InternalMed_Harrison

InternalMed_Harrison. C. diphtheriae is transmitted via the aerosol route, usually during close contact with an infected person. There are no significant reservoirs other than humans. The incubation period for respiratory diphtheria is 2–5 days, but disease onset has occurred as late as 10 days after exposure. Prior to the vaccination era, most individuals over the age of 10 were immune to C. diphtheriae; infants were protected by maternal IgG antibodies but became susceptible after ~6 months of age. Thus, the disease primarily affected children and nonimmune young adults. In temperate regions, respiratory diphtheria occurs year-round but is most common during winter months.


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InternalMed_Harrison. The development of diphtheria antitoxin in 1898 by von Behring and of the diphtheria toxoid vaccine in 1924 by Ramon led to the near-elimination of diphtheria in Western countries. The annual incidence rate in the United States peaked in 1921 at 191 cases per 100,000 population. In contrast, since 1980, the annual figure in the United States has been <5 cases per 100,000. Nevertheless, pockets of colonization persist in North America, particularly in South Dakota, Ontario, and recently the state of Washington. Immunity to diphtheria induced by childhood vaccination gradually decreases in adulthood. An estimated 30% of men 60–69 years old have antitoxin titers below the protective level. In addition to older age and lack of vaccination, risk factors for 977 diphtheria outbreaks include alcoholism, low socioeconomic status, crowded living conditions, and Native American ethnic background. An outbreak of diphtheria in Seattle, Washington, between 1972 and 1982 comprised 1100 cases, most


InternalMed_Harrison

InternalMed_Harrison. low socioeconomic status, crowded living conditions, and Native American ethnic background. An outbreak of diphtheria in Seattle, Washington, between 1972 and 1982 comprised 1100 cases, most of which were cutaneous. During the 1990s in the states of the former Soviet Union, a much larger diphtheria epidemic included more than 150,000 cases and more than 5000 deaths. Clonally related toxigenic C. diphtheriae strains of the ET8 complex were associated with this outbreak. Given that the ET8 complex expressed a toxin against which the prevalent diphtheria toxoid vaccine was effective, the epidemic was attributed to failure of the public health infrastructure to effectively vaccinate the population. Beginning in 1998, this epidemic was controlled by mass vaccination programs. During the epidemic, the incidence rate was high among individuals between 16 and 50 years of age. Socioeconomic instability, migration, deteriorating public health programs, frequent vaccine shortages, delayed


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InternalMed_Harrison. epidemic, the incidence rate was high among individuals between 16 and 50 years of age. Socioeconomic instability, migration, deteriorating public health programs, frequent vaccine shortages, delayed implementation of vaccination and treatment in response to cases, and lack of public education and awareness were contributing factors.


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InternalMed_Harrison. Significant outbreaks of diphtheria and diphtheria-related mortality continue to be reported from many developing countries, particularly in Africa and Asia. Statistics collected by the World Health Organization indicated the occurrence of ~7000 reported diphtheria cases in 2008 and ~5000 diphtheria deaths in 2004. Although ~82% of the global population has been adequately vaccinated, only 26% of countries have successfully vaccinated >80% of individuals in all districts.


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InternalMed_Harrison. Cutaneous diphtheria is usually a secondary infection that follows a primary skin lesion due to trauma, allergy, or autoimmunity. Most often, these isolates lack the tox gene and thus do not express diphtheria toxin. In tropical latitudes, cutaneous diphtheria is more common than respiratory diphtheria. In contrast to respiratory disease, cutaneous diphtheria is not reportable in the United States. Nontoxigenic strains of C. diphtheriae have also been associated with pharyngitis in Europe, causing outbreaks among men who have sex with men and persons who use illicit IV drugs.


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InternalMed_Harrison. Diphtheria toxin produced by tox+ strains of C. diphtheriae is the primary virulence factor in clinical disease. The toxin is synthesized in precursor form; is released as a 535-amino-acid, single-chain protein; and, in sensitive species (e.g., guinea pigs and humans, but not mice or rats), has a 50% lethal dose of ~100 ng/kg of body weight. The toxin is produced in the pseudomembranous lesion and is taken up in the bloodstream, from which it is distributed to all organ systems in the body. Once bound to its cell surface receptor (a heparin-binding epidermal growth factor–like precursor), the toxin is internalized by receptor-mediated endocytosis and enters the cytosol from an acidified early endosomal compartment. In vitro, the toxin may be separated into two chains by digestion with serine proteases: the N-terminal A fragment and the C-terminal B fragment. Delivery of the A fragment into the eukaryotic cell cytosol results in irreversible inhibition of protein synthesis by


InternalMed_Harrison

InternalMed_Harrison. with serine proteases: the N-terminal A fragment and the C-terminal B fragment. Delivery of the A fragment into the eukaryotic cell cytosol results in irreversible inhibition of protein synthesis by NAD+-dependent ADP-ribosylation of elongation factor 2. The eventual result is the death of the cell.


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InternalMed_Harrison. In 1926, Ramon at the Institut Pasteur found that formalinization of diphtheria toxin resulted in the production of a nontoxic but highly immunogenic diphtheria toxoid. Subsequent studies showed that immunization with diphtheria toxoid elicited antibodies that neutralized the toxin and prevented most disease manifestations. In the 1930s, mass immunization of children and susceptible adults with diphtheria toxoid commenced in the United States and Europe. Individuals with a diphtheria antitoxin titer of >0.01 U/mL are at low risk of disease. In populations where a majority of individuals have protective antitoxin titers, the carrier rate for toxigenic strains of C. diphtheriae decreases and the overall risk of diphtheria among susceptible individuals is reduced. Nevertheless, individuals with nonprotective titers may contract diphtheria through either travel or exposure to individuals who have recently returned from regions where the disease is endemic.


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InternalMed_Harrison. 978 Characteristic pathologic findings of diphtheria include mucosal ulcers with a pseudomembranous coating composed of an inner band of fibrin and a luminal band of neutrophils. Initially white and firmly adherent, in advanced diphtheria the pseudomembranes turn gray or even green or black as necrosis progresses. Mucosal ulcers result from toxin-induced necrosis of the epithelium accompanied by edema, hyperemia, and vascular congestion of the submucosal base. A significant fibrinosuppurative exudate from the ulcer develops into the pseudomembrane. Ulcers and pseudomembranes in severe respiratory diphtheria may extend from the pharynx into medium-sized bronchial airways. Expanding and sloughing membranes may result in fatal airway obstruction. APPROACH TO THE PATIENT:


InternalMed_Harrison

InternalMed_Harrison. Diphtheria, though rare in the United States and other developed countries, should be considered when a patient has severe pharyngitis, particularly when there is difficulty swallowing, respiratory compromise, or signs of systemic disease (e.g., myocarditis or generalized weakness). The leading causes of pharyngitis are respiratory viruses (rhinoviruses, influenza viruses, parainfluenza viruses, coronaviruses, adenoviruses; ~25% of cases), group A streptococci (15–30%), group C streptococci (~5%), atypical bacteria such as Mycoplasma pneumoniae and Chlamydia pneumoniae (15–20% in some series), and other viruses such as herpes simplex virus (~4%) and Epstein-Barr virus (<1% in infectious mononucleosis). Less common causes are acute HIV infection, gonorrhea, fusobacterial infection (e.g., Lemierre’s syndrome), thrush due to Candida albicans or other Candida species, and diphtheria. The presence of a pharyngeal pseudomembrane or an extensive exudate should prompt consideration of


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InternalMed_Harrison. Lemierre’s syndrome), thrush due to Candida albicans or other Candida species, and diphtheria. The presence of a pharyngeal pseudomembrane or an extensive exudate should prompt consideration of diphtheria (Figure 175-1).


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InternalMed_Harrison. FIGURE 175-1 Respiratory diphtheria due to toxigenic C. diphtheriae producing exudative pharyngitis in a 47-year-old female patient displaying neck edema and a pseudomembrane extending from the uvula to the pharyngeal wall. The characteristic white pseudomembrane is caused by diphtheria toxin–mediated necrosis of the respiratory epithelial layer, producing a fibrinous coagulative exudate. Submucosal edema adds to airway narrowing. The pharyngitis is acute in onset, and respiratory obstruction from the pseudomembrane may occur in severe cases. Inoculation of pseudomembrane fragments or submembranous swabs onto Löffler’s or tellurite selective medium reveals C. diphtheriae. (Photograph by P. Strebel, MD, used by permission. From R. Kadirova et al: J Infect Dis 181:S110, 2000. With permission of Oxford University Press.)


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InternalMed_Harrison. CLINICAL MANIFESTATIONS Respiratory Diphtheria The clinical diagnosis of diphtheria is based on the constellation of sore throat; adherent tonsillar, pharyngeal, or nasal pseudomembranous lesions; and low-grade fever. In addition, diagnosis requires the isolation of C. diphtheriae or histopathologic isolation of compatible gram-positive organisms. The Centers for Disease Control and Prevention (CDC) recognizes confirmed respiratory diphtheria (laboratory proven or epidemiologically linked to a culture-confirmed case) and probable respiratory diphtheria (clinically compatible but not laboratory proven or epidemiologically linked). Carriers are defined as individuals who have positive cultures for C. diphtheriae and who either are asymptomatic or have symptoms but lack pseudomembranes. Most patients seek medical care for sore throat and fever several days into the illness. Occasionally, weakness, dysphagia, headache, and voice change are the initial manifestations. Neck edema and


InternalMed_Harrison

InternalMed_Harrison. Most patients seek medical care for sore throat and fever several days into the illness. Occasionally, weakness, dysphagia, headache, and voice change are the initial manifestations. Neck edema and difficulty breathing are evident in more advanced cases and carry a poor prognosis.


InternalMed_Harrison

InternalMed_Harrison. The systemic manifestations of diphtheria stem from the effects of diphtheria toxin and include weakness as a result of neurotoxicity and cardiac arrhythmias or congestive heart failure due to myocarditis. Most commonly, the pseudomembranous lesion is located in the tonsillopharyngeal region. Less commonly, the lesions are located in the larynx, nares, and trachea or bronchial passages. Large pseudo-membranes are associated with severe disease and a poor prognosis. A few patients develop massive swelling of the tonsils and present with “bull-neck” diphtheria, which results from massive edema of the submandibular and paratracheal region and is further characterized by foul breath, thick speech, and stridorous breathing. The diphtheritic pseudomembrane is gray or whitish and sharply demarcated. Unlike the exudative lesion associated with streptococcal pharyngitis, the pseudomembrane in diphtheria is tightly adherent to the underlying tissues. Attempts to dislodge the membrane may cause


InternalMed_Harrison

InternalMed_Harrison. Unlike the exudative lesion associated with streptococcal pharyngitis, the pseudomembrane in diphtheria is tightly adherent to the underlying tissues. Attempts to dislodge the membrane may cause bleeding. Hoarseness suggests laryngeal diphtheria, in which laryngoscopy may be diagnostically helpful.


