InternalMed_Harrison

InternalMed_Harrison. (Table 197-2) Prolonged therapy with a macrolide or doxycycline is recommended for both bacillary angiomatosis and bacillary peliosis. Control of cat-flea infestation and avoidance of cat scratches (for prevention of B. henselae) and avoidance and treatment of body louse infestation (for prevention of B. quintana) are reasonable strategies for HIV-infected persons. Primary prophylaxis is not recommended, but suppressive therapy with a macrolide or doxycycline is indicated in HIV-infected patients with bacillary angiomatosis or bacillary peliosis until CD4+ T cell counts are >200/μL. Relapse may necessitate lifelong suppressive therapy in individual cases. Carrión’s disease is a biphasic disease caused by B. bacilliformis. Oroya fever is the initial, bacteremic, systemic form, and verruga peruana is its late-onset, eruptive manifestation.


InternalMed_Harrison

InternalMed_Harrison. Carrión’s disease is a biphasic disease caused by B. bacilliformis. Oroya fever is the initial, bacteremic, systemic form, and verruga peruana is its late-onset, eruptive manifestation. Infection is endemic to the geographically restricted Andes valleys of Peru, Ecuador, and Colombia (~500–3200 m above sea level). Sporadic epidemics occur. The disease is transmitted by the phlebotomine sandfly Lutzomyia verrucarum. Humans are the only known reservoir of B. bacilliformis. Sandfly control measures (e.g., insecticides) and personal protection measures (e.g., repellents, screening, bed nets) may decrease the risk of infection.


InternalMed_Harrison

InternalMed_Harrison. After inoculation by the sandfly, bacteria invade the blood vessel endothelium and proliferate; the reticuloendothelial system and various organs may also be involved. Upon reentry into blood vessels, B. bacilliformis 1083 invades, replicates, and ultimately destroys erythrocytes, with consequent massive hemolysis and sudden, severe anemia. Microvascular thrombosis results in end-organ ischemia. Survivors sometimes develop cutaneous hemangiomatous lesions characterized by various inflammatory cells, endothelial proliferation, and the presence of B. bacilliformis.


InternalMed_Harrison

InternalMed_Harrison. The incubation period is 3 weeks (range, 2–14 weeks). Oroya fever may present as a nonspecific bacteremic febrile illness without anemia or as an acute, severe hemolytic anemia with hepatomegaly and jaundice of rapid onset leading to vascular collapse and clouded sensorium. Myalgia, arthralgia, lymphadenopathy, and abdominal pain may develop. Temperature is elevated but not extremely so; high fever may suggest intercurrent infection. Subclinical asymptomatic infection also occurs. In verruga peruana, red, hemangioma-like, cutaneous vascular lesions of various sizes appear either weeks to months after systemic illness or with no previous suggestive history. These lesions persist for months up to 1 year. Mucosal and internal lesions may also develop.


InternalMed_Harrison

InternalMed_Harrison. Systemic illness (with or without anemia) or the development of cutaneous lesions in a person who has been to an endemic area raises the possibility of B. bacilliformis infection. Severe anemia with exuberant reticulocytosis—and sometimes thrombocytopenia—can occur. In systemic illness, Giemsa-stained blood films show typical intraerythrocytic bacilli, and blood and bone marrow cultures are positive. Serologic assays may be helpful. Biopsy may be required to confirm the diagnosis of verruga peruana. Differential diagnosis includes the spectrum of coendemic systemic febrile illnesses (e.g., typhoid fever, malaria, brucellosis) as well as diseases producing cutaneous vascular lesions (e.g., hemangiomata, bacillary angiomatosis, Kaposi’s sarcoma).


InternalMed_Harrison

InternalMed_Harrison. (Table 197-2) Antibiotic therapy for systemic B. bacilliformis infection usually results in rapid defervescence. Additional antibiotic treatment of intercurrent infection (particularly salmonellosis) is often required. Blood transfusion may be necessary. Treatment of verruga peruana usually is not required, although large lesions or those interfering with function may require excision. Patients with numerous lesions, especially lesions that have been present for only a short period, may respond well to antibiotic therapy. Mortality rates associated with Oroya fever have been reported to be as high as 40% without treatment but are considerably lower (~10%) with treatment. Complications such as bacterial superinfection and neurologic and cardiac manifestations occur frequently. Generalized massive edema (anasarca) and petechiae are associated with poor outcome. Permanent immunity usually develops.


InternalMed_Harrison

InternalMed_Harrison. This is a digital-only chapter. It is available on the dvd that accompanies this book, as well as on Access Medicine/Harrison’s Online, and the eBook and “app” editions of HPIM 19e. Donovanosis is a chronic, progressive bacterial infection that usually involves the genital region. The condition is generally regarded as a sexually transmitted infection of low infectivity. This infection has been known by many other names, the most common being granuloma inguinale. Nocardia brasiliensis is usually associated with disease limited to the skin. Actinomycetoma—an indolent, slowly progressive disease of skin and underlying tissues with nodular swellings and draining sinuses— 199 Gregory A. Filice is often associated with N. brasiliensis, Nocardia otitidiscaviarum, N. transvalensis complex strains, or other actinomycetes.


InternalMed_Harrison

InternalMed_Harrison. N. transvalensis complex strains, or other actinomycetes. Nocardia, a genus of saprophytic aerobic actinomycetes that are common worldwide, resides in soil, contributing to the decay of organic matter. Nearly 100 species have been identified, mostly on the basis of 16S rRNA gene sequences. Nocardiae are relatively inactive in standard biochemical tests, and speciation is difficult without molecular phylogenetic techniques. Historically, the majority of isolates associated with pneumonia and systemic disease were identified as Nocardia asteroides, but the lineage of the type strain was muddled, and it is now clear that human disease is associated with several species. Most clinical laboratories cannot speciate isolates accurately and may identify them simply as N. asteroides or Nocardia species.


InternalMed_Harrison

InternalMed_Harrison. Nine species or species complexes are commonly associated with human disease (Table 199-1). Most systemic disease involves Nocardia cyriacigeorgica, Nocardia farcinica, Nocardia pseudobrasiliensis, and species in the Nocardia transvalensis and Nocardia nova complexes. Species Susceptible to Resistant to N. abscessus Amikacin, amoxicillin/ Ciprofloxacin, clarithroclavulanic acid, ampicil-mycin, erythromycin, lin, ceftriaxone, genta-imipenem (v)a micin, linezolid, minocycline, TMP-SMX N. brevicatena/pauci-Amikacin, amoxicillin/ Ciprofloxacin, clarithrovorans complex (N. brevi-clavulanic acid, ampicil-mycin, erythromycin, catena, N. paucivorans, lin, ceftriaxone, cipro-gentamicin, imipenem N. carnea, others) floxacin, linezolid, mino-(v) cycline (v), moxifloxacin, tobramycin, TMP-SMX N. nova complex Amikacin, ampicillin, Amoxicillin/clavulanic (N. nova, N. veterana, ceftriaxone, clarithro-acid, ciprofloxacin, gen- N.


InternalMed_Harrison

InternalMed_Harrison. N. nova complex Amikacin, ampicillin, Amoxicillin/clavulanic (N. nova, N. veterana, ceftriaxone, clarithro-acid, ciprofloxacin, gen- N. africana, N. kruczakiae, mycin, erythromycin, tamicin, tobramycin N. elegans, others) imipenem, linezolid, minocycline, TMP-SMX N. transvalensis complex Amoxicillin/clavulanic Amikacin, ampicillin, (N. blacklockiae, acid (v), ceftriaxone (v), clarithromycin, eryth- N. wallacei, others) ciprofloxacin, linezolid, romycin, gentamicin, minocycline (v), TMP-imipenem (v) SMX N. farcinica Amikacin, amoxicillin/ Ampicillin, ceftriaxone, clavulanic acid, imipenem ciprofloxacin, clarithro(v), linezolid, minocy-mycin, erythromycin, cline (v), TMP-SMX gentamicin, tobramycin N. cyriacigeorgica Amikacin, ceftriaxone Amoxicillin/clavulanic (v), imipenem, linezolid, acid, ampicillin (v), cipminocycline (v), rofloxacin, erythromycin, TMP-SMX gentamicin N.


InternalMed_Harrison

InternalMed_Harrison. N. cyriacigeorgica Amikacin, ceftriaxone Amoxicillin/clavulanic (v), imipenem, linezolid, acid, ampicillin (v), cipminocycline (v), rofloxacin, erythromycin, TMP-SMX gentamicin N. brasiliensis Amikacin, amoxicillin/ Ampicillin, ceftriaxone, clavulanic acid, mino-ciprofloxacin, clarithrocycline, moxifloxacin, mycin, imipenem TMP-SMX N. pseudobrasiliensis Amikacin, ceftriaxone Amoxicillin/clavulanic (v), ciprofloxacin, clar-acid, ampicillin, ithromycin, TMP-SMX imipenem, minocycline Nocardiosis occurs worldwide. The annual incidence, esti mated on three continents (North America, Europe, and


InternalMed_Harrison

InternalMed_Harrison. Nocardiosis occurs worldwide. The annual incidence, esti mated on three continents (North America, Europe, and Australia), is ~0.375 cases per 100,000 persons and may be increasing. The disease is more common among adults than among children and more common among males than among females. Nearly all cases are sporadic, but outbreaks have been associated with contamination of the hospital environment, cosmetic procedures, and parenteral illicit drug use. Person-to-person spread is not well documented. There is no known seasonality.


InternalMed_Harrison

InternalMed_Harrison. The majority of cases of pulmonary or disseminated disease occur in people with a host defense defect. Most have deficient cell-mediated immunity, especially that associated with lymphoma, transplantation, glucocorticoid therapy, or AIDS. The incidence is ~140-fold greater among patients with AIDS and ~340-fold greater among bone marrow transplant recipients than in general populations. In AIDS, nocardiosis usually affects persons with <250 CD4+ T lymphocytes/ μL. Nocardiosis has also been associated with pulmonary alveolar proteinosis, tuberculosis and other mycobacterial diseases, chronic granulomatous disease, interleukin 12 deficiency, and treatment with monoclonal antibodies that interfere with tumor necrosis factor. Any child with nocardiosis and no known cause of immunosuppression should undergo tests to determine the adequacy of the phagocytic respiratory burst.


InternalMed_Harrison

InternalMed_Harrison. Cases of actinomycetoma occur mainly in tropical and subtropical regions, especially those of Mexico, Central and South America, Africa, and India. The most important risk factor is frequent contact with soil or vegetable matter, especially in laborers. Pneumonia and disseminated disease are both thought to follow inhalation of fragmented bacterial mycelia. The characteristic histologic feature of nocardiosis is an abscess with extensive neutrophil infiltration and prominent necrosis. Granulation tissue usually surrounds the lesions, but extensive fibrosis or encapsulation is uncommon.


