicrobial agents are active against Brucella spp. (Box 60-2). Combination therapy of two or more active antimicrobial agents is superior to monotherapy as evidenced by a reduction in relapse rates. Antimicrobial therapy shortens the duration of symptoms and reduces the incidence of complications. Tetracyclines are considered the cornerstone of therapy. Several possible combinations have been used: The World Health Organization recommends a 6-week combination regimen of doxycycline and rifampin. Doxycycline and streptomycin are considered equally efficacious.

The optimum therapy for endocarditis is unclear. Most patients will require a prolonged period (6 months) of combination antimicrobial therapy, and valvular replacement surgery is often necessary. Although rare, infective endocarditis represents 80% of human brucellosis-related deaths.


With appropriate antimicrobial therapy, the mortality rate of brucellosis is < 1%, although the mortality rate is 3%–5% in untreated cases. It appears that the humoral antibodies play a role in the protection against subsequent infection. Thus patients with brucellosis might be less susceptible to acquire a new infection.

BOX 60-2 Treatment of Brucellosis


Acute Brucellosis

Endocarditis-Meningitis-Spondylitis-Localized Forms1






First Choice

Doxycycline, 100 mg orally twice daily, PLUS rifampin, 600–900 mg orally daily for 4–6 weeks

Doxycycline, 2 2 mg/ kg orally twice daily, PLUS rifampin, 15 mg/kg orally daily for 4–6 weeks

Doxycycline, 100 mg orally twice daily, PLUS rifampin, 600–900 mg orally daily for 6 mo, PLUS streptomycin, 1 g IMdaily for the first 2–3 weeks

Doxycycline, 2 2 mg/kg orally twice daily, PLUS rifampin, 15 mg/kg orally daily for 6 mo, PLUS streptomycin, 10 mg/kg IMtwice daily for the first 7–14 days

Second Choice

Doxycycline, 100 mg orally twice daily for 4–6 weeks, PLUS streptomycin, 1 g IM daily for the first 15 days4

TMP/SMX, 3 2.5 mg/kg orally of TMP component 4 times daily, PLUS rifampin, 15 mg/kg orally daily for 4–6 weeks


TMP/SMX, 3 2.5 mg/kg orally of TMP component 4 times daily, PLUS rifampin, 15 mg/kg orally daily for 6 mo, PLUS gentamicin, 1.5–2 mg/kg (IV or IM) in three daily doses for the the first 7–14 days

1May require splenectomy or drainage of abscess.
2Should not be used in children under the age of 8 or in pregnant women after 6 months of gestation.
4Should be the regimen of choice in spondylitis.

Prevention & Control

The prevention of brucellosis requires the eradication or the control of the infection in animals (Box 60-3). The use of Brucella vaccines (B abortus strain 19, B melitensis strain Rev-1) has resulted in the elimination of the disease in some animals. The use of effective barriers such as gloves, masks, and goggles can protect individuals at risk from potentially infected animals. Pasteurization of milk will effectively kill Brucella spp. in dairy products.


Essentials of Diagnosis

  • Suspected in patients with fever, lymphadenopathy, and skin lesions who have a history of animal exposure (including to wild animals, ticks, or deerflies) or are coming from a high prevalence area or in laboratory personnel who work with Francisellaspp.
  • Blood culture or other biologic specimen cultures on appropriate culture media.
  • Serum antibody titer ≥ 1:160 or a fourfold increase or decrease in titer.

BOX 60-3 Control of Brucellosis

Prophylactic Measures

· Brucella vaccines (B abortus strain 19, B melitensis strain Rev-1) have eliminated the disease in some animals

· Gloves, masks, and goggles can protect individuals at risk from potentially infected animals

· Pasteurization of milk kills Brucella in dairy products

Isolation Precautions

· Standard precautions only

General Considerations

Francisella tularensis is the causative agent of tularemia (also called rabbit fever or deerfly fever), an infectious disease that occurs primarily in animals. It may occasionally cause human disease, which most often manifests itself by one or more skin lesions, regional lymphadenopathy, fever, and constitutional symptoms.

  1. Epidemiology.Tularemia is widely distributed, with a higher prevalence in the northern hemisphere. Once common before World War II in the United States, the incidence of tularemia has declined steadily since the 1950s. Currently, the incidence is 0.05–0.15 cases/100,000 population. More than one-half of the cases in the United States occur in Missouri, Arkansas, Oklahoma, Texas, and Illinois. The incidence is higher during the summer months because of the increase in tick-acquired disease.

