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InternalMed_Harrison. S. aureus and gram-negative bacilli. Tumor necrosis factor inhibitors (e.g., etanercept, infliximab), which increasingly are used for the treatment of rheumatoid arthritis, predispose to mycobacterial infections and possibly to other pyogenic bacterial infections and could be associated with septic arthritis in this population. Pneumococcal infections complicate alcoholism, deficiencies of humoral immunity, and hemoglobinopathies. Pneumococci, Salmonella species, and H. influenzae cause septic arthritis in persons infected with HIV. Persons with primary immunoglobulin deficiency are at risk for mycoplasmal arthritis, which results in permanent joint damage if tetracycline and replacement therapy with IV immunoglobulin are not administered promptly. IV drug users acquire staphylococcal and streptococcal infections from their own flora and acquire pseudomonal and other gram-negative infections from drugs and injection paraphernalia.


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InternalMed_Harrison. Clinical Manifestations Some 90% of patients present with involvement of a single joint—most commonly the knee; less frequently the hip; and still less often the shoulder, wrist, or elbow. Small joints of the hands and feet are more likely to be affected after direct inoculation or a bite. Among IV drug users, infections of the spine, sacroiliac joints, and sternoclavicular joints (Fig. 157-1) are more common than infections of the appendicular skeleton. Polyarticular infection is most FIGURE 157-1 Acute septic arthritis of the sternoclavicular joint.


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InternalMed_Harrison. FIGURE 157-1 Acute septic arthritis of the sternoclavicular joint. A man in his forties with a history of cirrhosis presented with a new onset of fever and lower neck pain. He had no history of IV drug use or previous catheter placement. Jaundice and a painful swollen area over his left sternoclavicular joint were evident on physical examination. Cultures of blood drawn at admission grew group B Streptococcus. The patient recovered after treatment with IV penicillin. (Courtesy of Francisco M. Marty, MD, Brigham and Women’s Hospital, Boston; with permission.) common among patients with rheumatoid arthritis and may resemble a flare of the underlying disease.


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InternalMed_Harrison. The usual presentation consists of moderate to severe pain that is uniform around the joint, effusion, muscle spasm, and decreased range of motion. Fever in the range of 38.3–38.9°C (101–102°F) and sometimes higher is common but may not be present, especially in persons with rheumatoid arthritis, renal or hepatic insufficiency, or conditions requiring immunosuppressive therapy. The inflamed, swollen joint is usually evident on examination except in the case of a deeply situated joint such as the hip, shoulder, or sacroiliac joint. Cellulitis, bursitis, and acute osteomyelitis, which may produce a similar clinical picture, should be distinguished from septic arthritis by their greater range of motion and less-than-circumferential swelling. A focus of extraarticular infection, such as a boil or pneumonia, should be sought. Peripheral-blood leukocytosis with a left shift and elevation of the erythrocyte sedimentation rate or C-reactive protein level are common.


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InternalMed_Harrison. Plain radiographs show evidence of soft-tissue swelling, joint-space widening, and displacement of tissue planes by the distended capsule. Narrowing of the joint space and bony erosions indicate advanced infection and a poor prognosis. Ultrasound is useful for detecting effusions in the hip, and CT or MRI can demonstrate infections of the sacroiliac joint, the sternoclavicular joint, and the spine very well.


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InternalMed_Harrison. Laboratory Findings Specimens of peripheral blood and synovial fluid should be obtained before antibiotics are administered. Blood cultures are positive in up to 50–70% of S. aureus infections but are less frequently positive in infections due to other organisms. The synovial fluid is turbid, serosanguineous, or frankly purulent. Gram-stained smears confirm the presence of large numbers of neutrophils. Levels of total protein and lactate dehydrogenase in synovial fluid are elevated, and the glucose level is depressed; however, these findings are not specific for infection, and measurement of these levels is not necessary for diagnosis. The synovial fluid should be examined for crystals, because gout and pseudogout can resemble septic arthritis clinically, and infection and crystal-induced disease occasionally occur together. Organisms are seen on synovial fluid smears in nearly three-quarters of infections with S. aureus and streptococci and in 30–50% of infections due to


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InternalMed_Harrison. disease occasionally occur together. Organisms are seen on synovial fluid smears in nearly three-quarters of infections with S. aureus and streptococci and in 30–50% of infections due to gram-negative and other bacteria. Cultures of synovial fluid are positive in >90% of cases. Inoculation of synovial fluid into bottles containing liquid media for blood cultures increases the yield of a culture, especially if the pathogen is a fastidious organism or the patient is taking an antibiotic. NAA-based assays for bacterial DNA, when available, can be useful for the diagnosis of partially treated or culture-negative bacterial arthritis.


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InternalMed_Harrison. Prompt administration of systemic antibiotics and drainage of the involved joint can prevent destruction of cartilage, postinfectious degenerative arthritis, joint instability, or deformity. Once samples of blood and synovial fluid have been obtained for culture, empirical antibiotics should be given that are directed against the bacteria visualized on smears or the pathogens that are likely in light of the patient’s age and risk factors. Initial therapy should consist of IV administration of bactericidal agents; direct instillation of antibiotics into the joint is not necessary to achieve adequate levels in synovial fluid and tissue. An IV third-generation cephalosporin such as cefotaxime (1 g every 8 h) or ceftriaxone (1–2 g every 24 h) provides adequate empirical coverage for most community-acquired infections in adults when smears show no organisms. IV vancomycin (1 g every 12 h) is used if there are gram-positive cocci on the smear. If methicillin-resistant S. aureus is an


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InternalMed_Harrison. community-acquired infections in adults when smears show no organisms. IV vancomycin (1 g every 12 h) is used if there are gram-positive cocci on the smear. If methicillin-resistant S. aureus is an unlikely pathogen (e.g., when it is not widespread in the community), either oxacillin or nafcillin (2 g every 4 h) should be given. In addition, an aminoglycoside or third-generation cephalosporin should be given to IV drug users and to other patients in whom P. aeruginosa may be the responsible agent.


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InternalMed_Harrison. Definitive therapy is based on the identity and antibiotic susceptibility of the bacteria isolated in culture. Infections due to staphylococci are treated with oxacillin, nafcillin, or vancomycin for 4 weeks. Pneumococcal and streptococcal infections due to penicillin-susceptible organisms respond to 2 weeks of therapy with penicillin G (2 million units IV every 4 h); infections caused by


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InternalMed_Harrison. H. influenzae and by strains of Streptococcus pneumoniae that are resistant to penicillin are treated with cefotaxime or ceftriaxone for 2 weeks. Most enteric gram-negative infections can be cured in 3–4 weeks by a secondor third-generation cephalosporin given IV or by a fluoroquinolone such as levofloxacin (500 mg IV or PO every 24 h). P. aeruginosa infection should be treated for at least 2 weeks with a combination regimen composed of an aminoglycoside plus either an extended-spectrum penicillin such as mezlocillin (3 g IV every 4 h) or an antipseudomonal cephalosporin such as ceftazidime (1 g IV every 8 h). If tolerated, this regimen is continued for an additional 2 weeks; alternatively, a fluoroquinolone such as ciprofloxacin (750 mg PO twice daily) is given by itself or with the penicillin or cephalosporin in place of the aminoglycoside.


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InternalMed_Harrison. Timely drainage of pus and necrotic debris from the infected joint is required for a favorable outcome. Needle aspiration of readily accessible joints such as the knee may be adequate if loculations or particulate matter in the joint does not prevent its thorough decompression. Arthroscopic drainage and lavage may be employed initially or within several days if repeated needle aspiration fails to relieve symptoms, decrease the volume of the effusion and the synovial white cell count, and clear bacteria from smears and cultures. In some cases, arthrotomy is necessary to remove loculations and debride infected synovium, cartilage, or bone. Septic arthritis of the hip is best managed with arthrotomy, particularly in young children, in whom infection threatens the viability of the femoral head. Septic joints do not require immobilization except for pain control before symptoms are alleviated by treatment. Weight bearing should be avoided until signs of inflammation have subsided, but


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InternalMed_Harrison. head. Septic joints do not require immobilization except for pain control before symptoms are alleviated by treatment. Weight bearing should be avoided until signs of inflammation have subsided, but frequent passive motion of the joint is indicated to maintain full mobility. Although addition of glucocorticoids to antibiotic treatment improves the outcome of S. aureus arthritis in experimental animals, no clinical trials have evaluated this approach in humans.


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InternalMed_Harrison. GONOCOCCAL ARTHRITIS Epidemiology Although its incidence has declined in recent years, gonococcal arthritis (Chap. 181) has accounted for up to 70% of episodes of infectious arthritis in persons <40 years of age in the United States. Arthritis due to N. gonorrhoeae is a consequence of 835 bacteremia arising from gonococcal infection or, more frequently, from asymptomatic gonococcal mucosal colonization of the urethra, cervix, or pharynx. Women are at greatest risk during menses and during pregnancy and overall are two to three times more likely than men to develop disseminated gonococcal infection (DGI) and arthritis. Persons with complement deficiencies, especially of the terminal components, are prone to recurrent episodes of gonococcemia. Strains of gonococci that are most likely to cause DGI include those which produce transparent colonies in culture, have the type IA outer-membrane protein, or are of the AUH-auxotroph type.


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InternalMed_Harrison. Clinical Manifestations and Laboratory Findings The most common manifestation of DGI is a syndrome of fever, chills, rash, and articular symptoms. Small numbers of papules that progress to hemorrhagic pustules develop on the trunk and the extensor surfaces of the distal extremities. Migratory arthritis and tenosynovitis of the knees, hands, wrists, feet, and ankles are prominent. The cutaneous lesions and articular findings are believed to be the consequence of an immune reaction to circulating gonococci and immune-complex deposition in tissues. Thus, cultures of synovial fluid are consistently negative, and blood cultures are positive in fewer than 45% of patients. Synovial fluid may be difficult to obtain from inflamed joints and usually contains only 10,000–20,000 leukocytes/μL.


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InternalMed_Harrison. True gonococcal septic arthritis is less common than the DGI syndrome and always follows DGI, which is unrecognized in one-third of patients. A single joint such as the hip, knee, ankle, or wrist is usually involved. Synovial fluid, which contains >50,000 leukocytes/μL, can be obtained with ease; the gonococcus is evident only occasionally in Gram-stained smears, and cultures of synovial fluid are positive in fewer than 40% of cases. Blood cultures are almost always negative.


