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InternalMed_Harrison. Confirmed epidemics, but not reported to WHO Yearly incidence rate [2010 2012], per 100,000 inhabitants >1000 [100–1000] [10–100] [1–10] [0.1–1] [0.01–0.1] <0.01 0 : No reported case FIGuRE 193-1 World distribution of cholera in 2010–2012. WHO, World Health Organization. (Courtesy of Drs. M. and R. Piarroux, Université de la Méditerranée, France; with permission.) before becoming a persistent endemic problem. Currently, >90% of cholera cases reported annually to the World Health Organization (WHO) are from Africa (Fig. 193-1), but the true burden in Africa as well as in Asia is unknown because diagnosis is often syndromic and because many countries with endemic cholera do not report cholera to the WHO. It is possible that >3 million cases of cholera occur yearly (of which only ~200,000 are reported to the WHO), resulting in >100,000 deaths annually (of which <5000 are reported to the WHO).


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InternalMed_Harrison. After a century without cholera in Latin America, the current cholera pandemic reached Central and South America in 1991. Following an initial explosive spread that affected millions, the burden of disease has markedly decreased in Latin America. In 2010, a severe cholera outbreak began in Haiti, a country with no recorded history of this disease. Several lines of evidence indicate that cholera was likely introduced into Haiti by United Nations security forces from Asia, raising the possibility that asymptomatic carriers of V. cholerae play an important role in transmitting cholera over long distances. To date, the outbreak has involved more than 700,000 individuals, resulting in thousands of deaths. The recent history of cholera has been punctuated by such severe outbreaks, especially among impoverished or displaced persons. These outbreaks are often precipitated by war or other circumstances that lead to the breakdown of public health measures. Such was the case in the camps for


InternalMed_Harrison

InternalMed_Harrison. among impoverished or displaced persons. These outbreaks are often precipitated by war or other circumstances that lead to the breakdown of public health measures. Such was the case in the camps for Rwandan refugees set up in 1994 around Goma, Zaire, and in 2008–2009 in Zimbabwe.


InternalMed_Harrison

InternalMed_Harrison. Sporadic endemic infections due to V. cholerae O1 strains related to the seventh-pandemic strain have been recognized along the U.S. Gulf Coast of Louisiana and Texas. These infections are typically associated with the consumption of contaminated, locally harvested shellfish. Occasionally, cases in U.S. locations remote from the Gulf Coast have been linked to shipped-in Gulf Coast seafood.


InternalMed_Harrison

InternalMed_Harrison. In October 1992, a large-scale outbreak of clinical cholera caused by a new serogroup, O139, occurred in southeastern India. The organism appears to be a derivative of El Tor O1 but has a distinct LPS and an immunologically related O-antigen polysaccharide capsule. (O1 organisms are not encapsulated.) After an initial spread across 11 Asian countries, V. cholerae O139 has once again been almost entirely replaced by O1 strains. The clinical manifestations of disease caused by V. cholerae O139 are indistinguishable from those of O1 cholera. Immunity to one, however, is not protective against the other.


InternalMed_Harrison

InternalMed_Harrison. In the final analysis, cholera is a toxin-mediated disease. The watery diarrhea characteristic of cholera is due to the action of cholera toxin, a potent protein enterotoxin elaborated by the organism in the small intestine. The toxin-coregulated pilus (TCP), so named because its synthesis is regulated in parallel with that of cholera toxin, is essential for V. cholerae to survive and multiply in (colonize) the small intestine. Cholera toxin, TCP, and several other virulence factors are coordinately regulated by ToxR. This protein modulates the expression of genes coding for virulence factors in response to environmental signals via a cascade of regulatory proteins. Additional regulatory processes, including bacterial responses to the density of the bacterial population (in a phenomenon known as quorum sensing), modulate the virulence of V. cholerae.


InternalMed_Harrison

InternalMed_Harrison. Once established in the human small bowel, the organism produces cholera toxin, which consists of a monomeric enzymatic moiety (the A subunit) and a pentameric binding moiety (the B subunit). The B pen-tamer binds to GM1 ganglioside, a glycolipid on the surface of epithelial cells that serves as the toxin receptor and makes possible the delivery of the A subunit to its cytosolic target. The activated A subunit (A1) irreversibly transfers ADP-ribose from nicotinamide adenine dinucleotide to its specific target protein, the GTP-binding regulatory component of adenylate cyclase. The ADP-ribosylated G protein upregulates the activity of adenylate cyclase; the result is the intracellular accumulation of high levels of cyclic AMP. In intestinal epithelial cells, cyclic AMP inhibits the absorptive sodium transport system in villus cells and activates the secretory chloride transport system in crypt cells, and these events lead to the accumulation of sodium chloride in the intestinal lumen.


InternalMed_Harrison

InternalMed_Harrison. sodium transport system in villus cells and activates the secretory chloride transport system in crypt cells, and these events lead to the accumulation of sodium chloride in the intestinal lumen. Because water moves passively to maintain osmolality, isotonic fluid accumulates in the lumen. When the volume of that fluid exceeds the capacity of the rest of the gut to resorb it, watery diarrhea results. Unless the wasted fluid and electrolytes are adequately replaced, shock (due to profound dehydration) and acidosis (due to loss of bicarbonate) follow. Although perturbation of the adenylate cyclase pathway is the primary mechanism by which cholera toxin causes excess fluid secretion, cholera toxin also enhances intestinal secretion via prostaglandins and/or neural histamine receptors.


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InternalMed_Harrison. The V. cholerae genome comprises two circular chromosomes. Lateral gene transfer has played a key role in the evolution of epidemic V. cholerae. The genes encoding cholera toxin (ctxAB) are part of the genome of a bacteriophage, CTXФ. The receptor for this phage on the V. cholerae surface is the intestinal colonization factor TCP. Because ctxAB is part of a mobile genetic element (CTXФ), horizontal transfer of this bacteriophage may account for the emergence of new toxigenic V. cholerae serogroups. Many of the other genes important for V. cholerae pathogenicity, including the genes encoding the biosynthesis of TCP, those encoding accessory colonization factors, and those regulating virulence gene expression, are clustered together in the V. cholerae pathogenicity island. Similar clustering of virulence genes is found in other bacterial pathogens. It is believed that pathogenicity islands are acquired by horizontal gene transfer.


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InternalMed_Harrison. V. cholerae O139 is probably derived from an El Tor O1 strain that acquired the genes for O139 O-antigen synthesis by horizontal gene transfer.


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InternalMed_Harrison. Individuals infected with V. cholerae O1 or O139 exhibit a range of clinical manifestations. Some individuals are asymptomatic or have only mild diarrhea; others present with the sudden onset of explosive and life-threatening diarrhea (cholera gravis). The reasons for the range in signs and symptoms of disease are incompletely understood but include the level of preexisting immunity, blood type, and nutritional status. In a nonimmune individual, after a 24to 48-h incubation period, cholera characteristically begins with the sudden onset of painless watery diarrhea that may quickly become voluminous. Patients often vomit. In severe cases, volume loss can exceed 250 mL/ kg in the first 24 h. If fluids and electrolytes are not replaced, hypovolemic shock and death may ensue. Fever is usually absent. Muscle cramps due to electrolyte disturbances are common. The stool has a characteristic appearance: a nonbilious, gray, slightly cloudy fluid with flecks of mucus, no blood, and a somewhat


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InternalMed_Harrison. absent. Muscle cramps due to electrolyte disturbances are common. The stool has a characteristic appearance: a nonbilious, gray, slightly cloudy fluid with flecks of mucus, no blood, and a somewhat fishy, inoffensive odor. It has been called “rice-water” stool because of its resemblance to the water in which rice has been washed (Fig. 193-2). Clinical symptoms


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InternalMed_Harrison. FIGuRE 193-2 Rice water cholera stool. Note floating mucus and gray watery appearance. (Courtesy of Dr. A. S. G. Faruque, International Centre for Diarrhoeal Disease Research, Dhaka; with permission.) parallel volume contraction: at losses of <5% of normal body weight, 1063 thirst develops; at 5–10%, postural hypotension, weakness, tachycardia, and decreased skin turgor are documented; and at >10%, oliguria, weak or absent pulses, sunken eyes (and, in infants, sunken fontanelles), wrinkled (“washerwoman”) skin, somnolence, and coma are characteristic. Complications derive exclusively from the effects of volume and electrolyte depletion and include renal failure due to acute tubular necrosis. Thus, if the patient is adequately treated with fluid and electrolytes, complications are averted and the process is self-limited, resolving in a few days.


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InternalMed_Harrison. Laboratory data usually reveal an elevated hematocrit (due to hemoconcentration) in nonanemic patients; mild neutrophilic leukocytosis; elevated levels of blood urea nitrogen and creatinine consistent with prerenal azotemia; normal sodium, potassium, and chloride levels; a markedly reduced bicarbonate level (<15 mmol/L); and an elevated anion gap (due to increases in serum lactate, protein, and phosphate). Arterial pH is usually low (~7.2).


InternalMed_Harrison

InternalMed_Harrison. Cholera should be suspected when a patient ≥2 years of age develops acute watery diarrhea in an area known to have cholera or when a patient ≥5 years of age develops severe dehydration or dies from acute watery diarrhea, even in an area where cholera is not known to be present. The clinical suspicion of cholera can be confirmed by the identification of V. cholerae in stool; however, the organism must be specifically sought. With experience, it can be detected directly by dark-field microscopy on a wet mount of fresh stool, and its serotype can be discerned by immobilization with specific antiserum. Laboratory isolation of the organism requires the use of a selective medium such as taurocholate-tellurite-gelatin (TTG) agar or thiosulfate–citrate–bile salts–sucrose (TCBS) agar. If a delay in sample processing is expected, Carey-Blair transport medium and/or alkaline-peptone water-enrichment medium may be used as well. In endemic areas, there is little need for biochemical confirmation


InternalMed_Harrison

InternalMed_Harrison. in sample processing is expected, Carey-Blair transport medium and/or alkaline-peptone water-enrichment medium may be used as well. In endemic areas, there is little need for biochemical confirmation and characterization, although these tasks may be worthwhile in places where V. cholerae is an uncommon isolate. Standard microbiologic biochemical testing for Enterobacteriaceae will suffice for identification of V. cholerae. All vibrios are oxidase-positive. A point-of-care antigen-detection cholera dipstick assay is now commercially available for use in the field or where laboratory facilities are lacking.