Transmission of F tularensis to humans occurs through dermal or mucosal contact with infected animals, mainly wild mammals, amphibians, fish, birds, or as the result of an insect bite (eg, ticks, deerflies, and mosquitoes). In the United States, the most common reservoirs are rabbits and ticks. Occasionally, the infection is acquired through inhalation of aerosolized organisms. The organism is highly infectious for laboratory personnel.

  1. Microbiology.F tularensisis a small aerobic, nonmotile, catalase-positive pleomorphic gram-negative coccobacilli. The cell wall of F tularensis is high in fatty acids. Some strains contain a lipid-rich capsule that increases virulence. F tularensis requires a sulphudryl-containing medium for growth and, therefore, does not grow on most routine commercially available media. Growth requires 2–4 days and produces small, smooth, opaque colonies. The organism may be identified on the basis of its morphology, growth requirements, fluorescent staining, and agglutinins with specific antisera. Most strains are β-lactamase producers.
  2. Pathogenesis.After contact with the microorganisms, penetration occurs through sites of inapparent skin disruption. Subsequently, F tularensismultiplies locally and in the skin produces papules that ulcerate, become encrusted, and form an eschar. The microorganisms then reach regional lymph nodes where they replicate and disseminate to the blood. The organisms are engulfed by cells of the reticuloendothelial system in which they may survive intracellularly for prolonged periods. Occasionally, the microorganisms are inhaled, and a pneumonic form of the disease occurs. Rarely, ingestion of the microorganisms can cause pharyngitis, cervical, and mesenteric lymphadenopathy. Early lesions are characterized histopathologically by focal necrosis occurring in organs of the reticuloendothelial system that subsequently undergo granulomatous reaction. Healing is associated with fibrosis and calcification of the granulomata.

Clinical Findings

  1. Signs and Symptoms.The clinical manifestations of tularemia are protean and depend on the portal of entry of the microorganism, virulence of the microorganism, and the immune status of the human host. It can vary from a subclinical illness to a fulminant disease with sepsis and death. Five different clinical syndromes have been described (Box 60-4). The incubation period is 3–5 days.

In the most common form of infection, the ulceroglandular type, a red, tender cutaneous papule is noted at the site of an insect bite or dermal penetration with ulceration on the affected limb and concomitant tender regional adenopathy. The ulcer becomes crusted and black-colored, forming an eschar, which is a characteristic feature of the cutaneous site of entry. Symptoms include fever (39–40.6°C), chills, headaches, and generalized malaise. Patients often are acutely ill with severe prostration and occasionally hypotension, septicemia, and death. If untreated, fever may persist for a month or longer. On physical examination, the temperature elevation is often associated with a paradoxically relative bradycardia. Hepatosplenomegaly is common, especially in untreated cases.

Tularemia should be suspected in febrile patients with skin lesions and lymphadenopathy especially when a history of contact with wild animals, ticks, or deerflies is present.

  1. Laboratory Findings.Organisms are rarely seen on Gram stain of affected tissue. Blood cultures or other biologic specimens need special culture media for growth. Serologic studies using the microagglutination test, or the enzyme immunoassay test, are reliable and widely available. A fourfold increase or decrease in the titers is diagnostic of infection. A titer of ≥ 1:160 may represent recent or acute infection. As many as 50% of cases will have positive titers by the second week of the illness. Titers may remain elevated for months to years after an acute infection.
  1. Imaging.In 30% of cases, a chest roentgenogram will show infiltrates, despite normal clinical findings. Typical chest roentgenogram findings in the pneumonic form would include lobar or subsegmental infiltrates, hilar adenopathy, or diffuse infiltrates.

BOX 60-4 Tularemia Infections


Ulceroglandular (75–85%)

Typhoidal (5–15%)

Pulmonary (7–10%)

Oculoglandular (0–5%)

Oropharyngeal (1%)

More Common

· Macular skin lesion that later becomes a pruritic papule, followed by ulceration and eschar formation

· Regional tender, warm, erythematous, fluctuant, lymphadenopathy

· Fever, chills

· Hepatosplenomegaly

· Fever, chills, weight loss

· Hepatosplenomegaly, abdominal pain

· Pulmonary infiltrates

· Nonproductive cough

· Bilateral patchy infiltrates

· Unilateral painful purulent conjunctivitis

· Preauricular or cervical lymphadenopathy

· Acute exudative or membranous pharyngitis

· Cervical lymphadenopathy

Less Common

· Generalized maculopapular rash

· Generalized adenopathy

· No skin lesions

· Pulmonary infiltrates

· Skin lesion

· Lymphadenopathy

· Lobar pneumonia

· Pleural effusion

· Nodular lesions or ulceration of the conjunctiva


Differential Diagnosis

The differential diagnosis of the ulceroglandular form is one of other diseases that are associated with skin ulcer and lymphadenopathy, such as pyoderma caused by streptococci or staphylococcus, sporotrichosis (Sporothrix schenckii), cat-scratch disease, rat-bite fever, plague, anthrax, brucellosis, typhoid fever, infectious mononucleosis, and hematologic malignancies.