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InternalMed_Harrison. Because it is difficult to isolate gonococci from synovial fluid and blood, specimens for culture should be obtained from potentially infected mucosal sites. NAA-based urine tests also may be positive. Cultures and Gram-stained smears of skin lesions are occasionally positive. All specimens for culture should be plated onto Thayer-Martin agar directly or in special transport media at the bedside and transferred promptly to the microbiology laboratory in an atmosphere of 5% CO2, as generated in a candle jar. NAA-based assays are extremely sensitive in detecting gonococcal DNA in synovial fluid. A dramatic alleviation of symptoms within 12–24 h after the initiation of appropriate antibiotic therapy supports a clinical diagnosis of the DGI syndrome if cultures are negative.


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InternalMed_Harrison. Initial treatment consists of ceftriaxone (1 g IV or IM every 24 h) to cover possible penicillin-resistant organisms. Once local and systemic signs are clearly resolving, the 7-day course of therapy can be completed with an oral fluoroquinolone such as ciprofloxacin (500 mg twice daily) if the organism is known to be susceptible. If penicillin-susceptible organisms are isolated, amoxicillin (500 mg three times daily) may be used. Suppurative arthritis usually responds to needle aspiration of involved joints and 7–14 days of antibiotic treatment. Arthroscopic lavage or arthrotomy is rarely required. Patients with DGI should be treated for Chlamydia trachomatis infection unless this infection is ruled out by appropriate testing. It is noteworthy that arthritis symptoms similar to those seen in DGI occur in meningococcemia. A dermatitis-arthritis syndrome, purulent monarthritis, and reactive polyarthritis have been described. All respond to treatment with IV penicillin.


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InternalMed_Harrison. Lyme disease (Chap. 210) due to infection with the spirochete Borrelia burgdorferi causes arthritis in up to 60% of persons who are not treated. Intermittent arthralgias and myalgias—but not arthritis—occur within days or weeks of inoculation of the spirochete by the Ixodes tick. Later, 836 there are three patterns of joint disease: (1) Fifty percent of untreated persons experience intermittent episodes of monarthritis or oligoarthritis involving the knee and/or other large joints. The symptoms wax and wane without treatment over months, and each year 10–20% of patients report loss of joint symptoms. (2) Twenty percent of untreated persons develop a pattern of waxing and waning arthralgias. (3) Ten percent of untreated patients develop chronic inflammatory synovitis that results in erosive lesions and destruction of the joint. Serologic tests for IgG antibodies to B. burgdorferi are positive in more than 90% of persons with Lyme arthritis, and an NAA-based assay detects Borrelia DNA


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InternalMed_Harrison. lesions and destruction of the joint. Serologic tests for IgG antibodies to B. burgdorferi are positive in more than 90% of persons with Lyme arthritis, and an NAA-based assay detects Borrelia DNA in 85%.


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InternalMed_Harrison. Lyme arthritis generally responds well to therapy. A regimen of oral doxycycline (100 mg twice daily for 30 days), oral amoxicillin (500 mg four times daily for 30 days), or parenteral ceftriaxone (2 g/d for 2–4 weeks) is recommended. Patients who do not respond to a total of 2 months of oral therapy or 1 month of parenteral therapy are unlikely to benefit from additional antibiotic therapy and are treated with anti-inflammatory agents or synovectomy. Failure of therapy is associated with host features such as the human leukocyte antigen DR4 (HLA-DR4) genotype, persistent reactivity to OspA (outer-surface protein A), and the presence of hLFA-1 (human leukocyte function–associated antigen 1), which cross-reacts with OspA.


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InternalMed_Harrison. Articular manifestations occur in different stages of syphilis (Chap. 206). In early congenital syphilis, periarticular swelling and immobilization of the involved limbs (Parrot’s pseudoparalysis) complicate osteochondritis of long bones. Clutton’s joint, a late manifestation of congenital syphilis that typically develops between ages 8 and 15 years, is caused by chronic painless synovitis with effusions of large joints, particularly the knees and elbows. Secondary syphilis may be associated with arthralgias, with symmetric arthritis of the knees and ankles and occasionally of the shoulders and wrists, and with sacroiliitis. The arthritis follows a subacute to chronic course with a mixed mononuclear and neutrophilic synovial-fluid pleocytosis (typical cell counts, 5000–15,000/μL). Immunologic mechanisms may contribute to the arthritis, and symptoms usually improve rapidly with penicillin therapy. In tertiary syphilis, Charcot’s joint results from sensory loss due to tabes dorsalis.


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InternalMed_Harrison. mechanisms may contribute to the arthritis, and symptoms usually improve rapidly with penicillin therapy. In tertiary syphilis, Charcot’s joint results from sensory loss due to tabes dorsalis. Penicillin is not helpful in this setting.


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InternalMed_Harrison. Tuberculous arthritis (Chap. 202) accounts for ~1% of all cases of tuberculosis and 10% of extrapulmonary cases. The most common presentation is chronic granulomatous monarthritis. An unusual syndrome, Poncet’s disease, is a reactive symmetric form of polyarthritis that affects persons with visceral or disseminated tuberculosis. No mycobacteria are found in the joints, and symptoms resolve with antituberculous therapy.


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InternalMed_Harrison. Unlike tuberculous osteomyelitis (Chap. 158), which typically involves the thoracic and lumbar spine (50% of cases), tuberculous arthritis primarily involves the large weight-bearing joints, in particular the hips, knees, and ankles, and only occasionally involves smaller non-weight-bearing joints. Progressive monarticular swelling and pain develop over months or years, and systemic symptoms are seen in only half of all cases. Tuberculous arthritis occurs as part of a disseminated primary infection or through late reactivation, often in persons with HIV infection or other immunocompromised hosts. Coexistent active pulmonary tuberculosis is unusual.


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InternalMed_Harrison. Aspiration of the involved joint yields fluid with an average cell count of 20,000/μL, with ~50% neutrophils. Acid-fast staining of the fluid yields positive results in fewer than one-third of cases, and cultures are positive in 80%. Culture of synovial tissue taken at biopsy is positive in ~90% of cases and shows granulomatous inflammation in most. NAA methods can shorten the time to diagnosis to 1 or 2 days. Radiographs reveal peripheral erosions at the points of synovial attachment, periarticular osteopenia, and eventually joint-space narrowing. Therapy for tuberculous arthritis is the same as that for tuberculous pulmonary disease, requiring the administration of multiple agents for 6–9 months. Therapy is more prolonged in immunosuppressed individuals such as those infected with HIV.


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InternalMed_Harrison. Various atypical mycobacteria (Chap. 204) found in water and soil may cause chronic indolent arthritis. Such disease results from trauma and direct inoculation associated with farming, gardening, or aquatic activities. Smaller joints, such as the digits, wrists, and knees, are usually involved. Involvement of tendon sheaths and bursae is typical. The mycobacterial species involved include Mycobacterium marinum, M. avium-intracellulare, M. terrae, M. kansasii, M. fortuitum, and M. chelonae. In persons who have HIV infection or are receiving immunosuppressive therapy, hematogenous spread to the joints has been reported for M. kansasii, M. avium complex, and M. haemophilum. Diagnosis usually requires biopsy and culture, and therapy is based on antimicrobial susceptibility patterns.


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InternalMed_Harrison. Fungi are an unusual cause of chronic monarticular arthritis. Granulomatous articular infection with the endemic dimorphic fungi Coccidioides immitis, Blastomyces dermatitidis, and (less commonly) Histoplasma capsulatum (Fig. 157-2) results from hematogenous seeding or direct extension from bony lesions in persons with disseminated disease. Joint involvement is an unusual complication of sporotrichosis (infection with Sporothrix schenckii) among gardeners and other persons who work with soil or sphagnum moss. Articular sporotrichosis is six times more common among men than among women, and alcoholics and other debilitated hosts are at risk for polyarticular infection.


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InternalMed_Harrison. Candida infection involving a single joint—usually the knee, hip, or shoulder—results from surgical procedures, intraarticular injections, or (among critically ill patients with debilitating illnesses such as diabetes mellitus or hepatic or renal insufficiency and patients receiving immunosuppressive therapy) hematogenous spread. Candida infections in IV drug users typically involve the spine, sacroiliac joints, or other fibrocartilaginous joints. Unusual cases of arthritis due to Aspergillus species, Cryptococcus neoformans, Pseudallescheria boydii, and the dematiaceous fungi also have resulted from direct inoculation or disseminated hematogenous infection in immunocompromised persons. In the United States, a 2012 national outbreak of fungal arthritis (and meningitis) caused by Exserohilum rostratum was linked to intraspinal and intraarticular injection of a contaminated preparation of methylprednisolone acetate.


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InternalMed_Harrison. The synovial fluid in fungal arthritis usually contains 10,000–40,000 cells/μL, with ~70% neutrophils. Stained specimens and cultures of synovial tissue often confirm the diagnosis of fungal arthritis when studies of synovial fluid give negative results. Treatment consists of drainage and lavage of the joint and systemic administration of an antifungal agent directed at a specific pathogen. The doses and duration of therapy are the same as for disseminated disease (see Part 8, Section 16). Intraarticular instillation of amphotericin B has been used in addition to IV therapy.


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InternalMed_Harrison. Viruses produce arthritis by infecting synovial tissue during systemic infection or by provoking an immunologic reaction that involves joints. As many as 50% of women report persistent arthralgias, and 10% report frank arthritis within 3 days of the rash that follows natural infection with rubella virus and within 2–6 weeks after receipt of live-virus vaccine. Episodes of symmetric inflammation of fingers, wrists, and knees uncommonly recur for >1 year, but a syndrome of chronic fatigue, low-grade fever, headaches, and myalgias can persist for months or years. IV immunoglobulin has been helpful in selected cases. Self-limited monarticular or migratory polyarthritis may develop within 2 weeks of the parotitis of mumps; this sequela is more common among men than among women. Approximately


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InternalMed_Harrison. FIGURE 157-2 Chronic arthritis caused by Histoplasma capsulatum in the left knee. A. A man in his sixties from El Salvador presented with a history of progressive knee pain and difficulty walking for several years. He had undergone arthroscopy for a meniscal tear 7 years before presentation (without relief) and had received several intraarticular glucocorticoid injections. The patient developed significant deformity of the knee over time, including a large effusion in the lateral aspect. B. An x-ray of the knee showed multiple abnormalities, including severe medial femorotibial joint-space narrowing, several large subchondral cysts within the tibia and the patellofemoral compartment, a large suprapatellar joint effusion, and a large soft tissue mass projecting laterally over the knee. C. MRI further defined these abnormalities and demonstrated the cystic nature of the lateral knee abnormality. Synovial biopsies demonstrated chronic inflammation with giant cells, and cultures grew H.