InternalMed_Harrison

InternalMed_Harrison. Death from cholera is due to hypovolemic shock; thus treatment of individuals with cholera first and foremost requires fluid resuscitation and management. In light of the level of dehydration (Table 193-1) and the patient’s age and weight, euvolemia should first be rapidly restored, and adequate hydration should then be maintained to replace ongoing fluid losses (Table 193-2). Administration of oral rehydration solution (ORS) takes advantage of the hexose-Na+ co-transport mechanism to move Na+ across the gut mucosa together with an actively transported molecule such as glucose (or galactose). Cl– and water follow. This transport mechanism remains intact even when cholera toxin is active. ORS may be made by adding safe water to prepackaged sachets containing salts and sugar or by adding 0.5 teaspoon of table salt and 6 teaspoons of table sugar to 1 L of safe water. Potassium intake in bananas or green coconut water should be encouraged. A number of ORS formulations are available, and


InternalMed_Harrison

InternalMed_Harrison. teaspoon of table salt and 6 teaspoons of table sugar to 1 L of safe water. Potassium intake in bananas or green coconut water should be encouraged. A number of ORS formulations are available, and the WHO now recommends “low-osmolarity” ORS for treatment of individuals with dehydrating diarrhea of any cause (Table 193-3). If available, rice-based ORS is considered superior to standard ORS in the treatment of cholera. ORS can be administered via a nasogastric tube to individuals who cannot ingest fluid; however, optimal management of individuals with severe dehydration includes the administration of IV fluid and electrolytes. Because profound acidosis (pH <7.2) is common in this group, Ringer’s lactate is the best choice among commercial products (Table 193-4); it must be used with additional potassium supplements, preferably given by mouth.


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InternalMed_Harrison. Degree of Dehydration Clinical Findings None or mild, but diarrhea Thirst in some cases; <5% loss of total body weight Moderate Thirst, postural hypotension, weakness, tachycardia, decreased skin turgor, dry mouth/ tongue, no tears; 5–10% loss of total body weight Severe Unconsciousness, lethargy, or “floppiness”; weak or absent pulse; inability to drink; sunken eyes (and, in infants, sunken fontanelles); >10% loss of total body weight TABLE 193-2 TREATMEnT OF CHOLERA, BAsEd On dEgREE OF dEHydRATIOna Degree of Dehydration, Patient’s Age (Weight) Treatmentb None or Mild, But Diarrheac <2 years 1/4–1/2 cup (50–100 mL) of ORS, to a maximum of 0.5 L/d 2–9 years 1/2–1 cup (100–200 mL) of ORS, to a maximum of 1 L/d ≥10 years As much ORS as desired, to a maximum of 2 L/d


InternalMed_Harrison

InternalMed_Harrison. Moderatec,d <4 months (<5 kg) 200–400 mL of ORS 4–11 months (5–<8 kg) 400–600 mL of ORS 12–23 months (8–<11 kg) 600–800 mL of ORS 2–4 years (11–<16 kg) 800–1200 mL of ORS 5–14 years (16–<30 kg) 1200–2200 mL of ORS ≥15 years (≥30 kg) 2200–4000 mL of ORS All ages and weights Undertake IV fluid replacement with Ringer’s lactate (or, if not available, normal saline). Give 100 mL/kg in the first 3-h period (or the first 6-h period for children <12 months old); start rapidly, then slow down. Give a total of 200 mL/ kg in the first 24 h. Continue until the patient is awake, can ingest ORS, and no longer has a weak pulse. aAdapted from World Health Organization: First steps for managing an outbreak of acute diarrhoea. Global Task Force on Cholera Control, 2009 (www.who.int/topics/cholera). bContinue normal feeding during treatment. cReassess regularly; monitor stool and vomit output. dVolumes of ORS listed should be given within the first 4 h. Abbreviation: ORS, oral rehydration solution.


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InternalMed_Harrison. Abbreviation: ORS, oral rehydration solution. TABLE 193-3 COMPOsITIOn OF wORLd HEALTH ORgAnIzATIOn REduCEd-OsMOLARITy ORAL REHydRATIOn sOLuTIOn (ORs)a,b Constituent Concentration, mmol/L aContains (per package, to be added to 1 L of drinking water): NaCl, 2.6 g; Na C H O ·2H O, 2.9 g; KCl, 1.5 g; and glucose (anhydrous), 13.5 g. bIf prepackaged ORS is unavailable, a simple homemade alternative can be prepared by combining 3.5 g (~1/2 teaspoon) of NaCl with either 50 g of precooked rice cereal or 6 teaspoons of table sugar (sucrose) in 1 L of drinking water. In that case, potassium must be supplied separately (e.g., in orange juice or coconut water). c10 mmol of citrate per liter, which supplies 30 mmol HCO3/L. Concentration, mmol/L aPotassium supplements, preferably administered by mouth, are required to replace the usual potassium losses from stool.


InternalMed_Harrison

InternalMed_Harrison. Concentration, mmol/L aPotassium supplements, preferably administered by mouth, are required to replace the usual potassium losses from stool. The total fluid deficit in severely dehydrated patients (>10% of body weight) can be replaced safely within the first 3–4 h of therapy, half within the first hour. Transient muscle cramps and tetany are common. Thereafter, oral therapy can usually be initiated, with the goal of maintaining fluid intake equal to fluid output. However, patients with continued large-volume diarrhea may require prolonged IV treatment to match gastrointestinal fluid losses. Severe hypokalemia can develop but will respond to potassium given either IV or orally. In the absence of adequate staff to monitor the patient’s progress, the oral route of rehydration and potassium replacement is safer than the IV route.


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InternalMed_Harrison. Although not necessary for cure, the use of an antibiotic to which the organism is susceptible diminishes the duration and volume of fluid loss and hastens clearance of the organism from the stool. Adjunctive antibiotics should therefore be administered to patients with moderate or severe dehydration due to cholera. In many areas, macrolides such as erythromycin (adults, 250 mg orally four times a day for 3 days; children, 12.5 mg/kg per dose four times a day for 3 days) or azithromycin (adults, a single 1-g dose; children, a single 20-mg/kg dose) are the agents of choice. Increasing resistance to tetracyclines is widespread; however, in areas with confirmed susceptibility, tetracycline (nonpregnant adults, 500 mg orally four times a day for 3 days; children >8 years old, 12.5 mg/kg per dose four times a day for 3 days) or doxycycline (nonpregnant adults, a 300-mg single dose; children >8 years old, a single dose of 4–6 mg/ kg) may be used. Similarly, increasing resistance to


InternalMed_Harrison

InternalMed_Harrison. per dose four times a day for 3 days) or doxycycline (nonpregnant adults, a 300-mg single dose; children >8 years old, a single dose of 4–6 mg/ kg) may be used. Similarly, increasing resistance to fluoroquinolones is being reported, but in areas with confirmed susceptibility, a fluoroquinolone such as ciprofloxacin may be used (adults, 500 mg twice a day for 3 days; children, 15 mg/kg twice a day for 3 days).


InternalMed_Harrison

InternalMed_Harrison. Provision of safe water and of facilities for sanitary disposal of feces, improved nutrition, and attention to food preparation and storage in the household can significantly reduce the incidence of cholera. In addition, precautions should be taken to prevent the spread of cholera via infected and potentially asymptomatic persons from endemic to nonendemic regions of the world (as was probably the case in the ongoing outbreak in Haiti; see “Microbiology and Epidemiology,” above).


InternalMed_Harrison

InternalMed_Harrison. Much effort has been devoted to the development of an effective cholera vaccine over the past few decades, with a particular focus on oral vaccine strains. In an attempt to maximize mucosal responses, two types of oral cholera vaccine have been developed: oral killed vaccines and live attenuated vaccines. Currently, two oral killed cholera vaccines have been prequalified by the WHO and are available internationally. WC-rBS (Dukoral®; Crucell, Stockholm, Sweden) contains several biotypes and serotypes of V. cholerae O1 supplemented with 1 mg of recombinant cholera toxin B subunit per dose. BivWC (Shanchol™; Shantha Biotechnics–Sanofi Pasteur, Mumbai, India) contains several biotypes and serotypes of V. cholerae O1 and


InternalMed_Harrison

InternalMed_Harrison. V. cholerae O139 without supplemental cholera toxin B subunit. The vaccines are administered as a twoor three-dose regimen, with doses usually separated by 14 days. They provide ~60–85% protection for the first few months. Booster immunizations of WC-rBS are recommended after 2 years for individuals ≥6 years of age and after 6 months for children 2–5 years of age. For BivWC, which was developed more recently, no formal recommendation regarding booster immunizations exists. However, BivWC was associated with ~60% protection over 5 years among recipients of all ages in a study in Kolkata, India; the rate of protection among children ≤5 years of age approximated 40%. Models predict significant herd immunity when vaccination coverage rates exceed 50%. The killed vaccines have been safely administered among populations with high rates of HIV.


InternalMed_Harrison

InternalMed_Harrison. Oral live attenuated vaccines for V. cholerae are also in development. These strains have in common the fact that they lack the genes encoding cholera toxin. One such vaccine, CVD 103-HgR, was safe and immunogenic in phase 1 and 2 studies but afforded minimal protection in a large field trial in Indonesia. Other live attenuated vaccine candidate strains have been prepared from El Tor and O139


InternalMed_Harrison

InternalMed_Harrison. V. cholerae and have been tested in studies of volunteers. A possible advantage of live attenuated cholera vaccines is that they may induce protection after a single oral dose. Conjugate and subunit cholera vaccines are also being developed. Recognizing that it may be decades before safe water and adequate sanitation become a reality for those most at risk of cholera, the WHO has now recommended incorporation of cholera vaccination into comprehensive control strategies and has established an international stockpile of oral killed cholera vaccine to assist in outbreak responses. No cholera vaccine is commercially available in the United States.


InternalMed_Harrison

InternalMed_Harrison. The genus Vibrio includes several human pathogens that do not cause cholera. Abundant in coastal waters throughout the world, noncholera vibrios can reach high concentrations in the tissues of filter-feeding mollusks. As a result, human infection commonly follows the ingestion of seawater or of raw or undercooked shellfish (Table 193-5). Most noncholera vibrios can be cultured on blood or MacConkey agar, which contains enough salt to support the growth of these halophilic species. In the microbiology laboratory, the species of noncholera vibrios are distinguished by standard biochemical tests. The most important of these organisms are Vibrio parahaemolyticus and Vibrio vulnificus.


InternalMed_Harrison

InternalMed_Harrison. The two major types of syndromes for which these species are responsible are gastrointestinal illness (due to V. parahaemolyticus, non-O1/O139 V. cholerae, Vibrio mimicus, Vibrio fluvialis, Vibrio hollisae, and Vibrio furnissii) and soft tissue infections (due to V. vulnificus, Vibrio alginolyticus, and Vibrio damselae). V. vulnificus is also a cause of primary sepsis in some compromised individuals.