InternalMed_Harrison

InternalMed_Harrison. Actinomycetoma is characterized by suppurative inflammation with sinus tract formation. Granules—microcolonies composed of dense masses of bacterial filaments extending radially from a central core—are occasionally observed in histologic preparations. The granules are frequently found in discharges from lesions of actinomycetoma but almost never in discharges from lesions in other forms of nocardiosis. Nocardiae have evolved a number of properties that enable them to survive within phagocytes, including neutralization of oxidants, prevention of phagosome-lysosome fusion, and prevention of phagosome acidification. Neutrophils phagocytose the organisms and limit their growth but do not kill them efficiently. Cell-mediated immunity is important for definitive control and elimination of nocardiae.


InternalMed_Harrison

InternalMed_Harrison. CLINICAL MANIFESTATIONS Respiratory Tract Disease Pneumonia, the most common form of nocardial disease in the respiratory tract, is typically subacute; symptoms have usually been present for days or weeks at presentation. The onset is occasionally more acute in immunosuppressed patients. Cough is prominent and produces small amounts of thick, purulent sputum that is not malodorous. Fever, anorexia, weight loss, and malaise are common; dyspnea, pleuritic pain, and hemoptysis are less common. Remissions and exacerbations over several weeks are frequent. Roentgenographic patterns vary, but some are highly suggestive of nocardial pneumonia. Infiltrates vary in size and are typically dense. Single or multiple nodules are common (Figs. 199-1 and 199-2), sometimes suggesting tumors or metastases. Infiltrates and nodules tend to cavitate (Fig. 199-2). Empyema is present in one-quarter of cases. Co-infection with Nocardia and Mycobacterium tuberculosis has been reported from regions where


InternalMed_Harrison

InternalMed_Harrison. Infiltrates and nodules tend to cavitate (Fig. 199-2). Empyema is present in one-quarter of cases. Co-infection with Nocardia and Mycobacterium tuberculosis has been reported from regions where tuberculosis is common.


InternalMed_Harrison

InternalMed_Harrison. FIGuRE 199-1 Nocardial pneumonia. A dense infiltrate with a pos-sible cavity and several nodules are apparent in the right lung. Nocardiosis may spread directly from the lungs to adjacent tissues. Pericarditis, mediastinitis, and the superior vena cava syndrome have all been reported. Nocardial laryngitis, tracheitis, bronchitis, and sinusitis are much less common than pneumonia. In the major airways, disease often presents as a nodular or granulomatous mass. Nocardiae are sometimes isolated from respiratory secretions of persons without apparent nocardial disease, usually individuals who have underlying lung or airway abnormalities. FIGuRE 199-2 Nocardial pneumonia. A computed tomography scan shows bilateral nodules, with cavitation in the nodule in the left lung. FIGuRE 199-3 Nocardial abscesses in the right occipital lobe.


InternalMed_Harrison

InternalMed_Harrison. FIGuRE 199-2 Nocardial pneumonia. A computed tomography scan shows bilateral nodules, with cavitation in the nodule in the left lung. FIGuRE 199-3 Nocardial abscesses in the right occipital lobe. Extrapulmonary Disease In half of all cases of pulmonary nocardiosis, disease appears outside the lungs. In one-fifth of cases of disseminated disease, lung disease is not apparent. The most common site of dissemination is the brain. Other common sites include the skin and supporting structures, kidneys, bone, muscle, and eye, but almost any organ can be involved. Peritonitis has been reported in patients undergoing peritoneal dialysis. Nocardiae have been recovered from blood in a few cases of pneumonia, disseminated disease, or central venous catheter infection. Nocardial endocarditis occurs rarely and can affect either native or prosthetic valves.


InternalMed_Harrison

InternalMed_Harrison. The typical manifestation of extrapulmonary dissemination is a subacute abscess. A minority of abscesses outside the lungs or central nervous system (CNS) form fistulas and discharge small amounts of pus. In CNS infections, brain abscesses are usually supratentorial, are often multiloculated, and may be single or multiple (Fig. 199-3). Brain abscesses tend to burrow into the ventricles or extend out into the subarachnoid space. The symptoms and signs are somewhat more indolent than those of other types of bacterial brain abscess. Meningitis is uncommon and is usually due to spread from a nearby brain abscess. Nocardiae are not easily recovered from cerebrospinal fluid (CSF). Disease Following Transcutaneous Inoculation Disease that follows transcutaneous nocardial inoculation usually takes one of three forms: cellulitis, lymphocutaneous syndrome, or actinomycetoma.


InternalMed_Harrison

InternalMed_Harrison. Disease Following Transcutaneous Inoculation Disease that follows transcutaneous nocardial inoculation usually takes one of three forms: cellulitis, lymphocutaneous syndrome, or actinomycetoma. Cellulitis generally begins 1–3 weeks after a recognized breach of the skin, often with soil contamination. Subacute cellulitis, with pain, swelling, erythema, and warmth, develops over days to weeks. The lesions are usually firm and not fluctuant. Disease may progress to involve underlying muscles, tendons, bones, or joints. Dissemination is rare. N. brasiliensis and species in the N. otitidiscaviarum complex are most common in cellulitis cases.


InternalMed_Harrison

InternalMed_Harrison. Lymphocutaneous disease usually begins as a pyodermatous nodule at the site of inoculation, with central ulceration and purulent or honey-colored drainage. Subcutaneous nodules often appear along lymphatics that drain the primary lesion. Most cases of nocardial lymphocutaneous syndrome are associated with N. brasiliensis. Similar disease occurs with other pathogens, most notably Sporothrix schenckii (Chap. 243) and Mycobacterium marinum (Chap. 204). Actinomycetoma usually begins with a nodular swelling, sometimes at a site of local trauma. Lesions (Fig. 199-4A) typically develop on the feet or hands but may involve the posterior part of the neck, the upper back, the head, and other sites. The nodule eventually breaks down,


InternalMed_Harrison

InternalMed_Harrison. FIGuRE 199-4 Nocardia brasiliensis mycetoma. A. Draining sinuses and giant white grains with a seropurulent discharge. B. Radiography of the foot showing marked soft tissue enlargement and bony lytic lesions. C. Direct microscopy of grains stained with Lugol's iodine (×40).


InternalMed_Harrison

InternalMed_Harrison. D. Periodic acid–Schiff stain of skin biopsy (×40). (Image provided by Roberto Arenas and Mahreen Ameen, St. John's Institute of Dermatology, Guy's & St Thomas' NHS Trust, London, UK. Reprinted with permission from R Arenas, M Ameen: Lancet Infect Dis 10:66, 2010.) and a fistula appears, typically followed by others. The fistulas tend to come and go, with new ones forming as old ones disappear. The discharge is serous or purulent, may be bloody, and often contains 0.1to 2-mm white granules consisting of masses of mycelia (Figs. 199-4C and 199-4D). The lesions spread slowly along fascial planes to involve adjacent areas of skin, subcutaneous tissue, and bone. Over months or years, there may be extensive deformation of the affected part. Lesions involving soft tissues are only mildly painful; those affecting bones or joints are more so (Fig. 199-4B). Systemic symptoms are absent or minimal. Infection rarely disseminates from actinomycetoma, and lesions on the hands and feet usually


InternalMed_Harrison

InternalMed_Harrison. those affecting bones or joints are more so (Fig. 199-4B). Systemic symptoms are absent or minimal. Infection rarely disseminates from actinomycetoma, and lesions on the hands and feet usually cause only local disability. Lesions on the head, neck, and trunk can invade locally to involve deep organs, with consequent severe disability or death.


InternalMed_Harrison

InternalMed_Harrison. Eye Infections Nocardia species are uncommon causes of subacute keratitis, usually following eye trauma. Nocardial endophthalmitis can develop after eye surgery. In one series, nocardiae accounted for more than half of culture-proved cases of endophthalmitis after cataract surgery. Endophthalmitis can also occur during disseminated disease. Nocardial infection of lachrymal glands has been reported.


InternalMed_Harrison

InternalMed_Harrison. The first step in diagnosis is examination of sputum or pus for crooked, branching, beaded, gram-positive filaments 1 μm wide and up to 50 μm long (Fig. 199-5). Most nocardiae are acid-fast in direct smears if a weak acid is used for decolorization (e.g., in the modified Kinyoun, Ziehl-Neelsen, and Fite-Faraco methods). The organisms often take up silver stains. Recovery from specimens containing a mixed flora can be improved with selective media (colistin–nalidixic acid agar, modified Thayer-Martin agar, or buffered charcoal–yeast extract agar). Nocardiae grow well on most fungal and mycobacterial media, but procedures used for decontamination of specimens for mycobacterial culture can kill nocardiae and thus should not be used when nocardiae are suspected. Nocardiae grow relatively slowly; colonies may take up to 2 weeks to appear and may not develop their characteristic appearance—white, yellow, or orange, with aerial mycelia and delicate, dichotomously branched substrate


InternalMed_Harrison

InternalMed_Harrison. slowly; colonies may take up to 2 weeks to appear and may not develop their characteristic appearance—white, yellow, or orange, with aerial mycelia and delicate, dichotomously branched substrate mycelia—for up to 4 weeks. Several blood culture systems support nocardial growth, although nocardiae may not be detected for up to 2 weeks. The growth of nocardiae is so different from that of more common pathogens that the laboratory should be alerted when nocardiosis is suspected in order to maximize the likelihood of isolation.


InternalMed_Harrison

InternalMed_Harrison. In nocardial pneumonia, sputum smears are often negative. Unless the diagnosis can be made in smear-negative cases by sampling lesions in more accessible sites, bronchoscopy or lung aspiration is usually necessary. To evaluate the possibility of dissemination in patients with nocardial pneumonia, a careful history should be obtained and a thorough physical examination performed. Suggestive symptoms or signs should be pursued with further diagnostic tests. Computed tomography (CT) or magnetic resonance imaging (MRI) of the head, with and without contrast material, should be undertaken if signs or symptoms suggest brain involvement. Some authorities recommend brain imaging in all cases of pulmonary or disseminated disease. When clinically indicated, CSF or urine should be concentrated and then cultured. Actinomycetoma, eumycetoma (cases involving fungi; Chap. 243), and botryomycosis (cases involving cocci or bacilli, often Staphylococcus aureus) are difficult to distinguish clinically


InternalMed_Harrison

InternalMed_Harrison. then cultured. Actinomycetoma, eumycetoma (cases involving fungi; Chap. 243), and botryomycosis (cases involving cocci or bacilli, often Staphylococcus aureus) are difficult to distinguish clinically but are readily distinguished with microbiologic testing or biopsy. Granules should be sought in any discharge. Suspect particles should be washed in saline, examined microscopically, and cultured. Granules in actinomycetoma cases are usually white, pale yellow, pink, or red. Viewed microscopically, they consist of tight masses of fine filaments (0.5–1 μm wide) radiating outward from a central core (Fig. 199-5). Granules from eumycetoma cases are white, yellow, brown, black, or green. Under the microscope, they appear as masses of broader filaments (2–5 μm wide) encased in a matrix. Granules of botryomycosis consist of loose masses of cocci or bacilli. Organisms can also be seen in wound discharge or histologic specimens. The most reliable way to differentiate among the various organisms


InternalMed_Harrison

InternalMed_Harrison. of botryomycosis consist of loose masses of cocci or bacilli. Organisms can also be seen in wound discharge or histologic specimens. The most reliable way to differentiate among the various organisms associated with mycetoma is by culture.