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InternalMed_Harrison. MRI further defined these abnormalities and demonstrated the cystic nature of the lateral knee abnormality. Synovial biopsies demonstrated chronic inflammation with giant cells, and cultures grew H. capsulatum after 3 weeks of incubation. All clinical cystic lesions and the effusion resolved after 1 year of treatment with itraconazole. The patient underwent a left total knee replacement for definitive treatment. (Courtesy of Francisco M. Marty, MD, Brigham and Women’s Hospital, Boston; with permission.) 10% of children and 60% of women develop arthritis after infection with parvovirus B19. In adults, arthropathy sometimes occurs without fever or rash. Pain and stiffness, with less prominent swelling (primarily of the hands but also of the knees, wrists, and ankles), usually resolve within weeks, although a small proportion of patients develop chronic arthropathy.


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InternalMed_Harrison. About 2 weeks before the onset of jaundice, up to 10% of persons with acute hepatitis B develop an immune complex–mediated, serum sickness–like reaction with maculopapular rash, urticaria, fever, and arthralgias. Less common developments include symmetric arthritis involving the hands, wrists, elbows, or ankles and morning stiffness that resembles a flare of rheumatoid arthritis. Symptoms resolve at the time jaundice develops. Many persons with chronic hepatitis C infection report persistent arthralgia or arthritis, both in the presence and in the absence of cryoglobulinemia.


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InternalMed_Harrison. Painful arthritis involving larger joints often accompanies the fever and rash of several arthropod-borne viral infections, including those caused by chikungunya, O’nyong-nyong, Ross River, Mayaro, and Barmah Forest viruses (Chap. 233). Symmetric arthritis involving the hands and wrists may occur during the convalescent phase of infection with lymphocytic choriomeningitis virus. Patients infected with an enterovirus frequently report arthralgias, and echovirus has been isolated from patients with acute polyarthritis.


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InternalMed_Harrison. Several arthritis syndromes are associated with HIV infection. Reactive arthritis with painful lower-extremity oligoarthritis often follows an episode of urethritis in HIV-infected persons. HIV-associated reactive arthritis appears to be extremely common among persons with the HLA-B27 haplotype, but sacroiliac joint disease is unusual and is seen mostly in the absence of HLA-B27. Up to one-third of HIV-infected persons with psoriasis develop psoriatic arthritis. Painless monarthropathy and persistent symmetric polyarthropathy occasionally complicate HIV infection. Chronic persistent oligoarthritis of the shoulders, wrists, hands, and knees occurs in women infected with human T-lymphotropic virus type I. Synovial thickening, destruction of articular cartilage, and leukemic-appearing atypical lymphocytes in synovial fluid are characteristic, but progression to T cell leukemia is unusual.


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InternalMed_Harrison. Arthritis due to parasitic infection is rare. The guinea worm Dracunculus medinensis may cause destructive joint lesions in the lower extremities as migrating gravid female worms invade joints or cause ulcers in adjacent soft tissues that become secondarily infected. Hydatid cysts infect bones in 1–2% of cases of infection with Echinococcus granulosus. The expanding destructive cystic lesions may spread to and destroy adjacent joints, particularly the hip and pelvis. In rare cases, chronic synovitis has been associated with the presence of schistosomal eggs in synovial biopsies. Monarticular arthritis in children with lymphatic filariasis appears to respond to therapy with diethylcarbamazine even in the absence of microfilariae in synovial fluid. Reactive arthritis has been attributed to hookworm, Strongyloides, Cryptosporidium, and Giardia infection in case reports, but confirmation is required.


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InternalMed_Harrison. Reactive polyarthritis develops several weeks after ~1% of cases of nongonococcal urethritis and 2% of enteric infections, particularly those due to Yersinia enterocolitica, Shigella flexneri, Campylobacter jejuni, and Salmonella species. Only a minority of these patients have the other findings of classic reactive arthritis, including urethritis, conjunctivitis, uveitis, oral ulcers, and rash. Studies have identified microbial DNA or antigen in synovial fluid or blood, but the pathogenesis of this condition is poorly understood.


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InternalMed_Harrison. Reactive arthritis is most common among young men (except after Yersinia infection) and has been linked to the HLA-B27 locus as a potential genetic predisposing factor. Patients report painful, asymmetric oligoarthritis that affects mainly the knees, ankles, and feet. Low-back pain is common, and radiographic evidence of sacroiliitis is found in patients with long-standing disease. Most patients recover within 6 months, but prolonged recurrent disease is more common in cases that follow chlamydial urethritis. Anti-inflammatory agents help relieve symptoms, but the role of prolonged antibiotic therapy in eliminating microbial antigen from the synovium is controversial.


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InternalMed_Harrison. Migratory polyarthritis and fever constitute the usual presentation of acute rheumatic fever in adults (Chap. 381). This presentation is distinct from that of poststreptococcal reactive arthritis, which also follows infections with group A Streptococcus but is not migratory, lasts beyond the typical 3-week maximum of acute rheumatic fever, and responds poorly to aspirin.


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InternalMed_Harrison. Infection complicates 1–4% of total joint replacements. The majority of infections are acquired intraoperatively or immediately postoperatively as a result of wound breakdown or infection; less commonly, 838 these joint infections develop later after joint replacement and are the result of hematogenous spread or direct inoculation. The presentation may be acute, with fever, pain, and local signs of inflammation, especially in infections due to S. aureus, pyogenic streptococci, and enteric bacilli. Alternatively, infection may persist for months or years without causing constitutional symptoms when less virulent organisms, such as coagulase-negative staphylococci or diphtheroids, are involved. Such indolent infections usually are acquired during joint implantation and are discovered during evaluation of chronic unexplained pain or after a radiograph shows loosening of the prosthesis; the erythrocyte sedimentation rate and C-reactive protein level are usually elevated in such cases. The


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InternalMed_Harrison. evaluation of chronic unexplained pain or after a radiograph shows loosening of the prosthesis; the erythrocyte sedimentation rate and C-reactive protein level are usually elevated in such cases. The diagnosis is best made by needle aspiration of the joint; accidental introduction of organisms during aspiration must be avoided meticulously. Synovial fluid pleocytosis with a predominance of polymorphonuclear leukocytes is highly suggestive of infection, since other inflammatory processes uncommonly affect prosthetic joints. Culture and Gram’s stain usually yield the responsible pathogen. Sonication of explanted prosthetic material can improve the yield of culture, presumably by breaking up bacterial biofilms on the surfaces of prostheses. Use of special media for unusual pathogens such as fungi, atypical mycobacteria, and Mycoplasma may be necessary if routine and anaerobic cultures are negative.


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InternalMed_Harrison. Treatment includes surgery and high doses of parenteral antibiotics, which are given for 4–6 weeks because bone is usually involved. In most cases, the prosthesis must be replaced to cure the infection. Implantation of a new prosthesis is best delayed for several weeks or months because relapses of infection occur most commonly within this time frame. In some cases, reimplantation is not possible, and the patient must manage without a joint, with a fused joint, or even with amputation. Cure of infection without removal of the prosthesis is occasionally possible in cases that are due to streptococci or pneumococci and that lack radiologic evidence of loosening of the prosthesis. In these cases, antibiotic therapy must be initiated within several days of the onset of infection, and the joint should be drained vigorously by open arthrotomy or arthroscopically. In selected patients who prefer to avoid the high morbidity rate associated with joint removal and reimplantation, suppression of


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InternalMed_Harrison. should be drained vigorously by open arthrotomy or arthroscopically. In selected patients who prefer to avoid the high morbidity rate associated with joint removal and reimplantation, suppression of the infection with antibiotics may be a reasonable goal. A high cure rate with retention of the prosthesis has been reported when the combination of oral rifampin and ciprofloxacin is given for 3–6 months to persons with staphylococcal prosthetic joint infection of short duration. This approach, which is based on the ability of rifampin to kill organisms adherent to foreign material and in the stationary growth phase, requires confirmation in prospective trials.


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InternalMed_Harrison. To avoid the disastrous consequences of infection, candidates for joint replacement should be selected with care. Rates of infection are particularly high among patients with rheumatoid arthritis, persons who have undergone previous surgery on the joint, and persons with medical conditions requiring immunosuppressive therapy. Perioperative antibiotic prophylaxis, usually with cefazolin, and measures to decrease intraoperative contamination, such as laminar flow, have lowered the rates of perioperative infection to <1% in many centers. After implantation, measures should be taken to prevent or rapidly treat extra-articular infections that might give rise to hematogenous spread to the prosthesis. The effectiveness of prophylactic antibiotics for the prevention of hematogenous infection after dental procedures has not been demonstrated; in fact, viridans streptococci and other components of the oral flora are extremely unusual causes of prosthetic joint infection. Accordingly, the


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InternalMed_Harrison. after dental procedures has not been demonstrated; in fact, viridans streptococci and other components of the oral flora are extremely unusual causes of prosthetic joint infection. Accordingly, the American Dental Association and the American Academy of Orthopaedic Surgeons do not recommend antibiotic prophylaxis for most dental patients with total joint replacements and have stated that there is no convincing evidence to support its use. Similarly, guidelines issued by the American Urological Association and the American Academy of Orthopaedic Surgeons do not recommend the use of prophylactic antibiotics for most patients with prosthetic joints who are undergoing urologic procedures but state that prophylaxis should be considered in certain situations—e.g., for patients (especially immunocompromised patients) who are undergoing a procedure posing a relatively high risk of bacteremia (such as lithotripsy or surgery involving bowel segments).


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InternalMed_Harrison. The contributions of James H. Maguire and the late Scott J. Thaler to this chapter in earlier editions are gratefully acknowledged. Osteomyelitis, an infection of bone, can be caused by various microorganisms that arrive at bone through different routes. Spontaneous hematogenous osteomyelitis may occur in otherwise healthy individuals, whereas local microbial spread mainly affects either individuals who have underlying disease (e.g., vascular insufficiency) or patients who have compromised skin or other tissue barriers, with consequent exposure of bone. The latter situation typically follows surgery involving bone, such as sternotomy or orthopedic repair. The manifestations of osteomyelitis are different in children and adults. In children circulating microorganisms seed mainly long bones, whereas in adults the vertebral column is the most commonly affected site.


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InternalMed_Harrison. Management of osteomyelitis differs greatly depending on whether an implant is involved. The most important aim of the management of either type of osteomyelitis is to prevent progression to chronic osteomyelitis by rapid diagnosis and prompt treatment. Device-related bone and joint infection necessitates a multidisciplinary approach requiring antibiotic therapy and, in many cases, surgical removal of the device. The optimal duration of antibiotic treatment has not been established for any type of osteomyelitis in clinical trials. Therefore, the recommendations for therapy in this chapter reflect only expert opinions.