InternalMed_Harrison

InternalMed_Harrison. V. parahaemolyticus Widespread in marine environments, the halophilic V. parahaemolyticus causes food-borne enteritis worldwide. This species was originally implicated in enteritis in Japan in 1953, accounting for 24% of reported cases in one study—a 1065 rate that presumably was due to the common practice of eating raw seafood in that country. In the United States, common-source outbreaks of diarrhea caused by this organism have been linked to the consumption of undercooked or improperly handled seafood or of other foods contaminated by seawater. Since the mid-1990s, the incidence of V. parahaemolyticus infections has increased in several countries, including the United States. Serotypes O3:K6, O4:K68, and O1:Kuntypable, which are genetically related to one another, account in part for this increase. Serotypes O4:K12 and O4:KUT were initially unique to the Pacific Northwest but caused recent outbreaks in the eastern United States and Spain. The enteropathogenicity of V.


InternalMed_Harrison

InternalMed_Harrison. in part for this increase. Serotypes O4:K12 and O4:KUT were initially unique to the Pacific Northwest but caused recent outbreaks in the eastern United States and Spain. The enteropathogenicity of V. parahaemolyticus is linked to its ability to cause hemolysis on Wagatsuma agar (i.e., the Kanagawa phenomenon). Although the mechanisms by which the organism causes diarrhea are not fully defined, the genome sequence of


InternalMed_Harrison

InternalMed_Harrison. V. parahaemolyticus contains two type III secretion systems, which directly inject toxic bacterial proteins into host cells. The activity of one of these secretion systems is required for intestinal colonization and virulence in animal models. V. parahaemolyticus should be considered a possible etiologic agent in all cases of diarrhea that can be linked epidemiologically to seafood consumption or to the sea itself.


InternalMed_Harrison

InternalMed_Harrison. Infections with V. parahaemolyticus can result in two distinct gastrointestinal presentations. The more common of the two presentations (including nearly all cases in North America) is characterized by watery diarrhea, usually occurring in conjunction with abdominal cramps, nausea, and vomiting and accompanied in ~25% of cases by fever and chills. After an incubation period of 4 h to 4 days, symptoms develop and persist for a median of 3 days. Dysentery, the less common presentation, is characterized by severe abdominal cramps, nausea, vomiting, and bloody or mucoid stools. V. parahaemolyticus also causes rare cases of wound infection and otitis and very rare cases of sepsis.


InternalMed_Harrison

InternalMed_Harrison. Most cases of V. parahaemolyticus–associated gastrointestinal illness, regardless of the presentation, are self-limited. Fluid replacement should be stressed. The role of antimicrobials is uncertain, but they may be of benefit in moderate or severe disease. Doxycycline, fluoroquinolones, or macrolides are usually used. Deaths are extremely rare among immunocompetent individuals. Severe infections are associated with underlying diseases, including diabetes, preexisting liver disease, iron-overload states, or immunosuppression. Non-O1/O139 (Noncholera) V. cholerae The heterogeneous non-O1/O139


InternalMed_Harrison

InternalMed_Harrison. Non-O1/O139 (Noncholera) V. cholerae The heterogeneous non-O1/O139 V. cholerae organisms cannot be distinguished from V. cholerae O1 or O139 by routine biochemical tests but do not agglutinate in O1 or O139 antiserum. Non-O1/O139 strains have caused several well-studied food-borne outbreaks of gastroenteritis and have also been responsible for sporadic cases of otitis media, wound infection, and bacteremia; although gastroenteritis outbreaks can occur, non-O1/O139 V. cholerae strains do not cause epidemics of cholera. Like other vibrios, non-O1/ O139 V. cholerae organisms are widely distributed in marine environments. In most instances, recognized cases in the United States have been associated with the consumption of raw oysters or with recent travel. The broad clinical spectrum of diarrheal illness caused by these aEspecially with liver disease or hemochromatosis. Source: Table 161-3 in Harrisons Principles of Internal Medicine, 14th edition.


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InternalMed_Harrison. 1066 organisms is probably due to the group’s heterogeneous virulence attributes. In the United States, about half of all non-O1/O139 V. cholerae isolates are from stool samples. The typical incubation period for gastroenteritis due to these organisms is <2 days, and the illness lasts for ~2–7 days. Patients’ stools may be copious and watery or may be partly formed, less voluminous, and bloody or mucoid. Diarrhea can result in severe dehydration. Many cases include abdominal cramps, nausea, vomiting, and fever. Like those with cholera, patients who are seriously dehydrated should receive oral or IV fluids; the value of antibiotics is not clear. Extraintestinal infections due to non-O1/O139 V. cholerae commonly follow occupational or recreational exposure to seawater. Around 10% of non-O1/O139 V. cholerae isolates come from cases of wound infection, 10% from cases of otitis media, and 20% from cases of bacteremia (which is particularly likely to develop in patients with liver disease).


InternalMed_Harrison

InternalMed_Harrison. V. cholerae isolates come from cases of wound infection, 10% from cases of otitis media, and 20% from cases of bacteremia (which is particularly likely to develop in patients with liver disease). Extraintestinal infections should be treated with antibiotics. Information to guide antibiotic selection and dosing is limited, but most strains are sensitive in vitro to tetracycline, ciprofloxacin, and third-generation cephalosporins.


InternalMed_Harrison

(See also Chap. 156)

InternalMed_Harrison. (See also Chap. 156)


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InternalMed_Harrison. V. vulnificus Infection with V. vulnificus is rare, but this organism is the most common cause of severe Vibrio infections in the United States. Like most vibrios, V. vulnificus proliferates in the warm summer months and requires a saline environment for growth. In the United States, infections in humans typically occur in coastal states between May and October and most commonly affect men >40 years of age. V. vulnificus has been linked to two distinct syndromes: primary sepsis, which usually occurs in patients with underlying liver disease, and primary wound infection, which generally affects people without underlying disease. (Vulnificus is Latin for “wound maker.”) Some authors have suggested that V. vulnificus also causes gastroenteritis independent of other clinical manifestations. V. vulnificus is endowed with a number of virulence attributes, including a capsule that confers resistance to phagocytosis and to the bactericidal activity of human serum as well as a cytolysin.


InternalMed_Harrison

InternalMed_Harrison. V. vulnificus is endowed with a number of virulence attributes, including a capsule that confers resistance to phagocytosis and to the bactericidal activity of human serum as well as a cytolysin. Measured as the 50% lethal dose in mice, the organism’s virulence is considerably increased under conditions of iron overload; this observation is consistent with the propensity of


InternalMed_Harrison

InternalMed_Harrison. V. vulnificus to infect patients who have hemochromatosis.


InternalMed_Harrison

InternalMed_Harrison. Primary sepsis most often develops in patients who have cirrhosis or hemochromatosis. However, V. vulnificus bacteremia can also affect individuals who have hematopoietic disorders or chronic renal insufficiency, those who are using immunosuppressive medications or alcohol, or (in rare instances) those who have no known underlying disease. After a median incubation period of 16 h, the patient develops malaise, chills, fever, and prostration. One-third of patients develop hypotension, which is often apparent at admission. Cutaneous manifestations develop in most cases (usually within 36 h of onset) and characteristically involve the extremities (the lower more often than the upper). In a common sequence, erythematous patches are followed by ecchymoses, vesicles, and bullae. In fact, sepsis and hemorrhagic bullous skin lesions suggest the diagnosis in appropriate settings. Necrosis and sloughing may also be evident. Laboratory studies reveal leukopenia more often than leukocytosis,


InternalMed_Harrison

InternalMed_Harrison. and hemorrhagic bullous skin lesions suggest the diagnosis in appropriate settings. Necrosis and sloughing may also be evident. Laboratory studies reveal leukopenia more often than leukocytosis, thrombocytopenia, or elevated levels of fibrin split products. V. vulnificus can be cultured from blood or cutaneous lesions. The mortality rate approaches 50%, with most deaths due to uncontrolled sepsis (Chap. 325). Accordingly, prompt treatment is critical and should include empirical antibiotic administration, aggressive debridement, and general supportive care. V. vulnificus is sensitive in vitro to a number of antibiotics, including tetracycline, fluoroquinolones, and third-generation cephalosporins. Data from animal models suggest that either a fluoroquinolone or the combination of a tetracycline and a third-generation cephalosporin should be used in the treatment of


InternalMed_Harrison

InternalMed_Harrison. V. vulnificus septicemia. V. vulnificus–associated soft tissue infection can complicate either a fresh or an old wound that comes into contact with seawater; the patient may or may not have underlying disease. After a short incubation period (4 h to 4 days; mean, 12 h), the disease begins with swelling, erythema, and (in many cases) intense pain around the wound. These signs and symptoms are followed by cellulitis, which spreads rapidly and is sometimes accompanied by vesicular, bullous, or necrotic lesions. Metastatic events are uncommon. Most patients have fever and leukocytosis. V. vulnificus can be cultured from skin lesions and occasionally from the blood. Prompt antibiotic therapy and debridement are usually curative. V. alginolyticus First identified as a pathogen of humans in 1973,


InternalMed_Harrison

InternalMed_Harrison. V. alginolyticus First identified as a pathogen of humans in 1973, V. alginolyticus occasionally causes eye, ear, and wound infections. This species is the most salt-tolerant of the vibrios and can grow in salt concentrations of >10%. Most clinical isolates come from superinfected wounds that presumably become contaminated at the beach. Although its severity varies, V. alginolyticus infection tends not to be serious and generally responds well to antibiotic therapy and drainage. A few cases of otitis externa, otitis media, and conjunctivitis due to this pathogen have been described. Tetracycline treatment usually results in cure. V. alginolyticus is a rare cause of bacteremia in immunocompromised hosts. The authors gratefully acknowledge the valuable contributions of Drs.≥Robert Deresiewicz and Gerald T. Keusch, coauthors of this chapter for previous editions.


InternalMed_Harrison

InternalMed_Harrison. The authors gratefully acknowledge the valuable contributions of Drs.≥Robert Deresiewicz and Gerald T. Keusch, coauthors of this chapter for previous editions. Brucellosis Nicholas J. Beeching, Michael J. Corbel DEFINITION Brucellosis is a bacterial zoonosis transmitted directly or indirectly to humans from infected animals, predominantly domesticated rumi-nants and swine. The disease is known colloquially as undulant fever 194e because of its remittent character. Although brucellosis commonly presents as an acute febrile illness, its clinical manifestations vary widely, and definitive signs indicative of the diagnosis may be lacking. Thus the clinical diagnosis usually must be supported by the results of bacteriologic and/or serologic tests.


