ACP medicine, 3rd Edition

Infectious Disease

Infections Due to Brucella, Francisella, Yersinia Pestis, and Bartonella

1. Conrad Liles M.D., Ph.D.¹

¹Associate Professor of Medicine, University of Washington School of Medicine

The author has no commercial relationships with manufacturers of products or providers of services discussed in this subsection.

March 2002

Brucellosis, tularemia, (bubonic) plague, and bartonellosis are zoonoses (i.e., infectious diseases that can be transmitted from animals to humans) caused by gram-negative bacilli. The causative agents of these diseases are Brucella species, Francisella tularensis, Yersinia pestis, and Bartonella species, respectively. Infected arthropods, such as ticks or fleas, can serve as vectors for the transmission of tularemia, plague, and bartonellosis. In general, the diagnosis of these zoonoses requires the physician to consider the clinical presentation (which is not always distinctive) in light of the epidemiology of these diseases [see Table 1]. Treatment is principally with appropriate empirical antimicrobials [see Table 2].

Table 1 Diagnosis of Diseases Caused by Brucella, Francisella, Yersinia, and BartonellaSpecies

Brucella(Brucellosis) Francisella tularensis(Tularemia) Yersinia pestis(Plague) Bartonella (Oroya Fever, Bacteremia, Cat-Scratch Disease) Animal reservoir Cattle, goats, sheep, swine, dogs Widespread: mammals, birds, fish, amphibians, arthropods Rodents (rats, ground squirrels, prairie dogs); other animals possible Cats, phlebotomine sandflies (Andes Mts.) Transmission Direct contact through skin lesions, airborne, ingestion of contaminated dairy products Direct contact, airborne, arthropod bites Flea bites, animal bites or scratches, airborne Oroya fever: sandfly bites Bacteremia: body lice Cat-scratch disease: cat bites or scratches; possibly, cat flea bites Incubation period (range) 10–14 days (5 days to several months) 3–7 days (1–21 days) Bubonic: 2–7 days Pneumonic: 2–3 days (1–14 days) Oroya fever: 3–12 wk Bacteremia: days to months Cat-scratch disease: 3–10 days Clinical manifestations Protean: fever and tachycardia, flulike syndrome, liver or spleen enlargement, lymphadenopathy, rashes or skin lesions Flulike illness, ulcer at site of skin inoculation, regional lymphadenopathy, rash, GI symptoms Flulike illness, buboes (inguinal/axillary lymphadenopathy) Septicemic: GI symptoms Oroya fever: flulike illness, lymphadenopathy, hemolytic anemia, thrombocytopenia Bacteremia: fever, malaise, anemia, thrombocytopenia, splenomegaly, cardiac murmur, bacillary angiomatosis (in HIV) Cat-scratch disease: inoculation-site lesion, regional lymphadenopathy, low-grade fever Laboratory tests WBCs normal or decreased; RBCs and platelets typically decreased; ESR variable; culture of body fluid and tissue; serology Screening tests often unremarkable; mild to moderate elevation of AST and ALT; serology (late) WBCs 15,000–25,000/µl, left shift; fibrin split products ↑; DIC possible; AST, ALT, and bilirubin elevated; culture of body fluid and tissue; direct immunofluorescence Oroya fever: blood culture Bacteremia: blood culture Cat-scratch disease: diagnosis usually clinical ALT—alanine aminotransferase AST—aspartate aminotransferase ESR—erythrocyte sedimentation rate RBC—red blood cell WBC—white blood cell

Table 2 Treatment of Diseases Caused by Brucella, Francisella, Yersinia, and Bartonella Species