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InternalMed_Harrison. There is no generally accepted, comprehensive system for classification of osteomyelitis, primarily because of the multifaceted presentation of this infection. Different specialists are confronted with different facets of bone disease. Most often, however, general practitioners or internists are the first to encounter patients with the initial signs and symptoms of osteomyelitis. These primary care physicians should be able to recognize this disease in any of its forms. Osteomyelitis cases can be classified by various criteria, including pathogenesis, duration of infection, location of infection, and presence or absence of foreign material. The widely used Cierny-Mader staging system classifies osteomyelitis according to anatomic site, comorbidity, and radiographic findings, with stratification of long-bone osteomyelitis to optimize surgical management; this system encompasses both systemic and local factors affecting immune status, metabolism, and local vascularity.


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InternalMed_Harrison. Any of three mechanisms can underlie osteomyelitis: (1) hematogenous spread; (2) spread from a contiguous site following surgery; and (3) secondary infection in the setting of vascular insufficiency or concomitant neuropathy. Hematogenous osteomyelitis in adults typically involves the vertebral column. In only about half of patients can a primary focus be detected. The most common primary foci of infection are the urinary tract, skin/soft tissue, intravascular catheterization sites, and the endocardium. Spread from a contiguous source follows either bone trauma or surgical intervention. Wound infection leading to osteomyelitis typically occurs after cardiovascular intervention involving the sternum, orthopedic repair, or prosthetic joint insertion. Osteomyelitis secondary to vascular insufficiency or peripheral neuropathy most often follows chronic, progressively deep skin and soft tissue infection of the foot. The most common underlying condition is diabetes. In diabetes that is


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InternalMed_Harrison. insufficiency or peripheral neuropathy most often follows chronic, progressively deep skin and soft tissue infection of the foot. The most common underlying condition is diabetes. In diabetes that is poorly controlled, the diabetic foot syndrome is caused by skin, soft tissue, and bone ischemia combined with motor, sensory, and autonomic neuropathy.


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InternalMed_Harrison. Classification of osteomyelitis according to the duration of infection, although ill defined (because there is no clear time limit for the transition from acute to chronic osteomyelitis), is useful because the management of acute and chronic osteomyelitis differs. Whereas acute osteomyelitis can generally be treated with antibiotics alone, antibiotic treatment for chronic osteomyelitis should be combined with debridement surgery. Acute hematogenous or contiguous osteomyelitis evolves over a short period—i.e., a few days or weeks. In contrast, subacute or chronic osteomyelitis lasts for weeks or months before treatment is started. Typical examples of a subacute course are vertebral osteomyelitis due to tuberculosis or brucellosis and delayed implant-associated infections caused mainly by low-virulence microorganisms (coagulase-negative staphylococci, Propionibacterium acnes). Chronic osteomyelitis develops when insufficient therapy leads to persistence or recurrence, most often after


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InternalMed_Harrison. low-virulence microorganisms (coagulase-negative staphylococci, Propionibacterium acnes). Chronic osteomyelitis develops when insufficient therapy leads to persistence or recurrence, most often after sternal, mandibular, or foot infection.


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InternalMed_Harrison. Classification by location distinguishes among cases in the long bones, the vertebral column, and the periarticular bones. Long bones are generally involved after hematogenous seeding in children or contiguous spread following trauma or surgery. The risk of vertebral osteomyelitis in adults increases with age. Periarticular osteomyelitis, which complicates septic arthritis that has not been adequately treated, is especially common in periprosthetic joint infection. Osteomyelitis involving a foreign device requires surgical management for cure. Even acute implant-associated infection calls for prolonged antimicrobial therapy. Therefore, identification of this type of disease is of practical importance.


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InternalMed_Harrison. Vertebral osteomyelitis, also referred to as disk-space infection, septic diskitis, spondylodiskitis, or spinal osteomyelitis, is the most common manifestation of hematogenous bone infection in adults. This designation reflects a pathogenic process leading to involvement of the adjacent vertebrae and the corresponding intervertebral disk. In adults, the disk is avascular. Microorganisms invade via the segmental arterial circulation in adjacent endplates and then spread into the disk. Alternative routes of infection are retrograde seeding through the prevertebral venous plexus and direct inoculation during spinal surgery, epidural infiltration, or trauma. In the setting of implant surgery, microorganisms are inoculated either during the procedure or, if wound healing is impaired, in the early postoperative period.


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InternalMed_Harrison. Vertebral osteomyelitis occurs more often in male than in female patients (ratio, 1.5:1). The overall incidence is 2.4 cases/100,000 population. There is a clear age-dependent increase from 0.3 cases/100,000 at ages <20 years to 6.5 cases/100,000 at ages >70 years. The observed increase in reported cases during the past two decades may reflect improvements in diagnosis resulting from the broad availability of MRI technology. In addition, the fraction of cases of vertebral osteomyelitis acquired in association with health care is certainly increasing as a consequence of the rising number of spinal interventions and local infiltrations.


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InternalMed_Harrison. Vertebral osteomyelitis is typically classified as pyogenic or nonpyogenic. However, this distinction is arbitrary because, in “nonpyogenic” cases (tuberculous, brucellar), macroscopic pus formation (caseous necrosis, abscess) is quite common. A more accurate scheme is to classify cases as acute or subacute/chronic. Whereas the micro-839 biologic spectrum of acute cases is similar in different parts of the world, the spectrum of subacute/chronic cases varies according to the geographic region. The great majority of cases are monomicrobial in etiology. Of episodes of acute vertebral osteomyelitis, 40–50% are caused by Staphylococcus aureus, 12% by streptococci, and 20% by gram-negative bacilli—mainly Escherichia coli (9%) and Pseudomonas aeruginosa (6%). Subacute vertebral osteomyelitis is typically caused by Mycobacterium tuberculosis or Brucella species in regions where these microorganisms are endemic. Osteomyelitis due to viridans streptococci also has a subacute presentation;


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InternalMed_Harrison. is typically caused by Mycobacterium tuberculosis or Brucella species in regions where these microorganisms are endemic. Osteomyelitis due to viridans streptococci also has a subacute presentation; these infections most often occur as secondary foci in patients with endocarditis. In vertebral osteomyelitis due to Candida species, the diagnosis is often delayed by several weeks; this etiology should be suspected in IV drug users who do not use sterile paraphernalia. In implant-associated spinal osteomyelitis, coagulase-negative staphylococci and P. acnes—which, in the absence of an implant, are generally considered contaminants—typically cause low-grade (chronic) infections. As an exception, coagulasenegative staphylococci can cause native spinal osteomyelitis in cases of prolonged bacteremia (e.g., in patients with infected pacemaker electrodes or implanted vascular catheters that are not promptly removed).


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InternalMed_Harrison. The signs and symptoms of vertebral osteomyelitis are nonspecific. Only about half of patients develop fever >38°C (100.4°F), perhaps because analgesic drugs are frequently used by these patients. Back pain is the leading initial symptom (>85% of cases). The location of the pain corresponds to the site of infection: the cervical spine in ~10% of cases, the thoracic spine in 30%, and the lumbar spine in 60%. One exception is involvement at the thoracic level in two-thirds of cases of tuberculous osteomyelitis and at the lumbar level in only one-third. This difference is due to direct mycobacterial spread via pleural or mediastinal lymph nodes in pulmonary tuberculosis.


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InternalMed_Harrison. Neurologic deficits, such as radiculopathy, weakness, or sensory loss, are observed in about one-third of cases of vertebral osteomyelitis. In brucellar vertebral osteomyelitis, neurologic impairment is less frequent; in tuberculous osteomyelitis, it is about twice as frequent as in cases of other etiologies. Neurologic signs and symptoms are caused mostly by spinal epidural abscess. This complication starts with severe localized back pain and progresses to radicular pain, reflex changes, sensory abnormalities, motor weakness, bowel and bladder dysfunction, and paralysis. A primary focus should always be sought but is found in only half of cases. Overall, endocarditis is identified in ~10% of patients. In osteomyelitis caused by viridans streptococci, endocarditis is the source in about half of patients.


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InternalMed_Harrison. Implant-associated spinal osteomyelitis can present as either earlyor late-onset infection. Early-onset infection is diagnosed within 30 days after implant placement. S. aureus is the most common pathogen. Wound healing impairment and fever are the leading findings. Late-onset infection is diagnosed beyond 30 days after surgery, with low-virulence organisms such as coagulase-negative staphylococci or P. acnes as typical infecting agents. Fever is rare. One-quarter of patients have a sinus tract. Because of the delayed course and the lack of classic signs of infection, rapid diagnosis requires a high degree of suspicion.


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InternalMed_Harrison. Leukocytosis and neutrophilia have low levels of diagnostic sensitivity (only 65% and 40%, respectively). In contrast, an increased erythrocyte sedimentation rate or C-reactive protein (CRP) level has been reported in 98% and 100% of cases, respectively; thus, these tests are helpful in excluding vertebral osteomyelitis. The fraction of blood cultures that yield positive results depends heavily on whether the patient has been pretreated with antibiotics; across studies, the range is from 30% to 78%. In view of this low rate of positive blood culture after antibiotic treatment, such therapy should be withheld until microbial growth is proven unless the patient has sepsis syndrome. In patients with negative blood cultures, CT-guided or open biopsy is needed. Whether a CT-guided biopsy with a negative result is repeated or followed by 840 open biopsy depends on the experience of personnel at the specific center. Bone samples should be cultured for aerobic, anaerobic, and fungal agents,


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InternalMed_Harrison. a negative result is repeated or followed by 840 open biopsy depends on the experience of personnel at the specific center. Bone samples should be cultured for aerobic, anaerobic, and fungal agents, with a portion of the sample sent for histopathologic study. In cases with a subacute/chronic presentation, a suggestive history, or a granuloma detected during histopathologic analysis, mycobacteria and brucellae also should be sought. When blood and tissue cultures are negative despite suggestive histopathology, broad-range polymerase chain reaction analysis of biopsy specimens or aspirated pus should be considered. This technique allows detection of unusual pathogens such as Tropheryma whipplei. Given that signs and symptoms of osteomyelitis are nonspecific, the clinical differential diagnosis of febrile back pain is broad, including pyelonephritis, pancreatitis, and viral syndromes. In addition, multiple noninfectious pathologies of the vertebral column, such as osteoporotic fracture,


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InternalMed_Harrison. of febrile back pain is broad, including pyelonephritis, pancreatitis, and viral syndromes. In addition, multiple noninfectious pathologies of the vertebral column, such as osteoporotic fracture, seronegative spondylitis (ankylosing spondylitis, psoriasis, reactive arthritis, enteropathic arthritis), and spinal stenosis must be considered. Imaging procedures are the most important tools not only for the diagnosis of vertebral osteomyelitis but also for the detection of pyogenic complications and alternative conditions (e.g., bone metastases or osteoporotic fractures). Plain radiography is a reasonable first step in evaluating patients without neurologic symptoms and may reveal an alternative diagnosis. Because of its low sensitivity, plain radiography generally is not helpful in acute osteomyelitis, but it can be useful in subacute or chronic cases. The gold standard is MRI, which should be performed expeditiously in patients with neurologic impairment in order to rule out a herniated


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InternalMed_Harrison. but it can be useful in subacute or chronic cases. The gold standard is MRI, which should be performed expeditiously in patients with neurologic impairment in order to rule out a herniated disk or to detect pyogenic complications in a timely manner. Even if the pathologic findings on MRI suggest vertebral osteomyelitis, alternative diagnoses should be considered, especially when blood cultures are negative. The most common alternative diagnosis is erosive osteochondrosis. Septic bone necrosis, gouty spondylodiskitis, and erosive diskovertebral lesions (Andersson lesions) in ankylosing spondylitis may likewise mimic vertebral osteomyelitis. CT is less sensitive than MRI but may be helpful in guiding a percutaneous biopsy. In the future, positron-emission tomography (PET) with 18F-fluorodeoxyglucose, which has a high degree of diagnostic accuracy, may be an alternative imaging procedure when MRI is contraindicated. 18F-fluorodeoxyglucose PET should be considered for patients with


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InternalMed_Harrison. which has a high degree of diagnostic accuracy, may be an alternative imaging procedure when MRI is contraindicated. 18F-fluorodeoxyglucose PET should be considered for patients with implants and patients in whom several foci are suspected.