InternalMed_Harrison

InternalMed_Harrison. Human brucellosis is caused by strains of Brucella, a bacterial genus that was previously suggested, on genetic grounds, to comprise a single species, B. melitensis, with a number of biologic variants exhibiting particular host preferences. This view was challenged on the basis of detailed differences in chromosomal structure and host preference. The traditional classification into nomen species is now favored both because of these differences and because this classification scheme closely reflects the epidemiologic patterns of the infection. The nomen system recognizes B. melitensis, which is the most common cause of symptomatic disease in humans and for which the main sources are sheep, goats, and camels; B. abortus, which is usually acquired from cattle or buffalo; B. suis, which generally is acquired from swine but has one variant enzootic in reindeer and caribou and another in rodents; and B. canis, which is acquired most often from dogs. B. ovis, which causes reproductive


InternalMed_Harrison

InternalMed_Harrison. generally is acquired from swine but has one variant enzootic in reindeer and caribou and another in rodents; and B. canis, which is acquired most often from dogs. B. ovis, which causes reproductive disease in sheep, and B. neotomae, which is specific for desert rodents, have not been clearly implicated in human disease. Two new species, B. ceti and B. pinnipedialis, have recently been identified in marine mammals, including seals and dolphins. At least one case of laboratory-acquired human disease due to one of these species has been described, and apparent cases of natural human infection have been reported. As infections in marine mammals appear to be widespread, more cases of zoonotic infection in humans may be identified. Other newly reported species include B. microti (isolated from field voles) and B. inopinata (isolated from a patient with a breast implant). Additional novel strains have been described from diverse species, including baboons, foxes, frogs, and various rodents,


InternalMed_Harrison

InternalMed_Harrison. field voles) and B. inopinata (isolated from a patient with a breast implant). Additional novel strains have been described from diverse species, including baboons, foxes, frogs, and various rodents, and the genus likely will expand further in forthcoming years. Moreover, it has become apparent that Brucella is closely related to the genus Ochrobactrum, which includes environmental bacteria sometimes associated with opportunistic infections. Genomics-based studies are beginning to elucidate the pathway of evolution from free-living soil bacteria to highly successful intracellular pathogens.


InternalMed_Harrison

InternalMed_Harrison. All brucellae are small, gram-negative, unencapsulated, nonsporulating, nonmotile rods or coccobacilli. They grow aerobically on peptonebased medium incubated at 37°C; the growth of some types is improved by supplementary CO2. In vivo, brucellae behave as facultative intracellular parasites. The organisms are sensitive to sunlight, ionizing radiation, and moderate heat; they are killed by boiling and pasteurization but are resistant to freezing and drying. Their resistance to drying renders brucellae stable in aerosol form, facilitating airborne transmission. The organisms can survive for up to 2 months in soft cheeses made from goat’s or sheep’s milk; for at least 6 weeks in dry soil contaminated with infected urine, vaginal discharge, or placental or fetal tissues; and for at least 6 months in damp soil or liquid manure kept under cool dark conditions. Brucellae are easily killed by a wide range of common disinfectants used under optimal conditions but are likely to be much more


InternalMed_Harrison

InternalMed_Harrison. months in damp soil or liquid manure kept under cool dark conditions. Brucellae are easily killed by a wide range of common disinfectants used under optimal conditions but are likely to be much more resistant at low temperatures or in the presence of heavy organic contamination.


InternalMed_Harrison

InternalMed_Harrison. Brucellosis is a zoonosis whose occurrence and control are closely related to its prevalence in domesticated animals. Its distribution is worldwide apart from the few countries where it has been eradicated from the animal reservoir. The true global 194e-1 prevalence of human brucellosis is unknown because of the imprecision of diagnosis and the inadequacy of reporting and surveillance systems in many countries. Recently, there has been increased recognition of the high incidence of brucellosis in India and parts of China and of importations to countries in Oceania, such as Fiji. In Europe, the incidence of brucellosis in a country is inversely related to gross domestic product, and, in both developed and less well-resourced settings, human brucellosis is related to rural poverty and inadequate access to medical care. Failure of veterinary control programs due to conflict or for economic reasons contributes further to the emergence and re-emergence of disease, as seen currently in some


InternalMed_Harrison

InternalMed_Harrison. access to medical care. Failure of veterinary control programs due to conflict or for economic reasons contributes further to the emergence and re-emergence of disease, as seen currently in some eastern Mediterranean countries.


InternalMed_Harrison

InternalMed_Harrison. Even in well-resourced settings, the true incidence of brucellosis in domesticated animals may be 10–20 times higher than the reported figures. Bovine brucellosis has been the target of control programs in many parts of the world and has been eradicated from the cattle populations of Australia, New Zealand, Bulgaria, Canada, Cyprus, Great Britain (including the Channel Islands), Japan, Luxembourg, Romania, the Scandinavian countries, Switzerland, and the Czech and Slovak Republics, among other nations. Its incidence has been reduced to a low level in the United States and most Western European countries, with a varied picture in other parts of the world. Efforts to eradicate B. melitensis infection from sheep and goat populations have been much less successful. These efforts have relied heavily on vaccination programs, which have tended to fluctuate with changing economic and political conditions. In some countries (e.g., Israel), B. melitensis has caused serious outbreaks in cattle.


InternalMed_Harrison

InternalMed_Harrison. on vaccination programs, which have tended to fluctuate with changing economic and political conditions. In some countries (e.g., Israel), B. melitensis has caused serious outbreaks in cattle. Infections with B. melitensis still pose a major public health problem in Mediterranean countries; in western, central, and southern Asia; and in parts of Africa and South and Central America.


InternalMed_Harrison

InternalMed_Harrison. Human brucellosis is usually associated with occupational or domestic exposure to infected animals or their products. Farmers, shepherds, goatherds, veterinarians, and employees in slaughterhouses and meat-processing plants in endemic areas are occupationally exposed to infection. Family members of individuals involved in animal husbandry may be at risk, although it is often difficult to differentiate food-borne infection from environmental contamination under these circumstances. Laboratory workers who handle cultures or infected samples also are at risk. Travelers and urban residents usually acquire the infection through consumption of contaminated foods. In countries that have eradicated the disease, new cases are most commonly acquired abroad. Dairy products, especially soft cheeses, unpasteurized milk, and ice cream, are the most frequently implicated sources of infection; raw meat and bone marrow may be sources under exceptional circumstances. Infections acquired through


InternalMed_Harrison

InternalMed_Harrison. unpasteurized milk, and ice cream, are the most frequently implicated sources of infection; raw meat and bone marrow may be sources under exceptional circumstances. Infections acquired through cosmetic treatments using materials of fetal origin have been reported. Person-to-person transmission is extremely rare, as is transfer of infection by blood or tissue donation. Although brucellosis is a chronic intracellular infection, there is no evidence for increased prevalence or severity among individuals with HIV infection or with immunodeficiency or immunosuppression of other etiologies.


InternalMed_Harrison

InternalMed_Harrison. Brucellosis may be acquired by ingestion, inhalation, or mucosal or percutaneous exposure. Accidental injection of the live vaccine strains of B. abortus (S19 and RB51) and B. melitensis (Rev 1) can cause disease. B. melitensis and B. suis have historically been developed as biological weapons by several countries and could be exploited for bioterrorism (Chap. 261e). This possibility should be borne in mind in the event of sudden unexplained outbreaks. Exposure to brucellosis elicits both humoral and cell-mediated immune responses. The mechanisms of protective immunity against human brucellosis are presumed to be similar to those documented in laboratory animals, but such generalizations must be interpreted with caution. The response to infection and its outcome are influenced by the virulence, phase, and species of the infecting strain. Differences have been reported between B. abortus and B. suis in modes of cellular entry and subsequent compartmentalization and processing.


InternalMed_Harrison

InternalMed_Harrison. Antibodies promote clearance of extracellular brucellae by bactericidal action and by facilitation of phagocytosis by polymorphonuclear and mononuclear phagocytes; however, antibodies alone cannot eradicate infection. Organisms taken up by macrophages and other cells can establish persistent intracellular infections. The key target cell is the macrophage, and bacterial mechanisms for suppressing intracellular killing and apoptosis result in very large intracellular populations. Opsonized bacteria are actively phagocytosed by neutrophilic granulocytes and by monocytes. In these and other cells, initial attachment takes place via specific receptors, including Fc, C3, fibronectin, and mannose-binding proteins. Opsonized—but not unopsonized—bacteria trigger an oxidative burst inside phagocytes. Unopsonized bacteria are internalized via similar receptors but at much lower efficiency. Smooth strains enter host cells via lipid rafts. Smooth lipopolysaccharide (LPS), β-cyclic glucan, and


InternalMed_Harrison

InternalMed_Harrison. Unopsonized bacteria are internalized via similar receptors but at much lower efficiency. Smooth strains enter host cells via lipid rafts. Smooth lipopolysaccharide (LPS), β-cyclic glucan, and possibly an invasion-attachment protein (IalB) are involved in this process. Tumor necrosis factor α (TNF-α) produced early in the course of infection stimulates cytotoxic lymphocytes and activates macrophages, which can kill intracellular brucellae (probably mainly through production of reactive oxygen and nitrogen intermediates) and may clear infection. However, virulent Brucella cells can suppress the TNF-α response, and control of infection in this situation depends on macrophage activation and interferon γ (IFN-γ) responses. Cytokines such as interleukin (IL) 12 promote production of IFN-γ, which drives TH1-type responses and stimulates macrophage activation. Inflammatory cytokines, including IL-4, IL-6, and IL-10, downregulate the protective response. As in other types of intracellular


InternalMed_Harrison

InternalMed_Harrison. which drives TH1-type responses and stimulates macrophage activation. Inflammatory cytokines, including IL-4, IL-6, and IL-10, downregulate the protective response. As in other types of intracellular infection, it is assumed that initial replication of brucellae takes place within cells of the lymph nodes draining the point of entry. Subsequent hematogenous spread may result in chronic localizing infection at almost any site, although the reticuloendothelial system, musculoskeletal tissues, and genitourinary system are most frequently targeted. Both acute and chronic inflammatory responses develop in brucellosis, and the local tissue response may include granuloma formation with or without necrosis and caseation. Abscesses may also develop, especially in chronic localized infection.


InternalMed_Harrison

InternalMed_Harrison. The determinants of pathogenicity of Brucella have not been fully characterized, and the mechanisms underlying the manifestations of brucellosis are incompletely understood. The organism is a “stealth” pathogen whose survival strategy is centered on several processes that avoid triggering innate immune responses and that permit survival within monocytic cells. The smooth Brucella LPS, which has an unusual O-chain and core-lipid composition, has relatively low endotoxin activity and plays a key role in pyrogenicity and in resistance to phagocytosis and serum killing in the nonimmune host. In addition, LPS is believed to play a role in suppressing phagosome–lysosome fusion and diverting the internalized bacteria into vacuoles located in endoplasmic reticulum, where intracellular replication takes place. Specific exotoxins have not been isolated, but a type IV secretion system (VirB) that regulates intracellular survival and trafficking has been identified. In B. abortus this system can


InternalMed_Harrison

InternalMed_Harrison. takes place. Specific exotoxins have not been isolated, but a type IV secretion system (VirB) that regulates intracellular survival and trafficking has been identified. In B. abortus this system can be activated extracellularly, but in B. suis it is activated (by low pH) only during intracellular growth. Brucellae then produce acid-stable proteins that facilitate the organisms’ survival in phagosomes and may enhance their resistance to reactive oxygen intermediates. A type III secretion system based on modified flagellar structures also has been inferred, although not yet confirmed. Virulent brucellae are resistant to defensins and produce a Cu-Zn superoxide dismutase that increases their resistance to reactive oxygen intermediates. A hemolysin-like protein may trigger the release of brucellae from infected cells.