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InternalMed_Harrison. Cutaneous Diphtheria This dermatosis is characterized by punched-out ulcerative lesions with necrotic sloughing or pseudomembrane formation (Figure 175-2). The diagnosis requires cultivation of C. diphtheriae from lesions, which most commonly occur on the lower and upper extremities, head, and trunk. Infections Due to Non-diphtheriae Corynebacterium Species and Nontoxigenic C. diphtheriae Non-diphtheriae species of Corynebacterium and related genera (discussed below) as well as nontoxigenic strains of C. diphtheriae itself have been found in bloodstream and respiratory infections, often in individuals with immunosuppression or chronic respiratory disease. These organisms can cause disease manifestations and should not necessarily be dismissed as colonizers. FIGURE 175-2 Cutaneous diphtheria due to nontoxigenic C. diphtheriae on the lower extremity. (From the Centers for Disease Control and Prevention.)


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InternalMed_Harrison. FIGURE 175-2 Cutaneous diphtheria due to nontoxigenic C. diphtheriae on the lower extremity. (From the Centers for Disease Control and Prevention.) Other Clinical Manifestations C. diphtheriae causes rare cases of endo carditis and septic arthritis, most often in patients with preexisting risk factors, such as abnormal cardiac valves, injection drug use, or cirrhosis. Airway obstruction poses a significant early risk in patients presenting with advanced diphtheria. Pseudomembranes may slough and obstruct the airway or may advance to the larynx or into the tracheobronchial tree. Children are particularly prone to obstruction because of their small airways. Polyneuropathy and myocarditis are late toxic manifesta tions of diphtheria. During a diphtheria outbreak in the


InternalMed_Harrison

InternalMed_Harrison. Polyneuropathy and myocarditis are late toxic manifesta tions of diphtheria. During a diphtheria outbreak in the Kyrgyz Republic in 1999, myocarditis was found in 22% and neuropathy in 5% of 656 hospitalized patients. The mortality rate was 7% among patients with myocarditis as opposed to 2% among those without myocardial manifestations. The median time to death in hospitalized patients was 4.5 days. Myocarditis is typically associated with dysrhythmia of the conduction tract and dilated cardiomyopathy.


InternalMed_Harrison

InternalMed_Harrison. Polyneuropathy is seen 3–5 weeks after the onset of diphtheria and has a slow indolent course. However, patients may develop severe and prolonged neurologic abnormalities. The disorders typically occur in the mouth and neck, with lingual or facial numbness as well as dysphonia, dysphagia, and cranial nerve paresthesias. More ominous signs include weakness of respiratory and abdominal muscles and paresis of the extremities. Sensory manifestations and sensory ataxia also are observed. Cranial nerve dysfunction typically precedes disturbances of the trunk and extremities because of proximity to the site of infection. Autonomic dysfunction also is associated with polyneuropathy and can lead to hypotension. Polyneuropathy is typically reversible in patients who survive the acute phase. Other complications of diphtheria include pneumonia, renal failure, encephalitis, cerebral infarction, pulmonary embolism, and serum sickness from antitoxin therapy.


InternalMed_Harrison

InternalMed_Harrison. Other complications of diphtheria include pneumonia, renal failure, encephalitis, cerebral infarction, pulmonary embolism, and serum sickness from antitoxin therapy. The diagnosis of diphtheria is based on clinical signs and symptoms plus laboratory confirmation. Respiratory diphtheria should be considered in patients with sore throat, pharyngeal exudates, and fever. Other symptoms may include hoarseness, stridor, or palatal paralysis. The presence of a pseudomembrane should prompt strong consideration of diphtheria. Once a clinical diagnosis of diphtheria is made, diphtheria antitoxin should be obtained and administered as rapidly as possible. Laboratory diagnosis of diphtheria is based either on cultivation of


InternalMed_Harrison

InternalMed_Harrison. Laboratory diagnosis of diphtheria is based either on cultivation of C. diphtheriae or toxigenic Corynebacterium ulcerans from the site of infection or on the demonstration of local lesions with characteristic histopathology. Corynebacterium pseudodiphtheriticum, a nontoxigenic organism, is a common component of the normal throat flora and does not pose a significant risk. Throat samples should be submitted to the laboratory for culture with the notation that diphtheria is being considered. This information should prompt cultivation on special selective medium and subsequent biochemical testing to differentiate C. diphtheriae from other nasopharyngeal commensal corynebacteria. All laboratory isolates of C. diphtheriae, including nontoxigenic strains, should be submitted to the CDC.


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InternalMed_Harrison. A diagnosis of cutaneous diphtheria requires laboratory confirmation since the lesions are not characteristic and are indistinguishable from other dermatoses. Diphtheritic ulcers occasionally—but not consistently—have a punched-out appearance (Fig. 175-2). Patients in whom cutaneous diphtheria is identified should have the nasopharynx cultured for C. diphtheriae. The laboratory medium for cutaneous diphtheria specimens is the same as that used for respiratory diphtheria: Löffler’s or Tinsdale’s selective medium in addition to nonselective medium such as blood agar. As has been mentioned, respiratory diphtheria remains a notifiable disease in the United States, whereas cutaneous diphtheria is not.


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InternalMed_Harrison. Prompt administration of diphtheria antitoxin is critical in the management of respiratory diphtheria. Diphtheria antitoxin, a horse antiserum, is effective in reducing the extent of local disease as well as the risk of complications of myocarditis and neuropathy. Rapid institution of antitoxin therapy is also associated with a significant reduction in mortality risk. Because diphtheria antitoxin cannot neutralize cell-bound toxin, prompt initiation is important. This product, which is no longer commercially available in the United States, can be obtained from the CDC by calling the Bacterial Vaccine Preventable Disease Branch of the National Immunization Program at 404-639-8257 (8:00 A.M. to 4:30 P.M., U.S. Eastern time) or, at other hours, the Emergency Operations Center at 770-488-7100; the relevant website is www.cdc.gov/diphtheria/dat.html. The current protocol for the use of diphtheria antitoxin involves a test dose to rule out immediate hypersensitivity. Patients who


InternalMed_Harrison

InternalMed_Harrison. the relevant website is www.cdc.gov/diphtheria/dat.html. The current protocol for the use of diphtheria antitoxin involves a test dose to rule out immediate hypersensitivity. Patients who demonstrate hypersensitivity require desensitization before a full therapeutic dose of antitoxin is administered.


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InternalMed_Harrison. Antibiotics are used in the management of diphtheria primarily to prevent transmission to susceptible contacts. Antibiotics also prevent further toxin production and reduce the severity of local infection. Recommended treatment options for patients with respiratory diphtheria are as follows: • Procaine penicillin G, 600,000 U IM q12h (for children: 12,500–25,000 U/kg IM q12h) until the patient can swallow comfortably; then oral penicillin V, 125–250 mg qid to complete a 14-day course • Erythromycin, 500 mg IV q6h (for children: 40–50 mg/kg per day


InternalMed_Harrison

InternalMed_Harrison. IV in two or four divided doses) until the patient can swallow com fortably; then 500 mg PO qid to complete a 14-day course ciated with a more rapid resolution of fever and a lower rate of bacterial resistance than erythromycin; however, relapses were more common in the penicillin group. Erythromycin therapy targets protein synthesis and thus offers the presumed benefit of stopping toxin synthesis more quickly than a cell wall– active β-lactam agent. Alternative therapeutic agents for patients who are allergic to penicillin or cannot take erythromycin include rifampin and clindamycin. Eradication of C. diphtheriae should be documented after antimicrobial therapy is complete. A repeat throat culture 2 weeks later is recommended. For patients in whom the organism is not eradicated after a 14-day course of erythromycin or penicillin, an additional 10-day course followed by repeat culture is recommended. Drug-resistant strains of C. diphtheriae exist, and several reports have described


InternalMed_Harrison

InternalMed_Harrison. 14-day course of erythromycin or penicillin, an additional 10-day course followed by repeat culture is recommended. Drug-resistant strains of C. diphtheriae exist, and several reports have described multidrugresistant strains, predominantly in Southeast Asia. Drug resistance should be considered when efforts at pathogen eradication fail.


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InternalMed_Harrison. Cutaneous diphtheria should be treated as described above for respiratory disease. Individuals infected with toxigenic strains should receive antitoxin. It is important to treat the underlying cause of the dermatoses in addition to the superinfection with C. diphtheriae. Patients who recover from respiratory or cutaneous diphtheria should have antitoxin levels measured. If diphtheria antitoxin has been administered, this test should be performed 6 months later. Patients who recover from respiratory or cutaneous diphtheria should receive the appropriate vaccine to ensure the development of protective antibody titers.


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InternalMed_Harrison. Patients in whom diphtheria is suspected should be hospitalized in respiratory isolation rooms, with close monitoring of cardiac and respiratory function. A cardiac workup is recommended to assess the possibility of myocarditis. In patients with extensive pseudomembranes, an anesthesiology or an ear, nose, and throat consultation is recommended because of the possible need for 980 tracheostomy or intubation. In some settings, pseudomembranes can be removed surgically. Treatment with glucocorticoids has not been shown to reduce the risk of myocarditis or polyneuropathy.


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InternalMed_Harrison. Fatal pseudomembranous diphtheria typically occurs in patients with nonprotective antibody titers and in unimmunized patients. The pseudomembrane may actually increase in size from the time it is first noted. Risk factors for death include bullneck diphtheria; myocarditis with ventricular tachycardia; atrial fibrillation; complete heart block; an age of >60 years or <6 months; alcoholism; extensive pseudo-membrane elongation; and laryngeal, tracheal, or bronchial involvement. Another important predictor of fatal outcome is the interval between the onset of local disease and the administration of antitoxin. Cutaneous diphtheria has a low mortality rate and is rarely associated with myocarditis or peripheral neuropathy.