Infection Drug Dosage Relative Efficacy Cost Comments Brucella(Brucellosis) Doxycycline 100 mg p.o., b.i.d., for 6 wk   $0.05–0.12/day   plus         Gentamicin 3–5 mg/kg/day I.V. in divided doses for 2–3 wk First choice 120 mg I.V. q. 8 hr: $5.00–5.99/day Relapse rate ~6% or         Streptomycin 1 g I.M. q.d. for 2–3 wk   500 mg I.M. b.i.d.: $3.00–3.99/day             Doxycycline 100 mg p.o., b.i.d., for 6 wk   $0.05–0.12/day   plus             Alternative choice   Relapse rate ~15% Rifampin 600–900 mg p.o., b.i.d., for 6 wk   600 mg p.o. once daily: $60.00–69.99/mo.     Ciprofloxacin 500 mg p.o., b.i.d., for 30 days, ith rifampin (see above) Adjunctive therapy — Adjunctive therapy   Francisella tularensis(Tularemia) Streptomycin 500 mg-1 g I.M. q. 12 hr for 7–14 days First choice 500 mg I.M. b.i.d.: $3.00–3.99/day — Gentamicin 3–5 mg/kg/day I.V. in divided doses q. 8 hr for 7–14 days Equally effective 120 mg I.V. q. 8 hr: $5.00–5.99/day — Tetracycline 500 mg p.o., q.i.d., for 21–28 days Alternative choice 500 mg p.o., q.i.d.: $0.10–0.24/day Relapse can occur if therapy < 21 days Doxycycline 100 mg p.o., b.i.d., for 21–28 days Alternative choice — Relapse can occur if therapy < 21 days Chloramphenicol 1 g I.V., p.o.*q. 6 hr for 21–28 days Alternative choice 1 g I.V. q. 6 hr: $150.00–199.99/day Relapse can occur if therapy < 21 days; consider for treatment if signs or symptoms of meningitis are present Ciprofloxacin 500 mg p.o., b.i.d., for 14–21 days Alternative choice 500 mg p.o., b.i.d.: $7.00–7.99/day Limited data Yersinia pestis(Bubonic Plague) Streptomycin 30 mg/kg/day I.M. in divided doses q.12 hr, for 10 days or at least 3 days after clinical recovery; or for 5 days, followed by gentamicin for 5–10 days (see below) First choice 500 mg I.M. b.i.d.: $3.00–3.99/day Continue antibiotic therapy for 10 days, or at least 3 days after clinical recovery Gentamicin 2 mg/kg I.V. loading dose, then 1.7 mg/kg I.V. q. 8 hr Equally effective 120 mg I.V. q. 8 hr: $5.00–5.99/day Continue antibiotic therapy for 10 days, or at least 3 days after clinical recovery Tetracycline 500 mg I.V./p.o., q.i.d. Alternative choice 500 mg p.o., q.i.d.: $0.10–0.24/day Continue antibiotic therapy for 10 days, or at least 3 days after clinical recovery Doxycycline 100 mg I.V./p.o., b.i.d. Alternative choice 100 mg p.o., b.i.d.: $0.05–0.12/day Continue antibiotic therapy for 10 days, or at least 3 days after clinical recovery Chloramphenicol 500 mg-1 g I.V./p.o.*q.i.d. Alternative choice 1 g I.V. q. 6 hr: $150.00–199.99/day Continue antibiotic therapy for 10 days, or at least 3 days after clinical recovery Tetracycline 500 mg p.o., q.i.d. Chemoprophylaxis $0.10–0.24/day Chemoprophylaxis for contacts of patients with pneumonic plague Doxycycline 100 mg p.o., b.i.d. Chemoprophylaxis $0.05–0.12/day Chemoprophylaxis for contacts of patients with pneumonic plague Streptomycin 20 mg/kg/day I.M. in two divided doses Chemoprophylaxis 500 mg I.M., b.i.d.: $3.00–3.99/day Chemoprophylaxis for contacts younger than 8 yr of age of patients with pneumonic plague Trimetho-primsulfamethoxazole 40 mg/kg p.o., b.i.d. Chemoprophylaxis 800/160 mg p.o., b.i.d.: $0.10–0.24/day Chemoprophylaxis for contacts younger than 8 yr of age of patients with pneumonic plague Bartonella(Bartonellosis) OROYA FEVER           Chloramphenicol 500 mg p.o.*/I.V. q.i.d. for ≥ 1 wk First choice 1 g I.V. q. 6 hr: $150.00–199.99/day —   Tetracycline 500 mg p.o./I.V. q.i.d. for ≥ 2 wk Alternative choice $0.10–0.24/day —   Doxycycline 100 mg p.o./I.V. q.i.d. for ≥ 2 wk Alternative choice $0.05–0.12/day —   Ampicillin 500 mg p.o./I.V. q.i.d. for ≥ 2 wk Alternative choice 500 mg p.o., q.i.d.: $0.75–0.99/day — URBAN TRENCH FEVER WITH BACTEREMIA           Erythromycin 500 mg p.o., q.i.d., for 14 days — — Azithromycin and clarithromycin are probably equally effective   Doxycycline 100 mg p.o., b.i.d., for 14 days — $0.05–0.12/day — URBAN TRENCH FEVER WITH ENDOCARDITIS           Gentamicin 2 mg/kg I.V. loading dose, then 1.7 mg/kg I.V. q. 8 hr — 120 mg I.V. q. 8 hr: $5.00–5.99/day In conjunction with valve replacement   Ciprofloxacin Ciprofloxacin, 500 mg p.o., b.i.d., plus rifampin, 600 mg p.o., q.d, for ≥ 4–6 mo — — Limited data; monitor for surgical valve replacement; levofloxacin can be substituted for ciprofloxacin plus           Rifampin           Ciprofloxacin Ciprofloxacin, 500 mg p.o., b.i.d., plus an oral macrolide (erythromycin, clarithromycin, or azithromycin) for ≥ 4–6 mo — — Limited data; monitor for surgical valve replacement; levofloxacin can be substituted for ciprofloxacin plus           a macrolide         CAT-SCRATCH DISEASE           Azithromycin 500 mg p.o. once, then 250 mg p.o., q.d., for 4 days — 250 mg p.o., q.d.: $6.00–6.99/day Azithromycin is only agent shown to be effective in placebo-controlled, double-blind clinical trial; alternative choices include rifampin, gentamicin, trimethoprim-sulfamethoxazole, doxycycline, ciprofloxacin, and levofloxacin           BACILLARY ANGIOMATOSIS           Erythromycin 500 mg p.o., q.i.d., for 2 mo (4 mo for osteomyelitis or peliosis hepatis) First choice 250 mg (base) p.o., q.i.d.: $1.00–1.49/day —   Doxycycline 100 mg p.o., b.i.d., for 2 mo (4 mo for osteomyelitis or peliosis hepatis) First choice $0.05–0.12/day —   Clarithromycin 500 mg p.o., b.i.d., for 2 mo (4 mo for osteomyelitis or peliosis hepatis) Alternative choice 500 mg p.o., b.i.d.: $7.00–7.99/day —   Azithromycin 250 mg p.o., q.d., for 2 mo (4 mo for osteomyelitis or peliosis hepatis) Alternative choice 250 mg p.o., q.d.: $6.00–6.99/day —   Ciprofloxacin 500–750 mg p.o., b.i.d., for 2 mo (4 mo for osteomyelitis or peliosis hepatis) Alternative choice 500 mg p.o., b.i.d.: $7.00–7.99/day —   Doxycycline Doxycycline: 100 mg I.V./po., b.i.d., plus rifampin, 300 mg p.o., b.i.d., for 2 mo (4 mo for osteomyelitis or peliosis hepatis) Alternative choice $0.05–0.12/day For severe or relapsed cases plus           Rifampin         *Note: Chloramphenicol is not distributed as an oral drug in the United States.

Brucellosis

Brucellosis continues to be a major zoonosis worldwide.¹ The animal reservoirs for the disease include a variety of domesticated animals: cattle, goats, sheep, pigs, and dogs. Human brucellosis (variously known as undulant fever, Malta fever, and Mediterranean fever) is rare in the United States but remains a significant health problem in developing countries. In humans, brucellosis is a disease of protean manifestations, ranging from an indolent febrile syndrome to fulminant endocarditis. Like plague and tularemia, brucellosis is recognized as a potential agent of biological terrorism.²

EPIDEMIOLOGY

Virtually all cases of brucellosis arise from direct or indirect exposure to animals.^1,3,4,5 In animals, brucellosis is a chronic disease that persists lifelong and causes infectious abortion and sterility. B. abortus infects predominantly cattle; B. melitensis, goats and sheep; and B. suis, domestic and wild swine. B. canis, the least common cause of human brucellosis, is mostly found in kennel-raised dogs. Infected animals shed large numbers of Brucella organisms in their milk, urine, and afterbirth. Hence, brucellosis is considered an occupational hazard for farmers, ranchers, veterinarians, abattoir workers, and laboratory personnel.^3,4,6

Brucellosis is distributed worldwide, but its incidence varies markedly, depending largely on the degree of its control in domestic animals and the pasteurization of milk. The disease is relatively common in southern Europe, the Middle East, the Indian subcontinent, parts of Africa, Mexico, and Central and South America.^1,3,4,5