InternalMed_Harrison

InternalMed_Harrison. FIGuRE 199-5 Gram-stained sputum from a patient with nocardial pneumonia. (Image provided by Charles Cartwright and Susan Nelson, Hennepin County Medical Center, Minneapolis, MN.) Isolation of nocardiae from sputum or blood occasionally represents colonization, transient infection, or contamination. In typical cases of respiratory tract colonization, Gram-stained specimens are negative and cultures are only intermittently positive. A positive sputum culture in an immunosuppressed patient usually reflects disease. When nocardiae are isolated from sputum of an immunocompetent patient without apparent nocardial disease, the patient should be observed carefully without treatment. A patient with a host-defense defect that increases the risk of nocardiosis should usually receive antimicrobial treatment.


InternalMed_Harrison

InternalMed_Harrison. For mild or moderate cases, therapy with drugs known to be effective against most isolates is usually adequate. For severe cases or cases that do not respond promptly to antimicrobial therapy, isolates should be sent to a laboratory experienced with Nocardia for identification and susceptibility testing. Identification of an isolate to the species level is accomplished with molecular testing, and susceptibility is assessed with a Clinical Laboratory Standards Institute (CLSI)–approved broth dilution test. Nocardial growth is slower than the growth of most clinically important bacteria, and nocardiae tend to clump in suspension so that susceptibility test endpoints are unusual; thus experience is necessary for reliable results. Because nocardiosis is uncommon, data on the relation between susceptibility test results for specific drugs and clinical outcomes in patients treated with these drugs are meager. Careful clinical monitoring is essential, and consultation with clinicians who


InternalMed_Harrison

InternalMed_Harrison. susceptibility test results for specific drugs and clinical outcomes in patients treated with these drugs are meager. Careful clinical monitoring is essential, and consultation with clinicians who have experience with nocardiosis is often needed.


InternalMed_Harrison

InternalMed_Harrison. Sulfonamides are the drugs of choice (Tables 199-1 and 199-2). The combination of sulfamethoxazole (SMX) and trimethoprim (TMP) is at least equivalent to a sulfonamide alone and may be slightly more effective, but the combination also poses a modestly greater risk of hematologic toxicity. At the outset, 10–20 mg/kg of TMP and 50–100 mg/kg of SMX are given each day in two divided doses. Later, daily doses can be decreased to as little as 5 mg/kg and 25 mg/kg, respectively. In persons with sulfonamide allergies, desensitization usually allows continuation of therapy with these effective and inexpensive drugs. Sulfonamide susceptibility testing is difficult. The CLSI standard methodology includes a technique for TMP-SMX but not for a sulfonamide alone. Reported rates of sulfonamide susceptibility have varied widely, and controversy has ensued about the reliability of sulfonamides for therapy. However, clinical responses to Cellulitis, lymphocutaneous 2 months syndrome


InternalMed_Harrison

InternalMed_Harrison. Cellulitis, lymphocutaneous 2 months syndrome Osteomyelitis, arthritis, laryngitis, 4 months sinusitis Keratitis Topical: until apparent cure Systemic: until 2–4 months after apparent cure aIn some patients with AIDS and CD4+ T lymphocyte counts of <200/μL or with chronic granulomatous disease, therapy for pulmonary or systemic disease must be continued indefinitely. bIf all apparent CNS disease has been excised, the duration of therapy may be reduced to 6 months. appropriate sulfonamide treatment are nearly always satisfactory. Sulfonamides remain the drugs of choice in nearly all cases.


InternalMed_Harrison

InternalMed_Harrison. appropriate sulfonamide treatment are nearly always satisfactory. Sulfonamides remain the drugs of choice in nearly all cases. Clinical experience with other oral drugs is limited. Minocycline (100–200 mg twice a day) is often effective; other tetracyclines are usually less effective. Linezolid is active against all species in vitro and in vivo, but adverse effects are common with long-term use. Tigecycline appears to be active in vitro against some species, but little clinical experience has been reported. Amoxicillin (875 mg) combined with clavulanic acid (125 mg), given twice a day, has been effective but should be avoided in cases involving strains of the N. nova complex, in which clavulanate induces β-lactamase production. Among the quinolones, moxifloxacin and gemifloxacin appear to be most active.


InternalMed_Harrison

InternalMed_Harrison. N. nova complex, in which clavulanate induces β-lactamase production. Among the quinolones, moxifloxacin and gemifloxacin appear to be most active. Amikacin, the best-established parenteral drug except in cases involving the N. transvalensis complex, is given in doses of 5–7.5 mg/ kg every 12 h or 15 mg/kg every 24 h. Serum drug levels should be monitored during prolonged therapy in patients with diminished renal function and in the elderly. Ceftriaxone and imipenem are usually effective except as indicated in Table 199-1.


InternalMed_Harrison

InternalMed_Harrison. Patients with severe disease are initially treated with a combination including TMP-SMX, amikacin, and ceftriaxone or imipenem. Clinical improvement is usually noticeable after 1–2 weeks of therapy but may take longer, especially with CNS disease. After definite clinical improvement, therapy can be continued with a single oral drug, usually TMP-SMX. Some experts use two or more drugs for the entire course of therapy, but whether multiple drugs are better than a single agent is not known, and additional drugs increase the risk of toxicity. In patients with nocardiosis who need immunosuppressive therapy for an underlying disease or prevention of transplant rejection, immunosuppressive therapy should be continued. Use of SMX and TMP in high-risk populations to prevent Pneumocystis disease or urinary tract infections appears to reduce but not eliminate the risk of nocardiosis. The incidence of nocardiosis is low enough that prophylaxis solely to prevent this disease is not recommended.


InternalMed_Harrison

InternalMed_Harrison. Surgical management of nocardial disease is similar to that of other bacterial diseases. Brain abscesses should be aspirated, drained, or excised if the diagnosis is unclear, if an abscess is large and accessible, or if an abscess fails to respond to chemotherapy. Small or inaccessible brain abscesses should be treated medically; clinical improvement should be noticeable within 1–2 weeks. Brain imaging should be repeated to document the resolution of lesions, although abatement on images often lags behind clinical improvement. Antimicrobial therapy usually suffices for nocardial actinomycetoma. In deep or extensive cases, drainage or excision of heavily involved tissue may facilitate healing, but structure and function should be preserved whenever possible. Keratitis is treated with topical sulfonamide or amikacin drops plus a sulfonamide or an alternative drug given by mouth.


InternalMed_Harrison

InternalMed_Harrison. Actinomycosis and whipple’s disease Thomas A. Russo Actinomycosis and Whipple’s disease share characteristics that confound even the skilled diagnostician. Because both diseases are 200 1088 Nocardial infections tend to relapse (particularly in patients with chronic granulomatous disease), and long courses of antimicrobial therapy are necessary (Table 199-2). If disease is unusually extensive or if the response to therapy is slow, the recommendations in Table 199-2 should be exceeded. With appropriate treatment, the mortality rate for pulmonary or disseminated nocardiosis outside the CNS should be <5%. CNS disease carries a higher mortality rate. Patients should be followed carefully for at least 6 months after therapy has ended.


InternalMed_Harrison

InternalMed_Harrison. uncommon, the physician’s personal experience with their clinical presentations is limited. The laboratory identification of the etiologic agents from the order Actinomycetales is not routine. Thus they remain a diagnostic challenge. However, both of these chronic infections are curable, usually with medical therapy alone. Therefore, an awareness of the full spectrum of these diseases, prompting clinical suspicion, can expedite their diagnosis and treatment and minimize unnecessary surgical interventions (especially with actinomycosis), morbidity, and mortality risk.


InternalMed_Harrison

InternalMed_Harrison. Actinomycosis is an indolent, slowly progressive infection caused by anaerobic or microaerophilic bacteria, primarily of the genus Actinomyces, that colonize the mouth, colon, and vagina. Mucosal disruption may lead to infection at virtually any site in the body. In vivo growth of actinomycetes usually results in the formation of characteristic clumps called grains or sulfur granules. The clinical presentations of actinomycosis are myriad. Common in the preantibiotic era, actinomycosis has diminished in incidence, as has its timely recognition. Actinomycosis has been called the most misdiagnosed disease, and it has been said that no disease is so often missed by experienced clinicians.


InternalMed_Harrison

InternalMed_Harrison. Three “classic” clinical presentations that should prompt consideration of this unique infection are (1) the combination of chronicity, progression across tissue boundaries, and mass-like features (mimicking malignancy, with which it is often confused); (2) the development of a sinus tract, which may spontaneously resolve and recur; and (3) a refractory or relapsing infection after a short course of therapy, since cure of established actinomycosis requires prolonged treatment. Actinomycosis is most commonly caused by A. israelii, A. naeslundii,


InternalMed_Harrison

InternalMed_Harrison. Actinomycosis is most commonly caused by A. israelii, A. naeslundii, A. odontolyticus, A. viscosus, A. meyeri, and A. gerencseriae. Most if not all actinomycotic infections are polymicrobial. Aggregatibacter (Actinobacillus) actinomycetemcomitans, Eikenella corrodens, Enterobacteriaceae, and species of Fusobacterium, Bacteroides, Capnocytophaga, Staphylococcus, and Streptococcus are commonly isolated with actinomycetes in various combinations, depending on the site of infection. Their contribution to the pathogenesis of actinomycosis is uncertain. Comparative 16S rRNA gene sequencing has led to the identification of an ever-expanding list of Actinomyces species and a reclassification of some species to other genera. At present, 46 species and 2 subspecies have been recognized (www.bacterio.cict.fr/a/actinomyces .html). A. europaeus, A. neuii, A. radingae, A. graevenitzii, A. turicensis,


InternalMed_Harrison

InternalMed_Harrison. A. cardiffensis, A. houstonensis, A. hongkongensis, A. lingnae, A. massiliensis, A. timonensis, and A. funkei as well as two former Actinomyces species—Arcanobacterium pyogenes and Arcanobacterium bernardiae— are additional causes of human actinomycosis, albeit not always with a “classic” presentation.


InternalMed_Harrison

InternalMed_Harrison. Actinomycosis has no geographic boundaries and occurs throughout life, with a peak incidence in the middle decades. Males have a threefold higher incidence than females, possibly because of poorer dental hygiene and/or more frequent trauma. Improved dental hygiene and the initiation of antimicrobial treatment before actinomycosis fully develops have probably contributed to a decrease in incidence since the advent of antibiotics. Individuals who do not seek or have access to health care, those who have an intrauterine contraceptive device (IUCD) in place for a prolonged period (see “Pelvic Disease,” below), and those who receive bisphosphonate treatment (see “Oral-Cervicofacial Disease,” below) are probably at higher risk.