The most common complication is suppuration of an involved lymph node. Other complications such as meningitis, osteomyelitis, endocarditis, and peritonitis occur rarely.


Aminoglycosides, mainly streptomycin or gentamicin, are considered the drugs of choice for all forms of tularemia (Box 60-5). Other antimicrobial agents such as tetracyclines and chloramphenicol have been used in patients who cannot tolerate aminoglycosides. Their bacteriostatic effect against F tularensis may account for the high relapse rates. Relapse is not caused by resistant microorganisms and may be treated with another course of the same antimicrobial regimen.


BOX 60-5 Treatment of Tularemia




First Choice

· Streptomycin, 7.5–15 mg/kg IM twice daily for 10 days

· Gentamicin, 1.5–2 mg/kg IM or IV three times daily for 10 days

· Streptomycin 15–20 mg/kg IM twice daily for 10 days

· Gentamicin, 2 mg/kg IM or IV three times daily for 10 days

Second Choice

· Chloramphenicol, 7.5–12.5 mg/kg orally four times daily for 14 days

· Tetracycline, 500 mg orallyfour times daily for 14 days

· Chloramphenicol, 7.5 mg/kg orally four times daily for 14 days


Immunity after infection with F tularensis is lifelong. The mortality rate is 5–15% in untreated cases and 1% in treated cases. The typhoidal form is associated with a high mortality rate.

Prevention & Control

Avoidance of exposure to contact with potential sources of infection is the best means of prevention (Box 60-6). Gloves, masks, and goggles should be worn when handling potentially infected animals. A live attenuated vaccine is available for individuals at high risk such as veterinarians and meatpacking plant employees.


Essentials of Diagnosis

  • Suspected in patients living in or traveling from an endemic area who have acute onset of fever, prostration, and tender adenopathy.
  • Yersinia pestismay be recovered from blood cultures or cultures of an aspirate from buboes or sputum in the pneumonic form in 80%–100% of cases.
  • Gram stains of bubo aspirate or sputum demonstrate the characteristic bipolar “safety pin” gram-negative microorganisms.
  • Y pestisgrows aerobically on most culture media after 48–72 h of incubation.

General Considerations

The genus Yersinia, named after Alexander Yersin (1863–1943), includes Y pestis, Y enterocolitica, and Y pseudotuberculosis. Y pestis is the cause of plague, a disease that has left its mark on human history since the medieval time. Y enterocolitica and Y pseudotuberculosis also cause mesenteric lymphadenitis.

  1. Epidemiology.Plague occurs worldwide. The most important reservoir for this enzootic disease is rodents: Rattus rattusand Rattus sylvaticus. The ectoparasite Xenopsylla cheopsis (oriental rat flea) represents the most important and efficient vector of transmission to humans. Humans acquire the disease by a fleabite.

Most cases currently occur in developing countries in Africa and Asia. In the United States, most cases occur in the southwestern states during the months of May to October when individuals are outdoors and in contact with rodents and fleas.

  1. Microbiology.Y Pestis, a member of the Enterobacteriaceaefamily, is a nonmotile gram-negative bacilli with bipolar Gram staining. This microorganism grows aerobically on most culture media after 48–72 h of incubation. It produces V and W antigens that play a role in the virulence of the organism.
  2. Pathogenesis.After inoculation by an infested flea, Y pestis cells are phagocytized quickly by leukocytes and macrophages, where they replicate rapidly and produce the virulence antigens. The microorganisms are resistant to intracellular killing and they multiply in the regional lymph nodes and disseminate to the blood and other viscera causing profound toxemia. A severe bleeding diathesis may occur as a result of the effect of plague toxin on blood vessel walls or as a consequence of disseminated intravascular coagulation.