InternalMed_Harrison

InternalMed_Harrison. Brucellosis almost invariably causes fever, which may be associated with profuse sweats, especially at night. In endemic areas, brucellosis may be difficult to distinguish from the many other causes of fever. However, two features recognized in the nineteenth century distinguish brucellosis from other tropical fevers, such as typhoid and malaria: (1) Left untreated, the fever of brucellosis shows an undulating pattern that persists for weeks before the commencement of an afebrile period that may be followed by relapse. (2) The fever of brucellosis is associated with musculoskeletal symptoms and signs in about one-half of all patients. The clinical syndromes caused by the different nomen species are similar, although B. melitensis tends to be associated with a more acute and aggressive presentation and B. suis with focal abscess induction.


InternalMed_Harrison

InternalMed_Harrison. B. abortus infections may be more insidious in onset and more likely to become chronic. B. canis infections are reported to present frequently with acute gastrointestinal symptoms. The incubation period varies from 1 week to several months, and the onset of fever and other symptoms may be abrupt or insidious. In addition to experiencing fever and sweats, patients become increasingly apathetic and fatigued; lose appetite and weight; and have nonspecific myalgia, headache, and chills. Overall, the presentation of brucellosis often fits one of three patterns: febrile illness that resembles typhoid but is less severe; fever and acute monoarthritis, typically of the hip or knee, in a young child; and long-lasting fever, misery, and low-back or hip pain in an older man. In an endemic area (e.g., much of the Middle East), a patient with fever and difficulty walking into the clinic would be regarded as having brucellosis until it was proven otherwise.


InternalMed_Harrison

InternalMed_Harrison. Diagnostic clues in the patient’s history include travel to an endemic area, employment in a diagnostic microbiology laboratory, consumption of unpasteurized milk products (including soft cheeses), contact with animals, accidental inoculation with veterinary Brucella vaccines, and—in an endemic setting—a history of similar illness in the family (documented in almost 50% of cases). Focal features are present in the majority of patients. The most common are musculoskeletal pain and physical findings in the peripheral and axial skeleton (~40% of cases). Osteomyelitis more commonly involves the lumbar and low thoracic vertebrae than the cervical and high thoracic spine. Individual joints that are most commonly affected by septic arthritis are the knee, hip, sacroiliac, shoulder, and sternoclavicular joints; the pattern may be one of monoarthritis or polyarthritis. Osteomyelitis may also accompany septic arthritis.


InternalMed_Harrison

InternalMed_Harrison. In addition to the usual causes of vertebral osteomyelitis or septic arthritis, the most important disease in the differential diagnosis is tuberculosis. This point influences the therapeutic approach as well as the prognosis, given that several antimicrobial agents used to treat brucellosis are also used to treat tuberculosis. Septic arthritis in brucellosis progresses slowly, starting with small pericapsular erosions. In the vertebrae, anterior erosions of the superior end plate are typically the first features to become evident, with eventual involvement and sclerosis of the whole vertebra. Anterior osteophytes eventually develop, but vertebral destruction or impingement on the spinal cord is rare and usually suggests tuberculosis (Table 194e-1).


InternalMed_Harrison

InternalMed_Harrison. Other systems may be involved in a manner that resembles typhoid. About one-quarter of patients have a dry cough, usually with few changes visible on the chest x-ray, although pneumonia, empyema, intrathoracic adenopathy, or lung abscess can occur. Sputum or pleural effusion cultures are rarely positive in such cases, which respond well to standard brucellosis treatment. One-quarter of patients have hepatosplenomegaly, and 10–20% have significant lymphadenopathy; the differential diagnosis includes glandular fever–like illness such as that caused by Epstein-Barr virus, Toxoplasma, cytomegalovirus, HIV, or Mycobacterium tuberculosis. Up to 10% of men have acute epididymoorchitis, which must be distinguished from mumps and from surgical problems such as torsion. Prostatitis, inflammation of the seminal vesicles, salpingitis, and pyelonephritis all occur. There is an increased incidence of fetal loss among infected pregnant women, although teratogenicity has not been described and the


InternalMed_Harrison

InternalMed_Harrison. of the seminal vesicles, salpingitis, and pyelonephritis all occur. There is an increased incidence of fetal loss among infected pregnant women, although teratogenicity has not been described and the tendency toward abortions is much less pronounced in humans than in farm animals.


InternalMed_Harrison

InternalMed_Harrison. Neurologic involvement is common, with depression and lethargy whose severity may not be fully appreciated by either the patient or the physician until after treatment. A small proportion of patients develop lymphocytic meningoencephalitis that mimics neurotuberculosis, atypical leptospirosis, or noninfectious conditions and that may be complicated by intracerebral abscess, a variety of cranial nerve deficits, or ruptured mycotic aneurysms. Endocarditis occurs in ~1% of cases, most often affecting the aortic valve (natural or prosthetic). Any site in the body may be involved in metastatic abscess formation or inflammation; the female breast and the thyroid gland are affected particularly often. Nonspecific maculopapular rashes and other skin manifestations are uncommon and are rarely noticed by the patient even if they develop.


InternalMed_Harrison

InternalMed_Harrison. Because the clinical picture of brucellosis is not distinctive, the diagnosis must be based on a history of potential exposure, a presentation consistent with the disease, and supporting laboratory findings. Results of routine biochemical assays are usually within normal limits, although serum levels of hepatic enzymes and bilirubin may be elevated. Peripheral leukocyte counts are usually normal or low, with relative lymphocytosis. Mild anemia may be documented. Thrombocytopenia and disseminated intravascular coagulation with raised levels of fibrinogen degradation products can develop. The erythrocyte sedimentation rate and C-reactive protein levels are often normal but may be raised.


InternalMed_Harrison

InternalMed_Harrison. In body fluids such as cerebrospinal fluid (CSF) or joint fluid, lymphocytosis and low glucose levels are the norm. Elevated CSF levels of adenosine deaminase cannot be used to distinguish tubercular meningitis, as they may also be found in brucellosis. Biopsied samples of tissues such as lymph node or liver may show noncaseating granulomas (Fig. 194e-1) without acid/alcohol-fast bacilli. The radiologic features of bony disease develop late and are much more subtle than those of FIGURE 194e-1 Liver biopsy specimen from a patient with brucellosis shows a noncaseating granuloma. (From Mandell’s Atlas of Infectious Diseases, Vol II, in DL Stevens [ed]: Skin, Soft Tissue, Bone and Joint Infections, Fig. 5-9; with permission.) tuberculosis or septic arthritis of other etiologies, with less bone and 194e-3 joint destruction. Isotope scanning is more sensitive than plain x-ray and continues to give positive results long after successful treatment.


InternalMed_Harrison

InternalMed_Harrison. Isolation of brucellae from blood, CSF, bone marrow, or joint fluid or from a tissue aspirate or biopsy sample is definitive, and attempts at isolation are usually successful in 50–70% of cases. Duplicate cultures should be incubated for up to 6 weeks (in air and 10% CO2, respectively). Concentration and lysis of buffy coat cells before culture may increase the isolation rate. Cultures in modern nonradiometric or similar signaling systems (e.g., Bactec) usually become positive within 7–10 days but should be maintained for at least 3 weeks before the results are declared negative. All cultures should be handled under containment conditions appropriate for dangerous pathogens. Brucella species may be misidentified as Agrobacterium, Ochrobactrum, or Psychrobacter (Moraxella) phenylpyruvicus by the gallery identification strips commonly used in the diagnostic laboratory. In recent years, matrix-assisted laser desorption ionization time-of-flight spectrometry (MALDI-TOF MS) has emerged as


InternalMed_Harrison

InternalMed_Harrison. by the gallery identification strips commonly used in the diagnostic laboratory. In recent years, matrix-assisted laser desorption ionization time-of-flight spectrometry (MALDI-TOF MS) has emerged as a powerful tool in bacterial identification. The relative homogeneity of classical Brucella species makes identification beyond the genus level by routine approaches challenging, although further improvements may facilitate discrimination at the species level. The place of this technique in routine diagnostic practice will depend on such refinements. Meanwhile, the authors are aware of cases in which blood culture isolates have been identified incorrectly using MALDI-TOF MS.


InternalMed_Harrison

InternalMed_Harrison. The peripheral blood–based polymerase chain reaction has enormous potential to detect bacteremia, to predict relapse, and to exclude “chronic brucellosis.” This method is probably more sensitive and is certainly quicker than blood culture, and it does not carry the attendant biohazard risk posed by culture. Nucleic acid amplification techniques are now quite widely used, although no single standardized procedure has been adopted. Primers for the spacer region between the genes encoding the 16S and 23S ribosomal RNAs (rrs-rrl), various outer-membrane protein–encoding genes, the insertion sequence IS711, and the protein BCSP31 are sensitive and specific. Blood and other tissues are the most suitable samples for analysis.


InternalMed_Harrison

InternalMed_Harrison. Serologic examination often provides the only positive laboratory findings in brucellosis. In acute infection, IgM antibodies appear early and are followed by IgG and IgA. All these antibodies are active in agglutination tests, whether performed by tube, plate, or microagglutination methods. The majority of patients have detectable agglutinins at this stage. As the disease progresses, IgM levels decline, and the avidity and subclass distribution of IgG and IgA change. The result is reduced or undetectable agglutinin titers. However, the antibodies are detectable by alternative tests, including the complement fixation test, Coomb’s antiglobulin test, and enzyme-linked immunosorbent assay. There is no clear cutoff value for a diagnostic titer. Rather, serology results must be interpreted in the context of exposure history and clinical presentation. In endemic areas or in settings of potential occupational exposure, agglutinin titers of 1:320–1:640 or higher are considered diagnostic; in


InternalMed_Harrison

InternalMed_Harrison. the context of exposure history and clinical presentation. In endemic areas or in settings of potential occupational exposure, agglutinin titers of 1:320–1:640 or higher are considered diagnostic; in nonendemic areas, a titer of ≥1:160 is considered significant. Repetition of tests after 2–4 weeks may demonstrate a rising titer.


InternalMed_Harrison

InternalMed_Harrison. In most centers, the standard agglutination test is still the mainstay of serologic diagnosis, although some investigators rely on the rose bengal test, which has not been fully validated for human diagnostic use. Dipstick assays for anti-Brucella IgM are useful for the diagnosis of acute infection but are less sensitive for infection with symptoms of several months’ duration. In an endemic setting, more than 90% of patients with acute bacteremia have standard agglutination titers of at least 1:320. Other screening tests are used in some centers.