InternalMed_Harrison

InternalMed_Harrison. The etiologic agents of actinomycosis are members of the normal oral flora and are often cultured from the bronchi, the gastrointestinal tract, and the female genital tract. The critical step in the development of actinomycosis is disruption of the mucosal barrier. Local infection may ensue. Once established, actinomycosis spreads contiguously in a slow, progressive manner, ignoring tissue planes. Although acute inflammation may initially develop at the infection site, the hallmark of actinomycosis is the characteristic chronic, indolent phase manifested by lesions that usually appear as single or multiple indurations. Central necrosis consisting of neutrophils and sulfur granules develops and is virtually diagnostic. The fibrotic walls of the mass are typically described as “wooden.” The responsible bacterial and/or host factors have not been identified. Over time, sinus tracts to the skin, adjacent organs, or bone may develop. In rare instances, distant hematogenous seeding may


InternalMed_Harrison

InternalMed_Harrison. The responsible bacterial and/or host factors have not been identified. Over time, sinus tracts to the skin, adjacent organs, or bone may develop. In rare instances, distant hematogenous seeding may occur. As mentioned above, these unique features of actinomycosis mimic malignancy, with which it is often confused.


InternalMed_Harrison

InternalMed_Harrison. Foreign bodies appear to facilitate infection. This association most frequently involves IUCDs. Reports have described an association of actinomycosis with HIV infection; transplantation; common variable immunodeficiency; chronic granulomatous disease; treatment with infliximab, glucocorticoids, or bisphosphonates; and radioor chemotherapy. Ulcerative mucosal infections (e.g., by herpes simplex virus or cytomegalovirus) may facilitate disease development.


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InternalMed_Harrison. CLINICAL MANIFESTATIONS Oral-Cervicofacial Disease Actinomycosis occurs most frequently at an oral, cervical, or facial site, usually as a soft tissue swelling, abscess, or mass lesion that is often mistaken for a neoplasm. The angle of the jaw is generally involved, but a diagnosis of actinomycosis should be considered with any mass lesion or relapsing infection in the head and neck (Chap. 44). Radiation therapy and especially bisphosphonate treatment have been recognized as contributing to an increasing incidence of actinomycotic infection of the mandible and maxilla (Fig. 200-1). Canaliculitis (also commonly due to Propionibacterium propionicum), otitis, and sinusitis also can develop. Pain, fever, and leukocytosis are variably reported. Contiguous extension to the cranium, cervical spine, or thorax is a potential sequela.


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InternalMed_Harrison. Thoracic Disease Thoracic actinomycosis, which may be facilitated by foreign material, usually follows an indolent progressive course, with involvement of the pulmonary parenchyma and/or the pleural space. Chest pain, fever, and weight loss are common. A cough, when present, is variably productive. The usual radiographic finding is either a mass lesion or pneumonia. On CT, central areas of low attenuation and ringlike rim enhancement may be seen. Cavitary disease or mediastinal or hilar adenopathy may develop. More than 50% of cases include pleural thickening, effusion, or empyema (Fig. 200-2). Rarely, pulmonary nodules or endobronchial lesions occur. Lesions suggestive of actinomycosis include those that cross fissures or pleura; extend into the mediastinum, contiguous bone, or chest wall; or are associated with a sinus tract. In the absence of these findings, thoracic actinomycosis is usually mistaken for a neoplasm or pneumonia due to more usual causes.


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InternalMed_Harrison. FIGuRE 200-1 Bisphosphonate-associated maxillary osteomy-elitis due to A. viscosus. A sulfur granule is seen within the bone. (Reprinted with permission from NH Naik, TA Russo: Bisphosphonate related osteonecrosis of the jaw: The role of Actinomyces. Clin Infect Dis 49:1729, 2009. © 2009 University of Chicago Press.) Mediastinal infection is uncommon, usually arising from thoracic extension but rarely from perforation of the esophagus, trauma, or extension of head and neck or abdominal disease. The structures within the mediastinum and the heart can be involved in various combinations; consequently, the possible presentations are diverse. Primary endocarditis (in which A. neuii has been increasingly described) and isolated disease of the breast occur.


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InternalMed_Harrison. Abdominal Disease Abdominal actinomycosis poses a great diagnostic challenge. Months or years usually pass from the inciting event (e.g., appendicitis, diverticulitis, peptic ulcer disease, spillage of gall stones or bile during laparoscopic cholecystectomy, foreign-body perforation, bowel surgery, or ascension from IUCD-associated pelvic disease) to clinical recognition. Because of the flow of peritoneal fluid and/ or the direct extension of primary disease, virtually any abdominal organ, region, or space can be involved. The disease usually presents as an abscess, a mass, or a mixed lesion that is often fixed to underlying tissue and mistaken for a tumor. On CT, enhancement is most often heterogeneous and adjacent bowel is thickened. Sinus tracts to the abdominal wall, to the perianal region, or between the bowel and other organs may develop and mimic inflammatory bowel disease (Chap. 351). Recurrent disease or a wound or fistula that fails to heal suggests actinomycosis.


InternalMed_Harrison

InternalMed_Harrison. Hepatic infection usually presents as one or more abscesses or 1089 masses (Fig. 200-3). Isolated disease presumably develops via hematogenous seeding from cryptic foci. Imaging and percutaneous techniques have resulted in improved diagnosis and treatment. All levels of the urogenital tract can be infected. Renal disease usually presents as pyelonephritis and/or renal and perinephric abscess. Bladder involvement, usually due to extension of pelvic disease, may result in ureteral obstruction or fistulas to bowel, skin, or uterus. Actinomyces can be detected in urine with appropriate stains and cultures.


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InternalMed_Harrison. Pelvic Disease Actinomycotic involvement of the pelvis occurs most commonly in association with an IUCD. When an IUCD is in place or has recently been removed, pelvic symptoms should prompt consideration of actinomycosis. The risk, although not quantified, appears small. The disease rarely develops when the IUCD has been in place for <1 year, but the risk increases with time. Actinomycosis can also present months after IUCD removal. Symptoms are typically indolent; fever, weight loss, abdominal pain, and abnormal vaginal bleeding or discharge are the most common. The earliest stage of disease—often endometritis—commonly progresses to pelvic masses or a tuboovarian abscess (Fig. 200-4). Unfortunately, because the diagnosis is often delayed, a “frozen pelvis” mimicking malignancy or endometriosis can develop by the time of recognition. Ca125 levels may be elevated, further contributing to misdiagnosis.


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InternalMed_Harrison. Actinomyces-like organisms (ALOs), which are identified in Papanicolaou-stained specimens in (on average) 7% of women using an IUCD, have a low positive predictive value for diagnosis. Nonetheless, although the risk appears small, the consequences of infection are significant. Therefore, until more quantitative data become available, it seems prudent to remove the IUCD in the presence of symptoms that cannot be accounted for, regardless of whether ALOs are detected, and—if advanced disease is excluded—to initiate a 14-day course of empirical treatment for possible early endometritis. The detection of ALOs in the asymptomatic patient warrants education and close follow-up but not removal of the IUCD unless a suitable contraceptive alternative is agreed on.


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InternalMed_Harrison. Central Nervous System Disease Actinomycosis of the central nervous system (CNS) is rare. Single or multiple brain abscesses are most common. An abscess usually appears on CT as a ring-enhancing lesion with a thick wall that may be irregular or nodular. Magnetic resonance perfusion and spectroscopy findings have also been described, as have primary meningitis, epidural or subdural space infection, and cavernous sinus syndrome. Musculoskeletal and Soft Tissue Infection Actinomycotic infection of bone and joints is usually due to adjacent soft-tissue infection but may be associated with trauma (e.g., fracture of the mandible), injections, FIGuRE 200-2 Thoracic actinomycosis. A. A chest wall mass from extension of pulmonary infection. B. Pulmonary infection is complicated by empyema (open arrow) and extension to the chest wall (closed arrow). (Courtesy of Dr. C. B. Hsiao, Division of Infectious Diseases, Department of Medicine, State University of New York at Buffalo.)


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InternalMed_Harrison. FIGuRE 200-3 Hepatic-splenic actinomycosis. A. Computed tomogram showing multiple hepatic abscesses and a small splenic lesion due to A. israelii. Arrow indicates extension outside the liver. Inset: Gram’s stain of abscess fluid demonstrating beaded filamentous gram-positive rods. B. Subsequent formation of a sinus tract. (Reprinted with permission from Saad M: Actinomyces hepatic abscess with cutaneous fistula. N Engl J Med 353:e16, 2005. © 2005 Massachusetts Medical Society. All rights reserved.) surgery, osteoradionecrosis and bisphosphonate osteonecrosis (limited to mandibular and maxillary bones), or hematogenous spread. Because of slow disease progression, new bone formation and bone destruction are seen concomitantly. Infection of an extremity is uncommon and is usually a result of trauma. Skin, subcutaneous tissue, muscle, and bone (with periostitis or acute or chronic osteomyelitis) are involved alone or in various combinations. Cutaneous sinus tracts frequently develop.


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InternalMed_Harrison. Disseminated Disease Hematogenous dissemination of disease from any location rarely results in multiple-organ involvement. A. meyeri is most commonly involved. The lungs and liver are most commonly affected, with the presentation of multiple nodules mimicking disseminated malignancy. The clinical presentation may be surprisingly indolent given the extent of disease.


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InternalMed_Harrison. The diagnosis of actinomycosis is rarely considered. All too often, actinomycosis is first mentioned by the pathologist after extensive surgery. Since medical therapy alone is frequently sufficient for cure, the challenge for the clinician is to consider the possibility of actinomycosis, to diagnose it in the least invasive fashion, and to avoid unnecessary surgery. The clinical and radiographic presentations that suggest actinomycosis are discussed above. Of note, hypermetabolism has been demonstrated by 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) in actinomycotic disease. Aspirations and biopsies (with or without CT or ultrasound guidance) are being used successfully to obtain clinical material for diagnosis, although surgery may be required. The diagnosis is most commonly made by microscopic identification of sulfur granules (an in vivo matrix of bacteria, calcium phosphate, and host material) in pus or tissues. Occasionally, these granules are identified grossly


InternalMed_Harrison

InternalMed_Harrison. made by microscopic identification of sulfur granules (an in vivo matrix of bacteria, calcium phosphate, and host material) in pus or tissues. Occasionally, these granules are identified grossly from draining sinus tracts or pus. Although sulfur granules are a defining characteristic of actinomycosis, granules also are found in mycetoma (Chaps. 199 and 243) and botryomycosis (a chronic suppurative bacterial infection of soft tissue or, in rare cases, visceral tissue that produces clumps of bacteria resembling granules). These entities can easily be differentiated from actinomycosis with appropriate histopathologic and microbiologic studies. Microbiologic identification of actinomycetes is often precluded by prior antimicrobial therapy or failure to perform appropriate micro-biologic cultures. For optimal yield, the avoidance of even a single dose of antibiotics is mandatory. Primary isolation usually requires 5–7 days under anaerobic conditions but may take as long as 2–4 weeks.