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InternalMed_Harrison. The aims of therapy for vertebral osteomyelitis are (1) elimination of the pathogen(s), (2) protection from further bone loss, (3) relief of back pain, (4) prevention of complications, and (5) stabilization, if needed.


InternalMed_Harrison

InternalMed_Harrison. Table 158-1 summarizes suggested antimicrobial regimens for infections attributable to the most common etiologic agents. For optimal antimicrobial therapy, identification of the infecting agent is required. Therefore, in patients without sepsis syndrome, antibiotics should not be administered until the pathogen is identified in a blood culture, a bone biopsy, or an aspirated pus collection. Traditionally, bone infections are at least initially treated by the IV route. Unfortunately, relevant controlled trials are lacking, and the preference for the IV route is not evidence based. There are no good arguments for the assumption that IV therapy is superior to oral administration if the following requirements are met: (1) optimal antibiotic spectrum, (2) excellent bioavailability of the oral drug, (3) clinical studies confirming efficacy of the oral drug, (4) normal intestinal function, and (5) no vomiting. However, a short initial course of parenteral therapy with a β-lactam antibiotic


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InternalMed_Harrison. drug, (3) clinical studies confirming efficacy of the oral drug, (4) normal intestinal function, and (5) no vomiting. However, a short initial course of parenteral therapy with a β-lactam antibiotic may lower the risk of emergence of fluoroquinolone resistance, especially if P. aeruginosa infection is treated with ciprofloxacin or staphylococcal infection with the combination of a fluoroquinolone plus rifampin. These suggestions are based on observational studies and expert opinion. There are no data from controlled trials on the optimal duration of therapy. Most experts suggest 6 weeks for patients


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InternalMed_Harrison. Microorganism Antimicrobial Agent (Dose,b Route) Staphylococcus spp. Streptococcus spp. Penicillin Gc (5 million units IV q6h) or ceftriaxone (2 g IV q24h)


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InternalMed_Harrison. Piperacillin-tazobactam (4.5 g IV q8h) plus an aminoglycosideg for 2–4 weeks aUnless otherwise indicated, the total duration of antimicrobial treatment is generally 6 weeks. bAll dosages are for adults with normal renal function. cWhen the patient has delayed-type penicillin hypersensitivity, cefuroxime (1.5 g IV q6–8h) can be administered. When the patient has immediate-type penicillin hypersensitivity, the penicillin should be replaced by vancomycin (1 g IV q12h). dTarget vancomycin trough level: 15–20 μg/ mL.e Trimethoprim-sulfamethoxazole. A double-strength tablet contains 160 mg of trimethoprim and 800 mg of sulfamethoxazole.f Including isolates producing extended-spectrum β-lactamase. gThe need for addition of an aminoglycoside has not yet been proven. However, this addition may decrease the risk of emergence of resistance to the β-lactam. hThe rationale for starting ciprofloxacin treatment only after pretreatment with a β-lactam is the increased risk of emergence of quinolone


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InternalMed_Harrison. the risk of emergence of resistance to the β-lactam. hThe rationale for starting ciprofloxacin treatment only after pretreatment with a β-lactam is the increased risk of emergence of quinolone resistance in the presence of a heavy bacterial load. iAlternatively, penicillin G (5 million units IV q6h) or ceftriaxone (2 g IV q24h) can be used against gram-positive anaerobes (e.g., Propionibacterium acnes), and metronidazole (500 mg IV/PO q8h) can be used against gram-negative anaerobes (e.g., Bacteroides spp.).


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InternalMed_Harrison. Source: From W Zimmerli: N Engl J Med 362:1022, 2010. © Massachusetts Medical Society. Reprinted with permission. who have acute osteomyelitis without an implant. According to an observational study, prolonging antibiotic therapy beyond 6 weeks does not improve the rate of recovery or lower the risk of recurrence. However, prolonged antibiotic therapy is recommended for patients with abscesses that have not been drained and patients with spinal implants. Treatment efficacy should be regularly monitored through inquiries about signs and symptoms (fever, pain) and assessment for signs of inflammation (elevated CRP concentrations). Follow-up MRI is appropriate only for patients with pyogenic complications, since the correlation between clinical healing and improvement on MRI is very poor.


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InternalMed_Harrison. Surgical treatment generally is not needed in acute hematogenous vertebral osteomyelitis. However, it is always necessary in implant-associated spinal infection. Early infections (those occurring up to 30 days after internal stabilization) can be cured with debridement, implant retention, and a 3-month course of antibiotics (Table 158-2). In contrast, in late infection with a duration of >30 days, implant removal and a 6-week-course of antibiotics (Table 158-1) Microorganism Antimicrobial Agenta (Dose, Route) Staphylococcus spp. Recommendation for initial treatment phase (2 weeks with implant) Methicillin-susceptible Rifampin (450 mg PO/IV q12hb) Vancomycin (15 mg/kg IV q12h) or daptomycin (6–8 mg/kg IV q24h) Staphylococcus spp. Recommendation after completion of initial treatment phase Streptococcus spp.e Penicillin Gc (18–24 million units/d IV in 6 divided doses) or ceftriaxone (2 g IV q24h) for 4 weeks Enterococcus spp.f


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InternalMed_Harrison. Streptococcus spp.e Penicillin Gc (18–24 million units/d IV in 6 divided doses) or ceftriaxone (2 g IV q24h) for 4 weeks Enterococcus spp.f Enterobacteriaceae A β-lactam selected in light of in vitro susceptibility profile for 2 weeksh Enterobacter spp.i and Cefepime or ceftazidime (2 g IV q8h) or meropenem (1 g IV q8hk) for 2–4 weeks nonfermenters j (e.g., aeruginosa) Propionibacterium spp. Penicillin Gc (18–24 million units/d IV in 6 divided doses) or clindamycin (600–900 mg IV q8h) for 2–4 weeks Gram-negative anaer-Metronidazole (500 mg IV/PO q8h) obes (e.g., Bacteroides spp.) Mixed bacteria (without Ampicillin-sulbactam (3 g IV q6h) or amoxicillin-clavulanatel (2.2 g IV q6h) or piperacillin-tazobactam (4.5 g IV q8h) or imipenem (500 methicillin-resistant mg IV q6h) or meropenem (1 g IV q8hk) for 2–4 weeks staphylococci)


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InternalMed_Harrison. Individualized oral regimens chosen in light of antimicrobial susceptibility aAntimicrobial agents should be chosen in light of the isolate’s in vitro susceptibility, the patient’s drug allergies and intolerances, potential drug interactions, and contraindications to specific drugs. All dosages recommended are for adults with normal renal and hepatic function. See text for total durations of antibiotic treatment. bOther dosages and intervals of administration with equivalent success rates have been reported. cWhen the patient has delayed-type penicillin hypersensitivity, cefazolin (2 g IV q8h) can be administered. When the patient has immediate-type penicillin hypersensitivity, the penicillin should be replaced by vancomycin (1 g IV q12h). dTrimethoprim-sulfamethoxazole. A double-strength tablet contains 160 mg of trimethoprim and 800 mg of sulfamethoxazole. eDetermination of the minimal inhibitory concentration (MIC) of penicillin is advisable. fCombination therapy with an


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InternalMed_Harrison. tablet contains 160 mg of trimethoprim and 800 mg of sulfamethoxazole. eDetermination of the minimal inhibitory concentration (MIC) of penicillin is advisable. fCombination therapy with an aminoglycoside is optional since its superiority to monotherapy for prosthetic joint infection is unproved. When using combination therapy, monitor signs of aminoglycoside ototoxicity and nephrotoxicity; the latter is potentiated by other nephrotoxic agents (e.g., vancomycin). gFor patients with hypersensitivity to penicillin, see treatment options for penicillin-resistant enterococci. hCiprofloxacin (PO or IV) can be administered to patients with hypersensitivity to β-lactams. iCeftriaxone and ceftazidime should not be administered for treatment targeting Enterobacter species, even strains that test susceptible in the laboratory, but can be used against nonfermenters. Strains producing extended-spectrum β-lactamases should not be treated with any cephalosporin, including cefepime. Enterobacter


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InternalMed_Harrison. susceptible in the laboratory, but can be used against nonfermenters. Strains producing extended-spectrum β-lactamases should not be treated with any cephalosporin, including cefepime. Enterobacter infections can also be treated with ertapenem (1 g IV q24h); however, ertapenem is not effective against Pseudomonas spp. and other nonfermenters. jAddition of an aminoglycoside is optional. Use of two active drugs can be considered in light of the patient’s clinical condition. kThe recommended dosage is in line with the guidelines of the Infectious Diseases Society of America. In Europe, 2 g IV q8h is suggested for P. aeruginosa infections. lNot available as an IV formulation in the United States.


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InternalMed_Harrison. Source: Modified from W Zimmerli et al: N Engl J Med 351:1645, 2004. © Massachusetts Medical Society. Reprinted with permission. are required for complete elimination of the infection. If implants (12%). Persistent pain despite normalization of CRP values indicates cannot be removed, oral suppressive long-term treatment should mechanical complications such as severe osteonecrosis or spinal instafollow the initial course of IV antibiotics. The optimal duration of bility. These patients require a consult with an experienced orthopedic suppressive therapy is unknown. However, if antibiotic therapy is surgeon. discontinued after, for example, 1 year, close clinical and laboratory (CRP) follow-up is needed.