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InternalMed_Harrison. PREVENTION Vaccination Sustained campaigns for vaccination of children and adequate boosting vaccination of adults are responsible for the exceedingly low incidence of diphtheria in most developed nations. Currently, diphtheria toxoid vaccine is coadministered with tetanus vaccine (with or without acellular pertussis). DTaP (a full-level diphtheria and tetanus toxoids and acellular pertussis vaccine) is currently recommended for children up to the age of 7; DTaP replaced the earlier whole-cell pertussis vaccine DTP in 1997. Tdap is a tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis vaccine formulated for adolescents and adults. Tdap was licensed for use in the United States in 2005 and is the recommended booster vaccine for children 11–12 years old and the recommended catch-up vaccine for children 7–10 and 13–18 years of age. It is recommended that all adults (i.e., persons >19 years old) receive a single dose of Tdap if they have not received it previously,


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InternalMed_Harrison. catch-up vaccine for children 7–10 and 13–18 years of age. It is recommended that all adults (i.e., persons >19 years old) receive a single dose of Tdap if they have not received it previously, regardless of the interval since the last dose of Td (tetanus and reduced-dose diphtheria toxoids, adsorbed). Tdap vaccination is a priority for health care workers, pregnant women, adults anticipating contact with infants, and adults not previously vaccinated for pertussis. Adults who have received acellular pertussis vaccine should continue to receive decennial Td booster vaccinations.


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InternalMed_Harrison. The vaccine schedule is detailed in Chap. 148. Prophylaxis Administration to Contacts Close contacts of diphtheria patients should undergo throat culture to determine whether they are carriers. After samples for throat culture are obtained, antimicrobial prophylaxis should be considered for all contacts, even those whose cultures are negative. The options are 7–10 days of oral erythromycin or one dose of IM benzathine penicillin G (1.2 million units for persons ≥6 years of age or 600,000 units for children <6 years of age). Contacts of diphtheria patients whose immunization status is uncertain should receive the appropriate diphtheria toxoid–containing vaccine. The Tdap vaccine (rather than Td) is now the booster vaccine of choice for adults who have not recently received an acellular pertussis– containing vaccine. Carriers of C. diphtheriae in the community should be treated and vaccinated when identified.


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InternalMed_Harrison. Nondiphtherial corynebacteria, referred to as diphtheroids or coryneforms, are frequently considered colonizers or contaminants; however, they have been associated with invasive disease, particularly in immunocompromised patients. These organisms have been isolated from the bloodstream, particularly in association with catheter infection, endocarditis, prosthetic valve infection, meningitis, neurosurgical shunt infection, brain abscess, and peritonitis and often in the setting of chronic ambulatory peritoneal dialysis, osteomyelitis, septic arthritis, urinary tract infection, empyema, and pneumonia, among other infections. Patients infected with these organisms usually have significant medical comorbidity or are immunosuppressed. The nondiphtherial coryneforms are a diverse collection of bacteria that are taxonomically grouped together in the genus Corynebacterium on the basis of their 16S rDNA signature nucleotides. Despite the shared rDNA signatures, these isolates are quite


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InternalMed_Harrison. of bacteria that are taxonomically grouped together in the genus Corynebacterium on the basis of their 16S rDNA signature nucleotides. Despite the shared rDNA signatures, these isolates are quite diverse. For example, their guanine-cytosine content ranges from 45% to 70%. Several nondiphtheroid corynebacteria, including Corynebacterium jeikeium and Corynebacterium urealyticum, are associated with resistance to multiple antibiotics. Rhodococcus equi is associated with necrotizing pneumonia and granulomatous infection, particularly in immunocompromised individuals.


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InternalMed_Harrison. These organisms are non-acid-fast, catalase-positive, aerobic or facultatively anaerobic rods. Their colonial morphologies vary widely; some species are small and α-hemolytic (similar to lactobacilli), whereas others form large white colonies (similar to yeasts). Many nondiphtherial coryneforms require special media, such as Löffler’s, Tinsdale’s, or telluride medium. These cultivation idiosyncrasies have led to a complex taxonomic categorization of the organisms. Humans are the natural reservoirs for several nondiphtherial coryneforms, including C. xerosis, C. pseudodiphtheriticum, C. striatum, C. minutissimum, C. jeikeium, C. urealyticum, and Arcanobacterium haemolyticum. Animal reservoirs are responsible for carriage of Arcanobacterium pyogenes, C. ulcerans, and C. pseudotuberculosis. Soil is the natural reservoir for R. equi.


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InternalMed_Harrison. C. pseudodiphtheriticum is a component of the normal flora of the human pharynx and skin. C. xerosis is found on the skin, nasopharynx, and conjunctiva; C. auris in the external auditory canal; and C. striatum in the anterior nares and on the skin. C. jeikeium and C. urealyticum are found in the axilla, groin, and perineum, particularly in hospitalized patients. Infections with C. ulcerans and C. pseudotuberculosis have been associated with the consumption of raw milk from infected cattle.


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InternalMed_Harrison. C. ulcerans This organism causes a diphtheria-like illness and produces both diphtheria toxin and a dermonecrotic toxin. The organism is a commensal in horses and cattle and has been isolated from cow’s milk. C. ulcerans causes exudative pharyngitis, primarily during summer months, in rural areas, and among individuals exposed to cattle. In contrast to diphtheria, this infection is considered a zoonosis whose person-to-person transmission has not been documented. Nevertheless, treatment with antitoxin and antibiotics should be initiated when respiratory C. ulcerans is identified, and a contact investigation (including throat cultures to determine the need for antimicrobial prophylaxis and, in unimmunized contacts, administration of the appropriate diphtheria toxoid–containing vaccine) should be conducted. The organism grows on Löffler’s, Tinsdale’s, and telluride agars as well as blood agar. In addition to exudative pharyngitis, cutaneous disease due to C. ulcerans has been reported.


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InternalMed_Harrison. be conducted. The organism grows on Löffler’s, Tinsdale’s, and telluride agars as well as blood agar. In addition to exudative pharyngitis, cutaneous disease due to C. ulcerans has been reported. C. ulcerans is susceptible to a wide panel of antibiotics. Erythromycin and macrolides appear to be the first-line agents.


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InternalMed_Harrison. C. pseudotuberculosis (ovis) Infection caused by C. pseudotuberculosis is rare and is reported almost exclusively from Australia. C. pseudo-tuberculosis causes suppurative granulomatous lymphadenitis and an eosinophilic pneumonia syndrome among individuals who handle horses, cattle, goats, and deer or who drink raw milk. The organism is an important veterinary pathogen, causing suppurative lymphadenitis, abscesses, and pneumonia, but is rarely a human pathogen. Successful treatment with erythromycin or tetracycline has been reported, with surgery also performed when indicated. C. jeikeium (Group JK) Originally described in American hospitals,


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InternalMed_Harrison. C. jeikeium (Group JK) Originally described in American hospitals, C. jeikeium infection was subsequently reported in Europe. After a 1976 survey of diseases caused by nondiphtherial corynebacteria, CDC group JK emerged as an important opportunistic pathogen among neutropenic and HIV-infected patients. The organism has now been designated a separate species. C. jeikeium forms small, gray to white, glistening, nonhemolytic colonies on blood agar. It lacks urease and nitrate reductase and does not ferment most carbohydrates. The predominant syndrome associated with C. jeikeium is sepsis with pneumonia, endocarditis, meningitis, osteomyelitis, and epidural abscess. Risk factors for C. jeikeium infection include hematologic malignancy, neutropenia from comorbid conditions, prolonged hospitalization, exposure to multiple antibiotics, and skin disruption. There is evidence that C. jeikeium is part of the inguinal, axillary, genital, and perirectal flora of hospitalized patients.


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InternalMed_Harrison. Broad-spectrum antimicrobial therapy appears to select for colonization. Gram’s staining shows gram-positive coccobacillary forms slightly resembling streptococci. Moreover, C. jeikeium is resistant to all antibiotics tested except vancomycin. Effective therapy involves removal of the infectious source, whether a catheter, prosthetic joint, or prosthetic valve. Efforts have been made to prevent C. jeikeium infection by improving hygienic conditions for high-risk patients in intensive care settings with antibacterial soap.


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InternalMed_Harrison. C. urealyticum (Group D2) Identified as a urease-positive nondiphtherial Corynebacterium in 1972, C. urealyticum is an opportunistic pathogen causing sepsis and urinary tract infection. C. urealyticum appears to be the etiologic agent of a severe urinary tract syndrome known as alkaline-encrusted cystitis, a chronic inflammatory bladder infection associated with deposition of ammonium magnesium phosphate on the surface and walls of ulcerating lesions in the bladder. In addition, C. urealyticum has been associated with pneumonia, peritonitis, endocarditis, osteomyelitis, and wound infection. It is similar to C. jeikeium in its resistance to most antibiotics except vancomycin. Vancomycin therapy has been used successfully in severe infections.


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InternalMed_Harrison. C. minutissimum (Erythrasma) Erythrasma is a cutaneous infection producing reddish-brown, macular, scaly, pruritic intertriginous patches. The dermatologic presentation under the Wood’s lamp is of coral red fluorescence. C. minutissimum appears to be a common cause of erythrasma, although there is evidence for a polymicrobial etiology in certain settings. This microbe has also been associated with bacteremia in patients with hematologic malignancy. Erythrasma responds to topical erythromycin, clarithromycin, clindamycin, or fusidic acid, although more severe infections may require oral macrolide therapy.


InternalMed_Harrison

InternalMed_Harrison. Other Nondiphtherial Corynebacterial Infections C. xerosis is a human commensal found in the conjunctiva, nasopharynx, and skin. This nontoxigenic organism is occasionally identified as a source of invasive infection in immunocompromised or postoperative patients and prosthetic joint recipients. C. striatum is found in the anterior nares, skin, face, and upper torso of healthy individuals. Also nontoxigenic, this organism has been associated with invasive opportunistic infections in severely ill or immunocompromised patients. C. amycolatum is isolated from human skin and is identified on the basis of a unique 16S ribosomal RNA sequence associated with opportunistic infection. C. glucuronolyticum is a nonlipophilic species that causes male genitourinary tract infections such as prostatitis and urethritis. These infections may be successfully treated with a wide variety of antibacterial agents, including β-lactams, rifampin, aminoglycosides, or vancomycin; however, the organism appears


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InternalMed_Harrison. and urethritis. These infections may be successfully treated with a wide variety of antibacterial agents, including β-lactams, rifampin, aminoglycosides, or vancomycin; however, the organism appears to be resistant to fluoroquinolones, macrolides, and tetracyclines. C. imitans has been identified in eastern Europe as a nontoxigenic cause of pharyngitis. C. auris has been identified in children with otitis media; it is susceptible to fluoroquinolones, rifampin, tetracycline, and vancomycin but resistant to penicillin G and variably susceptible to macrolides. C. pseudodiphtheriticum (C. hoffmanii) is a nontoxigenic species that is part of the normal human flora. Human infections—particularly endocarditis of either prosthetic or natural valves and invasive pneumonia—have been reported only rarely. Although C. pseudodiphtheriticum may be isolated from the nasopharynx of patients with suspected diphtheria, it is part of the normal flora and does not produce diphtheria toxin. 981


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InternalMed_Harrison. C. propinquum, a close relative of C. pseudodiphtheriticum, is part of CDC group ANF-3 and is isolated from the human respiratory tract and blood. C. afermentans subspecies lipophilum belongs to CDC group ANF-1 and has been isolated from human blood and abscesses. C. accolens has been isolated from wound drainage, throat swabs, and sputum and is typically identified as a satellite of staphylococcal organisms; this species has been associated with endocarditis. C. bovis is a veterinary commensal that has not been clearly associated with human disease. C. aquaticum is a water-dwelling organism that is occasionally isolated from patients using medical devices (e.g., for chronic ambulatory peritoneal dialysis or venous access).