BOX 60-6 Control of Tularemia

Prophylactic Measures

· Avoidance of exposure to potential sources of infection

· Gloves, masks, and eye covers should be worn when handling potentially infected animals

· Live attenuated vaccine is available for individuals at high risk

Isolation Precautions

· Standard precautions only

Clinical Findings

  1. Signs and Symptoms.After an incubation period of 2–8 days following the bite of an infected flea, patients present with sudden onset of fever, chills, weakness, and headaches (Box 60-7). The bubonic form of plague is characterized by the appearance of buboes, which are swollen, painful regional lymphadenopathy (typically inguinal or axillary), appearing after a few hours or on the next day. On physical examination, patients are toxic, lethargic, and agitated. The temperature is usually elevated to 41°C. Buboes are matted, extremely tender and are 2–10 cm in diameter. Rarely, a vesiculopapular lesion from the fleabite is present. Bleeding from the gastrointestinal tract, respiratory tract, or the genitourinary tract is common (so-called red death). Petechiae and large ecchymoses occur along with gangrene of the distal extremities, nose, or penis (so-called Black Death).

The septicemic form of plague is characterized by high-grade bacteremia without palpable lymphadenopathy. Signs and symptoms are otherwise similar to the bubonic form. In this form of the disease, death occurs in 3–5 days in ~ 50% of cases. Y pestis reaches the lungs by way of the hematogenous route or less commonly via the airborne route and causes pneumonia. The pneumonic form is highly contagious and is spread by inhalation of droplet nuclei from a patient with pneumonic plague.

  1. Laboratory Findings.Y pestismay be recovered from blood cultures or cultures of an aspirate from buboes or sputum in the pneumonic form in 80–100% of cases. Gram stains of bubo aspirate or sputum demonstrate the characteristic bipolar “safety pin” gram-negative microorganisms.

BOX 60-7 Plague


Bubonic (90–95%)

Pneumonic (5%)

Septicemic (5%)

More Common

· Abrupt fever (39–41°C), chills

· Nausea-vomiting

· Prostration

· Headaches and delirium

· Tender regional lymphadenopathy (buboes)

· Vasculitis, bleeding, gangrene

· Blood streaked sputum

· Cough, dyspnea, chest pain, cyanosis

· Prostration

· Cavitation or consolidation on chest radiogram

· Vasculitis, bleeding, gangrene

· Abrupt fever (39–41°C)

· Shaking chills

· Nausea/vomiting

· Prostration

· Headaches and delirium

· Vasculitis, bleeding, gangrene

Less Common

· Vesicopapular lesion (flea bite site)

· Generalized lymphadenopathy

· Distal extremity gangrene


· No detectable lymphadenopathy

Differential Diagnosis

The differential diagnosis includes tularemia, lymphogranuloma venereum, cat-scratch disease, or severe staphylococcal and streptococcal infections.


See Signs and Symptoms.


Streptomycin, the drug of choice for the treatment of plague, reduces the case fatality rate from > 50% in untreated cases to 10% in treated cases (Box 60-8). For patients who are allergic to or unable to tolerate streptomycin, tetracycline is a satisfactory alternative agent. In meningitis, the use of an antimicrobial agent with good penetration into the cerebrospinal fluid is essential. Chloramphenicol is administered at a loading dose of 25 mg/kg followed by 15 mg/kg intravenously every 6 h for a 10-day course.

Prevention & Control

  1. Primary prevention.Patients with suspected pulmonic plague should be placed in strict respiratory isolation until the sputum culture is negative (Box 60-9).

Chemoprophylaxis with tetracyclines or sulfonamides should be administered to individuals who have had close contact with patients with plague pneumonia and for household contacts of flea-borne plague cases.

  1. Secondary Prevention.For persons at high risk of exposure, two forms of vaccines are available: a live attenuated and a formalin-killed plague vaccine.

BOX 60-8 Treatment of Plague




First Choice

· Streptomycin, 15–22.5 mg/kg IMtwice daily for 10 days

· Gentamicin, 2 mg/kg IV three times daily for 10 days

· Streptomycin, 15 mg/kg IM twice daily for 10 days

· Gentamicin, 1–2.5 mg/kg IMor IV three times daily for 10 days

Second Choice

· Tetracycline, 500–1000 mg orally four times daily for 10 days

· Tetracycline, 1 7–12.5 mg/kg IV four times daily for 10 days

· Chloramphenicol, 25 mg/kg loading dose followed by 12.5 mg/kg IM four times daily for 10 days

1Should not be used in children under the age of 8 or in pregnant women after 6 months of gestation.