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InternalMed_Harrison. cultures. For optimal yield, the avoidance of even a single dose of antibiotics is mandatory. Primary isolation usually requires 5–7 days under anaerobic conditions but may take as long as 2–4 weeks. Although not routinely used, 16S rRNA gene amplification and sequencing have been successfully applied to increase diagnostic sensitivity and specificity. Because actinomycetes are components of the normal oral and genital-tract flora, their identification in the absence of sulfur granules in sputum, bronchial washings, and cervicovaginal secretions is of little significance.


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InternalMed_Harrison. FIGuRE 200-4 Computed tomogram showing pelvic actinomy-cosis associated with an intrauterine contraceptive device. The device is encased by endometrial fibrosis (solid arrow); also visible are paraendometrial fibrosis (open triangular arrowhead) and an area of suppuration (open arrow).


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InternalMed_Harrison. Decisions about treatment are based on the collective clinical experience of the past 65 years. Actinomycosis requires prolonged treatment with high doses of antimicrobial agents; suitable antimicrobial agents and those deemed unreliable are listed in Table 200-1. The need for intensive treatment is presumably due to the drugs’ poor penetration of the thick-walled masses common in this infection and/or the sulfur granules themselves, which may represent a biofilm. Although therapy must be individualized, the IV administration of 18–24 million units of penicillin daily for 2–6 weeks, followed by oral therapy with penicillin or amoxicillin (total duration, 6–12 months), is a reasonable guideline for serious infections and bulky disease. Less extensive disease, particularly that involving the oralcervicofacial region, may be cured with a shorter course. If therapy is extended beyond the resolution of measurable disease, the risk of relapse—a clinical hallmark of this infection—will be


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InternalMed_Harrison. the oralcervicofacial region, may be cured with a shorter course. If therapy is extended beyond the resolution of measurable disease, the risk of relapse—a clinical hallmark of this infection—will be minimized; CT and MRI are generally the most sensitive and objective techniques


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InternalMed_Harrison. Extensive successful clinical Penicillin: 3–4 million units IV q4hc experienceb Amoxicillin: 500 mg PO q6h Erythromycin: 500–1000 mg IV q6h or 500 mg PO q6h Tetracycline: 500 mg PO q6h Doxycycline: 100 mg IV or PO q12h Minocycline: 100 mg IV or PO q12h Clindamycin: 900 mg IV q8h or 300–450 mg PO q6h


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InternalMed_Harrison. Erythromycin: 500–1000 mg IV q6h or 500 mg PO q6h Tetracycline: 500 mg PO q6h Doxycycline: 100 mg IV or PO q12h Minocycline: 100 mg IV or PO q12h Clindamycin: 900 mg IV q8h or 300–450 mg PO q6h Agents predicted to be efficacious Moxifloxacin on the basis of in vitro activity aAdditional coverage for concomitant “companion” bacteria may be required. bControlled evaluations have not been performed. Dose and duration require individualization depending on the host, site, and extent of infection. As a general rule, a maximal parenteral antimicrobial dose for 2–6 weeks followed by oral therapy, for a total duration of 6–12 months, is required for serious infections and bulky disease, whereas a shorter course may suffice for less extensive disease, particularly in the oral-cervicofacial region. Monitoring the impact of therapy with CT or MRI is advisable when appropriate. cThese agents can be considered for at-home parenteral therapy; penicillin requires a continuous infusion pump.


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InternalMed_Harrison. by which to accomplish this goal. A similar approach is reasonable for immunocompromised patients, although refractory disease has been described in HIV-infected individuals. Although the role played by “companion” microbes in actinomycosis is unclear, many isolates are pathogens in their own right, and a regimen covering these organisms during the initial treatment course is reasonable.


InternalMed_Harrison

InternalMed_Harrison. Combined medical-surgical therapy is still advocated in some reports. However, an increasing body of literature now supports an initial attempt at cure with medical therapy alone, even in extensive disease. CT and MRI should be used to monitor the response to therapy. In most cases, either surgery can be avoided or a less extensive procedure can be used. This approach is particularly valuable in sparing critical organs, such as the bladder or the reproductive organs in women of childbearing age. For a well-defined abscess, percutaneous drainage in combination with medical therapy is a reasonable approach. When a critical location is involved (e.g., the epidural space, the CNS), when there is significant hemoptysis, or when suitable medical therapy fails, surgical intervention may be appropriate. In the absence of optimal data, the combination of a prolonged course of antimicrobial therapy and resection—at least of necrotic bone for bisphosphonate-related osteonecrosis of the jaw


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InternalMed_Harrison. appropriate. In the absence of optimal data, the combination of a prolonged course of antimicrobial therapy and resection—at least of necrotic bone for bisphosphonate-related osteonecrosis of the jaw (BRONJ)—is a reasonable approach.


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InternalMed_Harrison. Whipple’s disease, a chronic multiorgan infection caused by Tropheryma whipplei, was first described in 1907. The long-held belief that Whipple’s disease is an infection was supported by observations on its responsiveness to antimicrobial therapy in the 1950s and the identification of bacilli via electron microscopy in small-bowel biopsy 1091 specimens in the 1960s. This hypothesis was finally confirmed by amplification and sequencing of a partial 16S rRNA polymerase chain reaction (PCR)–generated amplicon from duodenal tissue in 1991. The subsequent successful cultivation of T. whipplei enabled whole-genome sequencing and the development of additional diagnostic tests. The development of PCR-based diagnostics has broadened our understanding of both the epidemiology and the clinical syndromes attributable to T. whipplei. Exposure to T. whipplei, which appears to be much more common than has been appreciated, can be followed by asymptomatic carriage, acute disease, or chronic


InternalMed_Harrison

InternalMed_Harrison. syndromes attributable to T. whipplei. Exposure to T. whipplei, which appears to be much more common than has been appreciated, can be followed by asymptomatic carriage, acute disease, or chronic infection. Chronic infection (Whipple’s disease) is a rare development after exposure. “Classic” Whipple’s disease is manifested variably by a combination of arthralgias/arthritis, weight loss, chronic diarrhea, abdominal pain, and fever; less commonly, involvement at sites other than the gastrointestinal tract is documented. Acute infection and chronic organ disease in the absence of intestinal involvement (see “Isolated Infection,” below) are described with increasing frequency. Since untreated Whipple’s disease is often fatal and delayed diagnosis may lead to irreparable organ damage (e.g., in the CNS), knowledge of the clinical scenarios in which Whipple’s should be considered and of an appropriate diagnostic strategy is mandatory.


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InternalMed_Harrison. T. whipplei is a weakly staining gram-positive bacillus. Genomic sequence data have revealed that the organism has a small (<1-megabase) chromosome, with many biosynthetic pathways absent or incomplete. This finding is consistent with a host-dependent intracellular pathogen or a pathogen that requires a nutritionally rich extracellular environment. A genotyping scheme based on a variable region has disclosed more than 70 genotypes (GTs) to date. GTs 1 and 3 are most commonly reported, but all GTs appear to be capable of causing similar clinical syndromes.


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InternalMed_Harrison. Whipple’s disease is rare but has been increasingly recognized since the advent of PCR-based diagnostic tools. It occurs in all parts of the globe, with an incidence presently estimated at 1 case per 1 million patient-years. Seroprevalence studies indicate that ~50% of Western Europeans and ~75% of Africans from rural Senegal have been exposed to T. whipplei. A predilection for chronic disease has been observed in middle-aged Caucasian men. Males are infected five to eight times more frequently than females. To date, no clear animal or environmental reservoir has been demonstrated. However, the organism has been identified by PCR in sewage water and human feces. Workers with direct exposure to sewage are more likely to be asymptomatically colonized than controls, a pattern suggesting fecal-oral spread. Recent data support oral-oral or fecal-oral spread among family members. Further, the development of acute T. whipplei pneumonia in children raises the possibility of droplet or


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InternalMed_Harrison. fecal-oral spread. Recent data support oral-oral or fecal-oral spread among family members. Further, the development of acute T. whipplei pneumonia in children raises the possibility of droplet or airborne transmission.


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InternalMed_Harrison. Since rates of exposure to T. whipplei appear to be much higher (e.g., ~50% in Western Europe, as stated above) than rates of chronic disease development (0.00001%), it has been hypothesized that chronically infected individuals possess a subtle host-defense abnormality that does not place them at risk for non–T. whipplei infection. The HLA alleles DRB1*13 and DQB1*06 may be associated with an increased risk of infection. Chronic infection results in a general state of immunosuppression characterized by low CD4+ T cell counts, high levels of interleukin 10 production, increased activity of regulatory T cells, alternative activation of macrophages with diminished antimicrobial activity (M2 polarization) and ensuing apoptosis, and blunted development of T. whipplei–specific T cells. Immunosuppressive glucocorticoid treatment or anti–tumor necrosis factor α therapy appears to accelerate progression of disease. Recently, asymptomatic HIV-infected individuals were found to have


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InternalMed_Harrison. Immunosuppressive glucocorticoid treatment or anti–tumor necrosis factor α therapy appears to accelerate progression of disease. Recently, asymptomatic HIV-infected individuals were found to have significantly higher levels of T. whipplei sequence in bronchoalveolar lavage fluid (BALF) than did non-HIV-infected individuals, and these levels decreased 1092 with antiretroviral therapy. A weak humoral response, perhaps due to bacterial glycosylation in patients with chronic disease, appears to differentiate persons who clear the bacillus from asymptomatic carriers. In the initiation of chronic infection, the relative importance of the host’s genetic background versus the modulation of the host response by T. whipplei is unknown.


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InternalMed_Harrison. T. whipplei has a tropism for myeloid cells, which it invades and in which it can avoid being killed. Infiltration of infected tissue by large numbers of foamy macrophages is a characteristic finding. In the intestine, villi are flat and wide with dilated lacteals. Involvement of lymphatic or hepatic tissue may manifest as noncaseating granulomas that can mimic sarcoid. CLINICAL MANIFESTATIONS Asymptomatic Colonization/Carriage Studies using primarily PCR have detected T. whipplei sequence in stool, saliva, duodenal tissue, and (rarely) blood in the absence of symptoms. Although prevalence rates are still being defined, in Western European countries, detection in saliva (0.2%) is less common than that in stool (1–11%) and appears to occur only with concomitant fecal carriage. The prevalence of fecal carriage is elevated in individuals with exposure to waste water or sewage (12–26%). However, in rural Senegal, 44% of children age 2–10 had


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InternalMed_Harrison. T. whipplei detected in fecal samples. The duration of carriage at these sites is still being examined but can be at least 1 year. It is not known how often the carrier state is associated with acute infection, but evolution into chronic disease is uncommon. Bacterial loads are lighter in asymptomatic carriage than in active disease. Acute Infection T. whipplei has been implicated as a cause of acute gastroenteritis in children. It was also detected via PCR in the blood of 6.4% of febrile patients (primarily children) from two villages in Senegal, often with concomitant cough and rhinorrhea. Further, T. whipplei has been implicated as a cause of acute pneumonia in the United States and France. These data suggest that primary acquisition can result in symptomatic pulmonary or intestinal infection, which may be more common than has been thought, and only rarely results in chronic disease.