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InternalMed_Harrison. Rhodococcus Rhodococcus species are phylogenetically related to the corynebacteria. These gram-positive coccobacilli have been associated with tuberculosis-like infections in humans with granulomatous pathology. While R. equi is best known, other species have been identified, including R. (Gordonia) bronchialis, R. (Tsukamurella) aurantiacus, R. luteus, R. erythropolis, R. rhodochrous, and R. rubropertinctus.


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InternalMed_Harrison. R. equi has been recognized as a cause of pneumonia in horses since the 1920s and as a cause of related infections in cattle, sheep, and swine. It is found in soil as an environmental microbe. The organisms vary in length; appear as spherical to long, curved, clubbed rods; and produce large irregular mucoid colonies. R. equi cannot ferment carbohydrates or liquefy gelatin and is often acid fast. An intracellular pathogen of macrophages, R. equi can cause granulomatous necrosis and caseation. This organism has most commonly been identified in pulmonary infection, but infections of brain, bone, and skin also have been reported. Most commonly, R. equi disease manifests as nodular cavitary pneumonia of the upper lobe—a picture similar to that seen in tuberculosis or nocardiosis. Most patients are immunocompromised, often by HIV infection. Subcutaneous nodular lesions have also been identified. The involvement of R. equi should be considered when any patient presents with a


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InternalMed_Harrison. Most patients are immunocompromised, often by HIV infection. Subcutaneous nodular lesions have also been identified. The involvement of R. equi should be considered when any patient presents with a tuberculosis-like syndrome.


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InternalMed_Harrison. Infection due to R. equi has been treated successfully with antibiotics that penetrate intracellularly, including macrolides, clindamycin, rifampin, and trimethoprim-sulfamethoxazole. β-Lactam antibiotics have not been useful. The organism is routinely susceptible to vancomycin, which is considered the drug of choice. Other Related Species • actinomyces pyogenes This organism, a well-known pathogen of cattle, sheep, goats, and pigs, causes seasonal leg ulcers in rural Thailand. A few human cases of sepsis, endocarditis, septic arthritis, pneumonia, meningitis, and empyema have been reported. This species is susceptible to β-lactams, tetracyclines, aminoglycosides, and fluoroquinolones.


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InternalMed_Harrison. arcanobacterium Haemolyticum A. haemolyticum was identified as an agent of wound infections in U.S. soldiers in the South Pacific during World War II. It appears to be a human commensal of the nasopharynx and skin, but has also been implicated in pharyngitis and chronic skin ulcers. In contrast to the much more common pharyngitis caused by Streptococcus pyogenes, A. haemolyticum pharyngitis is associated with a scarlatiniform rash on the trunk and proximal extremities in about half of cases; this illness is occasionally confused with toxic shock syndrome. Because A. haemolyticum pharyngitis primarily affects teenagers, it has been postulated that the rash-pharyngitis syndrome may represent copathogenicity, synergy, or opportunistic secondary infection with Epstein-Barr virus. A. haemolyticum has also been reported as a cause of bacteremia, soft tissue infections, osteomyelitis, and cavitary pneumonia, predominantly in the setting of underlying diabetes mellitus. The organism is


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InternalMed_Harrison. has also been reported as a cause of bacteremia, soft tissue infections, osteomyelitis, and cavitary pneumonia, predominantly in the setting of underlying diabetes mellitus. The organism is susceptible to β-lactams, macrolides, fluoroquinolones, clindamycin, vancomycin, and doxycycline. Penicillin resistance has been reported.


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InternalMed_Harrison. 982 Listeria monocytogenes Infections Elizabeth L. Hohmann, Daniel A. Portnoy Listeria monocytogenes is a food-borne pathogen that can cause serious infections, particularly in pregnant women and immunocompromised 176 individuals. A ubiquitous saprophytic environmental bacterium, L. monocytogenes is also a facultative intracellular pathogen with a broad host range. Humans are probably accidental hosts for this microorganism. L. monocytogenes is of interest not only to clinicians but also to basic scientists as a model intracellular pathogen that is used to study basic mechanisms of microbial pathogenesis and host immunity. L. monocytogenes is a facultatively anaerobic, nonsporulating, gram-positive rod that grows over a broad temperature range, including refrigeration temperatures. This organism is motile during growth at low temperatures but much less so at 37°C. The vast majority of cases of human listerial disease can be traced to serotypes 1/2a, 1/2b, and 4.


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InternalMed_Harrison. L. monocytogenes is weakly β-hemolytic on blood agar, and (as detailed below) its β-hemolysin is an essential determinant of its pathogenicity.


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InternalMed_Harrison. Infections with L. monocytogenes follow ingestion of contaminated food that contains the bacteria at high concentrations. The conversion from environmental saprophyte to pathogen involves the coordinate regulation of bacterial determinants of pathogenesis that mediate entry into cells, intracellular growth, and cell-to-cell spread. Many of the organism’s pathogenic strategies can be examined experimentally in tissue culture models of infection (Fig. 176-1). Like other enteric pathogens, L. monocytogenes induces its own internalization by cells that are not normally phagocytic. Its entry into cells is mediated by host surface proteins classified as internalins. Internalin-mediated entry is important in the crossing of intestinal, blood-brain, and fetoplacental barriers, although how L. monocytogenes traffics from the intestine to the brain or fetus is only beginning to be investigated. In a pregnant guinea pig model of infection, L. monocytogenes was shown


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InternalMed_Harrison. FIGURE 176-1 Stages in the intracellular life cycle of Listeria monocytogenes. The central diagram depicts cell entry, escape from a vacuole, actin nucleation, actin-based motility, and cell-to-cell spread. Surrounding the diagram are representative electron micro-graphs from which it was derived. ActA, surface protein mediating nucleation of host actin filaments to propel bacteria intraand inter-cellularly; LLO, listeriolysin O; PLCs, phospholipases C; Inl, internalin. See text for further details. (Adapted with permission from LG Tilney, DA Portnoy: J Cell Biol 109:1597, 1989. © Rockefeller University Press.) to traffic from maternal organs to the placenta; surprisingly, however, it also trafficked from the placenta back to maternal organs. These data are consistent with a model in which miscarriage can be viewed as a host defense strategy to eliminate a nidus of infection.


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InternalMed_Harrison. An essential determinant of the pathogenesis of L. monocytogenes is its β-hemolysin, listeriolysin O (LLO). LLO is a pore-forming, cholesterol-dependent cytolysin. (Related cytolysins include streptolysin O, pneumolysin, and perfringolysin O, all of which are produced by extracellular pathogens.) LLO is largely responsible for mediating the rupture of the phagosomal membrane that forms after phagocytosis of


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InternalMed_Harrison. L. monocytogenes. LLO probably acts by insertion into an acidifying phagosome, which prevents the vesicle’s maturation. In addition, LLO acts as a translocation pore for one or both of the L. monocytogenes phospholipases that also contribute to vacuolar lysis. LLO synthesis and activity are controlled at multiple levels to ensure that its lytic activity is limited to acidic vacuoles and does not affect the cytosol. Mutations in LLO that influence its synthesis, cytosolic half-life, or pH optimum cause premature toxicity to infected cells. There is an inverse relationship between toxicity and virulence—i.e., the more cytotoxic the strain, the less virulent it is in animals. This relationship may seem paradoxical, but, as an intracellular pathogen, L. monocytogenes benefits from leaving its host cell unharmed.


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InternalMed_Harrison. Shortly after exposure to the mammalian-cell cytosol, L. monocytogenes expresses a surface protein, ActA, that mediates the nucleation of host actin filaments to propel the bacteria intraand intercellularly. ActA mimics host proteins of the Wiskott-Aldrich syndrome protein (WASP) family by promoting the actin nucleation properties of the Arp2/3 complex. Thus, L. monocytogenes can enter the cytosol of almost any eukaryotic cell or cell extract and can exploit a conserved and essential actin-based motility system. Other pathogens as diverse as certain Shigella, Mycobacterium, Rickettsia, and Burkholderia species use a related pathogenic strategy that allows cell-to-cell spread without exposure to the extracellular milieu.


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InternalMed_Harrison. The innate and acquired immune responses to L. monocytogenes have been studied extensively in mice. Shortly after IV injection, most bacteria are found in Kupffer cells in the liver, with some organisms in splenic dendritic cells and macrophages. Listeriae that survive the bactericidal activity of initially infected macrophages grow in the cytosol and spread from cell to cell. L. monocytogenes triggers three innate immune pathways: a MyD88-dependent pathway leading to inflammatory cytokines, a STING/IRF3 pathway leading to a type I interferon response; and low-level inflammasome activation. Neutrophils are crucial to host defense during the first 24 h of infection, whereas an influx of activated macrophages from the bone marrow is critical subsequently. Mice that survive sublethal infection clear the organisms within a week, with consequent sterile immunity. Studies with knockout mice have been instrumental in dissecting the roles played by chemokines and cytokines during infection.


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InternalMed_Harrison. clear the organisms within a week, with consequent sterile immunity. Studies with knockout mice have been instrumental in dissecting the roles played by chemokines and cytokines during infection. For example, interferon γ, tumor necrosis factor, and CCR2 are essential in controlling infection. While innate immunity is sufficient to control infection, the acquired immune response is required for sterile immunity. Immunity is cell mediated; antibody plays no measurable role. The critical effector cells are cytotoxic (CD8+) T cells that recognize and lyse infected cells; the resulting extracellular bacteria are killed by circulating activated phagocytes.