Essentials of Diagnosis

  • Suspected in a child living in or traveling from a high-prevalence area who has fever, abdominal pain, and diarrhea followed by a reactive polyarthritis.
  • Yersiniaspp. are recovered from cultures of specimens of stool, mesenteric lymph nodes, blood, or abscess material.
  • Inoculation of duplicate sets of cultures for incubation at 37 and 25°C, respectively, enhances recovery of the microorganisms.

General Considerations

  1. Epidemiology.Conditions that are associated with increased risk for Yersiniaspp. infections (yersiniosis) include iron overload states (such as in patients who receive chronic blood transfusions or those with hemochromatosis) and the use of desferrioxamine, a bacterial siderophore. Infections caused by Y enterocolitica are more common in children than adults. The disease is more prevalent in northern Europe than in the United States. It is acquired by ingestion of contaminated food or water or by direct contact with an infected animal. The organism has been recovered from a variety of wild and domestic animals including pigs, rodents, rabbits, dogs, and horses, as well as from water and dairy products. The ability of the microorganism to grow at 4°C allows it to survive in refrigerated food and dairy products.

Y pseudotuberculosis infection occurs rarely. The microorganism has been recovered from many species of wild and domestic animals and from food, water, and other environmental sources. The disease is thought to be acquired by contact with infected animals or by ingestion of contaminated food. The disease is more common in Europe and typically affects children and adults during the winter months.

  1. Microbiology.Y enterocoliticaor Y pseudotuberculosis are the pathogens of the nonplague yersiniosis. They cause a gastrointestinal infection that may manifest itself by diarrhea or fever and abdominal pain that mimics acute appendicitis. These microorganisms are gram-negative bipolar stained bacilli, nonlactose fermenting and urease positive. They are motile at 25°C but not at 37°C. They are iron dependent and grow well on conventional culture media at 37°C and in normal saline at 4°C. Y enterocolitica produces a heat-stable enterotoxin and lipopolysaccharide endotoxin similar to that produced by other enteric gram-negative bacilli. The virulence of Y pseudotuberculosis appears to be related to the production of a lipopolysaccharide endotoxin and to the ability to survive intracellularly. Yersinia spp. lack siderophores and are dependent on siderophores produced by other bacteria for growth.
  2. Pathogenesis.The portal of entry of Y enterocoliticaand Y pseudotuberculosis is the gastrointestinal tract. These microorganisms cause terminal ileitis and adenitis. Pathogenic strains of Y enterocolitica cause mucosal ulceration and necrosis of Peyer's patches and therefore diarrhea. Bacteremia occurs rarely and is associated with suppurative lesions in the liver, spleen, and other organs. Reiter's syndrome is a reactive polyarthritis and occurs in 20%–30% of patients following infection with Y enterocolitica. Cross-reactions between the HLA-B27 antigen and the Yersinia antigen are postulated to be the underlying mechanism of arthritis.

BOX 60-9 Control of Plague

Prophylactic Measures

Chemoprophylaxis should be administered as follows to individuals who have had close contact with patients with plague pneumonia and for household contacts of fleaborne plague cases:

· Tetracycline, 7.5 mg/kg orally 4 times daily for 7 days (should not be used in children under the age of 8 or in pregnant women after 6 months of gestation)

· Sulfonamides, 7.5–15 mg/kg orally 4 times daily for 7 days

Isolation Precautions

· Patients with suspected pneumonic plague should be placed in strict respiratory isolation until the sputum culture is negative

Clinical Findings

The spectrum of disease caused by Y enterocolitica and Y pseudotuberculosis is wide and may be divided into two categories: infectious (intestinal and extraintestinal) and postinfectious (Box 60-10).

BOX 60-10 Yersiniosis





More Common

· Enteritis: abdominal pain, diarrhea

· Mesenteric adenitis

· Pseudoappendicitis syndrome

· Septicemia

· Pharyngitis

· Hepatic involvement

· Skin manifestations

· Lymphadenopathy syndrome

· Polyarthritis: knees, ankles, wrist, fingers, toes

· Erythema nodosum

Less Common

· Perforation of the bowel

· Toxic megacolon

· Transfusion-related sepsis

· Endocarditis

· Uveitis

· Glomerulonephritis

· Guillain-Barré syndrome

· Hemolytic uremic syndrome

BOX 60-11 Treatment of Yersiniosis




First Choice

· Gentamicin, 1.5 mg/kg IV three times daily for 10 days

· Gentamicin, 1–2.5 mg/kg IV three times daily for 10 days

Second Choice

· Tetracycline, 500–1000 mg orally four times daily for 10 days

· Chloramphenicol, 7.5–12.5 mg/kg orally or IV four times daily for 10 days

· Tetracycline, 1 7–12.5 mg/kg IV four times daily for 10 days

· Chloramphenicol, 25 mg/kg loading dose followed by 12.5 mg/kg IMfour times daily for 10 days

1Should not be used in children under the age of 8 or in pregnant women after 6 months of gestation.