In the United States, the incidence of brucellosis has declined to less than 100 cases annually, coincident with public health programs and the virtual elimination of B. abortus infection in cattle. Currently, most cases of brucellosis acquired in the United States are caused by B. melitensis and can be linked to ingestion of unpasteurized goat-milk products from foreign countries, such as Mexico, and exposure toBrucella cultures in microbiology laboratory personnel.^4,6,7,8 Transmission of brucellosis by bone marrow transplantation was recently reported.⁹

ETIOLOGY

Brucellosis is transmitted to humans by direct contact with infected animals or their body fluids (inoculation occurs through cuts or abraded skin); via inhalation of aerosolized organisms; or by ingestion of unpasteurized dairy products. Because of the low density of organisms in muscle, consumption of meat products has rarely been implicated in infection.^1,3,4,5

PATHOGENESIS

Brucella organisms are small, nonmotile, non-spore-forming, gram-negative coccobacilli. The organisms are relatively hardy and can survive in dairy products or refrigerated meats for weeks to months. Although they grow aerobically, some species require supplemental carbon dioxide for primary isolation. In culture, Brucella strains are relatively slow growing; isolation from clinical specimens can require incubation for 30 days or more.^1,4

Infection can occur via the gastrointestinal tract, broken skin, oral mucosa, conjunctiva, or respiratory tract. Once inoculated, bacteria travel to regional lymph nodes and multiply. They then enter the bloodstream and localize in cells of the reticuloendothelial system (particularly the liver, spleen, bone marrow, and lymph nodes) and kidney. At tissue sites of infection, noncaseating granulomas characteristically develop. Bacteremia can lead to metastatic infection at various sites, including bone, joints, meninges, and cardiac valves.^1,3,4,5

DIAGNOSIS

Clinical Manifestations

The incubation period for brucellosis is usually 10 to 14 days, but it ranges from 5 days to several months. Onset of illness can be abrupt or insidious. The presentation is nonspecific; fever, chills, headache, myalgias, anorexia, malaise, and fatigue are common. Fever and tachycardia are present in approximately 90% of cases, hepatomegaly in 25% to 30%, splenomegaly in about 40%, and lymphadenopathy (most commonly cervical) in 10% to 40%. Cutaneous manifestations, which occur in approximately 5% of patients, include a variety of nonspecific maculopapular rashes, erythema nodosum, petechiae, and purpura. Other symptoms and signs will depend on specific organ involvement in individual cases.

Brucellosis can follow an acute, subacute, or chronic course. Untreated disease may persist for months to years and may cause a syndrome of relapsing fevers. Because the symptoms and signs of brucellosis may be nonspecific, it is important to obtain a detailed history that includes occupation, travel, exposure to animals, or ingestion of high-risk foods, such as unpasteurized dairy products^1,3,4,5 [see Table 1].

Laboratory Tests

The leukocyte count is typically normal or decreased. Anemia and thrombocytopenia are relatively common. The erythrocyte sedimentation rate is variable and rarely helpful.

Definitive diagnosis of brucellosis depends on isolation of the organism from blood, bone marrow, urine, cerebrospinal fluid, or other body fluids or tissues. The sensitivity of a single blood culture ranges from 15% to 70%, depending on the method used and the length of incubation. Because Brucella organisms grow slowly, cultures should be maintained for at least 4 weeks to increase recovery. The use of lysis centrifugation culture systems has been reported to hasten recovery. Culture of bone marrow is reportedly more sensitive than conventional blood culture.

Presumptive diagnosis of brucellosis can be made by serologic studies showing specific brucella IgG antibodies or the presence of IgM antibody to Brucella. ^3,4,5,10 It should be noted that the standard brucella serum agglutination test does not detect antibodies to B. canis. In suspected B. canis infection, serologic tests specific for that species should be ordered. Molecular diagnosis using polymerase chain reaction has been developed but is currently not available for routine clinical use.¹¹

DIFFERENTIAL DIAGNOSIS

The differential diagnosis of brucellosis includes enteric fever, malaria, infectious mononucleosis (Epstein-Barr virus [EBV] infection), atypical mononucleosis (cytomegalovirus infection), Q fever, miliary tuberculosis, subacute bacterial endocarditis, HIV infection, and visceral leishmaniasis (kala-azar).⁴

TREATMENT

Brucellosis requires prolonged treatment with a tetracycline, typically supplemented with a second antibiotic: an aminoglycoside, rifampin, or perhaps a fluoroquinolone^1,3,4,5 [see Table 2]. Significant resistance to trimethoprim-sulfamethoxazole has limited the use of this agent.⁵Recent studies from Spain and the Middle East suggest that the best initial regimen is doxycycline (100 mg p.o., b.i.d.) for 6 weeks, plus either gentamicin (3 to 5 mg/kg a day I.V. in divided doses) or streptomycin (1 g/day I.M.) for the first 2 to 3 weeks. Relapse occurs in approximately 6% of patients treated with this regimen.¹² Doxycycline can also be combined with 6 weeks of rifampin (600 to 900 mg p.o., b.i.d.), although relapse has been reported in approximately 15% of patients treated with this regimen.¹³ Fluoroquinolones have demonstrated good activity against Brucella in vitro, but clinical results have been disappointing; therefore, those agents should be regarded as adjunctive rather than primary therapy.¹³ Although corticosteroid therapy has been recommended for management of brucellosis involving the central nervous system, no controlled studies have demonstrated its efficacy. No satisfactory vaccines for human brucellosis are currently available.¹

COMPLICATIONS

Brucellosis can cause complications in almost any organ system. Endocarditis occurs in less than 2% of cases but accounts for the majority of brucellosis-related deaths. Infected aneurysms of the brain, aorta, and other vessels can occur. Direct invasion of the central nervous system occurs in only about 5% of cases. Meningitis is the most frequent CNS complication. Bone and joint involvement is relatively common, with a reported occurrence of 20% to 60%. Sacroiliitis and spondylitis are the most common musculoskeletal complications.¹⁴ The GI tract is involved in as many as 70% of patients. Inflammation of Peyer patches can cause ileitis or colitis. Brucellosis can cause granulomatous hepatitis, pyogenic hepatic abscesses, or cholecystitis. Although renal involvement in brucellosis is unusual, orchitis has been reported in 20% of men with brucellosis. Respiratory tract involvement in brucellosis ranges from flulike symptoms to pneumonia with or without pleural effusions. A variety of ocular complications have been reported, including uveitis and endophthalmitis.