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InternalMed_Harrison. A hallmark of the L. monocytogenes model is that killed vaccines do not provide protective immunity. The explanation for this fundamental observation is multifactorial, involving the generation of appropriate cytokines and the compartmentalization of bacterial proteins for antigen processing and presentation. Because the organism has the capacity to induce a robust cell-mediated immune response, attenuated strains have been engineered to express foreign antigens and are undergoing clinical studies as therapeutic vaccines for cancer.


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InternalMed_Harrison. L. monocytogenes usually enters the body via the gastrointestinal tract in foods. Listeriosis is most often sporadic, although outbreaks do occur. No epidemiologic or clinical evidence supports person-toperson transmission (other than vertical transmission from mother to fetus) or waterborne infection. In line with its survival and multiplication at refrigeration temperatures, L. monocytogenes is commonly found in processed and unprocessed foods of animal and plant origin, especially soft cheeses, delicatessen meats, hot dogs, milk, and cold salads; fresh fruits and vegetables can also transmit the organism. Because food supplies are increasingly centralized and normal hosts tolerate the organism well, outbreaks may not be immediately apparent. The U.S. Food and Drug Administration has a zero-tolerance policy for L. monocytogenes in ready-to-eat foods.


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InternalMed_Harrison. Symptoms of listerial infection overlap greatly with those of other infectious diseases. Timely diagnosis requires that the illness be considered in groups at risk: pregnant women; elderly persons; neonates; individuals immunocompromised by organ transplantation, cancer, or treatment with tumor necrosis factor antagonists or glucocorticoids; and patients with a variety of chronic medical conditions, including alcoholism, diabetes, renal disease, and rheumatologic and hepatic illnesses. Meningitis in older adults (especially with parenchymal brain involvement or subcortical brain abscess) should trigger consideration of L. monocytogenes infection and treatment. Listeriosis occasionally affects healthy, young, nonpregnant individuals. HIV-infected patients are at risk; however, listeriosis seems to be prevented by trimethoprim-sulfamethoxazole (TMP-SMX) prophylaxis targeting other AIDS-related infections. The diagnosis is typically made by culture of blood, cerebrospinal fluid (CSF), or


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InternalMed_Harrison. to be prevented by trimethoprim-sulfamethoxazole (TMP-SMX) prophylaxis targeting other AIDS-related infections. The diagnosis is typically made by culture of blood, cerebrospinal fluid (CSF), or amniotic fluid.


InternalMed_Harrison

InternalMed_Harrison. L. monocytogenes may be confused with “diphtheroids” or pneumococci in Gram-stained CSF or may be gram-variable and confused with Haemophilus species. Polymerase chain reaction diagnostics have been described but are not widely available, and serology is not clinically useful. Listerial infections present as several clinical syndromes, of which meningitis and septicemia are most common. Monocytosis is seen in infected rabbits but is not a hallmark of human infection.


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InternalMed_Harrison. Gastroenteritis Appreciated only since the outbreaks of the late 1980s, listerial gastroenteritis typically develops within 48 h of ingestion of a large inoculum of bacteria in contaminated foods. Attack rates are high (50–100%). L. monocytogenes is neither sought nor found in routine fecal cultures, but its involvement should be considered in outbreaks when cultures for other likely pathogens are negative. Sporadic intestinal illness appears to be uncommon. Manifestations include fever, diarrhea, headache, and constitutional symptoms. The largest reported outbreak occurred in an Italian school system and included 1566 individuals; ~20% of patients were hospitalized, but only one person had a positive blood culture. Isolated gastrointestinal illness does not require antibiotic treatment. Surveillance studies show that 0.1–5% of healthy asymptomatic adults may have stool cultures positive for the organism.


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InternalMed_Harrison. Bacteremia L. monocytogenes septicemia presents with fever, chills, and myalgias/arthralgias and cannot be differentiated from septicemia involving other organisms. Meningeal symptoms, focal neurologic findings, or mental status changes may suggest the diagnosis. Bacteremia is documented in 70–90% of cancer patients with listeriosis. A nonspecific flulike illness with fever is a common presentation in pregnant women. Endocarditis of prosthetic and native valves is an uncommon complication, with reported fatality rates of 35–50% in case series. A lumbar puncture is often prudent, although not necessary, in pregnant women without central nervous system (CNS) symptoms.


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InternalMed_Harrison. Meningitis L. monocytogenes causes ~5–10% of all cases of community-acquired bacterial meningitis in adults in the United States. Case-fatality rates are reported to be 15–26% and do not appear to have changed over time. This diagnosis should be considered in all older or chronically ill adults with “aseptic” meningitis. The presentation is 983 more frequently subacute (with illness developing over several days) than in meningitis of other bacterial etiologies, and nuchal rigidity and meningeal signs are less common. Photophobia is infrequent. Focal findings and seizures are common in some but not all series. The CSF profile in listerial meningitis most often shows white blood cell counts in the range of 100–5000/μL (rarely higher); 75% of patients have counts below 1000/μL, usually with a neutrophil predominance more modest than that in other bacterial meningitides. Low glucose levels and positive results on Gram’s staining are found ~30–40% of the time. Hydrocephalus can occur.


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InternalMed_Harrison. Meningoencephalitis and Focal CNS Infection L. monocytogenes can directly invade the brain parenchyma, producing either cerebritis or focal abscess. Approximately 10% of cases of CNS infection are macroscopic abscesses resulting from bacteremic seeding; the affected patients often have positive blood cultures. Concurrent meningitis can exist, but the CSF may appear normal. Abscesses can be misdiagnosed as metastatic or primary tumors and, in rare instances, occur in the cerebellum and the spinal cord. Invasion of the brainstem results in a characteristic severe rhombencephalitis, usually in otherwise healthy older adults (although there are numerous other infectious and noninfectious causes of this syndrome). The presentation may be biphasic, with a prodrome of fever and headache followed by asymmetric cranial nerve deficits, cerebellar signs, and hemiparetic and hemisensory deficits. Respiratory failure can occur. The subacute course and the often minimally abnormal CSF findings may


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InternalMed_Harrison. by asymmetric cranial nerve deficits, cerebellar signs, and hemiparetic and hemisensory deficits. Respiratory failure can occur. The subacute course and the often minimally abnormal CSF findings may delay the diagnosis, which may be suggested by MRI showing ring-enhancing lesions after gadolinium contrast and hyperintense lesions on diffusion-weighted imaging. MRI is superior to CT for the diagnosis of these infections.


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InternalMed_Harrison. Infection in Pregnant Women and Neonates Listeriosis in pregnancy is a severe and important infection. The usual presentation is a nonspecific acute or subacute febrile illness with myalgias, arthralgias, backache, and headache. Pregnant women with listeriosis are usually bacteremic. This syndrome should prompt blood cultures, especially if there is no other reasonable explanation. Involvement of the CNS is rare in the absence of other risk factors. Preterm delivery is a common complication, and the diagnosis may be made only post-partum. As many as 70–90% of fetuses from infected women can become infected. Prepartum treatment of bacteremic women enhances the chances of delivery of a healthy infant. Women usually do well after delivery: maternal deaths are very rare, even when the diagnosis is made late in pregnancy or post-partum. Overall mortality rates for fetuses infected in utero approach 50% in some series; among live-born neonates treated with antibiotics, mortality rates are


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InternalMed_Harrison. is made late in pregnancy or post-partum. Overall mortality rates for fetuses infected in utero approach 50% in some series; among live-born neonates treated with antibiotics, mortality rates are much lower (~20%). Granulomatosis infantiseptica is an overwhelming listerial fetal infection with miliary microabscesses and granulomas, most often in the skin, liver, and spleen. Less severe neonatal infection acquired in utero presents at birth. “Late-onset” neonatal illness typically develops ~10–30 days post-partum. Mothers of infants with late-onset disease are not ill.


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InternalMed_Harrison. No clinical trials have compared antimicrobial agents for the treatment of L. monocytogenes infections. Data from studies conducted in vitro and in animals as well as observational clinical data indicate that ampicillin is the drug of choice, although penicillin also is highly active. Adults should receive IV ampicillin at high doses (2 g every 6 h). Many experts recommend the addition of gentamicin for synergy (1.0–1.7 mg/kg every 8 h); retrospective uncontrolled trials are not conclusive, but one study suggests that gentamicin may not help. TMP-SMX, given IV, is the best alternative for the penicillin-allergic patient (15–20 mg of TMP/kg per day in divided doses every 6–8 h). The dosages recommended cover CNS infection and 984 bacteremia (see below for duration); dosages must be reduced for patients with renal insufficiency. One small nonrandomized study supports a combination of ampicillin and TMP-SMX. Case reports document success with vancomycin, imipenem, meropenem, linezolid,


InternalMed_Harrison

InternalMed_Harrison. for patients with renal insufficiency. One small nonrandomized study supports a combination of ampicillin and TMP-SMX. Case reports document success with vancomycin, imipenem, meropenem, linezolid, tetracycline, and macrolides, although there are also reports of clinical failure or disease development with some of these agents. Acquired resistance to antimicrobial agents has been sought but not found in large strain collections. Cephalosporins are not effective and should not be used. Neonates should receive ampicillin and gentamicin at doses based on weight.


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InternalMed_Harrison. The duration of therapy depends on the syndrome: 2 weeks for bacteremia, 3 weeks for meningitis, 6–8 weeks for brain abscess/ encephalitis, and 4–6 weeks for endocarditis in both neonates and adults. Early-onset neonatal disease may be more severe and should be treated for >2 weeks. Many individuals who are promptly diagnosed and treated recover fully, but permanent neurologic sequelae are common in patients with brain abscess or rhombencephalitis. Focal infections of visceral organs; the eye; the pleural, peritoneal, and pericardial spaces; the bones; and both native and prosthetic joints have all been reported. Of 100 live-born, treated neonates in one series, 60% recovered fully, 24% died, and 13% had long-term neurologic or other complications.


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InternalMed_Harrison. Healthy persons should take standard precautions to prevent food-borne illness: fully cooking meats, washing fresh vegetables, carefully cleaning utensils, and avoiding unpasteurized dairy products. In addition, persons at risk for listeriosis, including pregnant women, should avoid soft cheeses (hard cheeses and yogurt are not problematic) and should avoid or thoroughly reheat ready-to-eat and delicatessen foods. Tetanus C. Louise Thwaites, Lam Minh Yen Tetanus is an acute disease manifested by skeletal muscle spasm and autonomic nervous system disturbance. It is caused by a powerful neurotoxin produced by the bacterium Clostridium tetani and is completely preventable by vaccination. C. 177 Infectious Diseases tetani is found throughout the world, and tetanus commonly occurs where the vaccination coverage rate is low. In developed countries, the disease is seen occasionally in individuals who are incompletely vaccinated. In any setting, established tetanus is a severe disease with a


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InternalMed_Harrison. coverage rate is low. In developed countries, the disease is seen occasionally in individuals who are incompletely vaccinated. In any setting, established tetanus is a severe disease with a high mortality rate.