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InternalMed_Harrison. Chronic Infection • “classic” wHipple’s disease So-called classic Whipple’s disease was the initial clinical syndrome recognized, with consequent identification of T. whipplei. This chronic infection is defined by involvement of the duodenum and/or jejunum that develops over years. In most individuals, the initial phase of disease manifests primarily as intermittent, occasionally chronic and destructive migratory oligoor polyarthralgias/seronegative arthritis. Spondylitis, sacroiliitis, and prosthetic hip infection also have been described. This initial stage is often confused with a variety of rheumatologic disorders and, on average, lasts 6–8 years before gastrointestinal symptoms commence. Treatment of presumed inflammatory arthritis with immunosuppressive agents (e.g., glucocorticoids, tumor necrosis factor α antagonists) can accelerate progression of the disease process. Alternatively, antimicrobial therapy used for another indication may reduce symptoms. In fact, the modulation


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InternalMed_Harrison. tumor necrosis factor α antagonists) can accelerate progression of the disease process. Alternatively, antimicrobial therapy used for another indication may reduce symptoms. In fact, the modulation of symptoms in these settings should prompt consideration of Whipple’s disease. The intestinal symptoms that develop in the majority of cases are characterized by diarrhea with accompanying weight loss and may be associated with fever and abdominal pain. Diagnostic misdirection can be caused by co-infection with Giardia lamblia, which is occasionally identified. Occult gastrointestinal blood loss, hepatosplenomegaly, and ascites are less common. Anemia and hypereosinophilia may be detected. Rheumatoid factor and antinuclear antibody tests are usually negative. The most common finding on abdominal CT is mesenteric and/ or retroperitoneal lymphadenopathy. The endoscopic or video capsule observation of pale, yellow, or shaggy mucosa with erythema or ulceration past the first portion of the


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InternalMed_Harrison. CT is mesenteric and/ or retroperitoneal lymphadenopathy. The endoscopic or video capsule observation of pale, yellow, or shaggy mucosa with erythema or ulceration past the first portion of the duodenum suggests Whipple’s disease (Fig. 200-5). In addition to rheumatologic and proximal intestinal disease, neurologic (6–63%), cardiac (17–55%), pulmonary (10–40%), lymphatic (10%), ocular (5–10%), dermal (1–5%), and (in rare instances) other sites are variably involved in classic Whipple’s disease.


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InternalMed_Harrison. FIGuRE 200-5 Endoscopic view of the jejunal mucosa demonstrating a thickened, granular mucosa and “white spots” due to dilated lacte-als. (Reprinted with permission from J Bureš et al: Whipple’s disease: Our own experience and review of the literature. Gastroenterol Res Pract , 2013. http://dx.doi.org/10.1155/2013/478349.) neurologic disease Asymptomatic neurologic involvement in Whipple’s disease has been documented by PCR-based detection in cerebrospinal fluid (CSF). A variety of neurologic manifestations have been reported, the most common of which are cognitive changes progressing to dementia; personality, mood, and sleep-cycle disorders; hypothalamic involvement; and supranuclear ophthalmoplegia. In addition to the latter, neuro-ophthalmologic manifestations of Whipple’s disease include supranuclear gaze palsy, oculomasticatory and oculofacial myorhythmia (highly suggestive of Whipple’s), nystagmus, and retrobulbar neuritis. Focal neurologic presentations (dependent on lesion


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InternalMed_Harrison. supranuclear gaze palsy, oculomasticatory and oculofacial myorhythmia (highly suggestive of Whipple’s), nystagmus, and retrobulbar neuritis. Focal neurologic presentations (dependent on lesion location), seizures, ataxia, meningitis, encephalitis, hydrocephalus, myelopathy, and distal polyneuropathy also have been described. Neurologic sequelae occur with CNS disease, and the mortality risk is significant.


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InternalMed_Harrison. MRI results may be normal. Identified lesions (solitary or multifocal) are usually T2 and fluid-attenuated inversion recovery (FLAIR) hyperintense and may enhance with gadolinium. Findings are myriad and not diagnostic, but the limbic system is commonly involved. FDG-PET may reveal increased uptake. CSF analysis may be abnormal; leukocytosis (generally lymphocyte-predominant) and an elevated protein concentration are common. A low CSF glucose level has been reported.


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InternalMed_Harrison. cardiac disease Endocarditis, which is increasingly recognized in Whipple’s disease, presents as culture-negative infection and/or congestive heart failure; hypotension occurs rarely. Embolic events or various arrhythmias may also be noted. Fever is often absent, and Duke clinical criteria are rarely met. Vegetations are identified by echocardiography in 50–75% of cases. All valves, alone or in combination, can be affected; most commonly involved are the aortic and mitral valves. Preexisting valvular disease is found in only a minority of cases, although infection of bioprosthetic valves has been described. Mural, myocardial, or pericardial disease also occurs alone or in combination with valvular involvement. Constrictive pericarditis develops infrequently.


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InternalMed_Harrison. pulmonary disease Some combination of interstitial disease, nodules, parenchymal infiltrate, and pleural effusion is observed. The clinical significance of T. whipplei dominating sequence reads in BALF from HIV-infected individuals is unresolved. lymphatic disease Mesenteric and retroperitoneal lymphadenopathy are common with intestinal disease, and mediastinal adenopathy may be associated with pulmonary infection. Peripheral adenopathy is less common.


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InternalMed_Harrison. ocular disease (non-neuro-ophthalmologic) Uveitis is the most common form of ocular disease, usually presenting as a change in vision or “floaters.” Anterior (anterior chamber), intermediate (vitreous), and posterior (retina/choroid) uveitis can occur alone or in combination. Postoperative acute or chronic ocular Whipple’s disease has been described in association with local or systemic glucocorticoid use; its detection in this setting raises the possibility that asymptomatic or subclinical disease has been unmasked. Keratitis and crystalline keratopathy also have been reported. Patients may be misdiagnosed with sarcoid or Behçet’s disease prior to the recognition of Whipple’s.


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InternalMed_Harrison. dermatologic disease Skin hyperpigmentation, particularly in light-exposed areas in the absence of adrenal dysfunction, should be suggestive of Whipple’s disease. A variety of other cutaneous manifestations have been described, including erythematous macular lesions, nonthrombocytopenic purpura, subcutaneous nodules, and hyperkeratosis. miscellaneous sites Thyroid, renal, testicular, epididymal, gallbladder, skeletal muscle, and bone marrow involvement have all been described. In fact, almost any organ can be involved in classic Whipple’s disease, with varying frequency, variable combinations, and myriad signs and symptoms. As a result, Whipple’s disease should be considered in the setting of a chronic multisystemic process. Despite its rarity, the combination of rheumatologic and intestinal disease with weight loss, with or without neurologic and cardiac involvement, warrants heightened suspicion.


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InternalMed_Harrison. isolated infection This entity has been defined as infection in the absence of intestinal symptoms, although an occasional small-bowel biopsy may be PCR-positive in this setting. “Isolated infection” is something of a misnomer since multiple nonintestinal sites of T. whipplei infection are not uncommon. Infection at the same nonintestinal sites (single or multiple) that are variably involved in classic Whipple’s disease may also present as “isolated infection.” Endocarditis, neurologic disease, uveitis, rheumatologic manifestations, and pulmonary involvement are most commonly described. Signs and symptoms are similar to those described for T. whipplei infection of these sites in classic Whipple’s disease. With enhanced PCR-based diagnostic capabilities, T. whipplei infection without concomitant intestinal involvement (of which endocarditis is the best example) will probably be diagnosed increasingly often.


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InternalMed_Harrison. reinfection/relapsing disease/immUne reconstitUtion inflammatory syndrome (iris) It has been suggested that, if an underlying host immune defect places an individual at risk for chronic infection, then that person may be at risk for reinfection due to occupational exposure or contact with family members who are asymptomatically colonized. One case of apparent relapse that was due to a different genotype supports this contention. Optimal treatment regimens and durations are still being defined. However, it is clear, especially in the setting of occult or overt CNS disease, that treatment with oral tetracycline or trimethoprimsulfamethoxazole (TMP-SMX) alone may result in disease relapse.


InternalMed_Harrison

InternalMed_Harrison. As in patients treated for HIV or mycobacterial disease, IRIS has been described in patients treated for T. whipplei infection. Prior immunosuppressive therapy increases the likelihood of IRIS, in which inflammation recurs after an initial clinical response to treatment and loss of PCR detection of T. whipplei. Manifestations include fever, arthritis, skin lesions, pleuritis, uveitis, and orbital and periorbital inflammation.


InternalMed_Harrison

InternalMed_Harrison. Considering T. whipplei infection and ensuring that the appropriate tests are performed are the critical steps in making the diagnosis, which otherwise will likely be missed. The clinical presentation will in part dictate which clinical specimens are most likely to enable the diagnosis. In the presence (and perhaps the absence) of gastrointestinal symptoms, postbulbar duodenal biopsies should be performed. As a 1093 general rule, diagnostic yield is greater for tissue specimens than for body fluids. Biopsy of normal-appearing skin may detect T. whipplei in the setting of classic Whipple’s disease and serve as a minimally invasive means to establish the diagnosis. It is unclear whether CSF should be obtained in the absence of CNS symptoms, but its collection should be considered: the CNS is the most common site for relapse, and thus the information gained by CSF examination could influence the design of the treatment regimen.


InternalMed_Harrison

InternalMed_Harrison. The development and implementation of PCR-based diagnostics have significantly increased the sensitivity and specificity of T. whipplei identification. PCR can be applied to affected tissues (fixed and nonfixed) and various body fluids (e.g., CSF; aqueous or vitreous humor; joint, pericardial, or pleural fluid; BALF; blood; feces). In some clinical scenarios, a generic 16S rRNA bacterial assay combined with amplicon sequencing can be used to detect and identify T. whipplei sequence. Delineation of the T. whipplei genomic sequence has enabled the development and broad availability of more sensitive and specific PCR-based assays. The interpretation of a PCR-based diagnostic approach must take into account limitations such as false-positive results due to sample contamination and false-negative results due to organism load, sample quality, and inadequate DNA extraction.