  1. Signs and Symptoms.An intestinal infection is the most common manifestation. Typically, patients present with fever, abdominal pain, and diarrhea that is occasionally bloody for a 1- to 3-week duration. A clinical syndrome indistinguishable from acute appendicitis may occur in older children and adolescents. On laparotomy, thickening of the terminal ileum and cecal wall is present. The appendix is normal. Perforation of the intestine or dilatation of the colon with marked systemic toxicity (toxic megacolon) occurs rarely.

Extraintestinal infections are rare. A septicemic syndrome preceding enterocolitis or associated with transfusions of contaminated blood has a mortality rate of 50%. The iron present in blood and storage at 4°C are favorable conditions for the growth of Yersinia spp. Other extraintestinal manifestations include cutaneous lesions such as cellulitis, vesicobullous lesions, and other manifestations including diffuse lymphadenopathy, splenomegaly, and acute pharyngitis.

Hepatic involvement is common in adults and can be present in two different forms. The acute form mostly occurring in patients with iron overload states is the result of involvement of the liver and sometimes the spleen with abscesses. The chronic form is characterized by a granulomatous inflammation in the liver and can be associated with a positive rheumatoid factor or a positive antinuclear antibody in the serum. The chronic form is thought to be secondary to an immunological phenomenon.

Postinfectious manifestations include polyarthritis involving the weight-bearing joints and occurs in 10%–30% of Scandinavian adults with Y enterocoliticainfection. Of patients with arthritis, 70% have the histocompatibility antigen HLA-B27. Arthritis begins a few days to a month following the onset of diarrhea and can persist ≤ 4 months. Erythema nodosum occurs in 20%–30% of cases with arthritis. Other postinfectious manifestations include uveitis, glomerulonephritis, Guillain-Barré syndrome and the hemolytic-uremic syndrome.

  1. Laboratory Findings.Laboratory findings are nonspecific and might include leukocytosis, anemia, and elevated erythrocyte sedimentation rates.

Differential Diagnosis

The differential diagnosis of polyarthritis is wide and includes acute rheumatic fever, juvenile rheumatoid arthritis, Kawasaki disease, and other postinfectious arthritides.


See Signs and Symptoms.


Diarrhea and mesenteric adenitis are usually self-limited, and antimicrobial therapy has not been demonstrated to affect the course of the infection. Immunocompromised hosts and patients with extraintestinal infections should be treated with antimicrobial therapy (Box 60-11). The optimal therapy is unclear. Yersinia spp. are susceptible in vitro to gentamicin, fluoroquinolones, trimethoprim-sulfamethoxazole, third-generation cephalosporins, tetracycline, and chloramphenicol. Empirical therapy with an aminoglycoside alone or in combination with trimethoprim-sulfamethoxazole, or a third-generation cephalosporin, or chloramphenicol is recommended.


Mortality is rare, except in the septicemic form, where yersiniosis is associated with 50% mortality.

Prevention & Control

Hospitalized patients with Yersinia spp. infections should be placed in enteric isolation (Box 60-12). Pasteurization of dairy products and proper cooking of meat or boiling water kills the microorganism in contaminated food. Contact with potentially infected animals in endemic areas should be minimized.


Essentials of Diagnosis

  • History of a cat or dog bite or other exposure.
  • Pain, erythema, swelling, and drainage at the bite site.
  • Gram-negative bipolar bacilli on Gram stain of the drainage.
  • Culture of the organism confirms the diagnosis.

General Considerations

Pasteurella multocida infection, a disease that primarily affects animals, may occasionally affect humans, causing a wide variety of infections ranging from soft tissue infection to bacteremia and endocarditis.