PROGNOSIS

A relapse rate of 5% to 25% can be expected in patients treated for brucellosis, depending on the antibiotic regimen employed (see above). Relapse is especially common in spondylitis.¹⁴ Mortality is highest in cases of endocarditis. Cardiac valve replacement surgery, in addition to prolonged antimicrobial therapy, is often required for successful resolution of endocarditis.¹⁵

Tularemia

Infection by Francisella tularensis causes clinical tularemia. This disease is a zoonosis of substantial complexity whose natural hosts or vectors include more than 100 species of wild mammals; several species of birds, fish, and amphibians; and more than 50 species of blood-sucking arthropods (including ticks, fleas, and deerflies). Tularemia has been recognized widely throughout the Northern Hemisphere, where it was formerly known by a variety of names, such as rabbit fever, deerfly fever, market men's disease, wild-hare disease, Ohara disease (Japan), and water-rat trappers' disease (Russia). F. tularensis could potentially be used in biological warfare or terrorism.¹⁶

EPIDEMIOLOGY

Tularemia is most commonly found in the temperate zones of the Northern Hemisphere. Five subspecies of F. tularensis have been recognized on the basis of biologic properties and geographic location. Type A biovar (F. tularensis biovar tularensis), the most virulent, is found only in North America, where it causes 70% to 90% of all cases of tularemia. This biovar is transmitted by infected rabbits and ticks, and untreated infection can be fatal. The less virulent type B biovar (F. tularensis biovar palearctica) is present in temperate zones worldwide. It is transmitted by rodents or aquatic animals and can cause mild or subclinical disease. F. tularensis biovar palearctica mediasiatica and F. tularensis biovar palearctica japonica are found in central Asia and Japan, respectively. F. tularensis biovar novicidararely causes disease in humans or animals.

In the United States, human tularemia has been reported from every state except Hawaii.^17,18 In 1993, the last year in which tularemia was designated a notifiable disease by the Centers for Disease Control and Prevention (CDC), 132 cases were reported in the United States¹⁹[see Figure 1]. The disease clusters in the lower midwestern states, especially Arkansas, Oklahoma, and Missouri.^17,20

Figure 1. Distribution of Tularemia States in blue are those reporting cases of tularemia in 1993.

The most important reservoirs of F. tularensis are rabbits, hares, and hard ticks.¹⁸ The three major North American tick vectors of tularemia are Dermacentor variabilis (dog tick), which is widely distributed throughout North America; Amblyomma americanum (Lone star tick) in the southeastern and south central United States; and D. andersoni in the western United States. Infected Ixodes ticks can also transmit tularemia.^18,21,22 Aside from hard ticks, other reported arthropod vectors for transmission of tularemia to humans include deerflies, horseflies, and mosquitoes.^17,20,21

Hunters, trappers, game wardens, veterinarians, meat handlers, laboratory workers, and pet owners are considered populations at increased risk for tularemia. However, as many as 40% of patients with tularemia relate no history of contact with a potential animal reservoir or arthropod vector.

ETIOLOGY

Humans generally acquire tularemia by direct contact with infected wild mammals or via bites from infected arthropods. Domestic animals, such as pet cats and dogs that have preyed on infected wild animals, can serve as sources of tularemia transmission to humans via bites, scratches, or licks.^23,24 Transmission has also resulted from inhalation of aerosolized organisms or ingestion of contaminated meat or water.^17,18,25 No documented human-to-human transmission of tularemia has been reported.^17,18,25,26

The etiology of human tularemia shows some seasonal variation. During the summer, most cases occur as a result of arthropod bites. During the fall and winter, hunters and trappers may acquire tularemia while skinning and dressing wild game.

PATHOGENESIS

1. tularensisis a small, pleomorphic, nonmotile, intracellular, gram-negative coccobacillus that grows fastidiously as an obligate aerobe. In culture, it requires cysteine-enriched blood agar for growth. In the environment, it can remain viable at low temperatures for 3 to 4 months in mud, water, or decayed animal carcasses.
2. tularensisis highly infectious. As few as 10 to 50 organisms can cause clinical tularemia after inhalation or intradermal injection, and 10⁸organisms can cause disease if ingested. The skin and mucous membranes are the most common portals of entry for F. tularensis. After inoculation, the organism multiplies locally to produce an erythematous, tender papule within 2 to 5 days, which subsequently becomes an ulcer with a black base (chancriform lesion). Bacteria then usually spread to regional lymph nodes, causing lymphadenopathy. Sepsis syndrome can occur with bacteremia or in cases of widely disseminated disease.

Histopathologically, tularemia is characteristically associated with mononuclear cell infiltration and granuloma formation. Those features can resemble the pathology of tuberculosis.

DIAGNOSIS

Clinical Manifestations

The usual incubation period of tularemia is 3 to 7 days (range, 1 to 21 days). Classically, tularemia presents as a severe illness with a sudden onset of fever, chills, headache, malaise, fatigue, and generalized myalgias and arthralgias. However, the severity of illness, especially in tick-borne disease, is highly variable, ranging from mild, afebrile, self-limited disease to rare cases of septic shock. Typically, an ulcer with surrounding inflammation develops at the site of inoculation. The inoculation ulcer may persist for weeks to months in untreated cases.

Most patients (70% to 90%) acquire infection by inoculation of the skin. Regional lymphadenopathy often develops in the inguinal/femoral nodes in adults and the cervical nodes in children. A generalized rash, usually maculopapular but occasionally pustular, is seen in approximately 20% of patients. Erythema nodosum has been reported infrequently.

The clinical manifestations of tularemia have been categorized into six recognized syndromes: (1) ulceroglandular, (2) glandular, (3) oculoglandular, (4) oropharyngeal, (5) pleuropulmonary, and (6) typhoidal.

Ulceroglandular tularemia and glandular tularemia are the most common forms of clinical tularemia, accounting for 75% to 85% of cases. Both result from inoculation of the skin. Ulceroglandular disease is characterized by an ulcerated lesion at the site of inoculation and regional lymphadenopathy. The glandular and ulceroglandular syndromes are similar except that the skin lesion is absent in glandular tularemia.

Oculoglandular tularemia is caused by accidental inoculation of the eye with contaminated fingers. Conjunctival inflammation is extremely painful, and numerous ulcers and a yellow exudate are often apparent. Conjunctival involvement is typically associated with preauricular lymphadenopathy (Parinaud complex).