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InternalMed_Harrison. The diagnosis of classic Whipple’s disease was originally based on histologic findings in intestinal biopsy specimens, and this diagnostic procedure remains important. Infiltration of the lamina propria with macrophages containing inclusions (representing ingested bacteria) that are positive on periodic acid–Schiff (PAS) staining and resistant to diastase is observed. However, PAS is nonspecific, also yielding positive results with mycobacteria (which can be differentiated with Ziehl-Neelsen stain), Rhodococcus equi, Bacillus cereus, Corynebacterium species, and Histoplasma species. T. whipplei can also be detected by silver stain, Brown-Brenn (weakly positive), or acridine orange and is not stained by calcofluor. Staining of other tissues or fluids (e.g., ocular aspirations) for PAS-positive inclusions in macrophages can be performed to support the diagnosis. Electron microscopy can be used to identify the trilaminar cell wall of T. whipplei.


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InternalMed_Harrison. When available, immunohistochemistry has greater specificity and sensitivity than PAS staining and can be performed on archived fixed tissue. T. whipplei has been successfully cultured from blood, CSF, synovial fluid, BALF, valve tissue, duodenal tissue, skeletal muscle, and lymph nodes, but culture is not practical since it takes months to obtain a positive result. Likewise, serology is of limited value for the diagnosis of Whipple’s disease because the prevalence of exposure is much higher than that of chronic disease development and the antibody response to T. whipplei appears to be blunted in the disease state. Although histologic or cytologic detection of T. whipplei is less specific and sensitive than PCR, a positive result is strongly supportive within the appropriate clinical context and is definitive when combined with a more specific test (e.g., PCR, immunohistochemistry).


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InternalMed_Harrison. Data on treatment are emerging, but questions persist regarding the optimal regimen and duration, which may depend on the site of infection (e.g., CNS and heart valve). Appropriate treatment usually results in a rapid and at times remarkable clinical response (e.g., in CNS disease). Maintenance of a durable response has been more challenging. Rates of relapse, particularly of CNS disease, were unacceptable with oral tetracycline or TMP-SMX monotherapy. Sequence data now indicate that TMP is not active against T. whipplei due to the absence of dihydrofolate reductase, but this drug was used extensively before this fact was known. This information prompted a randomized controlled trial in 40 patients, who received either ceftriaxone (2 g IV q24h) or meropenem (1 g IV q8h) for 2 weeks followed by oral TMP-SMX (160/800 mg) twice a day for 1 year. The efficacy of these regimens was outstanding. The only instance of therapy failure—in a case of asymptomatic CNS infection that was


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InternalMed_Harrison. Infections due to Mixed Anaerobic Organisms Ronit Cohen-Poradosu, Dennis L. Kasper Anaerobes comprise the predominant class of bacteria of the normal human microbiota (formerly termed “the normal human flora”) that 201 1094 not eradicated by either regimen—was subsequently cured with oral minocycline and chloroquine (250 mg/d after a loading dose). A follow-up trial reported similar efficacy with a regimen of ceftriaxone (2 g IV q24h) for 2 weeks followed by oral TMP-SMX for 3 months. One issue in these trials was that the CNS doses—and perhaps the duration of ceftriaxone and meropenem treatment as well—were not optimal. Further, investigators have speculated that oral regimens with greater CNS penetrance, such as sulfadiazine (2–4 g/d in 3 or 4 divided doses) and/or doxycycline or minocycline (200 mg/d in 2 divided doses) plus hydroxychloroquine (200 mg three times a day, to raise phagosome pH and increase drug activity in vitro), might render the parenteral phase of treatment


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InternalMed_Harrison. minocycline (200 mg/d in 2 divided doses) plus hydroxychloroquine (200 mg three times a day, to raise phagosome pH and increase drug activity in vitro), might render the parenteral phase of treatment unnecessary, given that the one failure of therapy for CNS disease was cured with a similar regimen. Another issue is concern about the potential development of resistance to sulfa drugs. Lastly, it is unclear whether oral sulfaor tetracycline-based regimens will suffice in endocarditis. Until more data become available, it seems prudent—at least in asymptomatic/symptomatic CNS disease or cardiac infection—to administer CNS-optimized doses of IV ceftriaxone (2 g q12h) or meropenem (2 g q8h) for at least 2 weeks followed by oral doxycycline or minocycline plus hydroxychloroquine or chloroquine for at least 1 year, if tolerated. Although data on the use of PCR to guide therapy do not exist, it seems reasonable that continued T. whipplei detection by PCR, especially in the CSF, should


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InternalMed_Harrison. for at least 1 year, if tolerated. Although data on the use of PCR to guide therapy do not exist, it seems reasonable that continued T. whipplei detection by PCR, especially in the CSF, should dictate at least continuation of therapy and perhaps consideration of an alternative regimen. The occurrence of a Jarisch-Herxheimer reaction within 24 h of treatment initiation has been described, with rapid resolution. The addition of glucocorticoids may be beneficial in the management of clearly documented IRIS. Data on certain site-specific treatment issues are even more limited. Anecdotal reports describe successful treatment of uveitis with oral TMP-SMX with or without rifampin, whereas treatment with tetracycline alone has resulted in relapse. Although a role for adjunctive intraocular therapy has been reported, the data are unclear on this point. Surgery may be needed in the setting of endocarditis with significant valve dysfunction; however, timely recognition can result in cure with


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InternalMed_Harrison. has been reported, the data are unclear on this point. Surgery may be needed in the setting of endocarditis with significant valve dysfunction; however, timely recognition can result in cure with medical management alone. Although data on the treatment of foreign body–associated infection are virtually nonexistent, medical treatment for a prosthetic hip infection was apparently successful; however, follow-up was limited. Regardless of the therapeutic regimen chosen, an effort to ensure compliance and close follow-up for potential relapse (or perhaps reinfection), which can occur many years after an apparent cure, will maximize the chances for a good outcome.


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InternalMed_Harrison. reside on mucous membranes and predominate in many infectious processes, particularly those arising from mucosal surfaces. These organisms generally cause disease subsequent to the breakdown of mucosal barriers and the leakage of the microbiota into normally sterile sites. Infections resulting from contamination by the microbiota are usually polymicrobial and involve both aerobic and anaerobic bacteria. However, the difficulties encountered in handling specimens in which anaerobes may be important and the technical challenges entailed in cultivating and identifying these organisms in clinical microbiology laboratories continue to leave the anaerobic etiology of an infectious process unproven in many cases. Therefore, an understanding of the types of infections in which anaerobes can play a role is crucial in selecting appropriate microbiologic tools to identify the organisms in clinical specimens and in choosing the most appropriate treatment, including antibiotics and surgical


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InternalMed_Harrison. play a role is crucial in selecting appropriate microbiologic tools to identify the organisms in clinical specimens and in choosing the most appropriate treatment, including antibiotics and surgical drainage or debridement of the infected site.


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InternalMed_Harrison. This chapter focuses on infections caused by nonsporulating anaerobic bacteria. It does not address clostridial infections and syndromes, which are covered elsewhere (Chaps. 161 and 179).


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InternalMed_Harrison. Anaerobic bacteria are organisms that require reduced oxygen tension for growth, failing to grow on the surface of solid media in 10% CO2 in air. (In contrast, microaerophilic bacteria can grow in an atmosphere of 10% CO2 in air or under anaerobic or aerobic conditions, although they grow best in the presence of only a small amount of atmospheric oxygen, and facultative bacteria can grow in the presence or absence of air). Most clinically relevant anaerobes, such as Bacteroides fragilis, Prevotella melaninogenica, and Fusobacterium nucleatum, are relatively aerotolerant. Although they can survive for sustained periods in the presence of up to 2–8% oxygen, they generally do not multiply in this environment. A smaller number of pathogenic anaerobic bacteria (which are also part of the microbiota) die after brief contact with oxygen, even in low concentrations.


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InternalMed_Harrison. Most human mucocutaneous surfaces harbor a rich indigenous normal microbiota composed of aerobic and anaerobic bacteria. These surfaces are dominated by anaerobic bacteria, which often account for 99.0–99.9% of the culturable microbiota and range in concentration from 109/mL in saliva to 1012/mL in gingival scrapings and the colon. It is interesting that anaerobes inhabit many areas of the body that are exposed to air: skin, nose, mouth, and throat. Anaerobes are thought to reside in the portions of these sites that are relatively well protected from oxygen, such as gingival crevices. New technologies based on analyses of microbial DNA have expanded our knowledge of these bacterial populations. For example, in an analysis of 13,555 prokaryotic ribosomal RNA gene sequences from the colon, most bacteria identified were considered uncultivated and novel microorganisms. Two immense projects based on these new technologies, the Human Microbiome Project funded by the U.S. National


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InternalMed_Harrison. colon, most bacteria identified were considered uncultivated and novel microorganisms. Two immense projects based on these new technologies, the Human Microbiome Project funded by the U.S. National Institutes of Health and MetaHIT financed by the European Commission, aim to characterize the normal microbiota of healthy individuals.


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InternalMed_Harrison. The major reservoirs of anaerobic bacteria are the mouth, lower gastrointestinal tract, skin, and female genital tract (Table 201-1). In the oral cavity, the ratio of anaerobic to aerobic bacteria ranges from 1:1 on the surface of a tooth to 1000:1 in the gingival crevices. Prevotella and Porphyromonas species comprise much of the indigenous oral anaerobic microbiota. Fusobacterium and Bacteroides (non–B. fragilis group) are present in lower numbers. Anaerobic bacteria are not found in appreciable numbers in the normal stomach and upper small intestine. In the distal ileum, the microbiota begins to resemble that of the colon. In the colon, the ratio of anaerobes to facultative species is high; for example, there are 1011–1012 organisms/g of stool, and >99% of these organisms are anaerobic, with an anaerobe-to-aerobe ratio of ~1000:1. The predominant anaerobes in the human intestine belong to the phyla Bacteroidetes and Firmicutes and include a number of Bacteroides species (e.g.,


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InternalMed_Harrison. with an anaerobe-to-aerobe ratio of ~1000:1. The predominant anaerobes in the human intestine belong to the phyla Bacteroidetes and Firmicutes and include a number of Bacteroides species (e.g., members of the


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InternalMed_Harrison. B. fragilis group, such as B. fragilis, B. thetaiotaomicron, B. ovatus, B. vulgatus, B. uniformis, and Parabacteroides distasonis) as well as various clostridial, peptostreptococcal, and fusobacterial species. In the female genital tract, there are ~109 organisms/mL of secretions, with an anaerobe-to-aerobe ratio of 1:1 to 10:1. The predominant anaerobes in the female genital tract are Prevotella, Bacteroides, Fusobacterium, Clostridium, and the anaerobic Lactobacillus species. The skin microbiota contains anaerobes as well, the predominant species being Propionibacterium acnes and, in lower numbers, other species of propionibacteria and peptostreptococci.