BOX 60-12 Control of Yersiniosis

Prophylactic Measures

· Pasteurization of dairy products and proper cooking of meat or boiling water kills the microorganisms in contaminated food

· Contact with potentially infected animals in endemic areas should be minimized

Isolation Precautions

· Hospitalized patients with Yersinia spp. infections should be placed in enteric isolation


BOX 60-13 Pasteurella Infection


Soft Tissue/Bone

Respiratory System

More Common

· Erythema, pain, and swelling

· Serosanguineous drainage

· Regional lymphadenopathy

· Low-grade fever

· Pharyngitis

· Pneumonia

Less Common

· Abscess

· Tenosynovitis

· Arthritis

· Sinusitis

· Otitis

· Mastoiditis

· Empyema

  1. Epidemiology.Pasteurella multocidahas been recovered from cultures of specimens from the nasopharynx and the gastrointestinal tract of a large number of asymptomatic wild and domestic animals. The highest carriage rates occur in cats (50%–90%), dogs or swine (50%), and rats (15%). Infections are usually preceded by a cat or dog bite or scratch on an extremity. Occasionally, infection may occur without a bite or scratch in persons who have frequent contact with animals. Fifteen percent of cases have no history of animal exposure.
  2. Microbiology.Pasteurellaspp. are small, nonmotile, non-spore-forming, bipolar staining gram-negative coccobacilli. Growth occurs aerobically at 37°C in ordinary culture media and is enhanced by using blood- or serum-enriched agar under increased carbon dioxide tension. Among the Pasteurella spp. that can cause disease in humans, P multocida is the most common. Different species of Pasteurella may be distinguished by their biochemical reactions and their requirements for V factor.
  3. Pathogenesis.A localized infection occurs after inoculation of the microorganism in soft tissue or a joint space. It is characterized by polymorphonuclear leukocyte infiltrates followed by necrosis and, in some cases, by abscess formation. When bacteremia occurs, microabscesses may develop in multiple organs.

BOX 60-14 Treatment of Pasteurella Infection




First Choice

Amoxicillin–clavulanic acid, 250–500 mg orally three times daily for 10 days

Amoxicillin–clavulanic acid 13.3 mg/kg orally three times daily for 10 days

β-Lactam Allergy

Ciprofloxacin, 500–750 mg orally twice daily

TMP/SMX, 4–6 mg/kg TMP orally twice daily

Clinical Findings

  1. Signs and Symptoms.Hours to days after direct contact with an animal (usually by way of a dog or cat bite), a soft tissue infection develops (Box 60-13). Patients complain of an acute onset of pain, erythema, and swelling at the site of inoculation, usually on the hand, leg, arm, or head and neck. Serosanguineous drainage occurs 1–2 days later. A low-grade fever and regional lymphadenopathy are commonly seen. Abscess formation and septic arthritis or osteomyelitis rarely complicate local infection of the extremity.
  2. Laboratory Findings.Gram-negative bipolar bacilli appear on Gram stain of the drainage. Cultures of the organism confirm the diagnosis.

Differential Diagnosis

After an animal bite, the differential diagnosis should include infection caused by anaerobes, staphylococci, streptococci, tularemia, and cat-scratch disease.


Occasionally, P multocida may affect the respiratory system. These infections occur in persons who have frequent contact with animals. P multocida has been recovered from the sputum cultures of asymptomatic patients with chronic obstructive pulmonary disease and in these patients may cause pneumonia.

Occasionally, pharyngitis occurs in patients with close contact with infected animals, especially cats. Rarely, P multocida may cause meningitis, sinusitis, pharyngeal abscess, otitis, empyema, peritonitis, pyelonephritis, surgical wound infection, and endocarditis. Associated bacteremia can occur with any organ infection.

BOX 60-15 Control of Pasteurella Infection

Prophylactic Measures

· Avoidance of contact with wild or domestic animals


Animal bites need to be carefully assessed. Examination of the joints, tendons, and neurovascular axis of a limb is mandatory. Bite wounds should be cleaned with normal saline, and devitalized tissue should be débrided. If necessary, the tetanus toxoid vaccine should be administered, and potential exposure to rabies should be assessed.

The microbiology of animal bites is polymicrobial and includes Pasteurella spp., staphylococci, streptococci, and anaerobes. Antimicrobial therapy should be active against these microorganisms (Box 60-14). Amoxicillin-clavulanic acid, cefuroxime, or doxycycline are effective therapy. Ciprofloxacin is effective against P multocida; however, it lacks activity against anaerobes, streptococci, and staphylococci. In patients unable to tolerate β-lactams, doxycycline or combination therapy with ciprofloxacin and clindamycin is an effective alternative therapy for animal bites. In monomicrobial infection with P multocida, penicillin is the treatment of choice.

Prevention & Control

Avoidance of contact with wild or domestic animals is probably the only means of preventing human P multocida infections (Box 60-15).