Oropharyngeal tularemia can follow oral inoculation. This syndrome is characterized by an exudative or membranous pharyngitis and cervical lymphadenopathy. A subcategory of oropharyngeal tularemia that can develop after massive ingestion of F. tularensis is gastrointestinal tularemia. It is characterized by fever, intestinal ulceration, mesenteric lymphadenopathy, diarrhea, abdominal pain, nausea, vomiting, and gastrointestinal bleeding.

Pleuropulmonary tularemia can be a primary infection, following inhalation of aerosolized organisms, or a secondary manifestation resulting from hematogenous spread of infection to the lungs. The latter occurs in about 10% to 15% of cases of ulceroglandular tularemia. Mediastinal lymphadenopathy may evolve during the course of pleuropulmonary tularemia.

Typhoidal tularemia is the most difficult presentation to diagnose and is associated with the highest mortality.^{17,18,25,26,27} Neither skin lesions nor lymphadenopathy are present; fever and malaise may be the only clinical manifestations. Secondary pleuropulmonary involvement occurs in approximately 50% of cases of typhoidal tularemia.

Laboratory Tests

Laboratory screening tests are often unremarkable in cases of tularemia. The leukocyte count may be slightly elevated or normal. Serum levels of hepatic aminotransferases tend to be mildly to moderately elevated. With pleuropulmonary involvement, chest films show parenchymal infiltrates (typically patchy, in one or multiple lobes), and pleural effusions are common.^17,18,25,26

Definitive laboratory diagnosis of tularemia is generally based on detection of antibodies to F. tularensis. Serum agglutinins are usually detectable by day 10 to 14 of illness and peak approximately 2 to 6 weeks later. Early, appropriate antimicrobial therapy may blunt the rise in antibody titer. A fourfold increase in titer between acute-phase and convalescent-phase specimens is considered diagnostic, but a single specimen with a titer of 1:160 or greater is highly suggestive. A specific enzyme-linked immunosorbent assay (ELISA) for F. tularensisantibodies is now available and may eventually replace the serum agglutinins assay. PCR technology has been employed for molecular diagnosis but is not widely available for clinical use.^28,29,30

Airborne transmission of F. tularensis is possible, so attempts to isolate and culture the organism should be avoided in most clinical laboratories. Biosafety level 2 is recommended for clinical laboratory work with material where contamination with F. tularensis is suspected. Biosafety level 3 is required for culture of the organism in large quantities.³¹

DIFFERENTIAL DIAGNOSIS

The skin lesion of ulceroglandular tularemia may resemble that seen in sporotrichosis, ecthyma from Staphylococcus aureus orStreptococcus pyogenes, skin infection with atypical mycobacteria (e.g., Mycobacterium marinum), syphilis, anthrax, rat-bite fever, or rickettsial disease. The lymphadenopathy of tularemia may be similar to that of plague, lymphogranuloma venereum, cat-scratch disease, or necrotizing lymphadenitis. Oropharyngeal tularemia can mimic the exudative pharyngitis caused by S. pyogenes, Arcanobacterium haemolyticus, Corynebacterium diphtheriae, and EBV. Pleuropulmonary tularemia is often similar to any of the atypical pneumonias, including those caused by respiratory viruses, Mycoplasma pneumoniae, Legionella pneumophila, Chlamydia pneumoniae, C. psittaci, Coxiella burnetii, Histoplasma capsulatum, and Coccidioides immitis.²⁶ Typhoidal tularemia may be confused with enteric fever (typhoid or paratyphoid fever), rickettsial infections, brucellosis, EBV, primary toxoplasmosis, miliary tuberculosis, sarcoidosis, or lymphoma.

TREATMENT

Because of the lack of rapid diagnostic laboratory tests for tularemia, initial treatment is often empirical and based on clinical suspicion. Although streptomycin (500 mg to 1 g I.M. every 12 hours) is the conventional drug of choice, evidence indicates that gentamicin (3 to 5 mg/kg daily I.V. in divided doses every 8 hours) is equally effective. With either agent, treatment should be given for 10 to 14 days in cases of severe clinical illness.³² Tetracycline (or chloramphenicol) can be used, but relapse may occur if the duration of therapy is less than 21 days.³³ Ciprofloxacin was recently reported to be effective for treatment, but clinical experience is limited.^34,35,36

Only partial immunity develops after infection with F. tularensis, and cases of reinfection have been documented. Chemoprophylaxis is not recommended for persons potentially exposed to tularemia. A live attenuated tularemia vaccine has been developed. It may be useful for the partial protection of laboratory workers but is not commerciallyavailable.^37,38

COMPLICATIONS

Tularemia can be complicated by bacteremia, meningitis (usually marked by a lymphocytic pleocytosis in the CSF), rhabdomyolysis, acute renal failure, endocarditis, osteomyelitis, pericarditis, and septic shock.

PROGNOSIS

Typhoidal and ulceroglandular tularemia have the worst prognosis, with approximately 5% mortality reported in untreated cases. Prognosis is excellent for patients treated with appropriate antibiotics, with significant clinical improvement generally occurring within 48 hours of starting therapy.^17,18,25

Plague

Yersinia infections primarily affect rodents, pigs, and birds; humans are accidental hosts. Nevertheless, Yersinia pestis (formerly Pasteurella pestis) has made its mark in human history as the causative agent of plague—also known as bubonic plague, black plague, and the Black Death. Plague was initially described in biblical times; in the Middle Ages, epidemic bubonic plague killed an estimated one fourth of Europe's population.³⁹ This disease of antiquity has persisted to the present. Although human plague is now relatively infrequent worldwide, aerosolized Y. pestis is well recognized for its potential use as a biological weapon.⁴⁰

EPIDEMIOLOGY

Plague currently exists in widely scattered foci in Asia, Africa, and the Americas. In the 1990s, countries with the greatest number of cases included Tanzania, Madagascar, Democratic Republic of Congo, Vietnam, Peru, India, Myanmar, Zimbabwe, Mozambique, Uganda, and China [see Figure 2]. In the United States, about 10 cases of plague are reported annually, primarily from the Four Corners area, where Utah, Colorado, New Mexico, and Arizona meet. In that region, plague is endemic in prairie dog colonies.^41,42

Figure 2. Distribution of Plague Shaded countries reported more than 100 cases of plague from 1990–1995.

