The importance of maintaining high suspicion for the unusual suspects cannot be stressed enough. The Spanish Registry revealed that in serious infections, especially pneumonia, a continuous problem remains to be lack of identification of the implicated bacterial organisms reported as a prevalence of 14.2% .
Listeriosis is the result of a gram-positive intracellular organism well known to cause meningitis, encephalitis, and septicemia in newborns, pregnant women, the elderly, and people with compromised immune system. Listeria carries a mortality rate of 15% to 30% . Patients often present with vague to severe flulike, gastrointestinal, or neurologic symptoms; index of suspicion must be high. TNF-a seems to be important in macrophage bactericidal activity in listeriosis [8,9,88,89].
By December 2001, there were 15 cases of listeriosis associated with TNF antagonists and 11 cases were identified 9 months later. Two cases involved etanercept with one death, and 24 cases involved infliximab with 7 deaths.  Median onset from initiation of infliximab was two to three doses. There were two additional case reports with infliximab presenting with brain abscess after cholecystectomy and fatal cholecystitis progressing to menin-goencephalitis with posthumous culture growth of Listeria . The latter patient received empiric treatment with ceftriaxone, metronidazole, and flu-conazole lacking Listeria coverage. Several case reports of Listeria meningo-encephalitis with empiric treatment including ampicillin on presentation resulted in rapid resolution of symptoms [92-96].
Preventive efforts in patients receiving anti-TNF therapy include education on food preparation and safety with thorough cooking of meats; washing raw vegetables; and avoidance of unpasteurized dairy products, soft cheeses (eg, as camembert), and precooked meats (hot dogs, deli meats) unless thoroughly reheated . Maintaining a high suspicion for Listeria with a low threshold for including ampicillin in patients presenting with neurologic symptoms is advised. TMP-SMX prophylaxis also covers for Listeria and might be considered in the elderly or patients with lymphocytopenia.
Pneumococcal infection in elderly and immunocompromised people may lead to sudden severe pneumonia and sepsis. Isolated case reports of pneumococcal pneumonia with one case progressing to fatal acute respiratory distress syndrome, bacteremia, and meningitis related to anti-TNF therapy has been described [48,97-99]. A case of pneumococcal necrotizing fasciitis with fatal sepsis being treated with etanercept and low-dose pred-nisone was reported whereby etanercept may not have been stopped in timely manner . That necrotizing fasciitis is uncommon in immuno-competent hosts suggests the addition of anti-TNF-a therapy may have led to a predisposing state. TNF-a prevents bacteremia and death in mouse models. TNF-a levels increase proportionally to bacterial burden  with TNF-a inhibition conferring impaired clearance of bacteria and early mortality  because of pneumococcal pneumonia and fatal peritonitis . Pneumococcal vaccine is preferably administered 2 weeks before anti-TNF-a therapy; however, it may be given during therapy. Patients should be counseled on signs and symptoms, such as shaking chills, fever, and rigor. Ellerin and colleagues  support a home dose of fluoroquino-lone at hand to be taken with symptoms while patient is on route to medical attention.
Legionellosis is caused by gram-negative bacteria that thrive in aqueous environments, such as air conditioner ducts and shower heads. It manifests as pneumonia in patients who are elderly, immunosuppressed, or who have pulmonary disease with transmission being by inhalation. Case reports with anti-TNF-a therapy have been described [104,105]. Depletion of TNF-a impairs pulmonary host immune response to Legionella with persistent pneumonitis in rats .
Three cases of salmonella septic arthritis have been reported with etaner-cept use  and one case with infliximab use . One case was of salmonella septicemia associated with adalimumab and the other was a fatal case associated with infliximab. Salmonella is transmitted by eggs, meat, and un-pasteurized dairy products. It may also be transmitted by pet turtles, iguanas, and other reptiles. Patient education of food safety is similar to that of Listeria: undercooked eggs, chicken, and instructions for handwash-ing after contact with pet reptiles.
Other bacteria reported to the AERS by 2002 included Bartonella and Brucella . Nocardia was found to be 4.85 times higher with infliximab versus etanercept (P = .046) .
There are limited data regarding the use of biologics perioperatively, most of which are what can be gleaned from surgery in patients with Crohn's disease . Although a fourfold increased risk of skin and soft tissue infection has been reported with anti-TNF agents compared with disease-modifying antirheumatic drug , it is uncertain how this relates to perioperative infection. A controlled cohort study reported infliximab before intestinal resection did not result in increased hospital stay or increased rate of postoperative complications (P < .05) . Another limited study found that patients with RA receiving unspecified anti-TNF-a therapy who underwent elective foot surgery had similar complication rates and healing times compared with those without anti-TNF therapy .
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