BOX 60-16 HACEK Infections



Other Sites

More Common

· Fever

· Periodontal disease

· New or changing cardiac murmur

· Splenomegaly

· Embolic phenomena

· Brain abscess: fever, confusion, focal findings

· Meningitis

· Arthritis: swelling, pain, and effusion of the affected joint

Less Common



Essentials of Diagnosis

  • Suspected in patients with periodontal disease with signs and symptoms suggestive of infective endocarditis.
  • Large valvular heart vegetation on echocardiography.
  • Small, pleomorphic gram-negative coccobacilli that grow best in enriched media and increased CO2tension.

General Considerations

The fastidious bacteria of the HACEK group include Haemophilus aphrophilus and H paraphrophilus, Actinobacillus actinomycetemcomitans, Cardiobacterium hominis, Eikenella corrodens, and Kingella kingae. These organisms may be considered part of the normal flora of the upper respiratory tract. Because they share common clinical and microbiological properties, they will be reviewed together.

All HACEK microorganisms produce a similar clinical syndrome including infective endocarditis, periodontal disease, and bacteremia (Box 60-16). Rarely, these microorganisms may cause brain abscess, meningitis, pneumonia, intra-abdominal infections, gynecologic infections, arthritis, osteomyelitis, and human bite wound infection (E corrodens).

  1. Epidemiology.The most common infectious disease caused by these microorganisms is infective endocarditis. These microorganisms account for 3% of infective endocarditis cases. The incidence of HACEK endocarditis is ~ 0.32/100,000 person years of life. HACEK microorganisms are part of the usual microflora of the oral cavity, and this serves as the portal of entry for bacteremia, which may result in infective endocarditis or, very rarely, infections in other organ systems.
  2. Microbiology.Microorganisms of the HACEK group are small, pleomorphic gram-negative coccobacilli that grow best in enriched media (such as sheep blood agar or chocolate agar) and increased CO2tension. Cultures often require prolonged incubation times (average 5–7 days) for growth. They are distinguished among each other by their biochemical reactions.

BOX 60-17 Treatment of HACEK Endocarditis




First Choice

· Ceftriaxone, 2 g IV daily for 4–6 weeks

· Cefotaxime, 2 g IV three times daily for 4–6 weeks

· Ceftriaxone, 100 mg/kg IV daily for 4–6 weeks

· Cefotaxime, 50 mg/kg IV three times daily for 4–6 weeks

Second Choice

· Ampicillin, 2 g IV 6 times daily PLUS gentamicin, 1 mg/kg IM or IV every 8 h for 4–6 weeks

· Ampicillin, 50–75 mg/kg IV every 6 h PLUS gentamicin, 1 mg/kg IMor IV every 8 h for 4–6 weeks

Clinical Findings

  1. Signs and Symptoms.The presentation of endocarditis is often insidious in onset and includes fever, splenomegaly, embolic phenomena, and a new or changing cardiac murmur. More than half of patients with endocarditis will have had a dental procedure within the 6 months before onset of symptoms or poor dentition at the time of diagnosis. Valvular or congenital structural heart disease or the presence of a prosthetic heart valve was present in 60% and 27% of cases, respectively. Cardiac valvular vegetation observed by echocardiography is characteristically large. This finding probably reflects the chronicity of infection before diagnosis. Signs and symptoms of other HACEK infections are related to the affected site of infection.
  2. Laboratory Findings.The diagnosis of HACEK infections requires the cultivation of the bacteria from sterile sites. Biological specimens need to be incubated in enriched media under increased CO2tension for 5–7 days.
  3. Imaging.Echocardiography can reveal large endocardial or valvular vegetation.

Differential Diagnosis

The differential diagnosis includes infective endocarditis caused by other microorganisms, such as staphylococci, enterococci, and fungi.


With the emergence of β-lactamase-producing HACEK organisms, third-generation cephalosporins (eg, cefotaxime or ceftriaxone) are now considered the treatment of choice (see Box 60-17). The treatment of infections other than infective endocarditis caused by HACEK organisms requires the same antimicrobial therapy used in infective endocarditis; however, the length of therapy might be shorter, depending on the site of infection. With susceptible microorganisms, combination therapy using penicillin or ampicillin and aminoglycoside is satisfactory. The American Heart Association recommends that native valve and prosthetic valve endocarditis be treated for 4 and 6 weeks, respectively.


Native or prosthetic valve endocarditis caused by HACEK organisms may be cured in 82%–87% of the cases by medical or medical and surgical therapies.

Prevention & Control

Follow American Heart Association guidelines for prevention of infective endocarditis, after dental and other procedures in patients at high risk. See Chapter 11 for cardiovascular-intravascular infection guidelines for subacute bacterial endocarditis prophylaxis.



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