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InternalMed_Harrison. Tetanus is diagnosed on clinical grounds (sometimes with supportive laboratory confirmation of the presence of C. tetani; see “Diagnosis,” below), and case definitions are often used to facilitate clinical and epidemiologic assessments. The Centers for Disease Control and Prevention (CDC) defines tetanus as “the acute onset of hypertonia or … painful muscular contractions (usually of the muscles of the jaw and neck) and generalized muscle spasms without other apparent medical cause.” Neonatal tetanus is defined by the World Health Organization (WHO) as “an illness occurring in a child who has the normal ability to suck and cry in the first 2 days of life but who loses this ability between days 3 and 28 of life and becomes rigid and has spasms.” Given the unique presentation of neonatal tetanus, the history generally permits accurate classification of the illness with a high degree of probability.


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InternalMed_Harrison. Maternal tetanus is defined by the WHO as tetanus occurring during pregnancy or within 6 weeks after the conclusion of pregnancy (whether with birth, miscarriage, or abortion). C. tetani is an anaerobic, gram-positive, spore-forming rod whose spores are highly resilient and can survive readily in the environment throughout the world. Spores resist boiling and many disinfectants. In addition, C. tetani spores and bacilli survive in the intestinal systems of many animals, and fecal carriage is common. The spores or bacteria enter the body through abrasions, wounds, or (in the case of neonates) the umbilical stump. Once in a suitable anaerobic environment, the organisms grow, multiply, and release tetanus toxin, an exotoxin that enters the nervous system and causes disease. Very low concentrations of this highly potent toxin can result in tetanus (minimum lethal human dose, 2.5 ng/kg).


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InternalMed_Harrison. In 20–30% of cases of tetanus, no puncture entry wound is found. Superficial abrasions to the limbs are the commonest infection sites in adults. Deeper infections (e.g., attributable to open fracture, abortion, or drug injection) are associated with more severe disease and worse outcomes. In neonates, infection of the umbilical stump can result from inadequate umbilical cord care; in some cultures, for example, the cord is cut with grass or animal dung is applied to the stump. Circumcision or ear-piercing also can result in neonatal tetanus.


InternalMed_Harrison

InternalMed_Harrison. Tetanus is a rare disease in the developed world. Two cases of neonatal tetanus have occurred in the United States since 1989. Between 2001 and 2008, a total of 231 cases of tetanus were reported to the U.S. national surveillance system. Most cases occur in incompletely vaccinated or unvaccinated individuals. Vaccination status is known in 50% of cases reported in the United States between 1972 and 2009; among these cases, only 16% of patients had had three or more doses of tetanus toxoid.


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InternalMed_Harrison. Persons >60 years of age are at greater risk of tetanus because antibody levels decrease over time. One-third of recent cases in the United States were in persons >65 years old. Injection drug users—particularly those injecting heroin subcutaneously (“skin-popping”)— are increasingly recognized as a high-risk group (15% of all cases in 2001–2008). In 2004, an outbreak of tetanus occurred in the United Kingdom, which had previously reported low rates among drug users. The reasons for this outbreak remain unclear but are thought to involve a combination of heroin contamination, skin-popping, and incomplete vaccination. Since then, only seven sporadic cases have been reported in the United Kingdom.


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InternalMed_Harrison. Genome sequencing of C. tetani has allowed identification of several exotoxins and virulence factors. Only those bacteria producing tetanus toxin (tetanospasmin) can cause tetanus. Although closely related to the botulinum toxins in structure and mode of action, tetanus toxin undergoes retrograde transport into the central nervous system and thus produces clinical effects different from those caused by the botulinum toxins, which remain at the neuromuscular junction.


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InternalMed_Harrison. Toxin is transported by intra-axonal transport to motor nuclei of the cranial nerves or ventral horns of the spinal cord. Tetanus toxin is produced as a single 150-kDa protein that is cleaved to produce heavy (100-kDa) and light (50-kDa) chains linked by a disulfide bond and noncovalent forces. The carboxy terminal of the heavy chain binds to specific membrane components in presynaptic α-motor nerve terminals; evidence suggests binding to both polysialogangliosides and membrane proteins. This binding results in toxin internalization and uptake into the nerves. Once inside the neuron, the toxin enters a retrograde transport pathway, whereby it is transported proximally to the motor neuron body in what appears to be a highly specific process. Unlike other components of the endosomal contents, which undergo acidification following internalization, tetanus toxin is transported in a carefully regulated pH-neutral environment that prevents an acid-induced conformational change that would


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InternalMed_Harrison. which undergo acidification following internalization, tetanus toxin is transported in a carefully regulated pH-neutral environment that prevents an acid-induced conformational change that would result in light-chain expulsion into the surrounding cytosol.


InternalMed_Harrison

InternalMed_Harrison. The next stage in toxin trafficking is less clearly understood but involves tetanus toxin’s escaping normal lysosomal degradation processes and undergoing translocation across the synapse to the GABA-ergic presynaptic inhibitory interneuron terminals. Here the light chain, which is a zinc-dependent endopeptidase, cleaves vesicle-associated membrane protein 2 (VAMP2, also known as synaptobrevin). This molecule is necessary for presynaptic binding and release of neurotransmitter; thus tetanus toxin prevents transmitter release and effectively blocks inhibitory interneuron discharge. The result is unregulated activity in the motor nervous system. Similar activity in the autonomic system accounts for the characteristic features of skeletal muscle spasm and autonomic system disturbance. The increased circulating catecholamine levels in severe tetanus are associated with cardiovascular complications.


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InternalMed_Harrison. Relatively little is known about the processes of recovery from tetanus. Recovery can take several weeks. Peripheral nerve sprouting is involved in recovery from botulism, and similar central nervous system sprouting may occur in tetanus. Other evidence suggests toxin degradation as a mechanism of recovery. APPROACH TO THE PATIENT: The clinical manifestations of tetanus occur only after tetanus toxin has reached presynaptic inhibitory nerves. Once these effects become apparent, there may be little that can be done to affect disease progression. Treatment should not be delayed while the results of laboratory tests are awaited. Management strategies aim to neutralize remaining unbound toxin and support vital functions until the effects of the toxin have worn off. Recent interest has focused on intrathecal methods of antitoxin administration to neutralize toxin within the central nervous system and limit disease progression (see “Treatment,” below).


InternalMed_Harrison

InternalMed_Harrison. Tetanus produces a wide spectrum of clinical features that are broadly divided into generalized (including neonatal) and local. In the usually mild form of local tetanus, only isolated areas of the body are affected and only small areas of local muscle spasm may be apparent. If the cra-985 nial nerves are involved in localized cephalic tetanus, the pharyngeal or laryngeal muscles may spasm, with consequent aspiration or airway obstruction, and the prognosis may be poor. In the typical progression of generalized tetanus (Fig. 177-1), muscles of the face and jaw often are affected first, presumably because of the shorter distances toxin must travel up motor nerves to reach presynaptic terminals. Neonates typically present with inability to suck.


InternalMed_Harrison

InternalMed_Harrison. In assessing prognosis, the speed at which tetanus develops is important. The incubation period (time from wound to first symptom) and the period of onset (time from first symptom to first generalized spasm) are of particular significance; shorter times are associated with worse outcome. In neonatal tetanus, the younger the infant is when symptoms occur, the worse the prognosis.


InternalMed_Harrison

InternalMed_Harrison. The commonest initial symptoms are trismus (lockjaw), muscle pain and stiffness, back pain, and difficulty swallowing. In neonates, difficulty in feeding is the usual presentation. As the disease progresses, muscle spasm develops. Generalized muscle spasm can be very painful. Commonly, the laryngeal muscles are involved early or even in isolation. This is a life-threatening event as complete airway obstruction may ensue. Spasm of the respiratory muscles results in respiratory failure. Without ventilatory support, respiratory failure is the commonest cause of death in tetanus. Spasms strong enough to produce tendon avulsions and crush fractures have been reported, but this outcome is rare.


InternalMed_Harrison

InternalMed_Harrison. Autonomic disturbance is maximal during the second week of severe tetanus, and death due to cardiovascular events becomes the major risk. Blood pressure is usually labile, with rapid fluctuations from high to low accompanied by tachycardia. Episodes of bradycardia and heart block can also occur. Autonomic involvement is evidenced by gastrointestinal stasis, sweating, increased tracheal secretions, and acute (often high-output) renal failure. The diagnosis of tetanus is based on clinical findings. As stated above, treatment should not be delayed while laboratory tests are conducted. Culture of C. tetani from a wound provides supportive evidence. Serum anti-tetanus immunoglobulin G may also be measured in a sample taken before the administration of antitoxin or immunoglobulin. Serum levels >0.1 IU/mL are deemed protective and do not support the diagnosis of tetanus. If levels are below this threshold, a Wound infection, multiplication of Ctetani


InternalMed_Harrison

InternalMed_Harrison. Wound infection, multiplication of Ctetani Initial symptoms: muscle aches, trismus, myalgia Tetanus toxin uptake into nervous system and VAMP cleavage in GABA inhibitory neurons Cardiovascular instability: labile BP, tachyor bradycardia Pyrexia, increased respiratory and GI secretions Muscle spasm: local and generalized Cardiovascular and autonomic control Cessation of spasms, restoration of normal muscle tone Toxin degradation Further toxin effects causing widespread disinhibition of motor and autonomic nervous system 4–6 weeks FIGURE 177-1 Clinical and pathologic progression of tetanus. BP, blood pressure; GABA, γ-aminobutyric acid; GI, gastrointestinal; VAMP, vesicle-associated membrane protein (synaptobrevin).


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InternalMed_Harrison. FIGURE 177-1 Clinical and pathologic progression of tetanus. BP, blood pressure; GABA, γ-aminobutyric acid; GI, gastrointestinal; VAMP, vesicle-associated membrane protein (synaptobrevin). 986 bioassay for serum tetanus toxin may be helpful, but a negative result does not exclude the diagnosis. Polymerase chain reaction also has been used for detection of tetanus toxin, but its sensitivity is unknown. The few conditions that mimic generalized tetanus include strychnine poisoning and dystonic reactions to antidopaminergic drugs. Abdominal muscle rigidity is characteristically continuous in tetanus but is episodic in the latter two conditions. Cephalic tetanus can be confused with other causes of trismus, such as oropharyngeal infection. Hypocalcemia and meningoencephalitis are included in the differential diagnosis of neonatal tetanus.