InternalMed_Harrison

InternalMed_Harrison. Antibody to the Brucella LPS O chain—the dominant antigen—is detected by all the conventional tests that employ smooth B. abortus cells as antigen. Since B. abortus cross-reacts with B. melitensis and B. suis, there is no advantage in replicating the tests with these antigens. Cross-reactions also occur with the O chains of some other gram-negative bacteria, including Yersinia enterocolitica O:9, Escherichia coli O157, Francisella tularensis, Salmonella enterica group N, Stenotrophomonas maltophilia, and Vibrio cholerae. Cross-reactions do not occur with the cell-surface antigens of rough Brucella strains such as B. canis or B. ovis; serologic tests for these nomen species must employ an antigen prepared from either one. The live B. abortus vaccine strain RB51 does not elicit antibody responses in serologic tests that use smooth antigens, and this fact must be taken into account if serologic tests are employed in attempts to identify or follow the course of infections in persons


InternalMed_Harrison

InternalMed_Harrison. responses in serologic tests that use smooth antigens, and this fact must be taken into account if serologic tests are employed in attempts to identify or follow the course of infections in persons accidentally exposed to the vaccine.


InternalMed_Harrison

InternalMed_Harrison. The broad aims of antimicrobial therapy are to treat and relieve the symptoms of current infection and to prevent relapse. Focal disease presentations may require specific intervention in addition to more prolonged and tailored antibiotic therapy. In addition, tuberculosis must always be excluded, or—to prevent the emergence of resistance—therapy must be tailored to specifically exclude drugs active against tuberculosis (e.g., rifampin used alone) or to include a full antituberculous regimen.


InternalMed_Harrison

InternalMed_Harrison. Early experience with streptomycin monotherapy showed that relapse was common; thus dual therapy with tetracyclines became the norm. This is still the most effective combination, but alternatives may be used, with the options depending on local or national policy about the use of rifampin for the treatment of nonmycobacterial infection. For the several antimicrobial agents that are active in vivo, efficacy can usually be predicted by in vitro testing. However, numerous Brucella strains show in vitro sensitivity to a whole range of antimicrobials that are therapeutically ineffective, including assorted β-lactams. Moreover, the use of fluoroquinolones remains controversial despite the good in vitro activity and white-cell penetration of most agents of this class. Low intravacuolar pH is probably a factor in the poor performance of these drugs.


InternalMed_Harrison

InternalMed_Harrison. For adults with acute nonfocal brucellosis (duration, <1 month), a 6-week course of therapy incorporating at least two antimicrobial agents is required. Complex or focal disease necessitates ≥3 months of therapy. Adherence to the therapeutic regimen is very important, and poor adherence underlies almost all cases of apparent treatment failure; such failure is rarely due to the emergence of drug resistance, although increasing resistance to trimethoprimsulfamethoxazole (TMP-SMX) has been reported at one center. There is good retrospective evidence that a 3-week course of two agents is as effective as a 6-week course for treatment and prevention of relapse in children, but this point has not yet been proven in prospective studies.


InternalMed_Harrison

InternalMed_Harrison. The gold standard for the treatment of brucellosis in adults is IM streptomycin (0.75–1 g daily for 14–21 days) together with doxycycline (100 mg twice daily for 6 weeks). In both clinical trials and observational studies, relapse follows such treatment in 5–10% of cases. The usual alternative regimen (and the current World Health Organization recommendation) is rifampin (600–900 mg/d) plus doxycycline (100 mg twice daily) for 6 weeks. The relapse/failure rate is ~10% in trial conditions but rises to >20% in many non-trial situations, possibly because doxycycline levels are reduced and clearance rates increased by concomitant rifampin administration. Patients who cannot tolerate or receive tetracyclines (children, pregnant women) can be given high-dose TMP-SMX instead (two or three standard-strength tablets twice daily for adults, depending on weight).


InternalMed_Harrison

InternalMed_Harrison. Increasing evidence supports the use of an aminoglycoside such as gentamicin (5–6 mg/kg per day for at least 2 weeks) instead of streptomycin, although this regimen is not approved by the


InternalMed_Harrison

InternalMed_Harrison. U.S. Food and Drug Administration. Shorter courses have been associated with high failure rates in adults. A 5to 7-day course of therapy with gentamicin and a 3-week course of TMP-SMX may be adequate for children with uncomplicated disease, but prospective trials are still needed to support this recommendation. Early experience with fluoroquinolone monotherapy was disappointing, although it was suggested that ofloxacin or ciprofloxacin, given together with rifampin for 6 weeks, might be an acceptable alternative to the other 6-week regimens for adults. A substantial meta-analysis did not support the use of fluoroquinolones in first-line treatment regimens, and these drugs are not recommended by an expert consensus group (Ioannina) except in the context of well-designed clinical trials. However, a more recent meta-analysis is more supportive of the efficacy of these drugs, and an adequately powered prospective study will be needed to resolve their role in standard combination therapy.


InternalMed_Harrison

InternalMed_Harrison. a more recent meta-analysis is more supportive of the efficacy of these drugs, and an adequately powered prospective study will be needed to resolve their role in standard combination therapy. A triple-drug regimen—doxycycline and rifampin combined with an initial course of an aminoglycoside—was superior to double-drug regimens in a meta-analysis. The triple-drug regimen should be considered for all patients with complicated disease and for those for whom treatment adherence is likely to be a problem.


InternalMed_Harrison

InternalMed_Harrison. Significant neurologic disease due to Brucella species requires prolonged treatment (i.e., for 3–6 months), usually with ceftriaxone supplementation of a standard regimen. Brucella endocarditis is treated with at least three drugs (an aminoglycoside, a tetracycline, and rifampin), and many experts add ceftriaxone and/or a fluoroquinolone to reduce the need for valve replacement. Treatment is usually given for at least 6 months, and clinical endpoints for its discontinuation are often difficult to define. Surgery is still required for the majority of cases of infection of prosthetic heart valves and prosthetic joints.


InternalMed_Harrison

InternalMed_Harrison. There is no evidence base to guide prophylaxis after exposure to Brucella organisms (e.g., in the laboratory), inadvertent immunization with live vaccine intended for use in animals, or exposure to deliberately released brucellae. Most authorities have recommended the administration of rifampin plus doxycycline for 3 weeks after a low-risk exposure (e.g., an unspecified laboratory accident) and for 6 weeks after a major exposure to aerosol or injected material. However, such regimens are poorly tolerated, and doxycycline monotherapy of the same duration may be substituted. (Monotherapy is now the standard recommendation in the United Kingdom but not in the United States.) Rifampin should be omitted after exposure to vaccine strain RB51, which is resistant to rifampin but sensitive to doxycycline. After significant brucellosis exposure, expert consultation is advised for women who are (or may be) pregnant.


InternalMed_Harrison

InternalMed_Harrison. Relapse occurs in up to 30% of poorly compliant patients. Thus patients should ideally be followed clinically for up to 2 years to detect relapse, which responds to a prolonged course of the same therapy used originally. The general well-being and the body weight of the patient are more useful guides than serology to lack of relapse. IgG antibody levels detected by the standard agglutination test and its variants can remain in the diagnostic range for >2 years after successful treatment. Complement fixation titers usually fall to normal within 1 year of cure. Immunity is not solid; patients can be reinfected after repeated exposures. Fewer than 1% of patients die of brucellosis. When the outcome is fatal, death is usually a consequence of cardiac involvement; more rarely, it results from severe neurologic disease. Despite the low mortality rate, recovery from brucellosis is slow, and the illness can cause prolonged inactivity, with domestic and economic consequences.


InternalMed_Harrison

InternalMed_Harrison. The existence of a prolonged chronic brucellosis state after successful treatment remains controversial. Evaluation of patients in whom this state is considered (often those with work-related exposure to brucellae) includes careful exclusion of malingering, nonspecific chronic fatigue syndromes, and other causes of excessive sweating, such as alcohol abuse and obesity. In the future, the availability of more sensitive assays to detect Brucella antigen or DNA may help to identify patients with ongoing infection. Vaccines based on live attenuated Brucella strains, such as B. abortus strain 19BA or 104M, have been used in some countries to protect high-risk populations but have displayed only short-term efficacy and


InternalMed_Harrison

InternalMed_Harrison. Tularemia Richard F. Jacobs, Gordon E. Schutze Tularemia is a zoonosis caused by Francisella tularensis. Humans of any age, sex, or race are universally susceptible to this systemic infec-tion. Tularemia is primarily a disease of wild animals and persists in contaminated environments, ectoparasites, and animal carriers. 195 Human infection is incidental and usually results from interaction with biting or blood-sucking insects, contact with wild or domestic animals, ingestion of contaminated water or food, or inhalation of infective aerosols. The illness is characterized by various clinical syndromes, the most common of which consists of an ulcerative lesion at the site of inoculation, with regional lymphadenopathy and lymphadenitis. Systemic manifestations, including pneumonia, typhoidal tularemia, meningitis, and fever without localizing findings, pose a greater diagnostic challenge.


InternalMed_Harrison

InternalMed_Harrison. F. tularensis is a class A bioterrorism agent (Chap. 261e). With rare exceptions, tularemia is the only disease produced by F. tularensis—a small (0.2 μm by 0.2–0.7 μm), gram-negative, pleomorphic, nonmotile, non-spore-forming bacillus. Bipolar staining results in a coccoid appearance. The organism is a thinly encapsulated, nonpiliated strict aerobe that invades host cells. In nature, F. tularensis is a hardy organism that persists for weeks or months in mud, water, and decaying animal carcasses. Dozens of biting and blood-sucking insects, especially ticks and tabanid flies, serve as vectors. Ticks and wild rabbits are the source for most human cases in endemic areas of the southeastern United States. In Utah, Nevada, and California, tabanid flies are the most common vectors. Animal reservoirs include wild rabbits, squirrels, birds, sheep, beavers, muskrats, and domestic dogs and cats. Person-to-person transmission is rare or nonexistent.


InternalMed_Harrison

InternalMed_Harrison. The four subspecies of F. tularensis are tularensis, holarctica, novicida, and mediasiatica. The first three of these subspecies are found in North America; in fact, subspecies tularensis has been isolated only in North America, where it accounts for >70% of cases of tularemia and produces more serious human disease than other subspecies (although, with treatment, the associated fatality rate is <2%). The progression of illness depends on the infecting strain’s virulence, the inoculum size, the portal of entry, and the host’s immune status.