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InternalMed_Harrison. Osteomyelitis in long bones is a consequence of hematogenous seed-COMPLICATIONS ing, exogenous contamination during trauma (open fracture), or peri-Complications include persistent pain, persistently increased CRP operative contamination during orthopedic repairs. Its presentation levels, and new-onset or persistent neurologic impairment. In cases is either acute (with a duration of days to a few weeks) or chronic. of persistent pain with or without signs of inflammation, paraver-Hematogenous infection in long bones typically occurs in children. tebral, epidural, or psoas abscesses (Fig. 158-1) must be sought. Ineffectively treated hematogenous osteomyelitis during childhood Epidural abscesses occur in 15–20% of cases. This complication is can progress to chronic disease. In adults, the leading pathogenic more common in the cervical column (30%) than in the lumbar spine source is exogenous infection, mainly associated with internal fixation devices. Chronic osteomyelitis can recur


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InternalMed_Harrison. leading pathogenic more common in the cervical column (30%) than in the lumbar spine source is exogenous infection, mainly associated with internal fixation devices. Chronic osteomyelitis can recur after a symptom-free interval of >50 years. Such recurrences are most common among elderly patients who developed osteomyelitis in the preantibiotic era.


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InternalMed_Harrison. FIGURE 158-1 CT scan of acute vertebral osteomyelitis (L1/L2) due to Staphylococcus aureus in a 64-year-old man. Low-grade fever persisted despite appropriate IV antibiotic therapy. The scan revealed a psoas abscess on the right side. In adults, most cases of long-bone osteomyelitis are posttraumatic or postsurgical; less frequently, late recurrence arises from hematogenous infections during childhood. The risk of infection depends on the type of fracture. After closed fracture, implant-associated infection occurs in fewer than 1% of patients. In contrast, after open fracture, the risk of osteomyelitis ranges from ~2% up to 16%, with the precise figure depending on the degree of tissue damage during trauma.


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InternalMed_Harrison. The spectrum of microorganisms causing hematogenous long-bone osteomyelitis does not differ from that in vertebral osteomyelitis. S. aureus is most commonly isolated from adult patients. In rare cases, mycobacteria or fungal agents such as Cryptococcus species, Sporothrix schenckii, Blastomyces dermatitidis, or Coccidioides species are found in patients who live or have traveled in endemic regions. Impaired cellular immunity (e.g., in HIV infection or after transplantation) predisposes to these etiologies. Coagulase-negative staphylococci are the second most common etiologic agents (after S. aureus) in implant-associated osteomyelitis. After open fracture, contiguous long-bone osteomyelitis is typically caused by gram-negative bacilli or a polymicrobial mixture of organisms.


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InternalMed_Harrison. The leading symptoms in adults with primary or recurrent hematogenous long-bone osteomyelitis are pain and low-grade fever. Infection occasionally manifests as clinical sepsis and local signs of inflammation (erythema and swelling). After internal fixation, osteomyelitis can be classified as acute (≤3 weeks) or chronic. Acute long-bone osteomyelitis manifests as signs of surgical site infection, such as erythema and impaired wound healing. Acute implant-associated infection may also follow hematogenous seeding at any time after implantation of a device. Typical symptoms are new-onset pain and signs of sepsis. Chronic infections are usually caused by low-virulence microorganisms or occur after ineffective treatment of early-onset infection.


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InternalMed_Harrison. FIGURE 158-2 A 42-year-old man who had had a malleolar frac-ture 6 weeks previously had persistent pain and slight inflam-mation after orthopedic repair. His infection was treated with oral antibiotics without debridement surgery. This insufficient manage-ment of an implant-associated Staphylococcus aureus infection was complicated by a sinus tract. Patients may present with persisting pain, subtle local signs of inflammation, intermittent discharge of pus, or fluctuating erythema over the scar (Fig. 158-2).


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InternalMed_Harrison. Patients may present with persisting pain, subtle local signs of inflammation, intermittent discharge of pus, or fluctuating erythema over the scar (Fig. 158-2). The diagnostic workup for acute hematogenous long-bone osteomyelitis is similar to that for vertebral osteomyelitis. Bone remodeling and thus marker uptake are increased for at least 1 year after surgery. Therefore, the three-phase bone scan is not useful during this interval. However, in late recurrences it allows rapid diagnosis at low cost. If the results are positive, CT is required in order to estimate the extent of inflamed tissue and to detect bone necrosis (sequesters). Implant-associated infection should be suspected if CRP values do not return to the normal range or rise after an initial decrease. Clinical and laboratory suspicion should prompt surgical exploration and sampling.


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InternalMed_Harrison. In chronic osteomyelitis of >1 year’s duration, single-photon emission CT plus conventional CT (SPECT/CT) is a good option, either with 99mTc methylene diphosphonate (99mTc-MDP)–labeled leukocytes or with labeled monoclonal antibodies to granulocytes. Surgical debridement is needed for diagnostic (biopsy culture, histology) and therapeutic reasons.


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InternalMed_Harrison. Treatment for acute hematogenous infection in long bones is identical to that for acute vertebral osteomyelitis (Table 158-1). The suggested duration of antibiotic therapy is 4–6 weeks. In contrast to chronic or implant-associated osteomyelitis, acute hematogenous infection does not require surgical intervention. Initial IV administration of antimicrobial agents is followed by long-term oral treatment. The duration of the initial IV phase of therapy has not been defined. The IV course can be as short as a couple of days if a drug with excellent bioavailability is available. In case of recurrence of chronic osteomyelitis as well as in each type of exogenous osteomyelitis (acute, chronic, with or without an implant), a combination of surgical debridement, obliteration of dead space, and long-term antibiotic therapy is needed.


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InternalMed_Harrison. The therapeutic aims in patients whose infections are associated with internal fixation devices are consolidation of the fracture and prevention of chronic osteomyelitis. Stable implants can be maintained except in patients with uncontrolled sepsis. Appropriate antimicrobial therapies are listed in Table 158-2. The cure rate for early staphylococcal implant-associated infections treated with a fluoroquinolone plus rifampin is >90%. Rifampin is efficacious against staphylococcal biofilms of ≤3 weeks’ duration. Similarly, fluoroquinolones are active against biofilms formed by gram-negative bacilli. In these cases, an initial 2-week course of IV therapy with a β-lactam is suggested in order to minimize the risk of emergence of resistance to the oral drugs. The total duration of treatment is 3 months, and the device can be retained even after antibiotics have been discontinued. In contrast, in cases caused by rifampin-resistant staphylococci or fluoroquinolone-resistant gram-negative


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InternalMed_Harrison. is 3 months, and the device can be retained even after antibiotics have been discontinued. In contrast, in cases caused by rifampin-resistant staphylococci or fluoroquinolone-resistant gram-negative bacilli, the hardware should be removed after consolidation of the fracture and before discontinuation of antibiotics. These patients are treated with an oral antibiotic (suppressive therapy) as long as retention of the hardware is necessary.


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InternalMed_Harrison. The main complication of long-bone osteomyelitis is the persistence of infection with progression to chronic osteomyelitis. This risk is especially high after internal fixation of an open fracture and among patients with implant-associated osteomyelitis that is treated without surgical debridement. In chronic osteomyelitis, recurrent sinus tracts result in severe damage to skin and soft tissue (Fig. 158-2). Patients who have chronic open wounds need a therapeutic approach combining orthopedic repair and plastic reconstructive surgery.


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InternalMed_Harrison. Implanted foreign material is highly susceptible to local infection due to local immunodeficiency around the device. Infection occurs by either the exogenous or the hematogenous route. More rarely, contiguous spread from adjacent sites of osteomyelitis or deep soft-tissue infection may cause periprosthetic joint infection (PJI). The fact that foreign devices are covered with host proteins such as fibronectin favors the adherence of staphylococci and the formation of a biofilm that resists phagocytosis. The risk of infection manifesting during the first 2 postoperative years varies according to the joint. It is lowest after hip and knee arthroplasty (0.3–1.5%) and highest after ankle and elbow replacement (4–10%). The risk of hematogenous PJI is highest in the early postoperative period. However, hematogenous seeding occurs throughout life, and most cases therefore develop >2 years after implantation.


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InternalMed_Harrison. About 70% of cases of PJI are caused by staphylococci (S. aureus and coagulase-negative staphylococci), 10% by streptococci, 10% by gram-negative bacilli, and the rest by various other microorganisms. All microorganisms can cause PJI, including fungi and mycobacteria. P. acnes causes up to one-third of episodes of periprosthetic shoulder infection. PJI is traditionally classified as early (<3 months after implantation), delayed (3–24 months after surgery), or late (>2 years after implantation). For therapeutic decision-making (see below), it is more useful to classify PJI as (1) acute hematogenous PJI with <3 weeks of symptoms, (2) early postinterventional PJI manifesting within 1 month after surgery, and (3) chronic PJI with symptom duration of >3 weeks.


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InternalMed_Harrison. Acute exogenous PJI typically presents with local signs of infection (Fig. 158-3). In contrast, acute hematogenous PJI, most often caused by S. aureus, is characterized by new-onset pain that initially is not accompanied by prominent local inflammatory signs. In most cases, an ongoing sepsis syndrome dominates the clinical picture. Key findings in chronic PJI are joint effusion, local pain, implant loosening, and occasionally a sinus tract. Chronic PJI is most commonly caused by low-virulence microorganisms such as coagulase-negative staphylococci or P. acnes. These infections are characterized by nonspecific symptoms, such as chronic pain caused by low-grade inflammation or early loosening. FIGURE 158-3 Early periprosthetic joint infection of the left hip caused by group B streptococci in a 68-year-old woman.


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InternalMed_Harrison. FIGURE 158-3 Early periprosthetic joint infection of the left hip caused by group B streptococci in a 68-year-old woman. Blood tests such as the measurement of CRP (elevated levels, ≥10 mg/L) and erythrocyte sedimentation rate (elevated rates, ≥30 mm/h) are sensitive (91–97%) but not specific (70–78%). Synovial fluid cell counts are ~90% sensitive and specific, with threshold values of 1700 leukocytes/μL in periprosthetic knee infection and 4200 leukocytes/μL in periprosthetic hip infection. During debridement surgery, at least three but optimally six tissue samples should be obtained for culture and histopathology. If implant material (modular parts, screws, or the prosthesis) is removed, sonication of this material followed by culture and/or use of molecular methods to examine the sonicate fluid allows the detection of microorganisms in biofilms.


InternalMed_Harrison

InternalMed_Harrison. The three-phase bone scan is very sensitive for detecting PJI but is not specific. As mentioned above, this test does not differentiate bone remodeling from infection and therefore is not useful during at least the first year after implantation. CT and MRI detect soft tissue infection, prosthetic loosening, and bone erosion, but imaging artifacts caused by metal implants limit their use. 18F-fluorodeoxyglucose PET is an alternative method with fair sensitivity and specificity for the detection of PJI. However, this technique is not yet an established procedure for this purpose.