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InternalMed_Harrison. If possible, the entry wound should be identified, cleaned, and debrided of necrotic material in order to remove anaerobic foci of infection and prevent further toxin production. Metronidazole (400 mg rectally or 500 mg IV every 6 h for 7 days) is the preferred antibiotic. An alternative is penicillin (100,000–200,000 IU/kg per day), although this drug theoretically may exacerbate spasms. Failure to remove pockets of ongoing infection may result in recurrent or prolonged tetanus.


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InternalMed_Harrison. Antitoxin should be given early in an attempt to deactivate any circulating tetanus toxin and prevent its uptake into the nervous system. Two preparations are available: human tetanus immune globulin (TIG) and equine antitoxin. TIG is the preparation of choice, as it is less likely to be associated with anaphylactoid reactions. Recommended therapy is 3000–5000 IU of TIG as a single IM dose, a portion of which should be injected around the wound. Equine-derived antitoxin is available widely and is used in low-income countries at a dosage of 10,000–20,000 U administered IM as a single dose or as divided doses after testing for hypersensitivity. Some evidence indicates that intrathecal administration of TIG inhibits disease progression and leads to a better outcome. The results of relevant studies have been supported by a meta-analysis of trials involving both adults and neonates, with TIG doses of 50–1500 IU administered intrathecally.


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InternalMed_Harrison. Spasms are controlled by heavy sedation with benzodiazepines. Chlorpromazine and phenobarbital are commonly used worldwide, and IV magnesium sulfate has been used as a muscle relaxant. A significant problem with all these treatments is that the doses necessary to control spasms also cause respiratory depression; thus, in resource-limited settings without mechanical ventilators, controlling spasms while maintaining adequate ventilation is problematic, and respiratory failure is a common cause of death. In locations with ventilation equipment, severe spasms are best controlled with a combination of sedatives or magnesium and relatively short-acting, cardiovascularly inert, nondepolarizing neuromuscular blocking agents that allow titration against spasm intensity. Infusions of propofol have also been used successfully to control spasms and provide sedation.


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InternalMed_Harrison. It is important to establish a secure airway early in severe tetanus. Ideally, patients should be nursed in calm, quiet environments because light and noise can trigger spasms. Tracheal secretions are increased in tetanus, and dysphagia due to pharyngeal involvement combined with hyperactivity of laryngeal muscles makes endotracheal intubation difficult. Patients may need ventilator support for several weeks. Thus tracheostomy is the usual method of securing the airway in severe tetanus.


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InternalMed_Harrison. Cardiovascular instability in severe tetanus is notoriously difficult to treat. Rapid fluctuations in blood pressure and heart rate can occur. Cardiovascular stability is improved by increasing sedation with IV magnesium sulfate (plasma concentration, 2–4 mmol/L or titrated against disappearance of the patella reflex), morphine, or other sedatives. In addition, drugs acting specifically on the cardiovascular system (e.g., esmolol, calcium antagonists, and inotropes) may be required. Short-acting drugs that allow rapid titration are preferred; particular care should be taken when longer-acting β antagonists are administered, as their use has been associated with hypotensive cardiac arrest. Complications arising from treatment are common and include thrombophlebitis associated with diazepam injection, ventilator-associated pneumonia, central-line infections, and septicemia. In some centers, prophylaxis against deep-vein thrombosis and thromboembolism is routine.


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InternalMed_Harrison. Recovery from tetanus may take 4–6 weeks. Patients must be given a full primary course of immunization, as tetanus toxin is poorly immunogenic and the immune response following natural infection is inadequate. Rapid development of tetanus is associated with more severe disease and poorer outcome; it is important to note time of onset and length of incubation period. More sophisticated modeling has revealed other important predictors of prognosis (Table 177-1). Few studies have formally addressed long-term outcomes of tetanus. However, it is generally accepted that recovery is typically complete unless periods of hypoventilation have been prolonged or other complications have ensued. Studies of children and neonates have suggested a higher incidence of neurologic sequelae. Neonates may be at increased risk of learning disabilities, behavioral problems, cerebral palsy, and deafness.


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InternalMed_Harrison. Tetanus is prevented by good wound care and immunization (Chap. 148). In neonates, use of safe, clean delivery and cord-care practices as well as maternal vaccination are essential. The WHO guidelines for tetanus vaccination consist of a primary course of three doses in infancy, boosters at 4–7 and 12–15 years of age, and one booster in adulthood. In the United States, the CDC suggests an additional dose at 14–16 months and boosters every 10 years. “Catch-up” schedules recommend a three-dose primary course for unimmunized adolescents followed by two further doses. For persons who have received a complete primary course in childhood but no further boosters, two doses at least 4 weeks apart are recommended.


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InternalMed_Harrison. Standard WHO recommendations for prevention of maternal and neonatal tetanus call for administration of two doses of tetanus toxoid at least 4 weeks apart to previously unimmunized pregnant women. However, in high-risk areas, a more intensive approach has been successful, with all women of childbearing age receiving a primary course along with education on safe delivery and postnatal practices. Individuals sustaining tetanus-prone wounds should be immunized if their vaccination status is incomplete or unknown or if their last booster was given >10 years earlier. Patients sustaining wounds not classified as clean or minor should also undergo passive immunization with TIG. It is recommended that tetanus toxoid be given in conjunction with diphtheria toxoid in a preparation with or without acellular pertussis: DTaP for children <7 years old, Td for 7to 9-year olds, and Tdap for children >9 years old and adults.


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InternalMed_Harrison. In the early 1980s, tetanus caused more than 1 million deaths a year, accounting for an estimated 5% of maternal deaths and 14% of all neonatal deaths. In 1989, the World Health Age >70 years Younger age, premature birth Incubation period <7 days Incubation period <6 days Short time from first symptom to Delay in hospital admission Grass used to cut cord Puerperal, IV, postsurgery, burn entry Period of onseta <48 h Heart rate >140 beats/minb Systolic blood pressure >140 mmHgb Severe disease or spasmsb Temperature >38.5°Cb aTime from first symptom to first generalized spasm. bAt hospital admission.


InternalMed_Harrison

InternalMed_Harrison. Assembly adopted a resolution to eliminate neonatal tetanus by the year 2000; elimination was defined as <1 case/1000 live births in every district in every country. By 1999, elimination was still to be achieved in 57 countries and the deadline was extended until 2005, with the additional target of eliminating maternal tetanus (tetanus occurring during pregnancy or within 6 weeks of its end). Ratification of the Millennium Development Goals, in particular goal 4 (achieving a two-thirds reduction in the mortality rate among children under 5 by 2015), has further focused attention on reducing deaths from vaccine-preventable disease, particularly in the first 4 weeks of life.


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InternalMed_Harrison. Because vaccination reduces the incidence of neonatal tetanus by an estimated 94%, immunization of pregnant women with two doses of tetanus toxoid at least 4 weeks apart has been the primary method of maternal and neonatal tetanus elimination. In some areas, all women of childbearing age have been targeted as a means of increasing vaccination coverage. In addition, educational programs have focused on improving hygiene during the birth process, an intervention that in itself is estimated to reduce neonatal tetanus deaths by up to 40%.


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InternalMed_Harrison. The latest available data show that 34 countries have yet to eliminate maternal and neonatal tetanus, although incidence has declined significantly. Worldwide, deaths from neonatal tetanus fell by 92% between 1990 and 2008; in the latter year, with 84% of newborns protected from the disease by maternal vaccination, there were an estimated 59,000 neonatal tetanus deaths. Despite this relative success, immunization programs need to be ongoing as there is no tetanus herd immunity effect and C. tetani contamination of soil and feces is widespread.


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InternalMed_Harrison. Botulism Susan Maslanka, Agam K. Rao Botulism, recognized at least since the eighteenth century, is a neu-roparalytic disease caused by botulinum toxin, one of the most toxic substances known. While initially thought to be caused only by the ingestion of botulinum toxin in contaminated food (food-borne 178 botulism), three additional forms caused by in situ toxin production after germination of spores in either a wound or the intestine are now recognized worldwide: wound botulism, infant botulism, and adult intestinal colonization botulism. In addition to occurring in these recognized natural forms of the disease, botulism symptoms have been reported in patients receiving injections of botulinum toxin for cosmetic or therapeutic purposes (iatrogenic botulism). Moreover, botulism was reported after inhalation of botulinum toxin in a laboratory setting. All forms of botulism manifest as a relatively distinct clinical syndrome of symmetric cranial-nerve palsies followed by descending


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InternalMed_Harrison. after inhalation of botulinum toxin in a laboratory setting. All forms of botulism manifest as a relatively distinct clinical syndrome of symmetric cranial-nerve palsies followed by descending bilateral flaccid paralysis of voluntary muscles, which may progress to respiratory compromise and death. The mainstays of therapy are meticulous intensive care and treatment with antitoxin as soon as botulism is suspected and before other illnesses have been ruled out.


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InternalMed_Harrison. Seven serologically distinct confirmed serotypes of botulinum toxin (A through G) have been confirmed. Botulinum toxin is produced by four recognized species of clostridia: Clostridium botulinum, Clostridium argentinense, Clostridium baratii, and Clostridium butyricum. Certain strains may produce more than one serotype. All are anaerobic gram-positive organisms that form subterminal spores; C. botulinum and C. argentinense spores have been recovered from the environment. The spores survive environmental conditions and ordinary cooking procedures. Toxin production, however, requires a rare confluence of product storage conditions: an anaerobic environment, a pH of >4.6, low salt and sugar concentrations, and temperatures of >4°C. Although commonly ingested, spores do not normally germinate and produce toxin in the adult human intestine.


InternalMed_Harrison

InternalMed_Harrison. Food-borne botulism is caused by consumption of foods contami-987 nated with botulinum toxin; no confirmed host-specific factors are involved in the disease. Wound botulism is caused by contamination of wounds with C. botulinum spores, subsequent spore germination, and toxin production in the anaerobic milieu of an abscess or a wound. Infant botulism results from absorption of toxin produced in situ by toxigenic clostridia colonizing the intestine of children ≤1 year of age. Colonization is thought to occur because the normal bowel microbiota is not yet fully established; this theory is supported by studies in animals. Adult intestinal colonization botulism, a very rare form that is poorly understood, has a pathology similar to that of infant botulism but occurs in adults; typically, patients have some anatomic or functional bowel abnormality or have recently used antibiotics that may help toxigenic clostridia compete more successfully against the normal bowel microbiota. Despite


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InternalMed_Harrison. patients have some anatomic or functional bowel abnormality or have recently used antibiotics that may help toxigenic clostridia compete more successfully against the normal bowel microbiota. Despite antitoxin treatment, relapse due to intermittent intraluminal production of toxin may be observed in patients with adult intestinal colonization botulism.