InternalMed_Harrison

InternalMed_Harrison. Ticks pass F. tularensis to their offspring transovarially. The organism is found in tick feces but not in large quantities in tick salivary glands. In the United States, the disease is carried by Dermacentor andersoni (Rocky Mountain wood tick), Dermacentor variabilis (American dog tick), Dermacentor occidentalis (Pacific Coast dog tick), and Amblyomma americanum (Lone Star tick). F. tularensis is transmitted frequently during blood meals taken by embedded ticks after hours of attachment. It is the taking of a blood meal through a fecally contaminated field that transmits the organism. Transmission by ticks and tabanid flies takes place mainly in the spring and summer. However, continued transmission in the winter by trapped or hunted animals has been documented. Tularemia is most common in the southeastern United States;


InternalMed_Harrison

InternalMed_Harrison. Arkansas, Missouri, and Oklahoma account for more than half of all reported cases in this country. Small outbreaks in higher-risk populations (e.g., professional landscapers cutting up brush, mowing, and using a leaf blower) have been reported. Although the irregular distribution of cases of tularemia makes worldwide estimates difficult, increasing numbers of cases have been reported between latitudes 30° and 71°N (the Holarctic region) in the Northern Hemisphere. Cases of tularemia have been reported from Europe, Turkey, Canada, Mexico, and Asia. If the disease is caused by subspecies tularensis, the clinical manifestations are similar to those in the United States. However, in areas where tularemia is due largely to subspecies holarctica, oropharyngeal disease is common. Disease acquisition results from the consumption of water contaminated by live organisms shed by animals (e.g., muskrats, beavers). Subspecies holarctica is known to cause milder disease than other subspecies and


InternalMed_Harrison

InternalMed_Harrison. results from the consumption of water contaminated by live organisms shed by animals (e.g., muskrats, beavers). Subspecies holarctica is known to cause milder disease than other subspecies and responds well to fluoroquinolones, especially ciprofloxacin.


InternalMed_Harrison

InternalMed_Harrison. The most common portal of entry for human infection is through skin or mucous membranes, either directly—through the bite of ticks, other arthropods, or other animals—or via inapparent abrasions. Inhalation or ingestion of F. tularensis also can result in infection. F. tularensis is extremely infectious: Although >108 organisms are usually required to produce infection via the oral route (oropharyngeal or gastrointestinal tularemia), as few as 10 organisms can result in infection when injected into the skin (ulceroglandular/glandular tularemia) or inhaled (pulmonary tularemia). After inoculation into the skin, the organism multiplies locally; within 2–5 days (range, 1–10 days), it produces an 1067 erythematous, tender, or pruritic papule. The papule rapidly enlarges and forms an ulcer with a black base (chancriform lesion). The bacteria spread to regional lymph nodes, producing lymphadenopathy (buboes). All forms can lead to bacteremia with spread to distant organs, including the


InternalMed_Harrison

InternalMed_Harrison. with a black base (chancriform lesion). The bacteria spread to regional lymph nodes, producing lymphadenopathy (buboes). All forms can lead to bacteremia with spread to distant organs, including the central nervous system.


InternalMed_Harrison

InternalMed_Harrison. Tularemia is characterized by mononuclear cell infiltration with pyogranulomatous pathology. The histopathologic findings can be quite similar to those in tuberculosis, although tularemia develops more rapidly. As a facultatively intracellular bacterium, F. tularensis can parasitize both phagocytic and nonphagocytic host cells and can survive intracellularly for prolonged periods. In the acute phase of infection, the primary organs affected (skin, lymph nodes, liver, and spleen) include areas of focal necrosis, which are initially surrounded by polymorphonuclear leukocytes (PMNs). Subsequently, granulomas form, with epithelioid cells, lymphocytes, and multinucleated giant cells surrounded by areas of necrosis. These areas may resemble caseation necrosis but later coalesce to form abscesses.


InternalMed_Harrison

InternalMed_Harrison. Conjunctival inoculation can result in infection of the eye, with regional lymph node enlargement (preauricular lymphadenopathy, Parinaud’s complex). Aerosolization and inhalation or hematogenous spread of organisms can result in pneumonia. In the lung, an inflammatory reaction develops, including foci of alveolar necrosis and cell infiltration (initially polymorphonuclear and later mononuclear) with granulomas. Chest roentgenograms usually reveal bilateral patchy infiltrates rather than large areas of consolidation. Pleural effusions are common and may contain blood. Lymphadenopathy occurs in regions draining infected organs. Therefore, in pulmonary infection, mediastinal adenopathy may be evident, whereas patients with oropharyngeal tularemia develop cervical lymphadenopathy. In gastrointestinal or typhoidal tularemia, mesenteric lymphadenopathy may follow the ingestion of large numbers of organisms. (The term typhoidal tularemia may be used to describe severe bacteremic disease,


InternalMed_Harrison

InternalMed_Harrison. or typhoidal tularemia, mesenteric lymphadenopathy may follow the ingestion of large numbers of organisms. (The term typhoidal tularemia may be used to describe severe bacteremic disease, irrespective of the mode of transmission or portal of entry.) Meningitis has been reported as a primary or secondary manifestation of bacteremia. Patients may also present with fever and no localizing signs.


InternalMed_Harrison

InternalMed_Harrison. Although a complete and widely accepted understanding of the protective immune response to F. tularensis is lacking, significant advances in the study of natural and protective immunity have been made in recent years and may ultimately result in a vaccine candidate. Complete genomic sequencing and the availability of attenuated F. tularensis strains developed through genetic manipulation are facilitating research that will expand our knowledge in this area. A number of investigators have studied various models and proposed various hypotheses regarding the induction of protective immunity to


InternalMed_Harrison

InternalMed_Harrison. A number of investigators have studied various models and proposed various hypotheses regarding the induction of protective immunity to F. tularensis. Although further research is needed, synergy between humoral and cell-mediated immune (CMI) responses appears to be critical in inducing effective immune protection. Elucidation of the molecular mechanisms for the organism’s evasion of the host response, pathogen-associated molecular patterns, and effective host immune protection has led to novel vaccination strategies tested in animal models. Antibodies to Fc receptors on antigen-presenting cells have been shown to be protective in animal models of pulmonary tularemia, resulting in both mucosal and CMI responses. This enhanced understanding of mucosal and serum antibodies in combination with a targeted CMI response holds great promise for future vaccine development.


InternalMed_Harrison

InternalMed_Harrison. Tularemia often starts with a sudden onset of fever, chills, headache, and generalized myalgias and arthralgias (Table 195-1). This onset takes place when the organism penetrates the skin, is ingested, or is inhaled. An incubation period of 2–10 days is followed by the formation of an ulcer at the site of penetration, with local inflammation. The ulcer may persist for several months as organisms are transported via the lymphatics to the regional lymph nodes. These nodes enlarge and may become necrotic and suppurative. If the organism enters the bloodstream, widespread dissemination can result. Rate of Occurrence, % Source: Adapted from RF Jacobs, JP Narain: Pediatrics 76:818, 1985; with permission.


InternalMed_Harrison

InternalMed_Harrison. Rate of Occurrence, % Source: Adapted from RF Jacobs, JP Narain: Pediatrics 76:818, 1985; with permission. In the United States, most patients with tularemia (75–85%) acquire the infection by inoculation of the skin. In adults, the most common localized form is inguinal/femoral lymphadenopathy; in children, it is cervical lymphadenopathy. About 20% of patients develop a generalized maculopapular rash, which occasionally becomes pustular. Erythema nodosum occurs infrequently. The clinical manifestations of tularemia have been divided into various syndromes, which are listed in Table 195-2.


InternalMed_Harrison

InternalMed_Harrison. ulceroglandular/Glandular Tularemia These two forms of tularemia account for ~75–85% of cases. The predominant form in children involves cervical or posterior auricular lymphadenopathy and is usually related to tick bites on the head and neck. In adults, the most common form is inguinal/femoral lymphadenopathy resulting from insect and tick exposures on the lower limbs. In cases related to wild game, the usual portal of entry for F. tularensis is either an injury sustained while skinning or cleaning an animal carcass or a bite (usually on the hand). Epitrochlear lymphadenopathy/lymphadenitis is common in patients with bite-related injuries.


InternalMed_Harrison

InternalMed_Harrison. In ulceroglandular tularemia, the ulcer is erythematous, indurated, and nonhealing, with a punched-out appearance that lasts 1–3 weeks. The papule may begin as an erythematous lesion that is tender or pruritic; it evolves over several days into an ulcer with sharply demarcated edges and a yellow exudate. The ulcer gradually develops a black base, and simultaneously the regional lymph nodes become tender and severely enlarged (Fig. 195-1). The affected lymph nodes may become fluctuant and drain spontaneously, but the condition usually resolves with effective treatment. Late suppuration of lymph nodes has been described in up to 25% of patients with ulceroglandular/glandular tularemia. Examination of material taken from these late fluctuant nodes after successful antimicrobial treatment reveals sterile necrotic tissue. In 5–10% of patients, the skin lesion may be inapparent, with lymphadenopathy plus systemic signs and symptoms the only physical findings (glandular tularemia).


InternalMed_Harrison

InternalMed_Harrison. reveals sterile necrotic tissue. In 5–10% of patients, the skin lesion may be inapparent, with lymphadenopathy plus systemic signs and symptoms the only physical findings (glandular tularemia). Conversely, a tick or deerfly bite on the trunk may result in an ulcer without evident lymphadenopathy.


InternalMed_Harrison

InternalMed_Harrison. Oculoglandular Tularemia In ~1% of patients, the portal of entry for F. tularensis is the conjunctiva, which the organism usually reaches through contact with contaminated fingers. The inflamed conjunctiva is painful, with numerous yellowish nodules and pinpoint ulcers. Rate of Occurrence, % Source: Adapted from RF Jacobs, JP Narain: Pediatrics 76:818, 1985; with permission. FIGuRE 195-1 An 8-year-old boy with inguinal lymphadenitis and associated tick-bite site characteristic of ulceroglandular tularemia. Purulent conjunctivitis with regional lymphadenopathy (preauricular, submandibular, or cervical) is evident. Because of debilitating pain, the patient may seek medical attention before regional lymphadenopathy develops. Painful preauricular lymphadenopathy is unique to tularemia and distinguishes it from tuberculosis, sporotrichosis, and syphilis. Corneal perforation may occur.


InternalMed_Harrison

InternalMed_Harrison. Oropharyngeal and Gastrointestinal Tularemia Rarely, tularemia follows ingestion of contaminated undercooked meat, oral inoculation of F. tularensis from the hands in association with the skinning and cleaning of animal carcasses, or consumption of contaminated food or water. Oral inoculation may result in acute, exudative, or membranous pharyngitis associated with cervical lymphadenopathy or in ulcerative intestinal lesions associated with mesenteric lymphadenopathy, diarrhea, abdominal pain, nausea, vomiting, and gastrointestinal bleeding. Infected tonsils become enlarged and develop a yellowish-white pseudomembrane, which can be confused with that of diphtheria. The clinical severity of gastrointestinal tularemia varies from mild, unexplained, persistent diarrhea with no other symptoms to a fulminant, fatal disease. In fatal cases, the extensive intestinal ulceration found at autopsy suggests an enormous inoculum.