ETIOLOGY

Plague is a zoonotic infection that affects predominately urban and sylvatic rodents (e.g., rats and ground squirrels, respectively). It is transmitted to its natural animal reservoirs by flea bites or ingestion of contaminated animal tissues. Humans represent accidental hosts who usually acquire infection via bites from infected fleas.³⁹ Bites or scratches from an infected animal can also transmit plague to humans. In endemic areas, risk factors for acquiring plague include direct contact with rodents or carnivores that prey on them (e.g., cats, dogs), the presence of wild rodents near the place of residence, and pet dogs or cats with fleas.⁴³

Plague may also result from inhalation of aerosolized bacilli. Airborne transmission can occur via the cough of an infected patient with pulmonary involvement or from close contact with an infected animal or cadaver.

PATHOGENESIS

1. pestisis a pleomorphic, non-spore-forming, gram-negative, bipolar-staining coccobacillary member of the family Enterobacteriaceae. It is a nonmotile, facultative anaerobe that is able to grow aerobically on routine microbiologic media. The organism can survive at room temperature in dried blood or the environment for weeks to months.
2. pestis is one of the most virulent bacteria known. It is usually inoculated through the skin or mucous membranes, where it invades cutaneous lymphatics. Monocytes and macrophages, which can phagocytize Y. pestiswithout killing it, may play a role in spread of infection from the inoculation site. Plague can involve almost any tissue or organ and cause massive destruction if left untreated. Initially, infected lymph nodes are tender and edematous. Later, hemorrhagic necrosis develops in affected nodes, and bacteria enter the bloodstream, where they disseminate to other sites (e.g., liver, spleen, lungs, and central nervous system). Infarcts and hemorrhagic, necrotic nodules are characteristic histopathologic findings at affected tissue sites.³⁹

DIAGNOSIS

Clinical Manifestations

The usual incubation periods for bubonic plague and pneumonic plague are 2 to 7 days and 2 to 3 days, respectively (range, 1 to 14 days). Plague generally presents as an acute illness characterized by the abrupt onset of fever, chills, headache, gastrointestinal symptoms, and local pain, followed within hours by the development of a painful, swollen mass of lymph nodes (buboes) in the groin or axilla. Skin overlying buboes is usually red-purple in color. Buboes are initially tense and hard but rapidly become fluctuant. Spontaneous rupture and drainage can occur. Buboes do not develop in patients with septicemic plague; instead, these patients have gastrointestinal signs and symptoms: nausea, vomiting, diarrhea, and abdominal pain. Severe pharyngitis, severe diarrhea, and cough with or without hemoptysis may also be early clinical manifestations of plague^39,44 [see Table 1].

Laboratory Tests

The leukocyte count is typically elevated in the range of 15,000 to 25,000 cells/µl, with a shift to the left; leukemoid reactions (> 50,000 cells/µl) can occur. The platelet count may be normal or mildly depressed or may be very low if disseminated intravascular coagulation (DIC) is present. The level of fibrin split products is frequently elevated, even in patients without frank DIC. Serum levels of hepatic aminotransferases and bilirubin are often increased.

Definitive diagnosis of plague is usually based on isolation of Y. pestis from cultures of blood, other body fluids, or tissues. Aspiration of buboes may readily yield material for diagnosis. The organism can be easily grown on blood and MacConkey agar, as well as in infusion broth. A direct immunofluorescence test has been developed for rapid identification of Y. pestis in clinical specimens, and a passive hemagglutination test is available for presumptive diagnosis based on serology. Both of those tests are available from the CDC Division of Vector-Borne Infectious Diseases, Fort Collins, Colorado (970-221-6400).

DIFFERENTIAL DIAGNOSIS

Clinical suspicion based on knowledge of plague epidemiology is essential for timely diagnosis and institution of appropriate antimicrobial therapy. Plague should be suspected in febrile individuals who have been exposed to rodents or other mammals in regions of the world where plague is endemic. Illness may resemble that caused by a number of other serious infectious diseases, especially tularemia. Other causes of acute, painful lymphadenitis include staphylococcal, streptococcal, and Pasteurella infection. Plague pneumonia can be confused with other causes of atypical pneumonia or the hantavirus pulmonary syndrome. The combination of plague-associated abdominal symptoms and DIC can resemble an acute surgical abdomen or Capnocytophaga canimorsus sepsis.⁴⁴

TREATMENT

Streptomycin (30 mg/kg I.M. in divided doses every 12 hours) remains the drug of choice for the treatment of plague. Timely administration of streptomycin reduces mortality to approximately 5%. Gentamicin, which is more widely available than streptomycin, also appears to be effective. To prevent relapses, antibiotic treatment should be continued for 10 days or for at least 3 days after defervescence and clinical recovery. Most patients improve rapidly and defervesce within 72 hours of initiation of antimicrobial therapy, although buboes can persist for weeks. Some authorities advocate switching from streptomycin to a different antibiotic for completion of therapy after 5 days of treatment in order to minimize the risk of ototoxicity and nephrotoxicity.

Tetracycline or doxycycline can also be used for plague. Chloramphenicol is the preferred agent for the treatment of plague meningitis, pleuritis, endophthalmitis, and myocarditis because of superior penetration into those tissues. Penicillins, cephalosporins, and macrolides are suboptimal agents for treatment of plague. Trimethoprim-sulfamethoxazole and fluoroquinolones appear to be active against plague in vitro and in animal models, but clinical experience with these agents for the treatment of plague is limited^39,44,45 [see Table 2].

All cases of suspected or documented plague should be reported to the state and city or county health departments, the CDC, and the World Health Organization. Plague patients with cough or other signs or symptoms of pneumonia should be placed in strict respiratory isolation for at least 48 hours after initiation of appropriate antibiotic therapy.

Contacts of patients with pneumonic plague or suspected septicemic plague with pulmonary involvement should receive chemoprophylaxis with either tetracycline (500 mg p.o., q.i.d.) or doxycycline (100 mg p.o., b.i.d.). Streptomycin (20 mg/kg/day I.M. in two divided doses) or trimethoprim-sulfamethoxazole (40 mg/kg p.o., b.i.d.) can be used for children younger than 8 years.

Plague vaccine (Cutter Laboratories) is a killed, formalin/phenol-fixed whole-bacteria vaccine that provides only partial protection against infection. Vaccinated individuals who are exposed to plague should still receive chemoprophylaxis.⁴⁶

COMPLICATIONS

Septic shock, DIC, acute respiratory distress syndrome (ARDS), and meningitis are recognized complications of plague, especially in cases in which antimicrobial therapy is inadequate or delayed. Plague meningitis, a rare complication that typically occurs more than 1 week after inadequate antimicrobial therapy, is characterized by fever, headache, menigismus, and neutrophilic pleocytosis of the cerebrospinal fluid.