InternalMed_Harrison

InternalMed_Harrison. Treatment of PJI requires a multidisciplinary approach involving an experienced orthopedic surgeon, an infectious disease specialist, a plastic reconstructive surgeon, and a microbiologist. Therefore, most patients are referred to a specialized center. In general, the goal of treatment is cure—i.e., a pain-free functional joint with complete eradication of the infecting pathogen(s). However, for patients with severe comorbidity, lifelong suppressive antimicrobial therapy may be preferred. As a rule, antimicrobial therapy without surgical intervention is not curative but merely suppressive. There are four curative surgical options: debridement and implant retention, one-stage implant exchange, two-stage implant exchange, and implant removal without replacement. Implant retention offers a good chance of infection-free survival (>80%) only if the following conditions are fulfilled: (1) acute infection, (2) stable implant, (3) pathogen susceptible to a biofilm-active antimicrobial agent


InternalMed_Harrison

InternalMed_Harrison. good chance of infection-free survival (>80%) only if the following conditions are fulfilled: (1) acute infection, (2) stable implant, (3) pathogen susceptible to a biofilm-active antimicrobial agent (see below), and (4) skin and soft tissue in good condition.


InternalMed_Harrison

InternalMed_Harrison. Table 158-2 summarizes pathogen-specific antimicrobial therapy for PJI. Initial IV therapy is followed by long-term oral antibiotics. Efficacious treatment is best defined in staphylococcal implant-associated infections. Rifampin exhibits excellent activity against 844 biofilms composed of susceptible staphylococci. Because of the risk of rapid emergence of resistance, rifampin must always be combined with another effective antibiotic. If gram-negative infections are treated with implant retention, fluoroquinolones should be used because of their activity against gram-negative biofilms.


InternalMed_Harrison

InternalMed_Harrison. As mentioned above, hematogenous seeding may occur throughout life. This risk is highest during S. aureus bacteremia from a distant focus. Therefore, documented bacterial infections should be promptly treated in patients with prosthetic joints. However, according to a large, prospective, case-control study, the risk of prosthetic hip or knee infection is not increased following dental procedures. Therefore, antibiotic prophylaxis is not needed during dental work.


InternalMed_Harrison

InternalMed_Harrison. Sternal osteomyelitis occurs primarily after sternal surgery (with the entry of exogenous organisms) and more rarely by hematogenous seeding or contiguous extension from adjacent sites of sternocostal arthritis. Exogenous sternal osteomyelitis after open sternal surgery is also called deep sternal wound infection. Exogenous infection may also follow minor sternal trauma, sternal fracture, and manubriosternal septic arthritis. Tuberculous sternal osteomyelitis typically manifests during hematogenous seeding in children or as reactivated infection in adults. Reactivation is sometimes preceded by blunt trauma. In rare cases, tuberculous sternal osteomyelitis is caused by continuous infection from an infected internal mammary lymph node.


InternalMed_Harrison

InternalMed_Harrison. The incidence of poststernotomy wound infection varies from 0.5% to 5%, but figures are even higher among patients with risk factors such as diabetes, obesity, chronic renal failure, emergency surgery, use of bilateral internal mammary arteries, and reexploration for bleeding. Rapid diagnosis and correct management of superficial sternal wound infection prevent its progression to sternal osteomyelitis. Primary (hematogenous) sternal osteomyelitis accounts for only 0.3% of all cases of osteomyelitis. Risk factors are IV drug use, HIV infection, radiotherapy, blunt trauma, cardiopulmonary resuscitation, alcohol abuse, liver cirrhosis, and hemoglobinopathy.


InternalMed_Harrison

InternalMed_Harrison. Poststernotomy osteomyelitis is generally caused by S. aureus (40–50% of cases), coagulase-negative staphylococci (15–30%), enterococci (5–12%), or gram-negative bacilli (15–25%). Fungal infections caused by Candida species also play a role. The fact that ~20% of cases are polymicrobial is indicative of exogenous superinfection during therapy. Hematogenous sternal osteomyelitis is caused most commonly by S. aureus. Other microorganisms play a role in special populations— e.g., P. aeruginosa in IV drug users, Salmonella species in individuals with sickle cell anemia, and M. tuberculosis in patients from endemic areas who have previously had tuberculosis.


InternalMed_Harrison

InternalMed_Harrison. Exogenous sternal osteomyelitis manifests as fever, increased local pain, erythema, wound discharge, and sternal instability (Fig. 158-4). Contiguous mediastinitis is a feared complication, occurring in ~10–30% of patients with sternal osteomyelitis. Hematogenous sternal osteomyelitis is characterized by sternal pain, swelling, and erythema. In addition, most patients have systemic signs and symptoms of sepsis. The differential diagnosis of hematogenous sternal osteomyelitis includes immunologic processes typically presenting as systemic or multifocal inflammation of the sternum or the sternoclavicular or sternocostal joints (e.g., SAPHO [synovitis, acne, pustulosis, hyperostosis, osteitis], vasculitis, and chronic multifocal relapsing osteomyelitis). FIGURE 158-4 Sternal osteomyelitis caused by Staphylococcus epi-dermidis 5 weeks after sternotomy for aortocoronary bypass in a 72-year-old man.


InternalMed_Harrison

InternalMed_Harrison. In primary sternal osteomyelitis, the diagnostic workup does not differ from that in other types of hematogenous osteomyelitis (see above). When a patient has grown up in regions where tuberculosis is endemic, a specific workup for mycobacterial infection should be performed, especially if osteomyelitis had its onset after a blunt sternal trauma. In secondary sternal osteomyelitis, leukocyte counts may be normal, but the CRP level is >100 mg/L in most cases. Tissue sampling for microbiologic studies is crucial. In osteomyelitis associated with sternal wires, low-virulence microorganisms, such as coagulasenegative staphylococci, play an important role. In order to differentiate between colonization and infection, samples from at least three deep biopsies should be subjected to microbiologic examination. Superficial swab cultures are not diagnostic and may be misleading. No studies have compared the value of the various imaging modalities in suspected primary sternal osteomyelitis.


InternalMed_Harrison

InternalMed_Harrison. examination. Superficial swab cultures are not diagnostic and may be misleading. No studies have compared the value of the various imaging modalities in suspected primary sternal osteomyelitis. However, MRI is the current gold standard for detection of each type of osteomyelitis.


InternalMed_Harrison

InternalMed_Harrison. In cases of deep sternal wound infection, antibiotic therapy should be started immediately after samples have been obtained for microbiologic analyses in order to control clinical sepsis. To protect a newly inserted heart valve, initial treatment should be directed against staphylococci, with consideration of the local susceptibility pattern. In centers with a high prevalence of methicillin-resistant


InternalMed_Harrison

InternalMed_Harrison. S. aureus, vancomycin or daptomycin should be added to a broad-spectrum β-lactam drug. As soon as cultures of blood and/or deep wound biopsies have confirmed the pathogen’s identity and susceptibility pattern, treatment should be optimized and narrowed accordingly. Tables 158-1 and 158-2 show appropriate therapeutic choices for the most frequently identified microorganisms causing sternal osteomyelitis in the absence and presence, respectively, of an implanted device. In a recent observational study of patients with staphylococcal deep sternal wound infection, the use of a rifampin-containing regimen was predictive of success. The optimal duration of antibiotic therapy has not been established. In acute sternal osteomyelitis without hardware, a 6-week course is the rule. In patients with remaining sternal wires, treatment duration is generally prolonged to 3 months (Table 158-2). Like other types of tuberculous bone infection, tuberculous sternal osteomyelitis is treated for 6–12


InternalMed_Harrison

InternalMed_Harrison. remaining sternal wires, treatment duration is generally prolonged to 3 months (Table 158-2). Like other types of tuberculous bone infection, tuberculous sternal osteomyelitis is treated for 6–12 months.


InternalMed_Harrison

InternalMed_Harrison. Primary sternal osteomyelitis can generally be treated without surgery. In contrast, in secondary sternal osteomyelitis, debridement is always required. This procedure should be performed by a team of experienced surgeons, since mediastinitis, bone infection, and skin and soft tissue damage may need to be treated during the same intervention. Primary sternal osteomyelitis poses a minimal mortality risk. In contrast, the in-hospital mortality rates from secondary sternal osteomyelitis are 15–30% after sternal surgery.


InternalMed_Harrison

InternalMed_Harrison. Primary sternal osteomyelitis poses a minimal mortality risk. In contrast, the in-hospital mortality rates from secondary sternal osteomyelitis are 15–30% after sternal surgery. Osteomyelitis of the foot usually occurs in patients with diabetes, peripheral arterial insufficiency, or peripheral neuropathy and after foot surgery. These entities are often linked to each other, especially in diabetic patients with late complications. However, foot osteomyelitis is also seen in patients with isolated peripheral neuropathy and can manifest as implant-associated osteomyelitis in patients without comorbidity due to a deep wound infection after foot surgery (hallux valgus surgery, arthrodesis, total ankle arthroplasty). Foot osteomyelitis is acquired almost exclusively by the exogenous route. It is a complication of deep pressure ulcers and of impaired wound healing after surgery.


InternalMed_Harrison

InternalMed_Harrison. The incidence of diabetic foot infection is 30–40 cases/1000 persons with diabetes per year. The condition starts with skin and soft tissue lesions and progresses to osteomyelitis, especially in patients with risk factors. About 60–80% of patients with diabetic foot infection have confirmed osteomyelitis. Diabetic foot osteomyelitis increases the risk of amputation. With adequate management of the early stage of diabetic foot infections, the rate of amputation can be lowered. Risk factors for diabetic foot infection are (1) peripheral motor, sensory, and autonomic neuropathy; (2) neuro-osteoarthropathic deformities (Charcot foot; Fig. 158-5); (3) arterial insufficiency; (4) uncontrolled hyperglycemia; (5) disabilities such as reduced vision; and (6) maladaptive behavior.


InternalMed_Harrison

InternalMed_Harrison. The correlation between cultures from bone biopsy and those from wound swabs or even deep soft tissue punctures is poor. Consistent results have been found in only 13–43% of cases in various studies. The 845 correlation is better when S. aureus is isolated (40–50%) than when anaerobes (20–35%), gram-negative bacilli (20–30%), or coagulasenegative staphylococci (0–20%) are identified. When only bone biopsy samples are considered, the leading pathogens are S. aureus (30–40%), anaerobes (10–20%), and various gram-negative bacilli (30–40%). The precise distribution depends on whether the patient already has been treated with antibiotics. Anaerobes are especially prevalent in chronic wounds. Pretreatment typically selects for P. aeruginosa or enterococci. FIGURE 158-5 Neuropathic joint disease (Charcot foot) compli-cated by chronic foot osteomyelitis in a 78-year old woman with diabetes mellitus complicated by severe neuropathy.