InternalMed_Harrison

InternalMed_Harrison. Pulmonary Tularemia Pneumonia due to F. tularensis presents as variable parenchymal infiltrates that are unresponsive to treatment with β-lactam antibiotics. Tularemia must be considered in the differential diagnosis of atypical pneumonia in a patient with a history of travel to an endemic area. The disease can result from inhalation of an infectious aerosol or can spread to the lungs and pleura via bacteremia. Inhalation-related pneumonia has been described in laboratory workers after exposure to contaminated materials and, if untreated, can be associated with a relatively high mortality rate. Exposure to F. tularensis in aerosols from live domestic animals or dead wildlife (including birds) has been reported to cause pneumonia. Hematogenous dissemination to the lungs occurs in 10–15% of cases of ulceroglandular tularemia and in about half of cases of typhoidal tularemia. Previously, tularemia pneumonia was thought to be a disease of older patients, but as many as 10–15% of children


InternalMed_Harrison

InternalMed_Harrison. cases of ulceroglandular tularemia and in about half of cases of typhoidal tularemia. Previously, tularemia pneumonia was thought to be a disease of older patients, but as many as 10–15% of children with clinical manifestations of tularemia have parenchymal infiltrates detected by chest roentgenography. Patients with pneumonia usually have a nonproductive cough and may have dyspnea or pleuritic chest pain. Roentgenograms of the chest usually reveal bilateral patchy infiltrates (described as ovoid or lobar densities), lobar parenchymal infiltrates, and cavitary lesions. Pleural effusions may have a predominance of mononuclear leukocytes or PMNs and sometimes red blood cells. Empyema may develop. Blood cultures may be positive for F. tularensis.


InternalMed_Harrison

InternalMed_Harrison. Typhoidal Tularemia The typhoidal presentation is now considered rare in the United States. The source of infection in typhoidal tularemia is usually associated with pharyngeal and/or gastrointestinal inoculation or bacteremic disease. Fever usually develops without apparent skin lesions or lymphadenopathy. Some patients have cervical and mesenteric lymphadenopathy. In the absence of a history of possible contact with a vector, diagnosis can be extremely difficult. Blood cultures may be positive and patients may present with classic sepsis or septic shock in this acute systemic form of the infection. Typhoidal tularemia is usually associated with a huge inoculum or with a preexisting compromising condition. High continuous fevers, signs of sepsis, and severe headache are common. The patient may be delirious and may develop prostration and shock. If presumptive antibiotic therapy in culture-negative cases does not include an aminoglycoside, the estimated mortality rate is relatively


InternalMed_Harrison

InternalMed_Harrison. may be delirious and may develop prostration and shock. If presumptive antibiotic therapy in culture-negative cases does not include an aminoglycoside, the estimated mortality rate is relatively high.


InternalMed_Harrison

InternalMed_Harrison. Other Manifestations F. tularensis infection has been associated with meningitis, pericarditis, hepatitis, peritonitis, endocarditis, osteomyelitis, and sepsis and septic shock with rhabdomyolysis and acute renal failure. In cases of tularemia meningitis, a mean white blood cell count of 1788/ μL, a predominantly mononuclear cell response (70–100%), a depressed glucose level, an elevated protein concentration, and a negative Gram’s stain are typically found on examination of cerebrospinal fluid.


InternalMed_Harrison

InternalMed_Harrison. When patients in endemic areas present with fever, chronic ulcerative skin lesions, and large tender lymph nodes (Fig. 195-1), a diagnosis of tularemia should be made presumptively, and confirmatory diagnostic testing and appropriate therapy should be undertaken. When the possibility of tularemia is considered in a nonendemic area, an attempt should be made to identify contact with a potential animal vector. The level of suspicion should be especially high in hunters, trappers, game wardens, professional landscapers, veterinarians, laboratory workers, and individuals exposed to an insect or another animal vector. However, up to 40% of patients with tularemia have no known history of epidemiologic contact with an animal vector.


InternalMed_Harrison

InternalMed_Harrison. The characteristic presentation of ulceroglandular tularemia does not pose a diagnostic problem, but a less classic progression of regional lymphadenopathy or glandular tularemia must be differentiated from other diseases (Table 195-3). The skin lesion of tularemia may resemble those seen in various other diseases but is generally accompanied by more impressive regional lymphadenopathy. In children, the differentiation of tularemia from cat-scratch disease is made more difficult by the chronic papulovesicular lesion associated with Bartonella henselae infection (Chap. 197). Oropharyngeal tularemia can resemble and must be differentiated from pharyngitis due to other bacteria or viruses. Pulmonary tularemia may resemble any atypical pneumonia. Typhoidal tularemia and tularemia meningitis may resemble a variety of other infections.


InternalMed_Harrison

InternalMed_Harrison. The diagnosis of tularemia is most frequently confirmed by agglutination testing. Microagglutination and tube agglutination are the techniques most commonly used to detect antibody to F. tularensis. In the standard tube agglutination test, a single titer of ≥1:160 is interpreted as a presumptive positive result. A fourfold increase in titer between paired serum samples collected 2–3 weeks apart is considered diagnostic. False-negative serologic responses are obtained early in infection; up to 30% of patients infected for 3 weeks have sera that test negative. Late in infection, titers into the thousands are common, and titers of 1:20–1:80 may persist for years. Enzyme-linked immunosorbent assays have proved useful for the detection of both antibodies and antigens.


InternalMed_Harrison

InternalMed_Harrison. Culture and isolation of F. tularensis are difficult. In one study, the organism was isolated in only 10% of more than 1000 human cases, 84% of which were confirmed by serology. The medium of choice is cysteine-glucose-blood agar. F. tularensis can be isolated directly from infected ulcer scrapings, lymph node biopsy specimens, gastric washings, sputum, and blood cultures. Colonies are blue-gray, round, smooth, and slightly mucoid. On media containing blood, a small zone of α hemolysis usually surrounds the colony. Slide agglutination tests or direct fluorescent antibody tests with commercially available antisera can be applied directly to culture suspensions for identification. Most clinical laboratories will not attempt to culture F. tularensis because of the infectivity of the organism from the culture media and the consequent risk of a laboratory-acquired infection. Although tularemia is not spread from person to person, the organism can be inhaled from culture plates and infect


InternalMed_Harrison

InternalMed_Harrison. from the culture media and the consequent risk of a laboratory-acquired infection. Although tularemia is not spread from person to person, the organism can be inhaled from culture plates and infect unsuspecting laboratory workers. In most clinical laboratories, biosafety level 2 practices are recommended to handle clinical specimens thought to contain F. tularensis; however, biosafety level 3 conditions are required for procedures that produce aerosols or droplets during manipulation of cultures containing or possibly containing this organism.


InternalMed_Harrison

InternalMed_Harrison. A variety of polymerase chain reaction (PCR) methods have been used to detect F. tularensis DNA in many clinical specimens but mostly in ulceroglandular disease. The majority of these methods target the genes encoding outer-membrane proteins (e.g., fopA or tul4). A 16S rDNA sequence identification PCR may be helpful when the patient’s clinical information does not lead the clinician to suspect a diagnosis of tularemia. Only aminoglycosides, tetracyclines, chloramphenicol, and rifampin are currently approved by the U.S. Food and Drug Administration for the treatment of tularemia. Gentamicin is considered the drug of choice for both adults and children. The dosage for adults and children is 5 mg/kg daily in two divided doses. Gentamicin therapy is typically continued for 7–10 days; however, in mild to moderate


InternalMed_Harrison

InternalMed_Harrison. TABLE 195-3 TuLAREMIA: dIFFEREnTIAL dIAgnOsIs, By CLInICAL dIsEAsE CATEgORy aStaphylococcus aureus, Streptococcus pyogenes. bAdenovirus, enteroviruses, parainfluenza virus, influenza viruses A and B, respiratory syncytial virus. cHematologic and reticuloendothelial malignancies. dInfluenza viruses A and B, parainfluenza virus, respiratory syncytial virus, adenovirus, enteroviruses, hantavirus.


InternalMed_Harrison

InternalMed_Harrison. 1070 cases of tularemia in which the patient becomes afebrile within the first 48–72 h of gentamicin treatment, a 5to 7-day course has been successful. If available, streptomycin given intramuscularly is also effective. The dosage for adults is 2 g/d in two divided doses. For children, the dosage is 30 mg/kg daily in two divided doses (maximal daily dose, 2 g). After a clinical response is demonstrated at 3–5 days, the dosage for children can be reduced to 10–15 mg/kg daily in two divided doses. The total duration of streptomycin therapy in both adults and children is usually 10 days. Unlike streptomycin and gentamicin, tobramycin is ineffective in the treatment of tularemia and should not be used. Because doxycycline is bacteriostatic against F. tularensis, there is a risk of relapse if the patient is not treated for a long enough period. Therefore, if doxycycline is used, it should be given for at least 14 days. The lack of availability of chloramphenicol limits the utility of this


InternalMed_Harrison

InternalMed_Harrison. the patient is not treated for a long enough period. Therefore, if doxycycline is used, it should be given for at least 14 days. The lack of availability of chloramphenicol limits the utility of this agent as a viable treatment option. Fluoroquinolones— specifically, ciprofloxacin and levofloxacin—have been used with good outcomes to treat infections caused by subspecies holarctica, which is most often found in Europe. The lack of data on the efficacy of these agents against subspecies tularensis limits their use in North America at this time.


InternalMed_Harrison

InternalMed_Harrison. F. tularensis cannot be subjected to standardized antimicrobial susceptibility testing because the organism will not grow on the media used. A wide variety of antibiotics, including all β-lactam antibiotics and the cephalosporins, are ineffective for the treatment of tularemia. Several studies indicated that third-generation cephalosporins were active against F. tularensis in vitro, but clinical case reports suggested nearly universal failure of ceftriaxone in pediatric patients with tularemia. Although in vitro data indicate that imipenem may be active, therapy with imipenem, sulfanilamides, and macrolides is not presently recommended because of the lack of relevant clinical data.


InternalMed_Harrison

InternalMed_Harrison. Virtually all strains of F. tularensis are susceptible to streptomycin and gentamicin. Hearing screening should be considered before initiation of streptomycin or gentamicin therapy. In successfully treated patients, defervescence usually occurs within 2 days, but skin lesions and lymph nodes may take 1–2 weeks to heal. When therapy is not initiated within the first several days of illness, defervescence may be delayed. Relapses are uncommon with streptomycin or gentamicin therapy. Late lymph-node suppuration, however, occurs in ~40% of children, regardless of the treatment received. These nodes have typically been found to contain sterile necrotic tissue without evidence of active infection. Patients with fluctuant nodes should receive several days of antibiotic therapy before drainage to minimize the risk to hospital personnel.