PROGNOSIS

Reported mortality of untreated plague ranges from 40% to 90%. Mortality is greatest in pneumonic plague. The overall mortality for cases of plague in the United States during the past 20 years has been approximately 15%.⁴²

Bartonella Infections

Bartonella (formerly Rochalimaea) organisms are small, gram-negative bacilli that are extremely fastidious. They require specialized culture methods for isolation and specific staining techniques for detection in clinical specimens.^47,48,49 Infections by these organisms can occur in both immunocompromised and immunocompetent individuals.^47,49 Four Bartonella species have been documented to be pathogenic in humans: B. bacilliformis, B. quintana, B. henselae, and B. elizabethae.^47,49 The spectrum of diseases caused by Bartonella can be divided into five categories: (1) Oroya fever (classic bartonellosis), (2) trench fever, (3) bacteremia and endocarditis, (4) cat-scratch disease, and (5) bacillary angiomatosis.

OROYA FEVER (CLASSIC BARTONELLOSIS)

Oroya fever (chronic bartonellosis; Carrión disease) is caused by infection with B. bacilliformis transmitted to humans by the bite of infected phlebotomine sandflies. The disease is geographically restricted to valleys of the Andes Mountains at elevations between 800 m (2,624 ft) and 2,500 m (8,200 ft) above sea level, which are found in Peru, Ecuador, and Colombia.

Diagnosis

Oroya fever, caused by primary bacteremia, develops 3 to 12 weeks after inoculation. The onset of illness can be either insidious or abrupt. Clinical manifestations include fever, chills, headache, myalgias and arthralgias, abdominal pain, generalized lymphadenopathy, progressive hemolytic anemia, and thrombocytopenia.^47,49,50

Definitive diagnosis of acute bartonellosis is based on the isolation of B. bacilliformis from blood cultures. The organism can be grown on Colombia agar with 5% defibrinated human blood or semisolid nutrient agar with 10% rabbit hemoglobin aerobically at 28° C. Colonies usually appear in 7 to 10 days. The presence of intraerythrocytic bacilli in a Giemsa-stained thin blood smear provides rapid confirmation of acute bartonellosis. Serologic tests have been developed in research laboratories but are not widely available.^47,49

Treatment

Standard treatment consists of chloramphenicol (2 g/day p.o. or I.V.) for at least 1 week. Alternative agents include tetracycline (or doxycycline) or ampicillin.⁵¹ Without treatment, mortality is high. Survivors are temporarily at risk for secondary salmonellosis or toxoplasmosis. Asymptomatic bacteremia is estimated to persist in approximately 15% of survivors.

In untreated cases, resolution of primary infection may be followed weeks to months later by the onset of verruca peruana. This manifestation of chronic bartonellosis consists of recurrent crops of nodular skin lesions, which may ulcerate and bleed. Mucosal and visceral lesions may also occur. Histopathologic examination of active lesions demonstrates neovascular proliferation and occasional bacilli in the interstitium.^47,49

TRENCH FEVER

Trench fever is caused by infection with B. quintana, which is transmitted to humans via feces of infected human body lice (Pediculus humanus).⁵² Epidemics of the disease occurred in troops engaged in trench warfare in World War I and in World War II troops deployed in crowded and unsanitary conditions.

Diagnosis

The incubation period of classic trench fever was 3 to 38 days, and illness was typically characterized by the abrupt onset of fever, associated with headache, dizziness, conjunctival injection, myalgias, arthralgias, hepatosplenomegaly, a transient maculopapular rash, leukocytosis, and albuminuria. The duration of acute illness was generally 3 to 5 days, and relapses were not uncommon. Less commonly, unremitting fever would persist for 2 to 6 weeks.^47,49

Treatment

Much of the clinical experience with trench fever predates the antibiotic era. It is not known whether one regimen is superior to another.

BACTEREMIA AND ENDOCARDITIS

Recently, a syndrome termed urban trench fever was recognized in urban homeless persons (usually with a history of alcoholism and malnutrition) and in HIV-infected individuals.^47,49,53,54 In the urban homeless population, the syndrome is caused by B. quintana bacteremia and is often associated with apparently culture-negative endocarditis.^{47,49,53,54,55,56} In the HIV-infected population, the bacteremia can be caused by either B. quintana or B. henselae, and concomitant bacillary angiomatosis (see below) is often present.^47,49,57,58 As with classic trench fever, the human body louse is the vector for transmission of B. quintana (the animal reservoir remains unknown); cats transmit B. henselae. Clinical manifestations of urban trench fever include fever, malaise, anemia, thrombocytopenia, splenomegaly, and cardiac murmurs.^{47,49,53,54,55,56}

Diagnosis

Diagnosis is based on the isolation of B. henselae or B. quintana from blood, which is best accomplished using lysis-centrifugation blood culture. Growth of those organisms is slow, and incubation for more than 30 days may be required. Acridine orange staining can be used to enhance detection of Bartonella organisms in culture. An antibody titer of 1:1,600 or higher against either B. henselae or B. quintana also strongly suggests bartonellosis as the cause of endocarditis in a patient with valvular vegetations.^47,49

Treatment

For bacteremia without endocarditis, a 14-day regimen of either a macrolide or a tetracycline (e.g., doxycyline, 100 mg p.o., b.i.d.) is recommended. No definitive treatment regimen has been established for endocarditis. Surgical valve replacement plus aminoglycoside therapy has been used. An alternative approach has been to give prolonged (4 to 6 months or more) combination therapy with a fluoroquinolone plus either rifampin or a macrolide. Patients treated with that regimen should be followed carefully for clinical deterioration that would necessitate valve replacement^{47,49,54,55,56} [see Table 2].

CAT-SCRATCH DISEASE

Although Afipia felis was first identified as the causative agent of cat-scratch disease, it is now clear that B. henselae causes the overwhelming majority of cases.^47,49,59 The domestic cat serves as the major reservoir of B. henselae, which is transmitted to humans by a scratch or bite—usually from a kitten or feral cat—or possibly via infected cat fleas.^47,49 The incubation period is generally 3 to 10 days.