InternalMed_Harrison

InternalMed_Harrison. FIGURE 158-5 Neuropathic joint disease (Charcot foot) compli-cated by chronic foot osteomyelitis in a 78-year old woman with diabetes mellitus complicated by severe neuropathy. In many cases, foot osteomyelitis can be diagnosed clinically, without imaging procedures. Most clinicians rely on the “probe-to-bone” test, which has a positive predictive value of ~90% in populations with a high pretest probability. Thus, in a patient with diabetes who is hospitalized for a chronic deep foot ulcer, the diagnosis of foot osteomyelitis is highly probable if bone can be directly touched with a metal instrument. In a patient with a lower pretest probability, MRI should be performed because of its high degree of sensitivity (80–100%) and specificity (80–90%). Plain radiography has a sensitivity of only 30–90% and a specificity of only 50–90%; it may be considered for follow-up of patients with confirmed diabetic foot osteomyelitis.


InternalMed_Harrison

InternalMed_Harrison. As mentioned above, correlation between cultures of bone and those of wound swabs or wound punctures is poor. Antibiotic treatment should be based on bone culture. If no bone biopsy is performed, empirical therapy chosen in light of the most common infecting agents and the type of clinical syndrome should be given. Wound debridement combined with a 4to 6-week course of antibiotics has been shown to render amputation unnecessary in about two-thirds of patients. According to the 2012 Infectious Diseases Society of America Clinical Practice Guideline for the Diagnosis and Treatment of Diabetic Foot Infections, the following management strategies should be considered. If a foot ulcer is clinically infected, prompt empirical antimicrobial therapy may prevent progression to osteomyelitis. When the risk of methicillin-resistant S. aureus is considered high, an agent active against these strains (e.g., vancomycin) should be chosen. If the patient has not recently received antibiotics, the


InternalMed_Harrison

InternalMed_Harrison. the risk of methicillin-resistant S. aureus is considered high, an agent active against these strains (e.g., vancomycin) should be chosen. If the patient has not recently received antibiotics, the spectrum of the selected antibiotic must include gram-positive cocci (e.g., clindamycin, ampicillin-sulbactam). If the patient has received antibiotics within the past month, the spectrum of empirical antibiotics should include gram-negative bacilli (e.g., clindamycin plus a fluoroquinolone). If the patient has risk factors for Pseudomonas infection (previous colonization, residence in a warm climate, frequent exposure of the foot to water), an empirical antipseudomonal agent (e.g., piperacillin-tazobactam, cefepime) is indicated. If osteomyelitis is suspected either on clinical grounds (probe to bone) or on the basis of imaging procedures (MRI), bone biopsy should be performed. If not all infected bone is surgically removed, the patient should be treated for 4–6 weeks in line with the


InternalMed_Harrison

InternalMed_Harrison. to bone) or on the basis of imaging procedures (MRI), bone biopsy should be performed. If not all infected bone is surgically removed, the patient should be treated for 4–6 weeks in line with the identified pathogen(s) and their susceptibility. Treatment should initially be given by the IV route. Whether therapy can later be administered by the oral route depends on the bioavailability of oral drugs that cover the infecting agents. If dead bone cannot be removed, longterm therapy (at least 3 months) should be considered. In such cases, cure of osteomyelitis is usually the exception, and repetitive suppressive treatment may be needed.


InternalMed_Harrison

InternalMed_Harrison. 846 Intraabdominal Infections and Abscesses Miriam Baron Barshak, Dennis L. Kasper Intraperitoneal infections generally arise because a normal anatomic barrier is disrupted. This disruption may occur when the appendix, a 159 diverticulum, or an ulcer ruptures; when the bowel wall is weakened by ischemia, tumor, or inflammation (e.g., in inflammatory bowel disease); or with adjacent inflammatory processes, such as pancreatitis or pelvic inflammatory disease, in which enzymes (in the former case) or organisms (in the latter) may leak into the peritoneal cavity. Whatever the inciting event, once inflammation develops and organisms usually contained within the bowel or another organ enter the normally sterile peritoneal space, a predictable series of events takes place. Intraabdominal infections occur in two stages: peritonitis and—if the patient survives this stage and goes untreated—abscess formation. The types of microorganisms predominating in each stage of infection are responsible


InternalMed_Harrison

InternalMed_Harrison. occur in two stages: peritonitis and—if the patient survives this stage and goes untreated—abscess formation. The types of microorganisms predominating in each stage of infection are responsible for the pathogenesis of disease.


InternalMed_Harrison

InternalMed_Harrison. Peritonitis is a life-threatening event that is often accompanied by bacteremia and sepsis syndrome (Chap. 325). The peritoneal cavity is large but is divided into compartments. The upper and lower peritoneal cavities are divided by the transverse mesocolon; the greater omentum extends from the transverse mesocolon and from the lower pole of the stomach to line the lower peritoneal cavity. The pancreas, duodenum, and ascending and descending colon are located in the anterior retroperitoneal space; the kidneys, ureters, and adrenals are found in the posterior retroperitoneal space. The other organs, including liver, stomach, gallbladder, spleen, jejunum, ileum, transverse and sigmoid colon, cecum, and appendix, are within the peritoneal cavity. The cavity is lined with a serous membrane that can serve as a conduit for fluids—a property exploited in peritoneal dialysis (Fig. 159-1).


InternalMed_Harrison

InternalMed_Harrison. FIGURE 159-1 Diagram of the intraperitoneal spaces, showing the circulation of fluid and potential areas for abscess formation. Some compartments collect fluid or pus more often than others. These compartments include the pelvis (the lowest portion), the subphrenic spaces on the right and left sides, and Morrison’s pouch, which is a posterosuperior extension of the subhepatic spaces and is the lowest part of the paravertebral groove when a patient is recumbent. The falciform ligament separating the right and left subphrenic spaces appears to act as a barrier to the spread of infection; consequently, it is unusual to find bilateral subphrenic collections. (Reprinted with permission from B Lorber [ed]: Atlas of Infectious Diseases, vol VII: Intra-abdominal Infections, Hepatitis, and Gastroenteritis. Philadelphia, Current Medicine, 1996, p 1.13.)


InternalMed_Harrison

InternalMed_Harrison. A small amount of serous fluid is normally present in the peritoneal space, with a protein content (consisting mainly of albumin) of <30 g/L and <300 white blood cells (WBCs, generally mononuclear cells) per microliter. In bacterial infections, leukocyte recruitment into the infected peritoneal cavity consists of an early influx of polymorphonuclear leukocytes (PMNs) and a prolonged subsequent phase of mononuclear cell migration. The phenotype of the infiltrating leukocytes during the course of inflammation is regulated primarily by resident-cell chemokine synthesis.


InternalMed_Harrison

InternalMed_Harrison. Peritonitis is either primary (without an apparent source of contamination) or secondary. The types of organisms found and the clinical presentations of these two processes are different. In adults, primary bacterial peritonitis (PBP) occurs most commonly in conjunction with cirrhosis of the liver (frequently the result of alcoholism). However, the disease has been reported in adults with metastatic malignant disease, postnecrotic cirrhosis, chronic active hepatitis, acute viral hepatitis, congestive heart failure, systemic lupus erythematosus, and lymph-edema as well as in patients with no underlying disease. Although PBP virtually always develops in patients with preexisting ascites, it is, in general, an uncommon event, occurring in ≤10% of cirrhotic patients. The cause of PBP has not been established definitively but is believed to involve hematogenous spread of organisms in a patient in whom a diseased liver and altered portal circulation result in a defect in the usual


InternalMed_Harrison

InternalMed_Harrison. has not been established definitively but is believed to involve hematogenous spread of organisms in a patient in whom a diseased liver and altered portal circulation result in a defect in the usual filtration function. Organisms multiply in ascites, a good medium for growth. The proteins of the complement cascade have been found in peritoneal fluid, with lower levels in cirrhotic patients than in patients with ascites of other etiologies. The opsonic and phagocytic properties of PMNs are diminished in patients with advanced liver disease. Cirrhosis is associated with alterations in the gut microbiota, including an increased prevalence of potentially pathogenic bacteria such as Enterobacteriaceae. Small-intestinal bacterial overgrowth is frequently present in advanced stages of liver cirrhosis and has been linked with pathologic bacterial translocation and PBP. Factors promoting these changes in cirrhosis may include deficiencies in Paneth cell defensins, reduced intestinal motility,


InternalMed_Harrison

InternalMed_Harrison. and has been linked with pathologic bacterial translocation and PBP. Factors promoting these changes in cirrhosis may include deficiencies in Paneth cell defensins, reduced intestinal motility, decreased pancreatobiliary secretions, and portal-hypertensive enteropathy.


InternalMed_Harrison

InternalMed_Harrison. The presentation of PBP differs from that of secondary peritonitis. The most common manifestation is fever, which is reported in up to 80% of patients. Ascites is found but virtually always predates infection. Abdominal pain, an acute onset of symptoms, and peritoneal irritation during physical examination can be helpful diagnostically, but the absence of any of these findings does not exclude this often-subtle diagnosis. Nonlocalizing symptoms (such as malaise, fatigue, or encephalopathy) without another clear etiology should also prompt consideration of PBP in a susceptible patient. It is vital to sample the peritoneal fluid of any cirrhotic patient with ascites and fever. The finding of >250 PMNs/μL is diagnostic for PBP, according to Conn (http://jac.oxfordjournals.org/cgi/content/full/47/3/369). This criterion does not apply to secondary peritonitis (see below). The microbiology of PBP is also distinctive. While enteric gram-negative bacilli such as Escherichia coli are most


InternalMed_Harrison

InternalMed_Harrison. This criterion does not apply to secondary peritonitis (see below). The microbiology of PBP is also distinctive. While enteric gram-negative bacilli such as Escherichia coli are most commonly encountered, gram-positive organisms such as streptococci, enterococci, or even pneumococci are sometimes found. In an important development, widespread use of quinolones to prevent PBP in high-risk subgroups of patients, frequent hospitalizations, and exposure to broad-spectrum antibiotics have led to a change in flora of infections in patients with cirrhosis, with more gram-positive bacteria and extended-spectrum β-lactamase–producing Enterobacteriaceae in recent years. Risk factors for multiresistant infections include nosocomial origin of infection, long-term norfloxacin prophylaxis, recent infection with multiresistant bacteria, and recent use of β-lactam antibiotics. In PBP, a single organism is typically isolated; anaerobes are found less frequently in PBP than in secondary peritonitis, in