InternalMed_Harrison

InternalMed_Harrison. Regardless of how exposure occurs, botulinum neurotoxin enters the vascular system and is transported to peripheral cholinergic nerve terminals, including neuromuscular junctions, postganglionic parasympathetic nerve endings, and peripheral ganglia. Botulinum toxin is a zinc-endopeptidase protein of ~150 kDa, consisting of a 100-kDa heavy chain and a 50-kDa light chain. Steps in neurotoxin activity include (1) heavy-chain binding to nerve terminals, (2) internalization in endocytic vesicles, (3) translocation of the light chain to cytosol, and (4) light-chain serotype-specific cleavage of one of several proteins involved in the release of the neurotransmitter acetylcholine. Inhibition of acetylcholine release by any of the seven toxin serotypes results in characteristic flaccid paralysis. Recovery follows sprouting of new nerve terminals.


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InternalMed_Harrison. All botulinum toxin serotypes have been demonstrated to cause botulism in nonhuman primates. Human cases associated with serotypes A, B, E, and F are reported each year. Serotype A produces the most severe syndrome, with the greatest proportion of patients requiring mechanical ventilation. Serotype B appears to cause milder disease than type A in both food-borne and infant botulism. Serotype E, most often associated with foods of aquatic origin, produces a syndrome of variable severity. The rare cases of illness caused by toxin serotype F, whether in infants or adults, are characterized by rapid progression to quadriplegia and respiratory failure but also by relatively rapid recovery. Recent studies have shown that at least some serotypes can be differentiated into subtypes through neurotoxin gene sequencing; however, the impact of these subtype differences on clinical illness is not yet known.


InternalMed_Harrison

InternalMed_Harrison. Botulism occurs worldwide, but the number of cases reported varies among countries and regions. The variation may be due not only to actual differences in incidence but also to (1) availability of resources to identify botulism, a rare disease; (2) differences in reporting requirements; and (3) limited external access to data collections. There is no universal surveillance system to capture worldwide botulism incidence. However, 30 countries currently participate in voluntary reporting of botulism cases to the European Union through an established surveillance system that includes standardized case definitions similar to those used in the United States and Canada. Other countries (e.g., Argentina, China, Thailand, Japan) maintain independent botulism surveillance.


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InternalMed_Harrison. Food-Borne Botulism From 1899 to 2011, 1225 food-borne botulism events (single cases or outbreaks) were reported in the United States; from 1990 to 2000, a median of 23 cases were reported annually. Most such events (~80%) involve vegetables or fish/ aquatic animals, usually home-preserved (canned, jarred). Native communities in both the United States (Alaska) and Canada have a high incidence of food-borne botulism due to traditional food-preparation practices; 85% of all cases in Canada occur in Native communities. Outbreaks typically involve two or three cases; however, one restaurant-associated outbreak in 1977 affected 59 persons. Worldwide, the highest incidence rate is reported from Georgia and Armenia in the southern Caucasus region, where illness is also associated with home-canning practices. Outbreaks in Asia are 988 attributable to consumption of home-preserved fish or vegetable products such as bean curd and bamboo shoots. In parts of Europe, including Poland, France, and


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InternalMed_Harrison. practices. Outbreaks in Asia are 988 attributable to consumption of home-preserved fish or vegetable products such as bean curd and bamboo shoots. In parts of Europe, including Poland, France, and Germany, illness is often associated with home-preserved meat such as ham or sausage. Since 1950, commercial products have rarely been implicated in botulism in the United States, and botulism from commercial products is most often attributed to consumer error in storage or cooking. However, manufacturer deficiencies do occur. In 2007, botulism developed in eight persons in the United States who consumed a commercially canned hot-dog chili sauce. Significant deficiencies discovered by regulatory authorities involved 91 different products and resulted in the recall of 111 million cans of food.


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InternalMed_Harrison. Wound Botulism This form of disease was first recognized in 1951 as a result of a review of the clinical records on an accidental injury in 1943. Between 1943 and 2011, 491 cases of wound botulism were reported in the United States; 97% of cases reported after 1990 were associated with injection drug use. The typical patient was a 30to 50-year-old resident of the western United States with a long history of black-tar heroin injection. In the early 2000s, wound botulism associated with drug use emerged in Europe, and at least two case clusters have been reported. Infant Botulism More than 3900 infant botulism cases have been reported worldwide (84% in the United States alone) since this form of the disease was first recognized in 1976; ~80–100 cases (commonly caused by serotypes A and B) are reported annually in the United States.


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InternalMed_Harrison. Adult Intestinal Colonization Botulism This form of botulism is difficult to confirm because it is poorly understood and because no clear guidelines are available to help differentiate it from other adult botulism cases. Often these cases are caused by C. baratii type F, but the involvement of both C. botulinum type A and C. butyricum type E has been reported.


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InternalMed_Harrison. Iatrogenic Botulism Paralysis of variable severity has followed injection of licensed botulinum toxin products for treatment of conditions involving hypertonicity of large muscle groups. The U.S. Food and Drug Administration received 658 reports of adverse events related to botulinum toxin use—some very serious—between 1997 and 2006. Although some patients had symptoms consistent with botulism, no cases were laboratory confirmed. Injection of approved doses of licensed products for cosmetic purposes has not been associated with botulism. However, four cases of laboratory-confirmed botulism resulted from illegal injection of research-grade toxin for cosmetic purposes in a U.S. medical facility in 2004. Inhalational Botulism Inhalational botulism does not occur naturally. One report from Germany has described botulism resulting from possible inhalational exposure to botulinum toxin in a laboratory incident.


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InternalMed_Harrison. Intentional Botulism Botulinum toxin has been “weaponized” by governments and terrorist organizations. An attack might use aerosolization of toxin or contamination of foods or beverages ranging in scope from small-scale tampering to contamination of a widely distributed food item. An unnatural event may be suggested by unusual relationships between patients (e.g., a visit to the same building), atypical exposure vehicles, or atypical toxin serotypes.


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InternalMed_Harrison. The distinctive clinical syndrome of botulism consists of symmetric cranial-nerve palsies followed by bilateral descending flaccid paralysis that may progress to respiratory failure and death. The incubation period from ingestion of contaminated food to onset of symptoms in food-borne botulism is usually 8–36 h but can be as long as 10 days and is dose dependent. Incubation periods of 4–17 days have been documented in wound botulism associated with accidental injury. However, estimation is difficult in cases involving injection drug users because most of these patients inject drugs several times daily. Similarly, the incubation period for infant botulism has not been established, but the fact that the illness has affected infants <3 days old suggests that this interval may be very short.


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InternalMed_Harrison. Cranial nerve deficits may include some of the following: diplopia, dysarthria, dysphonia, ptosis, ophthalmoplegia, facial paralysis, and impaired gag reflex. Pupillary reflexes may be depressed, and fixed or dilated pupils are sometimes noted. Autonomic symptoms such as dizziness, dry mouth, and very dry, occasionally sore throat are common. Constipation due to paralytic ileus is nearly universal, and urinary retention is also common. Patients are afebrile and remain alert and oriented. Respiratory failure may occur due to either paralysis of the diaphragm and accessory breathing muscles or pharyngeal collapse secondary to cranial nerve paralysis. Weakness descends, often rapidly, from the head to involve the neck, arms, thorax, and legs; occasionally, weakness is asymmetric. Deep tendon reflexes may be normal or may progressively disappear. Paresthesias, while rare, have been reported and may represent secondary nerve compression from immobility due to paralysis. Absence of cranial


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InternalMed_Harrison. reflexes may be normal or may progressively disappear. Paresthesias, while rare, have been reported and may represent secondary nerve compression from immobility due to paralysis. Absence of cranial nerve palsies or their onset after the appearance of other true neurologic symptoms makes botulism highly unlikely. Nausea, vomiting, and abdominal pain may precede or follow the onset of paralysis in food-borne botulism. Infants with botulism typically present with reduced ability to suck and swallow, constipation, weakened voice, ptosis, sluggish pupils, hypotonia, and floppy neck; as in adults, illness can progress to generalized flaccidity and respiratory compromise.


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InternalMed_Harrison. Even when intubated, patients can respond to questions by moving their fingers or toes unless paralysis has affected the digits. In some instances, unfortunately, the severe ptosis, expressionless face, and weak phonation of patients with botulism have been interpreted as signs of mental status changes due to alcohol intoxication, drug overdose, encephalitis, or meningitis—a conclusion that delays an accurate diagnosis. Because of skeletal muscle paralysis, patients experiencing respiratory distress may appear placid and detached even as they near respiratory arrest. Death in untreated botulism is usually due to airway obstruction from pharyngeal muscle paralysis and inadequate tidal volume resulting from paralysis of diaphragmatic and accessory respiratory muscles. Death can also result from hospital-associated infections and other sequelae of long-term paralysis, hospitalization, and mechanical ventilation.


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InternalMed_Harrison. A history of preparing home-canned foods may assist with the diagnosis. Patients with wound botulism may or may not have a discernible wound or abscess. A history of injection drug use or the presence of track marks may raise suspicion of the diagnosis. Clinical improvement follows sprouting of new nerve terminals and may take weeks to months. Patients often require outpatient rehabilitation therapy and may experience residual deficits.


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InternalMed_Harrison. Botulism is diagnosed primarily on clinical grounds, with laboratory confirmation by specific tests that identify botulinum toxin in clinical and food samples. In the setting of an outbreak with multiple patients presenting to the same treatment facility, the diagnosis is apparent as long as physicians recognize that cases within a cluster may have varied signs and symptoms. The temporal occurrence of two or more cases with symptoms compatible with botulism is essentially pathognomonic because other illnesses that resemble botulism do not usually occur in clusters. In lone (sporadic) cases, the diagnosis is often missed. The rarity of this disease prevents many physicians from gaining experience with its clinical diagnosis, and some patients present with signs and symptoms that do not fit the classic pattern. Assessing clinical characteristics of other paralytic illnesses in single cases is sometimes critical to rule in or rule out the diagnosis of botulism.