Typically, a primary cutaneous papule or pustule develops at the site of inoculation. Regional lymphadenopathy follows in approximately 90% of cases and persists for 10 to 120 days. Lymphadenopathy is most common at axillary, cervical, and submandibular sites. Less commonly, epitrochlear, inguinal, femoral, or supraclavicular nodes may be involved. Approximately 10% of involved nodes suppurate spontaneously. Low-grade fever occurs in approximately 50% of patients and lasts for several days. Less frequent symptoms and signs include malaise, fatigue, headache, and rash.^47,49

Relatively common presentations of atypical cat-scratch disease are Parinaud oculoglandular syndrome—a self-limited syndrome of granulomatous conjunctivitis and preauricular lymphadenitis—and encephalitis, which occurs primarily in children.^47,49,60,61 About one half of patients with cat-scratch disease encephalitis experience seizures. Although full recovery from cat-scratch disease encephalitis may require weeks to months, the overall prognosis is good, with few patients experiencing permanent neurologic sequelae.^47,49,61 Other atypical manifestations of cat-scratch disease include self-limited granulomatous hepatitis or splenitis, atypical pneumonitis, osteitis, and neuroretinitis.^{47,49,62,63,64,65,66}

Most cases of cat-scratch disease are diagnosed presumptively, on the basis of the clinical presentation and a history of exposure to cats. The differential diagnosis of typical cat-scratch disease includes tularemia, mycobacterial infection, plague, brucellosis, mononucleosis, syphilis, lymphogranuloma venereum, sporotrichosis, histoplasmosis, toxoplasmosis, and lymphoma.

Serologic confirmation of cat-scratch disease is usually not required. When clinically warranted, either immunofluorescence antibody testing or ELISA, available through commercial clinical diagnostic laboratories, can be used to detect antibodies against B. henselae. Those serologic studies have essentially supplanted the cat-scratch disease skin test in clinical practice. In biopsy specimens obtained from lymph nodes, skin, or conjunctiva, cat-scratch disease can be confirmed by the detection of small, pleomorphic bacilli in sections prepared with a Warthin-Starry or Brown-Hopps stain.^47,48,49 PCR technology has been used to detect B. henselae in clinical specimens but is currently not widely available for routine clinical diagnosis.^47,48,49,67

In immunocompetent patients, both typical and atypical CSD generally resolve spontaneously without antimicrobial therapy. Most B. henselae isolates are susceptible in vitro to a wide variety of antimicrobials, including β-lactams, tetracyclines, macrolides, aminoglycosides, fluoroquinolones, vancomycin, and rifampin. However, clinical response does not correlate well with susceptibility testing for B. henselae.^47,49,68 Although a variety of agents have been reported to be effective in anecdotal reports and case series (including rifampin, gentamicin, trimethoprim-sulfamethoxazole, doxycycline, ciprofloxacin, and ofloxacin), only azithromycin (500 mg p.o. for 1 day, then 250 mg p.o. daily for 4 days) has been shown to accelerate resolution of typical cat-scratch disease lymphadenopathy in a placebo-controlled, double-blind clinical trial.⁶⁹

BACILLARY ANGIOMATOSIS

Bacillary angiomatosis (epithelioid angiomatosis, bacillary epithelioid angiomatosis) is a form of neovascular proliferation associated with infection by either B. henselae or B. quintana. It was first described as a disease of the skin and regional lymph nodes of HIV-infected persons. Subsequently, bacillary angiomatosis was documented in a large variety of tissues, including liver, spleen, bone, brain, respiratory tract, gastrointestinal tract, and uterine cervix. It has also been found, albeit rarely, in other immunocompromised hosts and in apparently immunocompetent patients. In HIV-infected persons, it is a relatively late opportunistic infection, usually occurring after the CD4⁺lymphocyte count has declined to less than 100 cells/µl.^47,49,57,58

Cutaneous disease is the most frequently recognized manifestation of bacillary angiomatosis. Lesions generally appear in crops and can have verrucous, papular, or pedunculated features. They often have an erythematous base and vascular appearance but may occasionally be dry, scaly, hyperkeratotic, or plaquelike. Painful subcutaneous nodules and osseous lesions can develop. Regional lymphadenopathy is common, but involved nodes rarely suppurate or drain.^47,49

Peliosis hepatis, consisting of venous lakes in the hepatic parenchyma, is a relatively common manifestation of bacillary angiomatosis. Splenitis can also occur. Hepatosplenomegaly is often present, and an increased serum alkaline phosphatase level is a common laboratory finding. Peliotic spaces in the liver and spleen appear as hypodense lesions on abdominal computed tomography. Thrombocytopenia and pancytopenia may develop, as well as concomitant bacteremia or endocarditis, in patients with bacillary peliosis.^47,49,57,58

The lesions of bacillary angiomatosis may be indistinguishable clinically from Kaposi sarcoma, and biopsy is usually necessary to distinguish between the two disorders and guide management. Both hematoxylin-eosin staining, which differentiates bacillary angiomatosis from Kaposi sarcoma, and Warthin-Starry staining, which detects Bartonella bacilli, should be performed on biopsy specimens. Lesions of bacillary angiomatosis are characterized by lobular proliferation of endothelial-lined capillaries; the endothelial cells are protuberant, unlike the spindle-shaped endothelial cells in Kaposi sarcoma. Recovery of Bartonella organisms by culture from lesions of bacillary angiomatosis is difficult.^47,48,49

The recommended first-line therapy for bacillary angiomatosis in HIV-infected patients is either erythromycin (500 mg p.o., q.i.d.) or doxycycline (100 mg p.o., b.i.d.). Alternative agents include clarithromycin (500 mg p.o., b.i.d.), azithromycin (250 mg p.o. daily), and ciprofloxacin (500 to 750 mg p.o., b.i.d.). For severe cases, consideration should be given to combination therapy with doxycycline (100 mg p.o. or I.V., b.i.d.) plus rifampin (300 mg p.o., b.i.d.). Bacillary angiomatosis usually responds rapidly to either erythromycin or doxycycline therapy. A Jarisch-Herxheimer reaction may occur with the initiation of antimicrobial therapy. Patients who have only cutaneous lesions should receive at least 2 months of treatment; in those with osteomyelitis or peliosis hepatis, therapy should be continued for a minimum of 4 months. Relapses can occur after discontinuance of therapy. HIV-infected patients who experience relapses should be treated lifelong with either a tetracycline or a macrolide.^47,49

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Editors: Dale, David C.; Federman, Daniel D.