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InternalMed_Harrison. Commensal bacteria in general and commensal anaerobes in particular have been implicated as crucial mediators of physiologic, metabolic, and immunologic functions in the mammalian host. One of the most important roles that anaerobes serve as components of the normal colonic microbiota is the promotion of resistance to colonization; the presence of anaerobic bacteria effectively interferes with colonization by potentially pathogenic bacterial species through the depletion of oxygen and nutrients, the production of enzymes and toxic end products, and the modulation of the host’s intestinal innate immune response. For example, B. thetaiotaomicron stimulates Paneth cells to produce RegIIIγ, a bactericidal lectin that can result in killing of gram-positive bacteria. The normal colonic microbiota plays an important role in protection against Clostridium difficile–associated diarrhea or colitis—a toxin-mediated, potentially life-threatening disease that results when C. difficile spores in


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InternalMed_Harrison. plays an important role in protection against Clostridium difficile–associated diarrhea or colitis—a toxin-mediated, potentially life-threatening disease that results when C. difficile spores in the colon transform into toxin-producing vegetative forms after antibiotic elimination of critical components of the competing colonic microbiota.


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InternalMed_Harrison. Bacteroides and other intestinal bacteria ferment carbohydrates and produce volatile fatty acids that are reabsorbed and used by the host as an energy source. The anaerobic intestinal microbiota is also responsible for the production of secreted products that promote human health (e.g., vitamin K and bile acids useful in fat absorption and cholesterol regulation). Moreover, the anaerobic intestinal microbiota influences the development of an intact mucosa and of mucosa-associated lymphoid tissue. Colonization of germ-free mice with a single species,


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InternalMed_Harrison. B. thetaiotaomicron, affects the expression of various host genes and corrects deficiencies of nutrient uptake, metabolism, angiogenesis, mucosal barrier function, and enteric nervous system development. The symbiosis factor polysaccharide A (PSA) of B. fragilis influences the normal development and function of the mammalian immune system and protects mice against colitis in a model of inflammatory bowel disease. It has also been shown that PSA can confer protection both prophylactically and therapeutically, restraining inflammatory processes at an extraintestinal site (the central nervous system [CNS]) and ameliorating disease in a mouse model of multiple sclerosis. Anaerobes can stimulate specific lymphocyte populations of the small and large intestine and can influence immunologic balance (including TH1/TH2 balance) as well as the number of TH17 and regulatory T cells in gut tissues.


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InternalMed_Harrison. Clearly, the gut microbiota confers many benefits, and its dysregulation may play a role in the pathogenesis of diseases characterized by inflammation and aberrant immune responses, such as inflammatory bowel disease, rheumatoid arthritis, multiple sclerosis, asthma, and type 1 diabetes. Furthermore, the gut microbiota has been associated with obesity and metabolic syndrome. An interesting association between certain microbes found in the microbiota and testosterone production has been suggested as well.


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InternalMed_Harrison. Thousands of species of anaerobic bacteria have been identified as components of the complete human microbiota, with each individual colonized by hundreds of these species. Despite the complex array of bacteria in the normal microbiota, relatively few species are isolated commonly from human infections. Anaerobic infections occur when the harmonious relationship between the host and the host’s microbiota is disrupted. Any site in the body is susceptible to infection with these indigenous organisms when a mucosal barrier or the skin is compromised by surgery, trauma, tumor, ischemia, or necrosis, all of which can reduce local tissue redox potentials. Because the sites that are colonized by anaerobes contain many species of bacteria, disruption of anatomic barriers allows contamination of normally sterile sites by many organisms, resulting in mixed infections involving multiple species of anaerobes in combination with synergistically acting facultative or microaerophilic organisms.


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InternalMed_Harrison. Severe mixed infections of the head and neck may arise from an abscessed tooth infected with commensal microbiota of the mouth. Examples of infections arising from an oral source are chronic sinusitis, chronic otitis media, Ludwig’s angina, and periodontal abscesses. Brain abscesses and subdural empyema are also commonly associated with the oral microbiota. Oral anaerobes are usually responsible for pleuropulmonary diseases such as aspiration pneumonia, necrotizing pneumonia, lung abscess, and empyema.


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InternalMed_Harrison. Anaerobes from the intestine play an important role in various intraabdominal infections, such as peritonitis and intraabdominal abscesses (Chap. 159). Colonic contents are the source of microorganisms in the case of these infections, which usually follow disruption of intestinal continuity and contamination of the peritoneal cavity. Anaerobic bacteria are isolated frequently in female genital tract infections, such as salpingitis, pelvic peritonitis, tuboovarian abscess, vulvovaginal abscess, septic abortion, and endometritis (Chap. 163). In addition, these bacteria are often found in bacteremia and in infections of the skin, soft tissues, and bones. Predominant among the anaerobic gram-positive cocci that produce disease are the peptostreptococci; the species of this genus that are most commonly involved in infections are P. micros,


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InternalMed_Harrison. Predominant among the anaerobic gram-positive cocci that produce disease are the peptostreptococci; the species of this genus that are most commonly involved in infections are P. micros, P. magnus, P. asaccharolyticus, P. anaerobius, and P. prevotii. Clostridia (Chap. 179) are anaerobic spore-forming gram-positive rods that are isolated from wounds, abscesses, sites of abdominal infection, and blood. Gram-positive anaerobic non-spore-forming bacilli are uncommon as etiologic agents of human infection. P. acnes, a component of the skin microbiota and a rare cause of foreign-body infections, is one of the few nonclostridial gram-positive rods associated with infections. The principal anaerobic gram-negative bacilli found in human infections belong to the B. fragilis group and to Fusobacterium, Prevotella, and Porphyromonas species. The most important potential anaerobic pathogens found in the upper airways and isolated from clinical specimens of oral and


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InternalMed_Harrison. Infections Due to Mixed Anaerobic Organisms 1096 pleuropulmonary infections are the Fusobacterium species F. necrophorum, F. nucleatum, and F. varium; P. melaninogenica; the Prevotella oralis group; Porphyromonas gingivalis; Porphyromonas asaccharolytica; Peptostreptococcus species; and the Bacteroides ureolyticus group. The B. fragilis group contains the anaerobic pathogens most frequently isolated from clinical infections. Members of this group are part of the normal bowel microbiota; they include several distinct species, such as B. fragilis, B. thetaiotaomicron, B. vulgatus, B. uniformis, B. ovatus, and P. distasonis. B. fragilis is the most important clinical isolate, although it is isolated in lower numbers than some other Bacteroides species from cultures of the commensal fecal microbiota. In female genital tract infections, organisms normally colonizing the vagina (e.g., Prevotella bivia and Prevotella disiens) are the most common isolates. However, B. fragilis is not


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InternalMed_Harrison. microbiota. In female genital tract infections, organisms normally colonizing the vagina (e.g., Prevotella bivia and Prevotella disiens) are the most common isolates. However, B. fragilis is not uncommon.


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InternalMed_Harrison. Anaerobic bacterial infections usually occur when an anatomic barrier is disrupted and constituents of the local microbiota enter a site that was previously sterile. Because of the specific growth requirements of anaerobic organisms and their presence as commensals on mucosal surfaces, conditions must arise that allow these organisms to penetrate mucosal barriers and enter tissue with a lowered oxidation-reduction potential. Therefore, tissue ischemia, trauma, surgery, perforated viscus, shock, and aspiration provide environments conducive to the proliferation of anaerobes. The introduction of many bacterial species into otherwise sterile sites leads to a polymicrobial infection in which certain organisms predominate. Three major factors are involved in the pathogenesis of anaerobic infections: bacterial synergy, bacterial virulence factors, and mechanisms of abscess formation. The ability of different anaerobic bacteria to act synergistically during polymicrobial infection


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InternalMed_Harrison. infections: bacterial synergy, bacterial virulence factors, and mechanisms of abscess formation. The ability of different anaerobic bacteria to act synergistically during polymicrobial infection contributes to the pathogenesis of anaerobic infections. It has been postulated that facultative organisms function in part to lower the oxidation-reduction potential in the microenvironment, allowing the propagation of obligate anaerobes. Anaerobes can produce compounds such as succinic acid and short-chain fatty acids that inhibit the ability of phagocytes to clear facultative organisms. In experimental models, facultative and obligate anaerobes synergistically potentiate abscess formation.


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InternalMed_Harrison. Virulence factors associated with anaerobes typically confer the ability to evade host defenses, adhere to cell surfaces, produce toxins and/or enzymes, or display surface structures such as capsular polysaccharides and lipopolysaccharide (LPS) that contribute to pathogenic potential. The ability of an organism to adhere to host tissues is important to the establishment of infection. Some oral species adhere to the epithelium in the oral cavity. P. melaninogenica actually attaches to other microorganisms. P. gingivalis, a common isolate in periodontal disease, has fimbriae that facilitate attachment. Some Bacteroides strains appear to be piliated, a characteristic that may account for their ability to adhere.


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InternalMed_Harrison. The most extensively studied virulence factor of the nonsporulating anaerobes is the capsular polysaccharide complex of B. fragilis. This organism is unique among anaerobes in its potential for virulence during growth at normally sterile sites. Although it constitutes only 0.5–1% of the normal colonic microbiota, B. fragilis is the anaerobe most commonly isolated from intraabdominal infections and bacteremia. In an animal model of intraabdominal sepsis, the capsular polysaccharide was identified as the major virulence factor of B. fragilis; this polymer plays a specific, central role in the induction of abscesses. A series of detailed biologic and molecular studies of this virulence factor showed that B. fragilis produces at least eight distinct capsular polysaccharides, far more than the number reported for any other encapsulated bacterium. B. fragilis can exhibit distinct surface polysaccharides either alone or in combination by regulating the expression of these different capsules


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InternalMed_Harrison. number reported for any other encapsulated bacterium. B. fragilis can exhibit distinct surface polysaccharides either alone or in combination by regulating the expression of these different capsules in an on–off manner through a reversible inversion of DNA segments within the promoters for operons containing the genes required for polysaccharide synthesis. Structural analysis of two of these polysaccharides, PSA and PSB, revealed that each polymer consists of repeating units with positively charged free amino groups and negatively charged groups. This structural feature is rare among bacterial polysaccharides, and the ability of PSA—and, to a lesser extent, PSB—to induce abscesses in animals depends on this zwitterionic charge motif. Intraabdominal abscess induction is related to the capacity of this polysaccharide to stimulate macrophages to release cytokines and chemokines—in particular, interleukin (IL) 8, IL-17, and tumor necrosis factor α (TNF-α)—from resident peritoneal cells


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InternalMed_Harrison. of this polysaccharide to stimulate macrophages to release cytokines and chemokines—in particular, interleukin (IL) 8, IL-17, and tumor necrosis factor α (TNF-α)—from resident peritoneal cells through a Toll-like receptor 2–dependent mechanism. The release of cytokines and chemokines results in the chemotaxis of polymorphonuclear neutrophils (PMNs) into the peritoneum, where they adhere to mesothelial cells induced by TNF-α to upregulate their expression of intercellular adhesion molecule 1 (ICAM-1). PMNs adherent to ICAM-1-expressing cells probably represent the nidus for an abscess. PSA also activates T cells to produce certain cytokines, including IL-17 and interferon γ, that are necessary for abscess formation.